Design and synthesis of a novel series of 4-heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 nicotinic receptor agonists 2. Development of 4-heteroaryl SAR

Article abstract of DOI:10.1016/j.bmcl.2017.01.058

Quinuclidine-containing spirooxazolines, as described in the previous report in this series, were demonstrated to have utility as α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonists. In this work, the SAR of this chemotype was expanded to include an array of diazine heterocyclic substitutions. Many of the heterocyclic analogs were potent partial agonists of the α7 receptor, selective against other nicotinic receptors and the serotinergic 5HT_3A receptor. (1′S,3′R,4′S)-N-(6-phenylpyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine, a potent and selective α7 nAChR partial agonist, was demonstrated to improve cognition in the mouse novel object recognition (NOR) model of episodic memory.

Full text of DOI:10.1016/j.bmcl.2017.01.058

Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of a novel series of 4-heteroarylamino-10-azaspiro
[oxazole-5,30-bicyclo[2.2.2]octanes as
a7 nicotinic receptor agonists 2.
Development of 4-heteroaryl SAR
⇑
Christiana Iwuagwu , Dalton King, Ivar M. McDonald, James Cook, F. Christopher Zusi, Matthew D. Hill,
Robert A. Mate, Haiquan Fang, Ronald Knox, Lizbeth Gallagher, Debra Post-Munson Amy Easton,
Regina Miller, Yulia Benitex, Judy Siuciak, Nicholas Lodge, Robert Zaczek, Daniel Morgan, Linda Bristow,
John E. Macor, Richard E. Olson
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Quinuclidine-containing spirooxazolines, as described in the previous report in this series, were demon-
Received 21 November 2016
Revised 12 January 2017
Accepted 13 January 2017
Available online 20 January 2017
strated to have utility as
SAR of this chemotype was expanded to include an array of diazine heterocyclic substitutions. Many of
the heterocyclic analogs were potent partial agonists of the 7 receptor, selective against other nicotinic
receptors and the serotinergic 5HT3A receptor. (10S,30R,40S)-N-(6-phenylpyrimidin-4-yl)-4H-10-azaspiro
[oxazole-5,30-bicyclo[2.2.2]octan]-2-amine, a potent and selective
7 nAChR partial agonist, was demon-
a7 nicotinic acetylcholine receptor (a7 nAChR) partial agonists. In this work, the
a
a
Keywords:
strated to improve cognition in the mouse novel object recognition (NOR) model of episodic memory.
a7 nicotinic acetylcholine receptor
Ó 2017 Elsevier Ltd. All rights reserved.
Schizophrenia
5HT3A receptor
Spirooxazolines
Schizophrenia is a chronic disabling psychiatric disorder affect-
ing approximately 0.5–1% of the general population. It is character-
ized by highly diverse symptoms which include hallucinations and
delusions (positive symptoms), loss of motivation and social with-
drawal (negative symptoms), and cognitive impairment including
deficits in executive cognitive function, selective attention and
working memory.1 In some patients, positive symptoms are well
managed with current antipsychotic drugs, while cognitive and
negative symptoms are inadequately treated. It has been demon-
strated that cognitive assessment is a predictor of functional out-
come, hence the need to develop a treatment for this area of
significant unmet medical need.2,3
with schizophrenia. A significantly increased rate of cigarette
smoking in patients with schizophrenia has been hypothesized as
self-medication.9
These observations suggest that the development of selective
a
7 nAChR agonists has the potential to improve cognitive deficits
associated with schizophrenia. Improvement in preclinical models
of memory and cognition have been observed with some 7 nAChR
a
agonists,10–15 and several compounds have progressed to human
clinical trials, including DMXB-A (GTS-21),16 EVP-6124,17 TC-
5619,18 ABT-126,19 and others.20 Of particular note, clinical efficacy
has been reported for EVP-6124,21 TC-561922 and ABT-12619 in
Phase II trials, although each has since failed to meet endpoints
in subsequent trials.
Genetic links between CHRNA7, which encodes for the
acetylcholine receptor ( 7 nAChR) and reductions in P50 gating
in patients with schizophrenia have been identified.4,5 Post-mor-
a7 N-
a
Some examples of a7 nAChR agonists are shown in Fig. 1. Most
of the compounds in Fig. 1 are characterized by a pharmacophore
model wherein the key structural components of acetylcholine
(charged amine and H-bond acceptor) are combined with a lipo-
philic aromatic group. Thus, these compounds generally consist
of three elements: (1) a rigid bicyclic amine which serves as a
cationic center at physiological pH, (2) an amide, carbamate, or
ether serving as a central H-bond acceptor, and (3) a lipophilic aro-
matic or heteroaromatic group.23–25 Our previous report in this
series described a set of conformationally restricted spirocyclic
tem analyses have shown reduced expression of a7 nAChR density
in the brain tissue isolated from schizophrenia patients.6 Nicotine,
whose pro-cognitive effects have been linked to its activity as a
non-selective a7 nAChR agonist, has shown improvements in P50
gating7 and cognitive deficits and negative symptoms8 in patients
⇑
Corresponding author.
E-mail address: christiana.iwuagwu@bms.com (C. Iwuagwu).
a
7 nAChR partial agonists exemplified by 1.26
http://dx.doi.org/10.1016/j.bmcl.2017.01.058
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.

