Liver X Receptor (LXR) partial agonists: Biaryl pyrazoles and imidazoles displaying a preference for LXRβ

Article abstract of DOI:10.1016/j.bmcl.2014.11.029

A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC₅₀ = 1.2 μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10 mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.

Full text of DOI:10.1016/j.bmcl.2014.11.029

Bioorganic & Medicinal Chemistry Letters 25 (2015) 372–377
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Liver X Receptor (LXR) partial agonists: Biaryl pyrazoles
and imidazoles displaying a preference for LXRb
b
b
b
b
b
Ellen Kick a, , Richard Martin , Yinong Xie , Brenton Flatt , Edwin Schweiger , Tie-Lin Wang ,
Brett Busch b, Michael Nyman b, Xiao-Hui Gu b, Grace Yan b, Brandee Wagner b, Max Nanao b,
Lam Nguyen b, Thomas Stout b, Artur Plonowski b, Ira Schulman b, Jacek Ostrowski c, Todd Kirchgessner c,
Ruth Wexler a, Raju Mohan b
⇑
a Discovery Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States
b Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States
c Cardiovascular Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized dis-
Received 11 September 2014
Revised 5 November 2014
Accepted 7 November 2014
Available online 15 November 2014
playing LXRb selectivity. The LXRb selective partial agonist 18 was identified with potent induction of ATP
binding transporters ABCA1 and ABCG1 in human whole blood (EC50 = 1.2 lM, 55% efficacy). In mice 18
displayed peripheral induction of ABCA1 at 3 and 10 mpk doses with no significant elevation of plasma or
hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Liver X Receptor
LXR
Partial agonist
ABCA1
Nuclear hormone receptor
Blood cholesterol is a major risk factor for coronary heart dis-
ease (CHD) due to the central role that cholesterol metabolism
plays in the disease.1 Oxidized forms of low density lipoprotein
(LDL) are taken up by macrophages leading to foam cell formation
and atherosclerotic plaque. Consequently, elevated LDL cholesterol
levels are associated with increased risk of CHD. Consistent with
this, statins decrease CHD risk by lowering LDL. In addition to
LDL cholesterol delivery mechanisms, there exists a cholesterol
removal process, termed reverse cholesterol transport (RCT), in
which excess cholesterol in peripheral tissues is trafficked back
to the liver where it is secreted via the bile into the intestine,
and eliminated in feces.2 The transfer of cholesterol to the liver is
mediated, in part, by high density lipoprotein (HDL), and this key
role in RCT is one of the reasons why improving HDL function is
expected to have a positive benefit in reducing cardiovascular
risk.3
(NHRs) that regulate many aspects of cholesterol and lipid metab-
olism in the RCT pathway.4 LXR agonists have been shown to
increase RCT in macrophages and other peripheral tissues, by
induction of the ATP binding cassette transporters, ABCA1 and
ABCG1.5–8 In addition, LXRs are involved in regulation of choles-
terol uptake and excretion in the liver and intestine.9 Multiple
LXR agonists such as TO-091317 (1a),10 GW3965 (1b),11 LXR-623
(2a)12 and 2c13 have been shown to reduce atherosclerosis burden
in mice.12–15 In addition, LXR agonists have been shown to have
anti-inflammatory properties so they are anticipated to favorably
decrease plaque inflammation, thereby reducing plaque burden
for patients.16,17
One of the challenges in developing LXR agonists for treatment
of cardiovascular disease is the induction of lipogenesis pathway
targets, such as sterol regulatory element binding protein-1c
(SREBP1c) and fatty acid synthase (FAS), by LXR agonists like
1a.10 This results in increased very-low-density lipoprotein (VLDL)
production in the liver with increased triglycerides in the liver and
plasma. In addition, in species that express cholesteryl ester trans-
fer protein (CETP) such as cynomolgus monkeys, rabbits and ham-
sters increases in LDL cholesterol are also observed with LXR pan
agonists.18
Enhancing removal of cholesterol from atherosclerotic plaque
through stimulating RCT is likely to have therapeutic benefits. Liver
X Receptors, LXR
a and LXRb, are nuclear hormone receptors
⇑
Corresponding author. Tel.: +1 609 818 5414.
