Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)

Article abstract of DOI:10.1016/j.bmcl.2016.05.029

Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu₄. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu₄.

Full text of DOI:10.1016/j.bmcl.2016.05.029

Bioorganic & Medicinal Chemistry Letters 26 (2016) 2984–2987
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and characterization of a novel series of N-phenylsulfonyl-
1H-pyrrole picolinamides as positive allosteric modulators of the
metabotropic glutamate receptor 4 (mGlu4)
Rocco D. Gogliotti a,b, Anna L. Blobaum a,b, Ryan M. Morrison a,b, J. Scott Daniels a,b, James M. Salovich a,b
,
Yiu-Yin Cheung a,b, Alice L. Rodriguez a,b, Matthew T. Loch a,b, P. Jeffrey Conn a,b,c, Craig W. Lindsley a,b,d
,
Colleen M. Niswender a,b,c, Corey R. Hopkins a,b,d,
⇑
a Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
b Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
c Vanderbilt Kennedy Center, Vanderbilt University, Nashville, TN 37232, United States
d Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole
picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding
phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone
compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-
pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
Received 22 April 2016
Revised 9 May 2016
Accepted 10 May 2016
Available online 11 May 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Metabotropic glutamate receptor 4
Positive allosteric modulator (PAM)
Pyrrole sulfonamide
Phenyl replacement
PK
The metabotropic glutamate receptors are Class C G-protein
coupled receptors (GPCRs) and are further separated into three
family classes based on their receptor structure, G-protein cou-
pling and ligand selectivity (Group I: mGlu1 and mGlu5; Group II:
mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7 and mGlu8).1
This family of GPCRs has received significant attention over the
past 10 years as potential therapeutic targets for a number of
CNS disorders, such as schizophrenia,2–4 Fragile X,5,6 generalized
anxiety disorder7,8 and Parkinson’s disease.9–14 Until recently, the
Group III family had received less attention than the Group I and
Group II family receptors; however, many tool compounds for
the mGlu4 subtype have been disclosed recently from our laborato-
ries,15–17 and others.18–20 A common motif in many of the disclosed
compounds is the presence of an N-phenyl picolinamide core scaf-
fold.15,16,21,22 There have been reports of efforts aimed at discover-
culminating in the discovery of a unique series of N-pyrrolesulfon-
amides as novel PAMs of mGlu4.
The starting point for our exploration centered around a series
of phenylsulfonamides and phenylsulfones that were previously
disclosed (Fig. 1).24,25 Our first attempts at replacing the phenyl
group centered on a thiazole ring and utilized the sulfone moiety
as in 2 in order to limit the number of H-bond donors in the
molecule.26 The synthesis started with the commercially available
5-bromo-thiazol-2-amine (4-Me, Et, or H) which was acylated to
yield the picolinamide
5 (picolinyl chloride, DiPEA, CH2Cl2)
(Scheme 1). Next, palladium catalyzed cross-coupling of the
bromothiazole, 5, with an appropriately substituted benzylthiol
(Pd2(dba)3, XantPhos, DIEA, 1,4-dioxane, 100 °C) yielded the
N-(5-(benzylthio)-thiazol-2-yl)picolinamide, 6.27 Lastly, oxidation
of the sulfide to the sulfone (m-CPBA, CH2Cl2) yielded the desired
compounds, 7a–h.
ing amide replacements23
; however, there have not been
disclosures around replacement of the central phenyl ring system.
Herein, we report our efforts towards phenyl ring replacements
The SAR analysis of the thiazole sulfone analogs is summarized
in Table 1. Gratifyingly, the thiazole is a tolerated replacement for
the internal phenyl ring as the thiazole derivative, 7a, is equipotent
with the phenyl derivative, 2 (7a, EC50 = 189 nM vs 2, EC50
=
237 nM). In addition to R1 = H, the methyl and ethyl substituents
⇑
Corresponding author. Tel.: +1 615 936 6892; fax: +1 615 778 1414.
