Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part II)

Article abstract of DOI:10.1016/j.bmcl.2013.03.081

A novel series of histamine H₃ receptor (H₃R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H₃R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H₃R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.

Full text of DOI:10.1016/j.bmcl.2013.03.081

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3421–3426
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of aryl ureas and aryl amides as potent and selective
histamine H3 receptor antagonists for the treatment of obesity
(Part II)
b,
Zhongli Gao a, , William J. Hurst , Etienne Guillot c, Werngard Czechtizky d, Ulrike Lukasczyk d,
⇑
Raisa Nagorny b, Marie-Pierre Pruniaux c, Lothar Schwink d, Juan Antonio Sanchez c,
Siegfried Stengelin d, Lei Tang b, Irvin Winkler d, James A. Hendrix b, Pascal G. George c
a LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA
b Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA
c Sanofi R&D, Chilly-Mazarin, France
d Sanofi R&D, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 28 March 2013
A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via
bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was opti-
mized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue
(analogs 2a–2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a–
5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/
inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition
in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with
improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3 receptor
Antagonist/inverse agonist
Obesity
Aryl amide
Obesity,1 characterized by the accumulation of an excessive
amount of body fat, is associated with an increased risk of meta-
bolic and cardiovascular conditions such as hypertension, dyslipi-
demia, diabetes mellitus, and obstructive sleep apnea. Obesity’s
prevalence has doubled in the United States and in many European
countries since the 1980s, and the number of those affected contin-
ues to rise at an alarming rate. Obesity is already responsible for 2–
8% of health costs and 10–13% of deaths in Western countries. Effi-
cacious treatments of this condition are certainly among the great-
est public health challenges of the 21st century. Although it has
been shown that even a modest weight loss reduces the risk of
acquiring these complications, very few effective therapies that
can facilitate a successful treatment are presently available. Even
though it is arguable that weight loss can be achieved through
dieting and other lifestyle changes, the long-term outcome is
uncertain due to lack of compliance. For this reason, the drug dis-
covery activities in finding an effective pharmacological treatment
of obesity have stimulated intensive research interests during re-
cent years.
The key to combat obesity appears to be in the restoration of the
energy intake/expenditure balance. Appetite and food intake are
centrally regulated by the hypothalamus through a number of
pathways involving orexigenic and anorexigenic signaling peptides
and neurotransmitters acting at the appropriate receptors. Hista-
minergic neurons are localized exclusively in the tuberomammil-
lary nucleus (TMN) in the posterior hypothalamus and send
projections throughout the CNS that are organized in functionally
distinct circuits impinging on different brain regions.2 Histamine
H3 receptors (H3R) is a presynaptic G protein coupled receptor
which regulates the intrasynaptic level of histamine via inhibiting
the conversion of L-histidine to histamine and the release of hista-
mine into the synaptic cleft. Brain histamine affects both sides of
energy balance: by decreasing intake and increasing expenditure.
The accumulative evidence is emerging on the potential role of
H3R as a target of antiobesity therapeutics.3 Many pharmaceutical
companies have embarked on discovery of H3R antagonists for
treatment of obesity. Multiple structural types of H3R antagonists
have been reported.4
The preceding letter described a set of arylurea compounds,
exemplified by compound 1, which displayed activity in human
H3R (h-H3R) FLIPR assays and h-H3R GTP
pound 1 was also active in in vitro binding assays by displacement
of [3H]N-
-methylhistamine in membranes isolated from CHO
cS functional assays. Com-
⇑
Corresponding author. Tel.: +1 781 434 3635.