E-mail address: ellen.kick@bms.com (E. Kick).
http://dx.doi.org/10.1016/j.bmcl.2014.11.029
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

E. Kick et al. / Bioorg. Med. Chem. Lett. 25 (2015) 372–377
373
O
Several different approaches have been undertaken in an
attempt to reduce the lipogenic properties of LXR agonists while
maintaining robust RCT and anti-inflammatory properties. Based
NHNH2
O
O
R1
R2
c
a or b
S
S
N
+
Br
Br
R1
11
on work with knock-out mice showing that LXR
lipid production in liver, whereas LXRb was able to maintain RCT
functionality in LXR null mice, it has been hypothesized that LXRb
a was able to drive
R1
a
R2
N
N
R2
d
N
SO2Me
S
selective agonists would induce lower levels of triglycerides and
LDL-C.19–21 Partial agonism of NHRs has also been shown to yield
differential recruitment of co-activators and co-repressors affect-
S
Br
12
R1
5, 6, 9
R1
ing tissue selectivity, so partial agonism of LXR
a may provide an
MeO
improved therapeutic window by differentially regulating genes
in liver.22–24,13 The goal for our optimization effort was to combine
partial agonism with LXRb selectivity to achieve LXR agonists that
maintain favorable RCT and anti-inflammatory effects with
reduced lipid liabilities.
HO
N
e
N
N
N
O
SO2Me
SO2Me
S
S
9
10
Scheme 1. Synthesis of pyrazole agonists. Reagents and conditions: (a) LiHMDS,
R2CO2Me, THF, ꢀ78 °C to rt, (>98% yield); (b) (CO2CH3)2, NaOMe, MeOH, (88% yield);
(c) MeOH, reflux or AcOH, DMF, 80 °C, (65–98% yield); (d) [(3-methylsulfo-
nyl)phenyl]boronic acid, Na2CO3, Pd(PPh3)4, dioxane, H2O, 90 °C, (25–80% yield);
(e) MeMgCl, THF, 20 °C, (52% yield).
Since we initiated our effort several LXRb selective agonists
have been reported in the literature including 2a,12 2b25 and
2c.13 Agonist 2a was shown to have an improved LDL and TG lipid
profile in cynomolgus monkey plasma, possibly due to weak partial
activity at LXRa.
26 While 2a was taken into the clinic, adverse CNS
effects during the single ascending dose clinical trial resulted in the
termination of further studies,27 so it is not known if the favorable
lipid results would have been observed in humans with chronic
dosing.
In pursuing the optimization of the full pan-agonist leads 3a,
3b, and 3c28 we discovered that a pyrazole was a good replacement
for the pyridone heterocycle, and benzyl pyrazole 4 was a potent,
full pan-agonist with efficacy >90% when compared to the refer-
ence 3b. Optimization of the pyrazole was undertaken with many
analogs prepared both in array synthesis and single compound
synthesis (data not shown), and from that effort the phenyl pyra-
zole 5 was prepared with potent 12 nM binding to LXRb and 5 fold
LXR
a activity, and to identify a potent, LXRb selective partial
agonist for study in animal models.
Investigation of pyrazole 5 indicated that the ortho chlorine (R1)
on the phenyl could be effectively replaced with a trifluoromethyl
(6) improving the LXRb binding selectivity to 15 fold (Table 1).
With this compound, LXR
a efficacy was reduced to 39% while
maintaining LXRb agonist activity. Replacement of the thiophene
with a phenyl provided the biphenyl sulfones 7 and 8, which both
had similar 10–14 fold binding selectivity. However, the 4-substi-
tuted phenyl (7) yielded the more potent LXRb activity (EC50 = 49 -
nM, 61% efficacy). Agonists 5–8 all were potent agonists inducing
selectivity against LXR
ity in a cellular transactivation assay (EC50 = 108 nM, 90% efficacy)
with 65% efficacy for LXR (Fig. 1, Table 1). We were very inter-
ested in pursuing compounds that afforded <40% LXR
activity when compared to 3b. Due to the partial LXR
a
. Pyrazole 5 had potent LXRb agonist activ-
ABCA1 in HeLa cells with endogenous LXRa and LXRb receptors
providing potencies of 8–38 nM (Table 1). In order to study induc-
tion in a more physiological system, potency was also assessed in a
human whole blood assay (hWBA) for selected compounds.29
When tested for ABCA1 induction in the hWBA 7 had potent
a
a
a
agonist
agonist
activity, additional optimization was undertaken to modulate the
0.48
30 mpk 7 had only 0.6
7.8 M liver exposure at 24 h (Table 3). Since efficacy is desired
in the arterial tissues, and the undesirable triglyceride and LDL-C
production was thought to be driven by hepatic LXR activity we
did not progress compounds such as 7 with high liver drug expo-
sures. Since other pyrazoles bearing the CF3 also had high liver lev-
els in pharmacokinetic (PK) studies (data not shown), alternative
substitutions at R2 were investigated.