E-mail address: corey.r.hopkins@vanderbilt.edu (C.R. Hopkins).
are also tolerated in the 4-position (7b, EC50 = 448 nM; 7e,
http://dx.doi.org/10.1016/j.bmcl.2016.05.029
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

R. D. Gogliotti et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2984–2987
2985
metabolic stability of these compounds, presumably due to a shift
of the site of instability to other areas of the molecule (Table 2).
Next, we turned our efforts to eliminating the benzylic site alto-
gether by evaluating a series of phenyl sulfonamides. Much like the
benzyl derivatives, the phenylsulfonamides were well tolerated as
a substituent. Alkyl substituted pyrrole sulfonamides were the
most potent of the series (11l, EC50 = 122 nM; 11m, EC50 = 104 nM;
11r, EC50 = 62 nM), with the halogen substituted analogs being less
potent (e.g., 11n, EC50 = 740 nM; 11o, EC50 = 1238 nM). Some
potency could be recaptured by the addition of an alkyl group as
in 11t (EC50 = 163 nM) and 11u (EC50 = 268 nM). The pyrazole moi-
ety was also tolerated as a phenyl replacement (Table 3).
O
O
O
O
S
S
O
N
O
H
N
Cl
N
Cl
N
H
Cl
N
H
2
VU0366674,
hmGlu4 EC50 = 237 nM
1
VU0364439,
hmGlu4 EC50 = 19.8 nM
O
O
N
H
S
O
N
Cl
N
H
4PAM2, 3
Having established the pyrrole scaffold as a novel phenyl
replacement as mGlu4 PAMs, we next evaluated the compounds
in our battery of Tier 1 in vitro PK assays (Table 4). The intrinsic
clearance (CLINT) was assessed in rat hepatic microsomes and the
subsequent predicted hepatic clearance (CLHEP) was calculated.23,32
Many of the compounds displayed high intrinsic and predicted
hepatic clearance, except for the 3,4-dimethylphenyl analog,
11r, which had moderate predicted hepatic clearance
(CLHEP = 38.3 mL/min/kg). Utilizing an equilibrium dialysis
approach, the protein binding of the compounds was evaluated
in rat plasma. The fraction unbound (Fu) of the analogs tested
was very low, except, again, in the case of 11r which showed
slightly better unbound fraction (Fu = 0.012).
hmGlu4 EC50 = 162 nM
Figure 1. Previously disclosed phenylsulfonamide and phenylsulfone mGlu4 PAMs.
EC50 = 217 nM). Overall, the replacement of the phenyl group with
a thiazole was a productive change in terms of potency with 7c
being one of the most potent compounds discovered to date
(EC50 = 83 nM). The sulfide intermediates, 6, were tested and were
significantly less potent (EC50’s = 5000–8000 nM); the sulfoxides
were not tested as the oxidation procedure led directly to the
sulfones. Unfortunately, these compounds suffered from signifi-
cant pharmacokinetic liabilities (poor brain penetration, metabolic
instability) limiting the utility of these compounds to in vitro tool
compounds.
