Structure property relationships of N-acylsulfonamides and related bioisosteres

Article abstract of DOI:10.1016/j.ejmech.2021.113399

The N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active molecules, including marketed drugs. Although this acidic moiety presents multiple points of attachments that could be exploited to introduce structural diversification, depending on the circumstances, the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to modulate both structure and physicochemical properties of this important structural motif. To enable an assessment of the relative impact on physicochemical properties that these replacements may have compared to the N-acylsulfonamide group, we conducted a structure-property relationship study based on matched molecular pairs, in which the N-acylsulfonamide moiety of common template reference structures is replaced with a series of bioisosteres. The data presented, which include an assessment of relative changes in acidity, permeability, lipophilicity and intrinsic solubility, provides a basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design.

Full text of DOI:10.1016/j.ejmech.2021.113399

European Journal of Medicinal Chemistry 218 (2021) 113399
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Structure property relationships of N-acylsulfonamides and related
bioisosteres
Karol R. Francisco a, Carmine Varricchio b, Thomas J. Paniak c, Marisa C. Kozlowski c,
,
*
Andrea Brancale b, Carlo Ballatore d
a Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
b School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF103NB, UK
c Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA, 19104, USA
d Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active
molecules, including marketed drugs. Although this acidic moiety presents multiple points of attach-
ments that could be exploited to introduce structural diversification, depending on the circumstances,
the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable.
A number of N-acylsulfonamide bioisosteres have been developed over the years that provide oppor-
tunities to modulate both structure and physicochemical properties of this important structural motif. To
enable an assessment of the relative impact on physicochemical properties that these replacements may
have compared to the N-acylsulfonamide group, we conducted a structure-property relationship study
based on matched molecular pairs, in which the N-acylsulfonamide moiety of common template
reference structures is replaced with a series of bioisosteres. The data presented, which include an
assessment of relative changes in acidity, permeability, lipophilicity and intrinsic solubility, provides a
basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design.
© 2021 Elsevier Masson SAS. All rights reserved.
Received 28 January 2021
Received in revised form
19 March 2021
Accepted 20 March 2021
Available online 28 March 2021
Keywords:
N-Acylsulfonamide isostere
Bioisostere
Isosteric replacement
Physicochemical properties
Structure property relationship (SPR)
Oxetane
Thietane
1. Introduction
[13,14], and antiproliferative agents [15e17]. The importance of N-
acylsulfonamides in the field of drug design and medicinal chem-
Acidic moieties are of great importance in drug design as they
can significantly impact, through ionic and electrostatic in-
teractions, both physicochemical properties (e.g., lipophilicity),
ADME-PK parameters, as well as on target/off target interactions
(e.g., with proteins) of biologically active compounds [1]. As a result,
the modulation of one or more properties of the acidic moiety of
candidate compounds can have important ramifications, especially
during the hit/lead optimization process.
The N-acylsulfonamide group is an acidic moiety that is
frequently employed in medicinal chemistry as a carboxylic acid
bioisostere [2e6], with several reported examples in which such a
replacement led to improved derivatives [7e10]. This structural
motif, however, can also be in itself a constituent of the pharma-
cophore as exemplified in many different classes of biologically
active compounds [11], including antivirals [12], antibacterial
istry is evident by the fact that as many as nine novel N-acylsul-
fonamide drugs (Fig. 1) have been marketed in the USA between
2015 and 2020 [18]. Moreover, a review of the literature revealed
that between 2019 and 2020, >50 research articles have been
published in medicinal chemistry journals in which N-acylsulfo-
namides were studied for a variety of indications.
Although the N-acylsulfonamide structural motif presents
alternative points of attachment that provide opportunities for
structural diversification and modulation of physicochemical
properties, on occasions, the replacement of this functional group
itself with a suitable bioisostere may be desirable. The success of
this strategy, however, like any isosteric replacement strategy, is
highly context dependent and ultimately relies upon the avail-
ability of alternative structures that could be considered as po-
tential surrogates. The concept of isosteric replacement has evolved
significantly since it was first introduced. The current conception,
which presents bioisosteres more as molecular metaphors rather
than close structural equivalents of what they are replacing, is
* Corresponding author.
E-mail address: cballatore@health.ucsd.edu (C. Ballatore).
https://doi.org/10.1016/j.ejmech.2021.113399
0223-5234/© 2021 Elsevier Masson SAS. All rights reserved.

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Fig. 1. Examples of N-acylsulfonamides that are either marketed or are in advanced stages of clinical development.
considerably broader than originally conceived and leads to the
evaluation of a relatively wide range of alternative structures that
could potentially emulate the desired biological activity [19e21]. In
the case of the N-acylsulfonamide, over the years, a select number
of surrogates have been introduced in which the carbonyl moiety is
replaced with an oxetane or a 5-membered ring heterocycle
(Fig. 2A). These structures likely originate from earlier observations
that 5-membered ring heterocycles, such as triazoles, isoxazoles
and others, have found broad applications as possible mimetics of
different carboxylic acid derived functional groups [22e25].