E-mail addresses: zhongli.gao@sanofi.com (Z. Gao), william.hurst@sanofi.com
(W.J. Hurst).
a
Tel.: +1 908 981 3723.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.081

3422
Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3421–3426
The choice of rhesus monkey H3R binding data as the first tier
H
N
N
H
N
screening was driven by the rationale that the rhesus monkey data
could be more useful for in vivo pharmacological screening of a few
more structurally diverse novel compounds in acute models in the
future when the program advanced to that stage. The selected
compounds will be further followed up in human and rat H3R affin-
ity, and many other assays, such as ADME, off-target selectivity,
and cardiovascular safety. Therefore, all the compounds synthe-
sized were evaluated in H3R binding assays by displacement of
N
O
Cl
H3C
Cl
1
h-H3R FLIPR IC50 = 0.95 nM;
rh-H3R binding Ki = 22.2 nM;
h-H3R GTPγS percent inhibition @ 10 μM = 126%
[3H]N-
a-methylhistamine in membranes isolated from a CHO cell
line stably transfected with the rhesus monkey H3 receptors (rh-
H3R). Only selected compounds were evaluated in H3R binding as-
says in human H3 receptors (h-H3R) and the rat H3 receptors (r-
H3R) in the same manner as for rhesus monkey H3R. The detailed
protocol for the binding assays was described in the preceding let-
ter. The SAR of the analogs 2a–2ag is summarized in Table 1.
The optimization strategy was guided by a Target Product Pro-
file (TPP), which required that the compounds of interest had to be
capable of penetrating the CNS. It was therefore essential to design
compounds considering both H3R affinity and physico-chemical
properties such as molecular weight, number of hydrogen bond
donors and acceptors, number of rotatable bonds, clogP, and polar
surface area. For simplicity, only clogP and polar surface area (cal-
culated using ACD/Labs methods) were used. The optimization
started from the lead compound 2a (without substituents in the
central aryl ring) by exploring the left-hand side aryl substituents
in terms of position, polarity, hydrogen bonding and hydrophobic
interactions. To reduce the lipophilicity of the molecule in order
to reduce clogP, more polar functional groups were selected. The
first compound, compound 2b, with a basic center and increased
polar surface area, displayed decreased H3R affinity (Ki = 70.2 nM)
with respect to lead compound 2a, suggesting that this position re-
quires a less polar group. We speculated that the second basic cen-
ter (as in 2b) might not be necessary. We then selected neutral
functional groups, exemplified by compounds 2c and 2d, which
showed 4 to 15 fold increase of the affinity compared to 2b, sug-
gesting that the position C-4 was in favor of lipophilic substituents.
However, the increase of lipophilicity led to an undesired increase
of hERG channel affinity. For example, 2d showed 19.9% and 95%
Cl
Cl
H
N
N
N
O
H3C
2a
h-H3R FLIPR IC50 = 0.48 nM;
rh-H3R binding Ki = 49.5 nM;
h-H3R GTPγS percent inhibition @ 10 μM = 119%
Figure 1. Bioisosteric replacement of the arylurea 1 leading to arylamide 2a.
cells transfected with cloned rhesus monkey H3 receptors (rh-H3R)
with a Ki of 22.2 nM (Fig. 1).
This set of the compounds represented by 1 offered valuable
tool compounds for our H3R program although the potential of
the series to furnish a drug candidate was limited due to a variety
of issues including poor aqueous solubility, poor oral exposure, and
metabolic/chemical instability. During SAR exploration of the
arylurea series, we observed that the arylureas composed of sec-
ondary amines displayed H3R antagonism activity in both binding
and functional assays. This led us to the design of arylamides 2
(Fig. 1) by bioisosteric replacement of the arylurea with an aryla-
mide. This would provide us with a new dimension of optimiza-
tion. The arylamides were supposed to offer several potential
advantages including (1) an increased solubility; (2) an increased
metabolic stability; (3) the potential to develop into a novel second
generation of H3R antagonists. Herein we describe the optimiza-
tion of the new lead compound 2 via SAR exploration leading to
the discovery of 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-
[1,30]bipyrrolidinyl-10-yl)phenyl] benzamide (2q) as a selective
and potent H3R antagonist which displayed oral activity in a mouse
food intake inhibition model.
Analogs 2a–2ag were conveniently prepared (Scheme 1) by
coupling of commercially available acids or acid chlorides (3) with
the arylamines (4) whose syntheses were described in the preced-
ing letter.