Lastly, we evaluated two analogs in an in vivo IV clearance
experiment in order to assess whether the in vitro data would be
Next, we turned our attention to other replacement groups,
namely, pyrrole and pyrazole.28,29 The synthesis of these groups
is detailed in Scheme 2. The nitro pyrrole (or pyrazole) was con-
verted to the sulfonamide (DBU, RSO2Cl) and then the nitro was
reduced to the amino compound using Raney Nickel, 10 (EtOH,
Ra–Ni, 40 psi H2). The final compounds were completed via acyla-
tion of the amino group with the acid chloride (picolinyl chloride,
DIEA) yielding the desired compounds, 11a–w.30,31
The initial set of compounds evaluated were the benzyl sulfon-
amides, comparators to the thiazole benzylsulfones. Similar to the
thiazole core compounds, the pyrrole compounds were well toler-
ated, with the 2-chlorobenzyl sulfonamide being equipotent to the
thiazole (7a) and phenyl (2) derivatives (11g, EC50 = 174 nM). As
seen previously, most of the benzyl compounds that we evaluated
were active as mGlu4 PAMs with most EC50’s < 500 nM. Although
these compounds were active as PAMs, they suffered from the
same PK liabilities as the thiazole compounds, namely, metabolic
stability issues. It was determined that oxidation of the benzylic
CH2 group was the major metabolic liability and efforts were
undertaken to block this site. Thus, compounds 11i–k were synthe-
sized. Unfortunately, these compounds were significantly less
potent as mGlu4 PAMs, with the mono-fluoro compound being
the most active (11j, EC50 = 1024 nM). In addition, blocking the
presumed site of metabolism did not inherently improve the
Table 1
SAR of the sulfonylthiazoles, 7a–h
R1
O
N
R2
S
O
N
O
S
N
H
7a-h
a
Compd R1
R2
mGlu4 EC50
(nM)
pEC50 SEMa %GluMaxb
Cl
Cl
F
7a
7b
7c
7d
7e
7f
H
189
448
83
6.72 0.13
30.6 0.5
94.8 3.6
35.1 1.2
112.5 1.6
119.9 1.3
93.5 1.8
∗
∗
∗
∗
∗
∗
∗
Me
H
6.35 0.06
7.08 0.14
5.38 0.06
6.66 0.09
6.26 0.05
Cl
Cl
Cl
F
F
Me
Et
4137
217
547
F
R
F
R
b
O
N
a
Me
N
Br
N
c
Br
S
N
H
S
F
H2N
O
5
4
7g
7h
Me
Et
295
150
6.53 0.09
6.82 0.12
99.3 1.7
R1
R
R1
F
F
R
O
N
S
O
N
N
O
S
N
H
S
N
∗
109.0 1.4
S
N
7a-h
6
H
F
a
Calcium mobilization human mGlu4 assay; values are the average of n = 3.
Amplitude of response in the presence of 30 lM test compound, normalized to
Scheme 1. Reagents and conditions. (a) Picolinyl chlorideÁHCl, diisopropylethy-
lamine, CH2Cl2, 24–39%; (b) Pd2(dba)3, XantPhos, HSCH2Ar, diisopropylethylamine,
1,4-dioxane, 100 °C, 51–87%; (c) m-CPBA, CH2Cl2, 38–87%.
b
a standard compound, PHCCC, and represented as %GluMax.

2986
R. D. Gogliotti et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2984–2987
of the cytochrome P450s. After PO dosing, a significant amount
b
a
X
X
R
O
of 11t was detected in the HPV (hepatic portal vein); however, only
ꢀ1% of that amount was detected in the plasma, indicating a signif-
icant amount of oxidative metabolism. The brain:plasma ratio was
ꢀ1:1, although the total amount in the brain was very low, which
is in contrast to the phenylsulfones which displayed low brain:-
plasma ratios. When co-dosed with ABT, the concentrations of
11t in the HPV were nearly identical with the non-ABT dosed ani-
mals; however, the concentrations detected in the plasma were
significantly higher (198.5 ng/mL vs 7.4 ng/mL). Again, while the
brain:plasma ratio was ꢀ1:1; as with the total plasma concentra-
tions, the total amount in the brain was higher when co-dosed
with ABT (Table 5).
N
S
O
NH
O2N
O2N
9
8
X = N, CH
X
O
R
O
c
X
N
R
O
N
S
O
N
S
O
N
H
H2N
11a-w
10
Scheme 2. Reagents and conditions. (a) DBU, ArSO2Cl or BnSO2Cl, CH2Cl2, 50–96%;
(b) EtOH, Ra–Ni, 40 psi H2, 2 h; 93–97%; (c) diisopropylethylamine, picolinyl
chloride, CH2Cl2, 39–43%.