2

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Fig. 2. (A) General outline of N-acylsulfonamide bioisosteres that are based on replacement of the carbonyl moiety with either an oxetane or a 5-membered heteroaromatic. (B)
comparison of Gaussian-optimized geometry and electrostatic potential maps of the N-acylsulfonamide moiety (center) and the corresponding oxetane (left) and isoxazole (right)
derivatives. The areas colored in red and blue represent respectively negative and positive regions of the electrostatic potential; the corresponding surface minima and maxima are
indicated as red and blue spheres. (C) Representative literature examples [37e39], including match paired comparisons, 4 and 5, as well as 6e8 [35,36].
Likewise, the oxetane ring is known to be a potentially effective
replacement of the carbonyl moiety of ketones, aldehydes, car-
boxylic acids, esters and amides [26e31], and this presumably led
to its incorporation in N-acylsulfonamides [32,33]. Compared to the
parent N-acylsulfonamide structure, these replacements can be
expected to introduce some changes in terms of properties (e.g.,
acidity), geometry and/or electrostatic potential (Fig. 2B). However,
interestingly, different examples have been reported in which
incorporation of such structural motifs resulted in biologically
active analogs in a variety of contexts (e.g., see 1e3, 5, 7 and 8,
Fig. 2C) [33e40]. Among these examples, the match paired mole-
cules, 4 and 5, as well as 6e8, are especially notable as they reveal a
comparable biological activity between the N-acylsulfonamide and
the corresponding surrogate [35,36].
Given the importance of N-acylsulfonamides in medicinal
chemistry and the potential utility of N-acylsulfonamide bio-
isosteres in analog design, an assessment of the relative impact on
physicochemical properties that these replacements can have,
compared to the parent N-acylsulfonamide group, may ultimately
facilitate informed decisions in the hit/lead optimization stage. As a
result, to enable an informative and meaningful comparison of the
properties of these structures, we constructed a focused set of
matched molecular pairs (MMP) comprised of different N-acylsul-
fonamides and related derivatives, as well as
a series of
3

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
corresponding surrogates, and evaluated how these replacements
can affect key physicochemical properties, such as: (a) acidity
(pKa); (b) lipophilicity (logD7.4); (c) intrinsic solubility; and (d)
passive diffusion in a parallel artificial membrane permeability
assay (PAMPA). Finally, an assessment of the hydrogen bonding
ability of selected examples was also conducted.
provided acetamide 14 [45].
Isoxazole derivatives 27e29 were obtained via cyclo-
condensation of -ketonitrile 47 in the presence of hydroxylamine,
followed by sulfonylation of the resulting amino-isoxazole 48 with
the appropriate sulfonyl chloride or sulfamoyl chloride [46]
(Scheme 2). Likewise, triazole compounds 30e32 were prepared
via sulfonylation of commercially available 1-phenyl-1H-1,2,3-
triazol-4-amine 49 (Scheme 2).
a
2. Results
In addition to the structures of final product being established
by 1H and 13C NMR, as well as IR, and HRMS, X-ray structures of
selected compounds (15, 16, 18, 19, 21) were also obtained (see
Supporting Information).
Library Design and Synthesis. The compound library was
designed following a general strategy utilized previously in struc-
ture property relationship (SPR) studies of carboxylic acid bio-
isosteres [41], in which the phenylpropionic acid fragment was
used as structural template for analog design. The N-acylsulfona-
mide derivative 9 and related sulfuric diamide derivative 10
(Table 1), the physicochemical properties of which had been
determined in these earlier studies [41], were chosen here as
reference N-acylsulfonamide molecules. In addition, to better
capture the differences in physicochemical properties that may
arise from different substitutions and alternative orientations of
the N-acylsulfonamide group, two additional control compounds,
11 and 12 (Table 1), were also included. For each of the four refer-
ence compounds, a series of related derivatives bearing different
surrogates of the N-acylsulfonamide group were synthesized
leading to a total of 24 entries (9e32, Table 1). Among the different
classes of bioisosteres evaluated in the study are structures that
have already been exemplified in analog design that are based on
N-acyl moiety replacement with either a 5-membered ring heter-
oaromatic, such as isoxazole and 1,2,3-triazole, or an oxetane ring.