Replacement of the CF3 with an ester afforded 9, which had
good binding and efficacy for LXRb, although poor stability in
mouse microsomes was observed. The ester 9 served as a chemical
intermediate for the preparation of gem-dimethyl carbinol 10
(Scheme 1). The carbinol 10 had an encouraging 18 fold binding
selectivity, although the LXRb agonist potency was 10 fold lower
than 9. In mouse PK studies, 10 had an improved profile with high
4 h plasma exposures and a 3 fold liver/plasma exposure ratio at
24 h (Table 3). Due to this favorable PK profile and partial agonist
activity the carbinol was a preferred substituent as the SAR
progressed.
l
M activity (Table 3). However, when dosed to mice at
lM plasma exposure at 4 h with high
l
F3C
OH
Cl
CF3
O
O
N
HO2C
CF3
N
a
O
S
Ph
F3C
Ph
GW3965, 1b
TO-091317, 1a
F
MeO OMe
F
S
O
S
O
N
N
N
N
F
N
O
Cl
N
F
CF3
CF3
F
LXR-623, 2a
2b
2c
F
F
F
S
O
F
O
O
F
O
F
O
S
NC
NC
NC
F3C
N
N
N
S
F3C
F3C
Ph
3b
3c
3a
O
The pyrazole synthesis was initiated by Claisen condensation of
2-acetyl-5-bromo thiophene with an appropriately substituted
ester to obtain the diketone 11 (Scheme 1). Condensation with
an aryl hydrazine provided the pyrazole 12. Coupling with [(3-
methylsulfonyl)phenyl]boronic acid using palladium tetrakistri-
phenyl phosphine gave the final biaryl pyrazoles 5, 6, and 9.30
The ester 9 was treated with a methyl Grignard reagent to afford
carbinol 10. The biphenyl analogs 7 and 8 were prepared by similar
routes.
F
O
OH
F
Cl
O
O
O
O
S
S
N
N
N
N
F3C
F3C
S
S
4
5
Figure 1. Examples of LXR agonists reported in literature, and leads 3a, 3b, 3c, 4
and 5 described herein (see Table 1 for associated data).

374
E. Kick et al. / Bioorg. Med. Chem. Lett. 25 (2015) 372–377
Table 1
LXR activities of lead compounds (Fig. 1) and pyrazole agonists31
R1
R1
R1
O
O
N
N
N
N
R2
R2
S
N
O
O
N
R2
S
S
5, 6, 9, 10
7
8
O
S
O
Cmpd
R1
R2
LXR
a
/LXRb Ki (nM)
LXR
a
EC50 (nM) % Effa
LXRb EC50 (nM) % Effa
ABCA1 HeLa EC50 (nM) % Effa
17 (89%)
1a
3a
3b
3c
4
31/26
11/11
26/9
36/9
20/7
28 (100%)
4 (100%)
20 (100%)
570 (96%)
18 (98%)
140 (140%)
2 (100%)
20 (100%)
320 (113%)
14 (92%)
7 (100%)
40 (93%)
5
6
7
8
Cl
CF3
Cl
CF3
CF3
CF3
CF3
O
68/12
240/16
180/13
300/31
140 (65%)
120 (39%)
220 (30%)
320 (66%)
110 (90%)
68 (85%)
49 (61%)
9 (73%)
8 (57%)
13 (50%)
38 (65%)
Cl
230 (95%)
9
Cl
Cl
150/10
65 (20%)
64 (68%)
310 (64%)
800 (66%)
O
H3C
H3C
10
1500/83
540 (13%)
620 (43%)
OH
a
Percent efficacy (% Eff) is the percent of maximal activity compared to full pan agonist 3b.