In conclusion, we report the discovery and characterization of
unique thiazolesulfone and pyrrolesulfonamide core scaffolds as
mGlu4 PAMs. These series were synthesized as a replacement for
the previously disclosed phenylsulfonamide/phenylsulfone com-
pounds. The thiazolesulfone analogs were potent mGlu4 PAMs
(EC50’s < 500 nM), but suffered from metabolic instability. The
pyrrolesulfonamide scaffold also was a well-tolerated change with
many compounds exhibiting EC50’s < 500 nM. Compounds from
this scaffold displayed an IV/IVC with regards to clearance (CLp)
following IV adminstration; however, the compounds were not
orally bioavailable and displayed poor exposure following PO dos-
ing (systemic:HPV ratio <0.01). Co-dosing in vivo with the pan-
irreversible P450 inhibitor, ABT, blocked extensive P450-mediated
predictive of in vivo PK (in vitro:in vivo correlation, IV/IVC). The
two compounds chosen were 11r and 11t, one predicted to be
moderately cleared and the other highly cleared. Both compounds
were dosed IV (1 mg/kg) and the in vivo plasma clearance closely
resembles the in vitro predicted hepatic clearance suggesting the
major route of clearance to be hepatic oxidative metabolism. In
order to more fully establish this route of metabolism, we co-dosed
11t with 1-aminobenzotriazole (ABT), a pan-irreversible inhibitor
Table 2
SAR of the pyrrole benzylsulfonamides, 11a–k
R3
R2
R1
O
N
S
O
N
O
N
H
Table 3
11a-k
SAR of the pyrrole phenylsulfonamides, 11l–w
Compd R1
R2
R3 mGlu4
pEC50 SEMa %GluMaxb
X
O
R1
O
a
N
S
O
EC50
(nM)
N
N
H
F
11l-w
11a
572 6.24 0.04
98.6 2.6
H
H
∗
a
Compd
X
R1
mGlu4 EC50
(nM)
pEC50 SEMa %GluMaxb
∗
11b
188 6.72 0.04
4179 5.38 0.16
88.7 4.4
CF
3
∗
11l
CH
CH
122
104
6.91 0.03
88.8 3.4
84.8 5.3
11c
112.3 5.3
∗
11m
6.98 0.04
∗
∗
∗
∗
Cl
11d
11e
11f
84 7.07 0.04
398 6.40 0.06
251 6.60 0.07
122.4 3.7
140.3 1.7
117.2 7.1
∗
∗
11n
11o
CH
CH
740
6.13 0.03
5.91 0.18
78.8 3.5
F
F
1238
102.8 6.2
Cl
Cl
Cl
F
11p
11q
CH
CH
440
344
6.36 0.10
6.46 0.10
72.9 2.5
83.0 0.3
N
∗
∗
∗
Cl
Cl
N
11g
11h
174 6.76 0.02
190 6.72 0.04
119.0 3.5
108.9 5.2
11r
11s
11t
11u
CH
N
62
148
163
268
7.21 0.01
6.83 0.04
6.79 0.05
6.57 0.06
80.3 4.3
92.9 1.9
72.2 1.7
98.9 2.3
∗
∗
∗
F
∗
∗
F
CH
CH
11i
11j
Me
F
H
H
2970 5.53 0.26
1021 5.99 0.02
59.6 12.7
71.0 2.6
Cl
F
F
∗
∗
∗
F
∗
∗
11v
N
242
739
6.62 0.06
6.13 0.07
35.3 3.0
35.6 3.7
CF3
CF3
11k
F
F
>30,000 <4.5
33.5 4.9
11w
CH
a
a
Calcium mobilization human mGlu4 assay; values are the average of n = 3.
Calcium mobilization human mGlu4 assay; values are the average of n = 3.
Amplitude of response in the presence of 30 lM test compound, normalized to
b
b
Amplitude of response in the presence of 30
lM test compound, normalized to
a standard compound, PHCCC, and represented as %GluMax.
a standard compound, PHCCC, and represented as %GluMax.

R. D. Gogliotti et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2984–2987
2987
Table 4
16. Jones, C. K.; Engers, D. W.; Thompson, A. D.; Field, J. R.; Blobaum, A. L.; Lindsley,
S. R.; Zhou, Y.; Gogliotti, R. D.; Jadhav, S.; Zamorano, R.; Bogenpohl, J.; Smith, Y.;
Morrison, R.; Daniels, J. S.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.; Niswender,
C. M.; Hopkins, C. R. J. Med. Chem. 2011, 54, 7639.
17. Jones, C. K.; Bubser, M.; Thompson, A. D.; Dickerson, J. W.; Turle-Lorenzo, N.;
Amalric, M.; Blobaum, A. L.; Bridges, T. M.; Morrison, R. D.; Jadhav, S.; Engers, D.