In addition, since previous studies from our laboratories suggested
that appropriately substituted thietanes may also serve as effective
surrogates of the acyl group [26], a series of examples of N-acyl-
sulfonamide derivatives bearing these 4-membered ring hetero-
cycles were also chosen so as to expand the scope of the study
beyond the examples of N-acylsulfonamide bioisosteres described
in the literature. A comparison of the geometry and electrostatic
potential of these structures relative to the corresponding N-acyl-
sulfonamides is presented in Supporting Information.
Reference N-acylsulfonamide-derived compounds, 9e11, were
either already available (9 and 10) or prepared (11) from phenyl-
propionic acid as described previously [41], while reference com-
pound 12 was obtained via aminolysis of phenethylsulfonyl
chloride, followed by N-acylation with acetic anhydride. The syn-
thesis of all other test compounds is highlighted in Schemes 1 and
2. Sulfonamide 13 was prepared by sulfonylating commercially
available 3-methyloxetan-3-amine (33) under basic conditions
(Scheme 1).
Oxetane and thietane derivatives, 15e20, were prepared in five
steps starting from commercially available oxetan-3-one (34) and
thietan-3-one (35). Condensation of the appropriate ketone and
(S)-(ꢀ)-2-methyl-2-propanesulfinamide to the corresponding im-
ines (36 and 37) followed by treatment with trimethylsulfoxonium
iodide (TMSOI), led to aziridines 38 and 39, which were then sub-
jected to ring opening using benzylmagnesium chloride to provide
N-protected amines 40 and 41 [42e44]. Finally, deprotection under
acidic conditions to the amine 42 and 43, followed by sulfonylation,
furnished the desired sulfonamides 15e20 (Scheme 1).
Determination of Physicochemical Properties. All test compounds
were initially evaluated for chemical stability in aqueous buffer (pH
7.4) by determining the percentage of remaining compound after
5 h of incubation. The results of this initial screening confirmed that
the test compounds were generally stable (i.e., >90% unchanged)
suggesting that spontaneous hydrolysis under typical assay buffer
conditions would not be a limiting factor. Next, evaluation of
physicochemical properties of test compounds included the
determination of: (a) acidity (pKa); (b) lipophilicity (logD7.4); (c)
intrinsic solubility; and (d) passive diffusion in a PAMPA assay.
Determination of pKa values was conducted via potentiometric ti-
trations using a Sirius T3 (Pion, Inc.). Likewise, the logP and logD7.4
values of compounds 9e13, 15, 21, 24, 26e32 were obtained via
potentiometric titrations, while for selected compounds (14,
16e20, 22, 23, 25) the logD7.4 determinations were conducted via
shake-flask method. Calculated logP, logD7.4, and pKa values were
also obtained for comparison employing ChemAxon [47]. For all
solid compounds, the melting point (mp) of crystalline material
was obtained and from the knowledge of mp and logP values, the
intrinsic solubility was estimated via the general solubility equa-
tion [48,49]. Finally, an estimation of hydrogen bonding ability of
selected compounds (i.e., 9, 12, 13, and 15) was conducted using
experimental
DlogP values in various solvents via potentiometric
titrations [50e54]. The results from these studies are summarized
in Tables 1 and 2.
From the data accumulated in this study, different elements of
SPRs can be identified. First, within each series of compounds
(denoted with different symbols in Fig. 3), the reference N-acyl-
sulfonamides, 9e12, were found to be generally the most acidic, as
well as the least permeable and lipophilic molecules, with 10 and
11 being comparatively more lipophilic and permeable than the
two other controls, 9 and 12. Although a good overall correlation
linking the logD7.4 values and the apparent permeability co-
efficients (Papp) was observed across the entire data set (r2 ¼ 0.890,
Fig. 3), some interesting discrepancies were noted. For example, the
results from the PAMPA assay indicate a possible difference in
permeability between 9 and 12, with the latter being more
permeable than the former. This result may be somewhat unex-
pected considering that these two compounds are structural iso-
mers characterized by very similar pKa and logD7.4 values.
We have previously observed that differences in PAMPA
permeability values of compounds having similar acidity and lip-
ophilicity may be ascribed to the differential degree of hydrogen
bonding and solvation [41]. However, in the particular case of 9 and
12, these two compounds are structural isomers that share iden-
tical polar surface area (tPSA ¼ 63.24 Å2) suggesting that the ability
to hydrogen bond of these two isomers may be closely comparable.