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C. Iwuagwu et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
Br
O
H
N
O
S
Cl
O
O
H
N
N
S
N
N
N
O
N
N
O
N
SSR 180711A
TC-5619
ABT-126
EVP-6124
N
O
N
O
N
N
O
O
O
NH
MeO
N
N
N
N
S
OMe
DMXB-A (GTS-21)
Mitsubishi
spirooxazolidinone
AR-17779
7 nAChR agonists.
AZD-0328
Fig. 1. Examples of known
a
In our early work, quinuclidine was found to be the preferred
bicyclic amine and a spirofused aminooxazoline (spiroimidate)
was determined to be effective as the central H-bond acceptor.
While we usually depict the spiroimidate double bond endocyclic
to the oxazoline ring, this model suggests that the preferred phar-
macological orientation may be the tautomer with the double bond
exocyclic to the ring as depicted in Fig. 2. This is supported by our
imidazole or thiocarbonyldi-2(1H)pyridone gave isothiocyanates 3
(Scheme 1). Some weakly basic amines 2 were alternatively treated
with excess base, carbon disulfide, and methyl iodide to afford
dimethylcarbonimidodithioates 4. Intermediate 3 or 4 was then
allowed to react with the quinuclidine amino alcohol 532 to give
6. Some analogs, synthesized early in this campaign, were obtained
as racemates from racemic 5. They are noted, where appropriate, in
this paper. With the later availability of homochiral (-)-5,26
homochiral analogs were exclusively synthesized.
earlier observation that for our compounds, an
heterocycle was required for potency, as the
a
-aza containing
a-nitrogen group
allowed for an intramolecular hydrogen bond forcing the spiroim-
Our earlier work demonstrated the potential for increasing a7
potency and 5HT3A selectivity through substitution of the hetero-
idate double bond into the exocyclic configuration.26 Many of the
spiroimidates demonstrated potent
a7 nAChR partial agonism, a
cycle. We thus focused on optimizing both of these parameters
profile expected to have reduced potential for receptor desensitiza-
as we attempted to decrease the lipophilicity inherent in 1. a7
nAChR agonist activity was determined using a Fluorometric Image
tion compared to agonists which fully activate the receptor.27,28
There is high sequence homology between
serotonergic 5HT3A receptor,29 which has resulted in many previ-
ously published 7 nAChR agonists having poor selectivity versus
a7 nAChR and the
Plate Reader (FLIPR) that measured calcium ion influx in HEK293
cells expressing the rat a7 nAChR. Antagonist activity at the human
a
5HT3A receptor was also measured using a functional FLIPR assay
5HT3A receptor antagonism. As this has been associated with off-
target gastric side effects,30,31 we prioritized the development of
compounds with high selectivity relative to this target. An opti-
mized member of this series, isoquinoline 1, showed excellent
potency and good selectivity versus the 5HT3A receptor (Table 1).
It also showed in vivo efficacy in the novel object recognition
(NOR) model of memory retention at doses as low as 0.1 mg/
kg.26 Isoquinoline 1 was selected as a candidate for development,
however, its progression was halted due to liver and kidney toxic-
ities. Although we did not understand the cause of the observed
toxicities, we hypothesized that the lipophilic nature of the
heteroaromatic portion of the compound, along with the requisite
highly basic quinuclidine amine was a potential liability for this
compound. This paper describes our effort to recapitulate the
in vitro and in vivo profile of 1 in a compound with a less lipophilic
heteroaromatic group and a differentiated structure.
as previously described.26
Starting with isoquinoline 1, a logical first step was to incorpo-
rate additional nitrogens into the aromatic ring as this would make
the heterocycle less lipophilic. To this end, 1,7-naphthyridine 7 and
quinazoline 8 were prepared. Both compounds maintained similar
potency to the lead isoquinoline, but the 5HT3A receptor selectivity
was reduced for both compounds with only modest selectivity
observed (Table 1). Given the limited number of commercially
available aza-isoquinolines and our desire for structural diversity,
we decided to refocus our efforts in re-examining monocyclic hete-
rocycles as there were a large number of commercially available or
synthetically accessible 6-membered heterocyclic diazines that
were not yet explored.
In our previous report,26 2-aminopyridine 9 was exemplified as
the prototypical
a-amino heterocycle with the desired potency at
the 7 nAChR but with poor selectivity against the 5HT3A receptor.
a
All compounds were synthesized according to the methods out-
lined in the previous publication in this series.26 Briefly, quinu-
clidine spiroimidates 6 were prepared according to Scheme 1.
Treatment of heteroaromatic amines 2 with either thiocarbonyldi-
This selectivity was shown to be greatly improved by appropriate
substitution at the pyridine C4- or C5-positions. We therefore
decided to revisit the monocyclic diazines, starting with the unsub-
stituted analogs (Table 2).
In agreement with our earlier observations, 2-aminopyrimidine
10, 2-aminopyrazine 13 and 4-aminopyrimidine 11 were moder-
H-Bond Acceptor
ately potent
a7 agonists, unlike 5-aminopyrimidine 12 (which
lacked the critical
a
-aza substitution), though none were selective
over 5HT3A. Our next efforts were to try to impart 5HT3A receptor
selectivity by appropriate diazine substitution as in the 2-
aminopyridine series.26 Since 10 was the most potent of the unsub-
stituted diazines, our efforts to explore diazine substitutions began
with the 2-aminopyrimidines.
H
N
N
O
O
N
N
N
N
N
N
H
Aromatic Group
1
Basic Amine
In the 2-aminopyrimidine series (Table 3), alkyl and methoxy
substitutions in the C4-position resulted in essentially no increase
Fig. 2. Lead compound from previous work.