W.; Italiano, K.; Bode, J.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R.; Conn, P. J.;
Niswender, C. M. J. Pharmacol. Exp. Ther. 2012, 340, 404.
18. Le Poul, E.; Boléa, C.; Girard, F.; Poli, S.; Charvin, D.; Campo, B.; Bortoli, J.; Bessif,
A.; Luo, B.; Koser, A. J.; Hodge, L. M.; Smith, K. M.; DiLella, A. G.; Liverton, N.;
Hess, F.; Browne, S. E.; Reynolds, I. J. J. Pharmacol. Exp. Ther. 2012, 343, 167.
19. Jimenez, H. N.; Liu, K. G.; Hong, S.-P.; Reitman, M. S.; Uberti, M. A.; Bacolod, M.
D.; Cajina, M.; Nattini, M.; Sabio, M.; Doller, D. Bioorg. Med. Chem. Lett. 2012, 22,
3235.
In vitro pharmacokinetic data for selected N-phenylsulfonamide pyrroles
Compd
CL (mL/min/kg)
Rat CLHEP
PPB (Fu)
Rat CLINT
Rat
11l
2704
4035.1
1126.4
293
3804
3445
68.2
68.8
65.9
38.3
68.7
68.6
0.009
0.001
0.004
0.012
0.005
0.004
11m
11o
11r
11s
11t
20. Bennouar, K.-E.; Uberti, M. A.; Melon, C.; Bacolod, M. D.; Jimenez, H. N.; Cajina,
M.; Kierkerian-Le Goff, L.; Doller, D.; Gubellini, P. Neuropharmacology 2013, 66,
158.
21. Engers, D. W.; Niswender, C. M.; Weaver, C. D.; Jadhav, S.; Menon, U. N.;
Zamorano, R.; Conn, P. J.; Lindsley, C. W.; Hopkins, C. R. J. Med. Chem. 2009, 52,
4115.
22. Cheung, Y.-Y.; Zamorano, R.; Blobaum, A. L.; Weaver, C. D.; Conn, P. J.; Lindsley,
C. W.; Niswender, C. M.; Hopkins, C. R. ACS Comb. Sci. 2011, 13, 159.
23. Engers, D. W.; Blobaum, A. L.; Gogliotti, R. D.; Cheung, Y.-Y.; Salovich, J. M.;
Garcia-Barrantes, P. M.; Daniels, J. S.; Morrison, R. D.; Jones, C. K.; Soars, M. G.;
Zhuo, X.; Hurley, J.; Macor, J. E.; Bronson, J. J.; Conn, P. J.; Lindsley, C. W.;
Niswender, C. M.; Hopkins, C. R. ACS Chem. Neurosci. 2016. http://dx.doi.org/
10.1021/acschemneuro.6b00035. Just accepted manuscript.
24. Reynolds, I. J. Metabotropic glutamate receptors as therapeutic targets in
Parkinson’s disease. In 6th International Meeting on Metabotropic Glutamate
Receptors 2008, Taormina, Sicily, Italy, 2008.
Table 5
In vivo Rat PK IV clearance (1 mg/kg)
11r
11t
CL (mL/min/kg)
T1/2 (min)
MRT (min)
Vss (L/kg)
AUC (h ng/mL)
37.2
252
149
5.5
86.8
167
84.7
7.4
447.5
191.7
po dosing of 11t with and without ABT, 1 h
Dose (mg/kg)
Concentration (ng/mg or g)
Plasma systemic
Plasma HPV
Brain
25. Engers, D. W.; Gentry, P. R.; Williams, R.; Bolinger, J. D.; Weaver, C. D.; Menon,
U. N.; Conn, P. J.; Lindsley, C. W.; Niswender, C. M.; Hopkins, C. R. Bioorg. Med.
Chem. Lett. 2010, 20.