Thus, to assess experimentally possible differences in hydrogen
bonding between 9 and 12, we evaluated the difference in the
Thietane-1-oxide (21e23) and ꢀ1,1-dioxide compounds
(24e26) were obtained from thietane 43. Thus, oxidation of 43 with
m-CPBA furnished a separable mixture of trans- and cis- 1-oxido-3-
phenethylthietan-3-amines, 44 and 45. The major cis-isomer, 45,
was then used for the synthesis of sulfonamides 21e23. Alterna-
tively, oxone mediated conversion of 43 to the corresponding 1,1-
dioxide, 46, followed by N-sulfonylation, yielded sulfonamides
24e26 (Scheme 1), while acylation of 46 with acetic anhydride
partition coefficients (DlogP) of each of the two test compounds
when the partition solvent is changed from the protic solvent, n-
octanol, to a non-polar aprotic hydrocarbon, such as cyclohexane,
heptane or toluene (Table 2). The
DlogP values have been used
4

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Table 1
Calculated and experimental properties of test compounds.
mp (ꢁC)a % Stability aq. buffer pH Intrinsic solubility logPd
logD7.4
logP logD7.4 PAMPA
pKa
pKa
e
j
Cmpd Structure
7.4e7.6b
(mol/L)c
calcf calcf
Pe
calcf
i
%
logPapp
(cm/s)g retentionh
9
105.5
e106.5
99.6
3.89Ee2
1.10 0.01 ꢀ0.64
0.86 ꢀ0.27
0.99 ꢀ0.15
2.92 1.78
0.78 ꢀ0.36
0.83 0.83
3.45E 1.35Ee2 ꢀ6.46 4.75 0.01 4.08
(ꢀ1.02)
e7 (4.94)
10
11
12
13
103.0
e104.0
94.3
1.14Ee2
9.97Ee4
8.65Ee2
5.43Ee2
1.66 0.02 0.12
1.53E 2.15Ee2 ꢀ5.81 5.79 0.01 4.12
e6 (5.86)
(0.17)
107.8
e108.5
100.0
91.4
2.67 0.01 ꢀ0.09
1.64E ꢀ3.05E-2 ꢀ5.79 4.49
4.24
4.09
e6
0.04
76.2
e78.4
1.04 0.01 ꢀ0.87
1.00E ꢀ5.00Ee2 ꢀ6.00 4.91
e06
0.01
43.1
e44.0
100.0
1.58
0.06
1.58
6.79E ꢀ3.20Ee2 ꢀ5.17 10.45 0.01 9.59
e6
l
14
135.3
e136.8
94.5
1.62Ee3
1.18k
0.10 0.10
2.11E ꢀ1.20E-2 ꢀ5.68 >12
e6
13.53
15
16
17
18
19
20
21
71.4
e71.9
100.0
94.1
93.7
91.5
92.8
93.5
100.0
2.65Ee2
6.38Ee4
3.47Ee2
1.43Ee3
1.10Ee3
2.20Ee3
2.20Ee2
1.61 0.03 1.61
0.76 0.76
2.81 2.81
0.89 0.89
1.34 1.34
3.40 3.40
1.47 1.47
ꢀ0.43 ꢀ0.43
8.44E 0.157
e6
ꢀ5.1
ꢀ5.2
10.05
0.01
9.59
10.15
9.78
l
105.8
e107.2
2.76k
7.06E 0.260
e6
10.29
0.12
l
ND
1.96k
1.02E 5.89Ee2 ꢀ4.99 11.02
e5
0.01
l
115.2
e116.0
2.44k
1.46E 0.439
e05
ꢀ4.8
ND
10.45 0.02 10.70
l
74.2
e75.8
2.96k
ND
ND
>12
10.16
l
56.6
e58.9
2.83k
1.14E 0.373
e5
ꢀ4.9
ND
11.93 0.05 10.89
9.87 0.01 10.16
151.2
e154.2
0.88 0.02 0.87
ND
ND
l
22
23
24
135.3
e136.8
90.3
93.4
100.0
4.268Ee2
1.06Ee2
4.32Ee2
0.76k
1.62 1.62
ꢀ0.30 ꢀ0.31
ꢀ0.24 ꢀ0.25
2.91E 5.07Ee2 ꢀ5.54 9.80 0.06 10.16
e6
l
127.1
e127.8
1.45k
3.41E 7.13Ee2 ꢀ5.47 10.33 0.02 10.42
e6
108.3
e108.7
1.03
0.01
1.03
3.66E ꢀ3.00E-3 ꢀ5.4
e06
9.44 0.02 9.07
10.22 0.15 10.16
l
25
26
182.5
e184.2
98.3
1.06E-3
1.89k
1.81 1.81
ND
ND
ND
100.2
e101.5
100.0
8.16Ee3
1.83 0.05 1.82
ꢀ0.11 ꢀ0.12
4.43E 0.105
e6
ꢀ5.35 9.58 0.01 9.35
(continued on next page)
5

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Table 1 (continued)
e
j
Cmpd Structure
mp (ꢁC)a % Stability aq. buffer pH Intrinsic solubility logPd
logD7.4
0.58 0.02 ꢀ0.42
1.76 0.03 0.99
logP logD7.4 PAMPA
pKa
pKa
7.4e7.6b
(mol/L)c
calcf calcf
Pe
calcf
i
%
logPapp
(cm/s)g retentionh
27
28
158.0
97.7
3.85Ee2
1.21 0.42
3.26 2.24
1.33 0.95
0.57 ꢀ0.19
2.63 1.59
0.70 0.34
1.16E 3.42Ee2 ꢀ5.94 5.22 0.01 6.44
e6
e158.8
164.8
e166.0
95.5
97.3
93.5
93.3
93.9
2.17Ee3
2.36Ee2
1.05Ee2
3.62Ee4
2.75Ee3
5.79E ꢀ4.81Ee2 ꢀ5.24 6.62 0.02 5.82
e6
29
30
31
32
152.5
e152.9
0.85 0.01 0.42
1.16 0.03 0.06
2.55 0.04 1.06
1.72 0.01 0.69
2.87E 0.131
e6
ꢀ5.54 5.62 0.02 7.17
156.0
e157.5
2.42E ꢀ4.07Ee2 ꢀ5.62 6.34 0.01 6.48
e6
163.7
e164.5
4.09E 2.76Ee4 ꢀ5.39 5.93 0.05 5.72
e6
158.5
3.77E ꢀ4.43Ee2 ꢀ5.42 6.42 0.01 7.20
e6
e159.7
x
Test compound was an oil.