A relation between human and rhesus H3R binding affinity (see
the preceding letter) seemed apparent. The project team took
advantage of this observation by using rhesus monkey H3R binding
data as the first tier screening for all the synthesized compounds.
inhibition of the hERG channel at 1 lM and 10 lM, respectively.
In addition, the metabolic stability was generally poor for these
overly lipophilic compounds, such as 2d. We therefore envisioned
a strategy to introduce a heteroatom at C-4 with substituents of
‘shielded heteroatoms’, exemplified by 2e. This compound showed
some degree of increase in H3R affinity compared to 2b with de-
creased clogP compared to 2a. In a next step, the effect of the posi-
tion of the substituents was explored. The ortho dimethylamino
analog 2g showed an almost threefold increase in affinity as com-
pared to the close analogs 2e and 2f. Similar trends were also ob-
served in other examples (2i vs 2h). We hypothesized that this
affinity enhancement might be due to the steric effect of the ortho
substituents helping to maintain the perpetual-shaped confirma-
tion of the ligand. This hypothesized bioactive confirmation is de-
picted in Figure 2. If this were true, the substituents at C-20 position
R1
R1
O
O
R
R
a
+
H2N
X
N
N
H
N
N
N
X = OH, Cl
3
4
2
Scheme 1. Syntheses of analogs 2a–2ag. Reagents and conditions: (a) For acids: DCM, DMF, N-methylmorpholine, HOBt, EDCꢀHCl, 0 °C to rt, overnight, 75–95% yield; For acid
chlorides: DCM, pyridine, 0 °C to rt, 2 h, 85–90% yield.

Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3421–3426
3423
Table 1
rh-H3R binding affinity, calculated lipophilicity values (cLogP), calculated total polar surface area (tPSA), and in vitro PK properties of arylamides 2a–2ag
R1
O
2'
3'
R
2
N
N
H
3
N
4
2
No
R
R1
rh-H3R binding Kia (nM)
cLogP
tPSA (Å2)
Caco-2/TC7b (10ꢁ7 cm/s)
Microsome % metabolite
Human
Mouse
Rat
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
3,5-Di-Cl
4-(CH2)-N-morpholinyl
4-MeO-
4-Cl
4-Me2N
3-Me2N
2-Me2N
3-F
2-F
2-Me-5-F
3,5-Di-Cl
3,5-Di-Cl
4-Cl
4-Cl
3-F
2-F
2-Me-5-F
H
H
H
H
H
H
H
H
49.5
70.2
17.6
4.7
33.5
33.3
13.8
10.6
8.2
5.4
2.1
2.9
3.8
3.6
3.5
3.1
3.4
2.8
3.9
5.8
5.8
3.9
3.7
3.9
3.3
4.4
3.3
2.5
4.0
4.0
3.9
4.5
2.8
3.6
2.8
2.4
3.6
4.7
3.1
4.8
5.4
5.9
36
48
45
36
39
39
39
36
36
36
36
36
36
36
36
36
36
60
56
48
48
48
64
66
53
78
78
70
86
48
36
36
36
ND
ND
20
43
90
H
H
12
31
48
4.7
20-Me
30-Me
20-Me
30-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-Me
20-CF3
20-CF3
20-CF3
24.1
54.0
2.6
4.8
12.1
5.8
ND
ND
32
29
22
43
33
90
92.4
91.9
15
5
ND
ND
28
38
1.2
4-CN
4-CH2OH
11.3
12.7
12.2
18.8
26.7
4.3
2s
2t
4-(2-Pyridyl)-
4-(3-Pyridyl)
4-(4-Pyridyl)-
4-(3,5-Dimethyl-1H-pyrazolyl)
4-N-1H-[1,2,4]Triazolyl
4-N-Pyrazolyl
3-MeS(O)2, 4-Me
4-MeS(O)2
4-(2-Pyrimidinyl)-O-
4-Thiazolyl-2-O-
4-N-Morpholinyl
2-F
2u
2v
2w
2x
2y
87
14
89
44
79
45
8.1
39.1
11.9
25.6
22.8
24.0
44.0
16.9
40.0
4.0
2z
2aa
2ab
2ac
2ad
2ae
2af
2ag
ND
3-F
2-Me-5-F
a
Ki values were averages of three or more determinations. ND: not determined.