10/Veh
10/ABT
7.4
198.5
731
764.5
8.1
175.5
26. Conn, P. J.; Lindsley, C. W.; Hopkins, C. R.; Weaver, C. D.; Niswender, C. M.;
Gogliotti, R. D.; Cheung, Y. Y.; Salovich, J. M.; Engers, D. W. WO 2011/143466,
2011.
27. Mispeleare-Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetrahedron Lett.
2005, 61, 5253.
28. Conn, P. J.; Lindsley, C. W.; Hopkins, C. R.; Niswender, C. M.; Gogliotti, R. D. WO
2011/050305, 2011.
29. Conn, P. J.; Lindsley, C. W.; Hopkins, C. R.; Niswender, C. M.; Gogliotti, R. D.;
Salovich, J. M. WO 2011/050316, 2011.
metabolism and significantly improved the systemic plasma and
brain concentrations (plasma systemic:HPV ratio 0.26).
Acknowledgment
30. All final compounds were purified by high-throughput HPLC and characterized
by LCMS and/or 1H NMR and found to be in agreement with their structures
(>95% purity).
The authors would like to thank the Michael J. Fox Foundation
for Parkinson’s Research for their support.
31. 1-((3,4-Dimethylphenyl)sulfonyl)-3-nitro-1H-pyrrole (9): To a stirred solution of
3-nitro-1H-pyrrole (200 mg; 1.78 mmol) in CH2Cl2 (8 mL) was added 1,8-
References and notes
diazabicycloundec-7-ene, DBU, (347 lL; 2.32 mmol) followed by 3,4-
dimethylbenzenesulfonyl chloride (438 mg; 2.14 mmol). The reaction was
stirred at rt overnight and then was diluted with CH2Cl2 and washed with 2 N
HCl, satd NaHCO3, dried (MgSO4), filtered and concentrated under vacuum.
Material was purified by CombiFlash (Isco—40 g column) eluting with 0–30%
EtOAc/hexanes to give the final product (329 mg; 85%). LCMS: RT = 2.41 min,
>98% at 215 nm, m/z = 219.1 [M+H]+.
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N-(1-((3,4-Dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide
(11r):
To
reaction vessel was charged the 9 (180 mg; 0.826 mmol), EtOH (10 mL) and
Raney Nickel (cat.) and the mixture was subjected to 40 psi H2 in a Parr shaker
for 2 h. The reaction was worked up by adding a magnetic stir bar to bind the
Ra–Ni and the solution was transferred by pipette and filtered through a
Whatman filter disc. The filtrate was concentrated to give the crude amine
which was taken through without further purification. To the crude amine was
added CH2Cl2 (10 mL), diisopropylethylamine (374 lL; 2.15 mmol) and
picolinyl chlorideÁHCl (152 mg; 0.860 mmol) and the mixture was stirred at
rt overnight. The reaction mixture was diluted with CH2Cl2, washed with H2O,
dried (MgSO4) filtered and concentrated. The material was purified by
CombiFlash (Isco, 12 g) eluting with 0–40% EtOAc/hexanes to give the final
product as a yellow solid (136 mg; 54%). LCMS: RT = 1.078 min, >98% at 215
and 254 nm, m/z = 356 [M+H]+. 1H NMR (DMSO-d6) 400 MHz d 10.9 (s, 1H),
8.70 (d, 1H, J = 4.6 Hz), 8.11–8.03 (m, 2H), 7.74 (d, 2H, J = 7.5 Hz), 7.66 (d, 2H,
J = 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.29 (s, 1H), 6.71 (d, 1H, J = 2.3 Hz), 2.29, 2.27
(2 s, 6H).
14. Robichaud, A. J.; Engers, D. W.; Lindsley, C. W.; Hopkins, C. R. ACS Chem.
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15. Engers, D. W.; Field, J. R.; Le, U.; Zhou, Y.; Bolinger, J. D.; Zamorano, R.;
Blobaum, A. L.; Jones, C. K.; Jadhav, S.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.;
Niswender, C. M.; Hopkins, C. R. J. Med. Chem. 2011, 54, 1106.
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Nishime, J. A. Drug. Metab. Dispos. 1996, 24, 1111.