a
Melting point of crystalline material.
b
Test compound (%) remaining after 5 h of incubation at rt in aqueous buffer (BICCA® Simulated intestinal fluid, without pancreatin; pH 7.40e7.60) as determined by
relative changes in peak area of LC/MS chromatograms over time.
c
Intrinsic solubility determined from the general solubility equation (GSE) by using experimentally determined logP and mp values.
Log of the partition coefficient between n-octanol and water (unless otherwise noted, logP determinations were conducted via potentiometric titrations using a Sirius T3,
d
Pion, Inc).
e
Log of the distribution coefficient between n-octanol and aqueous buffer at pH 7.4 (unless otherwise noted, logD7.4 determinations were conducted via potentiometric
titrations using a Sirius T3, Pion, Inc).
f
Calculated values using ChemAxon [47].
Effective permeability (PAMPA assay run by Analiza, Inc).
Membrane retention.
Log of the apparent permeability coefficient (Papp).
pKa values determined by potentiometric titrations using a Sirius T3, Pion, Inc (values in brackets are from [41]).
logD7.4 value determined via shake-flask assay (experiment run by Analiza, Inc).
logP value is considered equal to the logD7.4 as these compounds exhibit pKa values > 9.4; ND ¼ not determined.
g
h
i
j
k
l
before to estimate the propensity of compounds to hydrogen bond
[50,55], and this parameter has been found to correlate well with
passive diffusion [51,53,56,57]. Interestingly, although 9 and 12
have identical tPSA, which would suggest a near identical hydrogen
associated with a reduction in hydrogen bonding ability as sug-
gested again by logP values (Table 2) that in the case of oxetane
derivative, 15, appear to be within the range of values registered for
N-acylsulfonamide 9 and 12. This is in agreement with other re-
ports of the oxetane ring being an excellent HB acceptor, often
better than carbonyls [58,59].
D
bonding ability, the
DlogP values of isomer 9 were found to be
consistently higher (0.15e0.50) than the corresponding values of 12
regardless of the aprotic solvent used in the experiment. By com-
Further comparison of the properties of different series of model
compounds suggests that in the case of 9 and 10 (circles and
squares in Fig. 3) the impact that each of the 4- and 5-membered
ring carbonyl replacements have on compound lipophilicity and
permeability follows a similar trend. Within each series of analogs
and for both parameters (i.e., logD7.4 and logPapp) the isoxazole
derivatives (27, 29) registered the smallest increase relative to the
corresponding N-acylsulfonamides, while the oxetane and thietane
derivatives (15, 17, 18, 20) produced the largest differential in lip-
ophilicity and permeability. This trend is less evident in the case of
compounds derived from 11 (triangles in Fig. 3). Although the
oxetane (16) and thietane (19) derivatives are still the most lipo-
philic members within this series, the corresponding thietane-1-
oxide (22), isoxazole (28) and triazole (31) compounds appear to
fall within a relatively narrow range of logD7.4 values. Some series-
specific differences can also be seen when plotting the relative
changes in intrinsic solubility values (Fig. 4). However, in the ma-
jority of cases, carbonyl replacement with a 1,2,3-triazole (i.e., 30,
parison, the relative difference in
DlogP values in the case for the
oxetane derivatives, 13 and 15, which are also structural isomers
but with more closely comparable PAMPA permeability values,
appeared to be generally narrower (0.09e0.14, Table 2). These re-
sults suggest that the N-acylsulfonamide, 9, has greater propensity
to hydrogen bond than the structural isomer, 12, and this likely
results in comparatively tighter solvation and lower permeability in
the PAMPA assay.