Table 2
LXR activities of imidazole agonists31
O
R1
X
O
S
R1'
N
N
R2
0
Cmpd
R2
X
LXR
a
/LXRb Ki (nM)
LXR
a
EC50 (nM) % Effa
LXRb EC50 (nM) % Effa
ABCA1 HeLa EC50 (nM) % Effa
5 (39%)
R1, R1
13
Cl, H
CF3
H3C
H3C
Bond
61/11
52 (19%)
>10000
61 (76%)
14
15
16
17
18
Cl, H
Cl, Cl
CF3, H
Cl, H
Cl, H
Bond
Bond
CH2
1600/59
600 (32%)
670 (44%)
140 (43%)
66 (55%)
140 (31%)
140 (28%)
27 (39%)
12 (48%)
33 (50%)
OH
OH
OH
OH
OH
H3C
H3C
2500/54
66/7
>10000
H3C
H3C
200 (15%)
85 (28%)
230 (38%)
H3C
H3C
CH2
25/1
H3C
H3C
C(CH3)2
68/14
250 (72%)
a
Percent efficacy (% Eff) is the percent of maximal activity compared to full pan agonist 3b.
Replacement of the pyrazole heterocycle in 7 with an imidazole
In an effort to improve the potency of the molecules, alterna-
tives to the phenyl substitution were prepared leading to the ben-
zylic imidazoles such as 16 and 17, which both had improved LXRb
agonist potency. Further investigation of the benzylic substitutions
afforded the gem-dimethyl analog 18. These benzyl imidazoles
maintained moderate LXRb binding selectivity and 15–38% partial
afforded agonist 13, which had potent LXRb binding affinity and
61 nM LXRb agonist potency (Table 2). As in the pyrazole series,
the carbinol 14, had an improved 27 fold LXRb binding selectivity,
albeit with diminished LXRb agonist potency, and no detectable
LXR
ents yielded analogs such as 2,6-dichloro phenyl 15 that had 48-fold
LXRb binding selectivity with no detectable LXR agonism. As was
observed in the pyrazole series, the CF3 imidazole 13 had high liver
exposure (32 M) at 24 h in mouse PK; whereas the carbinols 14
a
agonist activity. Further exploration of the aryl R1 substitu-
LXR
Importantly 18 had improved potency in the ABCA1 hWBA
(EC50 = 1.2 M) with partial efficacy (55%), which compares favor-
ably with 2a (hWBA EC50 = 4.6 M, 56%). As well 18 is a highly
selective LXR agonist when tested against a panel of 14 NHRs at
10 M, displaying agonist activity only for PXR (EC50 = 2 M). Both
16 and 18 had high 5–6 M 4 h plasma exposures in mouse PK
a agonist efficacy with 43–72% efficacy at LXRb (Table 2).
a
l
l
l
and 15 had more balanced liver to plasma drug levels (Table 3).
Whereas both 14 and 15 have excellent LXRb selectivity, when
tested for ABCA1 induction in the hWBA the potency was moderate
l
l
l
(EC50 = 7–8
l
M, Table 3). Based on PK data with additional species
with low 24 h liver exposures (Table 3), indicating they would
not have a long liver residence time that might result in increased
hepatic triglyceride production.
the human dose projections were anticipated to be too high for pro-
gression into clinical testing (unpublished data).

E. Kick et al. / Bioorg. Med. Chem. Lett. 25 (2015) 372–377
375
Table 3
Mouse PK and potency of ABCA1 induction in a human whole blood assay (hWBA)29,32
Compound
Mouse PK (30 mpk, p.o.)
hWBA ABCA1 EC50 (l
M) % Effa
4 h plasma (lM)
24 h plasma (
lM)
24 h liver (lM)
*
*
6
7
8
13
14
15
16
17
18
6.9
0.6
6.6
4.1
0.4
0.3
2.3
2.0
0.6
0.02
0.4
0.04
7.8
1.0
32
13.2
4.4
0.2
1.5
<0.05
0.48 (49%)
*
*
1.2
14.0
18.5
6.0
1.3
5.4
8.3 (31%)
7.0 (38%)
3.1 (30%)
3.2 (62%)
1.2 (55%)
*
Data not available.
a
Percent efficacy (% Eff) is the percent of maximal activity compared to full pan agonist 3c.