Caco-2/ TC7 (Papp, 10ꢁ7 cm/s) is the rate at which a compound crosses the TC7 monolayer under experimental conditions.
b
2n). Because of this observation, we decided to further optimize
substituents at the left hand side aromatic ring while keeping the
20-methyl substituted aromatic as the constant moiety in the hope
of generating a molecule with balanced lipophilicity (clogP and
PSA) for brain penetration, hERG selectivity, metabolic stability
and H3R affinity. A large variety of substituents was investigated.
Fortunately, wide ranges of substituents were tolerated. However,
the trends clearly indicated the preference towards small lipophilic
substituents in the left-hand side aromatic ring and small ortho-
substituents on the central aryl ring. The size of the 2-substituents
at the central aryl ring could not be too big; for example, 2ae vs 2p
(2- to 3-fold decrease in affinity).
Figure 2. Hypothesized bioactive confirmation of the ligand 2q.
To further explore the SAR, we synthesized and tested a set of
heteroaryl amides and the data are collected in Table 2.
in the central aromatic ring should have the similar effects. This
hypothesis was supported by two sets of examples, 2a, 2l, 2k
and 2d, 2m, 2n. In the first set (2a, 2l, 2k), 2k showed a higher
affinity than 2a and 2k; in the second set (2d, 2m, 2n), 2m was also
higher in affinity than 2d and 2n.
In general, most heteroaryl amides maintained H3R affinity. The
derivatives with 3,5-dimethyl-isoxazole group (5a, 5b and 5c) dis-
played the highest affinity, confirming the preferred perpetual-
shaped conformation (Fig. 2) of the ligands as observed in analogs
2a, 2l, 2k), 2k and 2d, 2m, 2n.
Another advantage of placing substituents in C-20 position at the
central aromatic ring was to suppress the amide hydrolysis rate
and to increase the overall metabolic stability (compare 2m vs
Next, we turned our attention to the distance between the ter-
minal basic center and the pyrrolidine adjacent to the central aryl

3424
Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3421–3426
Table 2
rh-H3R binding affinity, calculated lipophilicity values, and in vitro PK properties of arylamides 5a–5n
R1
O
2'
3'
N
H
N
Ar
N
5
No
Ar
R1
rh-H3R binding Kia (nM)
cLogP
tPSA (Å2)
Caco-2/TC7b (10ꢁ7 cm/s)
Microsome % metabolite
Human
13
Mouse
12
Rat
24
CH3
CH3
5a
5b
5c
H
2.1
2.6
3.2
2.2
2.5
2.5
64
62
62
20-Me
N
O
30-Me
5d
5e
5f
N
N
H
22.1
24.7
125.6
1.7
2.2
2.0
64
64
62
20-Me
3.5
2
16
28
30-Me
H
H
5g
H
44.5
2.3
64
91.9
78.1
2
16
21
37
64
N
N
N
5h
5i
20-Me
20-Me
20-Me
15.1
30.4
71.1
3.6
3.6
3.2
51
51
51
16
HN
5j
N
H
5k
5l
5m
H
14.0
12.4
19.9
2.8
3.3
3.3
64
64
64
20-Me
30-Me
20-Me
S
5n
10.1
2.8
48
9
30
57
N
a
Ki values were an average of three or more determinations.
b
Caco-2/TC7 (Papp, 10ꢁ7 cm/s) is the rate at which a compound crosses the TC7 monolayer under experimental conditions.
Table 3
rh-H3R binding affinities, calculated lipophilicity values, and in vitro PK properties of
analogs 6a–6e
(analogs 6a–6e, Table 3). The analogs 6a–6e were synthesized in
analogy to Scheme 1 by coupling of the amines5 with the acids
or acid chlorides. The compounds 6a–6e were then assayed in
the same way as analogs 2 and 5. The data indicated that increas-
ing the chain length was moderately tolerated. For example, 6a
was threefold lower in affinity than its close analog 2z; 6b was
fivefold lower in affinity than 2s; though 6d and 6e were compara-
ble with their corresponding close analog, 5h and 5i, respectively.