Among the different series of model compounds, the derivatives
of acylsulfonamide 9 (shown as circles in Fig. 3) exhibit a wider and
more evenly distributed change in properties compared to other
series, with relative increases in lipophilicity, permeability and
acidity that ranged respectively: 0.2e3.1 (logD7.4); 0.5e1.7 (logPapp);
0.5e5.7 (pKa). Notably, the oxetane/thietane derivatives of 9 (e.g.,
15, 18, 21 and 24) are significantly less acidic with pKa values that
are >5 units higher than the pKa value of 9. The reduced acidic
character of these compounds, however, may not be always
6

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Scheme 1. Reagents and conditions: (a) Et3N, 2-phenylethane-1-sulfonyl chloride, CH2Cl2, 0 ꢁC to rt, 16 h, (34%); (b) (S)-(ꢀ)-2-methyl-2-propanesulfinamide, Ti(iPrO)4, CH2Cl2,
reflux, 16 h, (77%); (c) TMSOI, NaH, DMSO, rt, 2 h, (39e49%); (d) benzylmagnesium chloride, CuI, THF, ꢀ30 to 0 ꢁC, 1 h, (48e90%); (e) HCl, CH3OH, 0 ꢁC to rt, 16 h, (62%); (f) Et3N,
appropriate sulfonyl chloride or sulfamoyl chloride, CH2Cl2, 0 ꢁC to rt, 16 h, (24e68%); (g) m-CPBA, CH2Cl2, e78 ꢁC, 2 h, (70%); (h) Et3N, appropriate sulfonyl or sulfamoyl chloride,
CH2Cl2, 0 ꢁC to rt, 16 h, (15e78%); (i) oxone, acetone/H2O (1:1), 0 ꢁC to rt, 16 h, (47%); (g) acetic anhydride, AgOTf, CH2Cl2, 0 ꢁC to rt, 2 h, (67%).
31, and 32) or a thietane (e.g., 18 and 20) appears to result in a
relative decrease in intrinsic solubility, whereas replacement with
an isoxazole (i.e., 27, 28, and 29) or a thietane-1-oxide (e.g., 22)
produces solubility values that are either similar or above the
intrinsic solubility of the corresponding control compound.
inexpensive availability of predicted pKa and lipophilicity values
remains undeniably a great resource to medicinal chemistry,
especially in programs requiring the rapid assessment of large
number of compounds, experimental determinations are clearly
necessary in SPR studies.
Finally, comparison of calculated and experimental values,
showed that the pKa predictions (ChemAxon [47]) are generally
accurate across the entire data set (r2 ¼ 0.95, Fig. 5A). However, the
r2 values are significantly lower if the linear regression analysis is
performed separately within the more and less acidic compound
clusters (Fig. 5A). A relatively modest correlation was also noted
between calculated and experimental logD7.4 values (r2 ¼ 0.57,
Fig. 5B). These observations suggest that although the rapid,
3. Discussion
The isosteric replacement of specific atoms, functional groups,
or fragments with appropriate surrogate structures is a validated
strategy in medicinal chemistry that can be utilized to modulate the
intrinsic physicochemical properties of compounds of interest,
resulting
in
derivatives
with
potentially
improved
7

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Scheme 2. Reagents and conditions: (a) NH2OH$HCl, NaOH, H2O/EtOH (1:1), 80 ꢁC, 2 h, (36%); (b) appropriate sulfonyl chloride or sulfamoyl chloride, pyridine, 0 ꢁC to rt, 16 h,
(18e75%); (c) appropriate sulfonyl chloride or sulfamoyl chloride, Et3N, CH2Cl2, 0 ꢁC to rt, 16 h, (21e27%).
Table 2
The D
logP values of selected compounds.a
DlogPcyclohexane
DlogPheptane
DlogPtoluene
2.13 0.04
1.63 0.05
0.89 0.03
1.63 0.05
1.48 0.04
0.40 0.06
1.87 0.04
1.60 0.05
0.43 0.04
2.01 0.09
1.72 0.13
0.52 0.07
a
D
logP ¼ logPoctanol-water e logPhydrocarbon-water; the partition coefficients in different solvents were experimentally determined via potentiometric titrations (see Supporting
Information).