R1
a or b
R1
CN
19
X
X
HN
Br
HN
20
R1 Cl, CF3
=
X = bond, CH2,
or C(CH3)2
R1
R1
X
X
Br
Br
c
d
N
N
N
N
EtO
21
22
O
OH
e
O
R1
X
O
S
N
N
R2
13-18
Figure 2. Compound 18 bound to the active site of LXRb (2.0 Å resolution) obtained
using butane diol in the crystallization media (PDB code: 4RAK).
e
O
Br
CF3
Cl
Cl
Br
+
g
f
N
The imidazole analogs were prepared using chemistry shown in
Scheme 2. For imidazoles 14–18, the synthesis was initiated using
commercially available benzyl or aryl nitrile (19) starting materi-
als. For the synthesis of compound 18, the 2-(2-chlorophenyl)-2-
methylpropanenitrile (19, X = C(CH3)2) was prepared by alkylation
of 2-chlorobenzyl cyanide with methyl iodide using potassium
tert-butoxide. The amidine 20 was formed by reaction of 19 with
4-bromoaniline in the presence of Al(CH3)3 at 80 °C. Alternatively,
KHMDS was added to 4-bromoaniline followed by slow addition of
N
N
NH
F3C
F3C
Br
Cl
CHO
23
24
Scheme 2. Synthesis of biphenyl imidazoles. Reagents and conditions: (a) 4-
bromoaniline, Al(CH3)3, toluene, 80 °C (49–80% yields); (b) KHMDS, 4-bromoani-
line, THF (66–83% yields); (c) EtO2CCOCH2Br, NaHCO3, THF or iPrOH (23–84%
yields); (d) CH3MgBr, THF/ CH2Cl2 (36–73% yields); (e) [(3-methylsulfo-
nyl)phenyl]boronic acid, PdCl2(dppf), K2CO3, DME, H2O (66–75% yields); (f) i)
NaOAc, H2O, 100 °C, ii) NH4OH, MeOH (76% yield); (g) 4-bromo-phenylboronic acid,
[Cu(OH)ꢁTMEDA]2Cl2, CH2Cl2, (25% yield).
19 to form amidine 20. Treatment of 20 with ethyl a-bromopyru-
vate and NaHCO3 in THF at 60 °C afforded imidazole 21.33 Methyl
grignard addition to the ester 21 in THF afforded the carbinol 22.
Subsequent coupling of [(3-methylsulfonyl)phenyl]boronic acid
to bromide 22 using K2CO3 and PdCl2(dppf) provided the biphenyl
imidazoles 14–18. Analog 13 was prepared by an alternative route,
by mixing 3,3-dibromo-1,1,1-trifluoroacetone with sodium acetate
to generate a glyoxal, which was reacted with 2-chlorobenzalde-
hyde and ammonium hydroxide to afford imidazole 23. Coupling
of 23 with 4-bromo-phenylboronic acid afforded the aryl imidazole
24,34 which was transformed to 13 following similar chemistry
described above.
not strong interactions evident with either His 435 or Trp 457, as
have been observed with potent pan-agonists.35,36 This lack of
strong interaction with the His-Trp pair may be the reason partial
agonist activity is observed with the series.
Based on the hWBA potency, partial LXR
a agonism and LXRb
selectivity, mice were dosed with 18 for 7 days at 0.3, 1, 3, 10
and 30 mpk per day to assess the ABCA1 and ABCG1 blood cell
gene induction, as well as plasma and liver triglyceride levels
(Fig. 3).37,38 Significant ABCA1 inductions were observed at the 3,
10 and 30 mpk doses, with ABCG1 showing a similar pattern, and
5 h drug exposures of 0.05, 0.20 and 2.0
mouse in vitro EC50 to induce ABCA1 in whole blood was
0.12 M, which was similar to the plasma drug exposures needed
for ABCA1 induction in vivo. The 3 and 10 mpk doses of 18 gave
significant ABCA1 mRNA inductions with no significant plasma or
lM, respectively. The
The crystal structure of 18 with LXRb shows there are three
hydrogen bonds: between the oxygen of the carbinol and Thr
272, between an oxygen of the methylsulfone and Arg 319, as well
as, the backbone NH of Leu 330. Other interactions are general van
der Waals’ interactions of the ligand with the active site. There are
l

376
E. Kick et al. / Bioorg. Med. Chem. Lett. 25 (2015) 372–377
significantly induced to 2.7 and 3.5 fold over vehicle at 10 and
30 mpk, compared to 7.7 fold induction with 3c treatment;
whereas FAS had no significant changes up to 30 mpk.