To further understand the relative orientation of the functional
groups, we synthesized compound 7 in which the terminal pyrrol-
idine ring was forced into a quasi-planar conformation correspond-
ing to the central pyrrolidine ring. It is interesting to point out that
this compound showed a 750-fold drop in affinity at rh-H3R com-
pared to compound 2q (Fig. 2). There could be a few explanations
for this observation; one could hypothesized that this specific ori-
entation of the terminal pyrrolidine ring was disfavored as the bio-
H3C
O
N
H
N
Ar
N
CH3
6
No.
Ar
rh-H3R binding Kia (nM)
cLogP
tPSA (Å2)
78
O
O
S
H3C
6a
29.0
3.7
H3C
HO
active conformation. The
further elucidation of
the
stereochemistry of 2-methyl-10-aryl-[1,30]-bipyrrolidinyl is cur-
rently under way and the results will be reported shortly.
6b
6c
62.1
3.1
2.9
3.9
56
53
The selected compounds 2p6 and 2q7 were profiled and the data
are summarized in Table 4. Both compounds were highly selective
toward a panel of 78 targets including GPCRs, ion channels, prote-
ases, and kinases (percent inhibition of radio ligand binding under
N
N
6d
6e
18.0
45.0
4.4
4.4
51
51
typical assay conditions were <50% at 10 lM).
HN
Compound 2q was evaluated preliminarily for its effects on
food intake8 in diet-induced obese (DIO) mice fed ad libitum on a
high fat, high sucrose diet (Fig. 3). The H3R antagonist 2q was
a
Ki values were averages of three or more determinations.

Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3421–3426
3425
Table 4
Partial profiling of selected H3R antagonists 2p and 2q
Compd
no.
rh-H3R binding Ki
(nM)
h-H3R binding Ki
(nM)
r-H3R binding Ki
(nM)
rh-H3 GTP
(nM)
c
S EC50
h-H1R binding Ki
M)
h-H2R
binding
Solubility (mg/
mL)
hERG IC50
M)
(
l
(l
2p
2q
5.8
1.2
13.8
8.6
55.4
16.5
2.9
1.1
>9.3
>9.3
Inactive
Inactive
ND
2.67
1.00
0.48
selective H3R antagonists/inverse agonists. The representative
compound, 2q, was orally active on food intake in a diet-induced
obese (DIO) mice model. This series of the compounds represents
a novel H3R antagonist template with improved in vitro potency
and oral efficacy. While 2q provides additional handles for further
optimization to derive a lead with acceptable hERG and safety pro-
file, further optimization and biology of the series will be reported
in due course.
H
N
N
N
O
F
2q
rh-H3 Ki = 1.2 nM
Acknowledgments
H
N
The authors greatly appreciate Sanofi R&D management for the
strong support, H3R project team members for their contributions
and Sanofi Analytical Department for their support on analytical
studies in confirmation of the structures.
N
N
O
F
7
rh-H3 Ki = 908 nM
References and notes
Figure 3. Orientation of the terminal pyrrolidine.
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tested at 1 and 3 mg/kg, po. Compound 2q inhibited feeding in a
dose-dependent manner as measured by reduction in accumulated
food intake up to 4 h, 6 h, and 12 h (see Fig. 4).
However, compound 2q is not suitable for further development
due to its potent inhibition of the hERG channel (IC50 = 0.48 lM).
But it has its merits as a tool compound and a lead for future
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West, R. E., Jr. Bioorg. Med. Chem. Lett. 2008, 18, 5032; (b) Jitsuoka, M.; Tsukahara,
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Dvorak, C. A.; Apodaca, R.; Xiao, W.; Jablonowski, J. A.; Bonaventure, P.; Dugovic,
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Eur. J. Med. Chem. 2009, 44, 4098; (e) Zhao, C.; Sun, M.; Bennani, Y. L.; Miller, T.
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optimization.