Fig. 3. Plot showing lipophilicity (i.e., logD7.4), acidity (i.e., pKa), and permeability (i.e., logPapp) of test compounds. Each of the four reference compounds (structures shown) and
their corresponding analogs are identified with different symbols.
pharmacokinetics and/or pharmacodynamics [20]. Considering
that the outcome of any isosteric replacement can vary consider-
ably depending on the particular context in which it is applied, a
screening and evaluation of alternative isosteres is almost
invariably needed. Under these circumstances, knowledge of the
relative ranking of different isosteres based on experimentally
determined physicochemical properties can be helpful to enable
informed decisions in the analog design process. Structure property
8

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Fig. 4. Plot of the log of the intrinsic solubility (S) of the different series of test compounds; logS values are obtained from the general solubility equation [logS ¼ elogP e 0.01 ꢂ (mp
e 25) þ 0.5] by using experimentally determined mp and logP values.
relationship studies that are based on comparisons between MMPs
comprise an effective strategy to reveal relative differences and
trends associated with specific chemical transformations. As such,
this strategy is especially suited to investigate the property space of
isosteric replacements [41]. The present study was aimed at
assessing the properties of different representative N-acylsulfona-
mides, as well as different classes of related surrogates. With
respect to the four N-acylsulfonamides examined in these studies,
the data collected illustrate that, as expected, relatively simple
manipulations of the substituent at the sulfur center (e.g., 9 e 12)
can be exploited to modulate the physicochemical properties of
these compounds. Perhaps of particular interest is the observation
that the alternative arrangement of the N-acylsulfonamide group,
as in 9 and 12, produces structural isomers that exhibit different
hydrogen bonding ability, as determined by
DlogP values, that in
turn correlates with different apparent permeability coefficients in
the PAMPA assay.
With respect to the N-acylsulfonamide surrogates examined,
examples were included where the carbonyl moiety is replaced
with either a 5-membered ring heteroaromatic or an oxetane ring,
as these structural motifs already found applications in drug design
as N-acylsulfonamide bioisosteres. Moreover, a series of thietane
derivatives were also included and depending on the particular
oxidation state of the thietane sulfur atom, these compounds could
significantly expand the range of properties of their respective se-
ries. Although the N-(thietan-3-yl)sulfonamide substructure is still
relatively rare and unexplored and the possible bioisosteric re-
lationships of these derivatives have not yet been investigated, a
comparison of geometry and electrostatic potential of the N-acyl-
sulfonamide 9, and the corresponding oxetane/thietane derivatives
(Fig. 6 and Supporting Information) would suggest that these types
of structures may potentially serve as candidate replacements. In
addition, considering that the model compounds studied here were
derived from the same phenylpropionyl structural template used in
earlier SPR studies of carboxylic acid bioisosteres [26,41], the
physicochemical properties of these novel structures could be
Fig. 5. Comparison between experimental and calculated pKa (A) and logD7.4 values
(B).
9

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Fig. 6. Overlay of the X-ray structures (A) and structures obtained via Gaussian geometry optimization (B) of compound 9 (grey), 15 (purple), and 18 (orange).
directly compared against different classes of acidic moieties,
gaining additional insight.
physicochemical properties of different N-acylsulfonamides, as
well as a series of corresponding surrogate structures. This data set
may be helpful in drug design efforts that involve the incorporation
or replacement of N-acylsulfonamides. In addition, by com-
plementing and expanding previous SPR studies of carboxylic acid
bioisosteres, the data presented may contribute in further defining
the property space of acidic moieties and their surrogates.
Indeed, comparison of the pKa, logD7.4 and PAMPA permeability
data of the different sets of compounds (Fig. 7 and Supporting In-
formation) shows that many of the thietane derivatives fall within
the property space of acidic moieties, with selected structures be-
ing near isometric with other acidic groups. For example, the
acidity, lipophilicity and permeability of 24 and 26 appear to be
closely comparable respectively to the hydroxamic ester 50 and
acid 51 derivatives. Likewise, interestingly, the physicochemical
properties of amide 14 are similar to the properties of the corre-
sponding phenethylsulfonamide 52. Although these similarities in
physicochemical properties cannot be used to infer bioisosteric
relationships, these results may help to further contextualize the
properties of the novel structures and to provide a rationale for
their possible use in medicinal chemistry programs.
5. Materials and methods
All solvents and reagents were reagent grade. The hexane sol-
vent was a mixture of isomers. All reagents were purchased from
reputable vendors and used as received. Thin layer chromatography
(TLC) was performed with 200 mM MilliporeSigma precoated silica
gel aluminum sheets. TLC spots were visualized under UV light or
using KMnO4 stain. Flash chromatography was performed with
Thus, taken together, these similarities as well as the general
trends of SPRs identified in this study may facilitate informed de-
cisions when deploying N-acylsulfonamides, or surrogates thereof,
in analog design.
SiliaFlash P60 (particle size 40e63
mM) supplied by Silicycle.