C. Iwuagwu et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
1263
Table 1
7 nAChR FLIPR data for selected compounds.
a
H
N
R
O
N
N
Cmpd
R
a
7 nAChR EC50 (nM)a
9.3
5HT3A IC50 (nM)a
480
Selectivity
1
52ꢀ
N
N
7
8
29
190
23
6.8ꢀ
N
6.7
3.4ꢀ
N
N
a
All values are averages of at least two independent experiments.
OH
a
ArNCS
NH2
N
3
NH
O
Ar
ArNH2
5
N
N
2
SMe
b
6
Ar N SMe
4
Scheme 1. Reagents and conditions (a) 1,10-thiocarbonyldiimidazole or 1,10thiocarbonyldipyridin-2(1H)-one, DMF or ACN; (b) 10 N NaOH, CS2, MeI.
Table 2
7 nAChR FLIPR data for selected compounds.
a
H
N
R
O
N
N
Cmpd
R
a
7 nAChR EC50 (nM)a
110
5HT3A IC50 (nM)a
15
Selectivity
9
0.14ꢀ
N
10
11 (rac)
12
130
840
27
440
0.22ꢀ
0.52ꢀ
–
N
N
N
N
N
>10,000
>10,000
N
13
630
180
0.28ꢀ
N
N
a
All values are averages of at least two independent experiments.
in
a
7 nAChR potency (14–16). However, aromatic substitution in
and increases in 5HT3A receptor selectivity. 5-aryl substituted com-
pound 20 was highly selective, but had lower 7 nAChR potency
relative to compounds with smaller substituents at the position.
While both superb 7 nAChR potency and 5HT3A receptor selectiv-
the C4-position yielded 19 with 16-fold increase in
a7 nAChR
a
potency relative to 10. None of the compounds substituted in the
pyrimidine C4-position showed a 5HT3A receptor selectivity advan-
tage. By contrast, small substituents in the C5-pyrimidyl position
a
ity were obtained independently in this series, we were unable to
(17, 18) resulted in compounds with improved a7 nAChR potency
combine these attributes in a single compound.