A
In summary, we have prepared pyrazole and imidazole biaryl
sulfones that are LXR partial agonists with selectivity for LXRb.
The carbinol containing molecules such as 10, 15, 16, 17 and 18
displayed favorable PK in mice. In particular, the imidazole 18
(EXEL-04286652, BMS-779788) is an LXR partial agonist with
moderate LXRb selectivity and potent induction of ABCA1 ex vivo
in human blood, making it a valuable molecule for further investi-
gation in more advanced in vivo PD studies that will be described
in the near term.39
Acknowledgments
The authors thank Joanne Molay for helping with preparation of
molecules described herein. We thank Susan Zimmerman, Nhin Lu,
Sihong Zhou, and Peter Ordentlich for their support on assay
optimization and routine screening, as well as, Gang Shao, and
Jay Hou for their contributions to the assay development. We
thank Hangjun Zhan, Doug Buckley, Chris Bonagura, and Doug
Yan for guidance and assistance with protein biochemistry and
crystallography, Jodi Muckelbauer for preparing Figure 2 for publi-
cation, and Nick Wurtz for proofreading the manuscript.
B
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.11.
029. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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Figure 3. Dose response of 18 compared to control 3c after 7 days of dosing to
mice: (A) Mouse blood cell ABC transporters; (B) plasma and liver TG; (C) liver
mRNA for SREBP1c and FAS.37 ⁄Denotes p <0.05, ⁄⁄denotes p <0.01, and ⁄⁄⁄ denotes p
<0.001 considered as significant compared to vehicle using one way ANOVA with
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hepatic triglyceride elevation. Plasma triglycerides were signifi-
cantly elevated 74–108% at only the 30 mpk dose, and no signifi-
cant hepatic triglyceride elevations were observed at any dose in
contrast to the control pan agonist, which had 4.8 fold increase
in hepatic triglyceride compared to vehicle. The reduced induction
of LXR target genes SREBP1c and FAS in the liver likely accounts for
the reduced lipogenic profile of 18. In the liver SREBP1c was

E. Kick et al. / Bioorg. Med. Chem. Lett. 25 (2015) 372–377
377
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a
a
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37. Mice (C57BL/6) were dosed in vehicle containing 0.75% carboxymethyl
cellulose (Sigma, C-9481) and 0.1% Tween 80 (Sigma, P-4780) in deionized
water for 7 days. ABC transporter mRNA was measured at 5 h post dose last
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post last dose. Pan-agonist 3c was used as a control in the experiment.
38. Characterization data for 18: 1H NMR (400 MHz, DMSO-d6) d ppm 1.45 (s, 6H),
1.71 (s, 6H), 3.29 (s, 3H), 4.63 (s, 1H), 6.77 (s, 1H), 6.87–6.94 (m, 1H), 6.96–7.02
(m, 3H), 7.02–7.08 (m, 1H), 7.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H),
7.73 (t, J = 7.7 Hz, 1H), 7.86–7.92 (m, 1H), 7.89–7.94 (m, 1H), 8.02 (t, J = 1.6 Hz,
1H). 13C NMR (101 MHz, DMSO-d6) d ppm 29.28, 30.72, 40.87, 43.42, 68.24,
116.81, 124.93, 126.07, 126.70, 127.64, 127.92, 130.19, 130.90, 131.61, 133.15,
137.94, 138.16, 140.21, 141.68, 143.05, 147.95, 151.47. Anal. Calcd for
C
28H29N2O3SClꢁ0.14C2H3N: C, 65.97; H, 5.76; N, 5.82; S, 6.22; Cl, 6.88. Found:
C, 66.09; H, 5.77; N, 5.74; S, 6.30; Cl, 7.05. Pd: 53 ppm, Fe, 27 ppm.
39. Kirchgessner, T. J.; Martin, R.; Sleph, P.; Grimm, D.; Liu, X.; Lupisella, J.; Smalley,
J.; Narayanan, R.; Xie, Y.; Ostrowski, J.; Cantor, G.; Mohan, R.; Kick, E. J.
Pharmacol. Exp. Ther. (accepted for publication).