In conclusion, bioisosteric replacement of the urea moiety of
lead 1 with an amide linkage led to a novel arylamide series. The
SAR of the series was explored by introducing wide ranges of sub-
stituents into the benzoyl residue, replacement of the benzoyl res-
idue by heteroarylcarbonyl residues, and by changing the length of
the side chain and orientation of the pyrrolidine with respect to the
central rings. Compounds 2p and 2q were identified as potent and
6
Control vehicle p.o. (n:11)
2q: 1 mg/kg p.o (n: 8)
6
Dark period 4 a.m.-4 p.m.
2q: 3 mg/kg p.o (n: 6)
5
5
27.3%
30.4%
4
4
30%
3
2
1
0
0.1%
3
-4.7%
39.6%
∗
59.8%
2
1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
0-4h
0-6
h
0-12
h
Time (hours)
* p< 0.05 vs Control group (ANOVA, Dunnett test)
Figure 4. Effect of 2q on food intake following oral acute administration in obese DIO mice.

3426
Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3421–3426
C.; Corsi, M.; Vaidya, D.; Glenn, E.; Jones, T. D.; Bailey, S.; Gemkow, M. J.; Fritz, U.;
DCM (10 mL). To this solution was transferred a solution of 4-fluoro-benzoyl
chloride (from Alfa Aesar, 222 mg, 1.4 mmol) in DCM (2 mL), followed by
pyridine (1 mL) at 0 °C. The solution was stirred at 0 °C for 30 min. The ice-water
bath was removed and the reaction was stirred at rt for 1.5 h when TLC (10%
MeOH in DCM) and LC/MS showed that the reaction was complete and the
product peak (m/z = 396, M+H+) was detected. The reaction was quenched with
polymer bounded diethylenetriamine (4 mmol/g, 0.25 g), stirring at rt for
30 min, then filtered and rinsed with DCM. The solvent was evaporated to
dryness, re-dissolved in DCM and washed with aqueous sodium bicarbonate
solution. The two layers were separated, and the aqueous layer was extracted
with DCM (5 mL ꢂ 2). The combined DCM extracts were again washed with
sodium bicarbonate solution (5 mL), and brine (5 mL ꢂ 2), dried (anhydrous
potassium carbonate), filtered, and concentrated in vacuo. The crude product
was purified on a silica gel column, eluted successively with 2%, 7.5%, and 10%
MeOH in DCM to obtain the title compound as a yellow tan solid in the form of a
free base. 1H NMR (CDCl3, 300 MHz), d (ppm): Two sets of signals were observed
in about 1:1.2 ratio and the spectra were closely overlapping. The observed
chemical shifts are as follows: 8.26 (m), 7.78 (m), 7.65 (m), 7.5 (m), 7.3 (m), 7.15
(m), 6.4 (m), 3.5–3.2 (m), 3.00 (m), 2.80 (m), 2.55 (m), 2.3 (m), 2.10–1.6 (m), 2.45
(m), 1.08 (d). LCMS: RT = 2.26 min, MS: 396 (M+H+).
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J. M.; Cianfrogna, J.; Cook, K. W.; James, L. C.; Chatman, L. A.; Iredale, P. A.;
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7. Analytical data: 1H NMR (CDCl3, 300 MHz), d (ppm): two sets of signals were
observed in about 1:1.5 ratio and the spectra were closely overlapping. The
observed chemical shifts are listed as follows: 7.48 (d, 7.4 Hz,), 7.23 (m), 7.04
(m), 6.42 (m), 3.53–3.05 (m), 2.81 (m), 2.54 (m), 2.49 (br s), 2.28 (br s), 2.2–1.95
(m), 1.70 (m), 1.15 (d, 6.0 Hz). LCMS: RT = 1.56 min, MS: 396 (M+H+).
6. Typical procedure, synthesis of 2p as example: 2-methyl-4-(2-methyl-
8. Gary-Bobo, M.; Elachouri, G.; Scatton, B.; Le Fur, G.; Oury-Donat, F.; Bensaid, M.
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[1,30]bipyrrolidinyl-10-yl)-phenylamine (200 mg, 0.77 mmol) was dissolved in