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C. Iwuagwu et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
Table 3
a
7 nAChR FLIPR data for selected 2-aminopyrimidines.
H
N
R
O
N
N
Cmpd
R
a
7 nAChR EC50 (nM)a
130
5HT3A IC50 (nM)a
27
Selectivity
10
0.22ꢀ
N
N
14
15
120
78
25
9
0.21ꢀ
0.11ꢀ
N
N
N
N
N
16
17
18
110
18
23
0.21ꢀ
8.4ꢀ
6.4ꢀ
N
O
150
120
N
N
18
N
N
O
19
20
7.9
3.8
0.48ꢀ
370ꢀ
N
N
120
44,000
N
N
a
All values are averages of at least two independent experiments.
In the 2-aminopyrazine series shown (Table 4), substitutions
in the C5-position generally provided the optimum combination
of 7 nAChR potency and selectivity over the 5HT3A receptor.
Two compounds were of particular interest: 24 and 25.
nAChR potency increased 20-fold for 24 and 25 compared to
parent 13, although the activity was still lower relative to 1.
Compounds 24 and 25 were respectively 200-fold and 11-fold
more selective relative to 5HT3A. Conversely, aryl substitution
profile. We utilized a patch clamp assay with HEK-293 cells
expressing rat 7 nAChR, and recorded both peak intensity and
a
a
area under the curve. In this experiment, both peak and area Ymax
(%) were obtained as measures of intrinsic activity relative to
acetylcholine with peak and area Ymax response as 13% and 49%,
respectively, confirming this compound to be a partial agonist as
desired.
Compound 31 was evaluated in the mouse novel object recogni-
tion (NOR) model of episodic memory (Fig. 3).33 This model utilizes
the natural tendency of mice to spend more time exploring unfa-
miliar objects relative to familiar objects encountered previously
during the training phase of the task. In all studies mice were
dosed subcutaneously (sc) with test compounds 30 min prior to
training, and object recognition memory retention was examined
24 h later. Compound 31 was found to be efficacious in NOR at
doses of 0.3 and 1 mg/kg, sc. The associated plasma and brain expo-
sures, determined 30 min after dosing in satellite groups of mice,
were 273 nM and 81 nM, respectively, at the minimum efficacious
dose (MED: 0.3 mg/kg).
a7
in the 5-position 26 resulted in a reduced
a7 nAChR potency.
While optimal pyrazine compound 24 exhibited excellent
5HT3A receptor selectivity, the
that of isoquinoline 1.
a
7 nAChR potency did not match
7 nAChR
Moving on to the 4-aminopyrimidine series (Table 5),
a
potency was unaffected by 6-alkyl and halo substitutions. The
bulkier isopropyl substituent in 28 uniquely increased 5HT3A
receptor selectivity. However, both
a7 nAChR potency and selec-
tivity over the 5HT3A receptor were markedly increased by substi-
tution with 6-OMe in 30 and 6-phenyl in 31. Phenyl-substituted 4-
aminopyrimidine 31 was the first compound that matched or
exceeded potency and selectivity previously obtained for isoquino-
line 1.
Additionally, as early lead 1 was found to have a cardiovascular
risk which was associated with hERG inhibition, we evaluated inhi-
bition of the hERG potassium channel by 31 in a patch clamp elec-
trophysiology assay. Although the hERG patch clamp IC50 of 31
All of the compounds cited in this study were weak agonists at
other nicotinic receptors (
a4b2, a3b4, and a1b1de) with EC50 val-
ues >100 M. While the FLIPR assay employed for screening pro-
l
(4.0 lM) was not significantly improved compared to 1 (3.2 lM),
vided a convenient method to assess potency and was able to
differentiate agonists from antagonists, it was not effective for dif-
ferentiating partial agonists from full agonists. Compound 31 was
therefore evaluated in a concentration-response electrophysiology
we were pleased that we had recapitulated the in vitro profile of
isoquinoline 1 in a system lacking the fused bicyclic aromatic
group.
Reviewing the pyridines and various 6-membered heterocyclic
diazines, it was interesting to note some trends in potency at the
(EP) experiment to confirm that it maintained a partial a7 agonist

C. Iwuagwu et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
1265
Table 4
7 nAChR FLIPR data for selected 2-aminopyrazines.
a
H
N
R
O
N
N
Cmpd
R
a
7 nAChR EC50 (nM)a
630
5HT3A IC50 (nM)a
170
Selectivity
13 (rac)
0.28ꢀ
N
N
N
N
21
2100
39,000
19ꢀ
22
23
84
1700
29
20ꢀ
N
N
1600
0.02ꢀ
N
N
24
25
26
34
33
6700
350
200ꢀ
11ꢀ
N
N
O
N
N
Cl
1800
>100,000
>45ꢀ
N
N
a
All values are averages of at least two independent experiments.
Table 5
a
7 nAChR FLIPR data for selected 4-aminopyrimidines.
H
N
R
O
N
N
Cmpd
R
a
7 nAChR EC50 (nM)a
840
5HT3A IC50 (nM)a
440
Selectivity
11 (rac)
0.52ꢀ
N
N
27
28
480
440
150
0.3ꢀ
N
N
>10,000
>220ꢀ
N
N
29
30
31
470
43
100
12,000
9200
0.22ꢀ
260ꢀ
840ꢀ
Cl
N
N
O
N
N
11
N
N
a
All values are averages of at least two independent experiments.
a
7 receptor and selectivity versus the 5HT3A receptor among the
potency. Aryl groups in this position were particularly potent. This
implied that these substituents may be accessing a lipophilic bind-
ing pocket.
different series (Fig. 4). Firstly, most bulky substitutions in the Y-
position of generic structure 32 generally increased 7 receptor
a

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C. Iwuagwu et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 1261–1266
ity. While the goal of reducing lipophilicity was not achieved with
40
30
20
10
0
Novel
Familiar
these modifications, the 4-aryl pyrimidine served as a framework
for further modifications to improve lipophilicity, hERG selectivity
and other properties. Efforts to further develop this series of 4-
aminopyrimidines leading to a clinical candidate will be the sub-
ject of a future report.
***
*
A. Supplementary material
Veh
0.3
1.0
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2017.01.
058.
Compound 31 (mg/kg s.c.)
Fig. 3. Effects of 31 in Mouse Novel Object Recognition Experiments. Filled bars
correspond to time of exploration of novel objects; Open bars correspond to time of
exploration of familiar objects. Paired t-tests were used to compare the statistical
difference between time exploring novel and familiar objects; *p < 0.05, ***p < 0.001.
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nes, this selectivity was reversed. This may be rationalized by con-
sidering that with two -aza positions, the 2-aminopyrimidines
a7 nAChR over the 5HT3A receptor, while for 2-aminopyrimidi-
a
can participate in an internally hydrogen-bonded structure (see
Fig. 2) in two possible conformations, whereas the 4-aminopyrim-
idines have only one possible conformation when internally hydro-
gen-bonded.
In conclusion, we have expanded the SAR of our quinuclidine
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