Melting points were taken from Mel-Temp II by Barnstead Ther-
molyne, using an Omega digital thermometer. Infrared (IR) spectra
were recorded on a PerkinElemer FT-IR spectrometer. Proton and
carbon NMR spectra were recorded on a 600 MHz NMR spec-
trometer. Chemical shifts were reported relative to residual sol-
vent’s peak. High-resolution mass spectra were measured at the
University of California San Diego Molecular Mass Spectrometry
4. Conclusions
The results from this study provide an assessment of the
Fig. 7. Comparison of lipophilicity (i.e., logD7.4), acidity (i.e., pKa), and permeability (i.e., logPapp) of test compounds vs other classes of carboxylic acid bioisosteres from [41] (crosses).
Structures and data for all compounds are in the Supporting Information.
10

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
Facility. Single crystal X-ray structure determinations were per-
formed at the University of California San Diego Crystallography
Facility. Analytical reverse phase high-performance liquid chro-
The resulting mixture was warmed to rt and stirred overnight. After
16 h, H2O was added, and the crude was extracted with EtOAc
( ꢂ 3). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by silica gel column
chromatography (up to 30% of EtOAc in hexane) provided the title
compound (0.050 g, 0.200 mmol, 34%). 1H NMR (600 MHz, CDCl3)
matography (HPLC) was performed using
a
SunFire C18
(4.6 ꢂ 50 mm, 5 mL) analytical column, while preparative reverse
phase HPLC purifications were performed using a SunFire prepar-
ative C18 OBD column (5
m
m 19 ꢂ 50 mm) on a Gilson instrument.
d
7.33 (t, J ¼ 7.6 Hz, 2H), 7.27 (s, 1H), 7.22 (d, J ¼ 7.5 Hz, 2H), 4.70 (d,
Samples were analyzed with analytical HPLC and employed 10%e
90% of CH3CN in H2O over 6e12 min and flow rate of 2 mL/min.
Samples purified by preparative HPLC employed 10%e90% of
CH3CN in H2O over 6e20 min and flow rate of 20 mL/min. All final
compounds were found to be >95% pure by HPLC/UV.
3-Phenyl-N-(phenylsulfonyl)propanamide (11). To a solution
of phenylpropionic acid (0.500 g, 3.33 mmol, 1.00 eq), EDC$HCl
(0.766 g, 4.00 mmol, 1.20 eq) and DMAP (0.488 g, 4.00 mmol, 1.20
eq) in anh. CH2Cl2 (20.0 mL), benzenesulfonamide (0.523 g,
3.33 mmol,1.00 eq) was added at rt under N2. The resulting mixture
was stirred at reflux for 8 h and then at rt for an additional 48 h. The
reaction was quenched with H2O, then extracted with CH2Cl2 ( ꢂ 3).
The combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by silica gel column chro-
matography (up to 15% of EtOAc in hexane) provided the title
compound as a white solid (0.641 g, 2.22 mmol, 67%). 1H NMR
J ¼ 6.8 Hz, 2H), 4.53 (s, 1H), 4.41 (d, J ¼ 6.8 Hz, 2H), 3.38e3.30 (m,
2H), 3.19e3.13 (m, 2H), 1.72 (s, 3H) ppm. 13C NMR (150 MHz, CDCl3)
d
137.80, 129.11, 128.57, 127.23, 83.13, 57.76, 56.19, 30.23, 24.71 ppm.
HRMS (ESþ) calculated for C12H18NO3S [M þ Na]þ 278.0821, found
278.0822. IR (neat)
n
3265.69, 2965.91, 2880.01, 1455.03, 1312.55,
1128.64, 1007.16 cmꢀ1
.
N-(1,1-Dioxido-3-phenethylthietan-3-yl)acetamide (14). To a
solution of 3-amino-3-phenethylthietane 1,1-dioxide 46 (0.060 g,
0.270 mmol, 1.00 eq) in anh. CH2Cl2, acetic anhydride (0.054 g,
0.530 mmol, 2.00 eq) was added at 0 ꢁC under N2, followed by
addition of silver triflate (0.001 g, 0.004 mmol, 0.01 eq). The
mixture was stirred at this temperature for 30 min, then stirred at rt
for 2 h. The solvent was evaporated in vacuo. Purification via silica
gel column chromatograph (up to 50% EtOAc in hexane) provided
the title compound (0.048 g, 0.180 mmol, 67%). 1H NMR (600 MHz,
CDCl3)
d
7.30 (t, J ¼ 7.5 Hz, 2H), 7.24e7.20 (m,1H), 7.18e7.14 (m, 2H),
(600 MHz, CDCl3)
d
8.03e7.96 (m, 2H), 7.66 (t, J ¼ 7.5 Hz,1H), 7.54 (t,
5.81 (s, 1H), 4.24e4.18 (m, 2H), 4.11e4.06 (m, 2H), 2.64 (dd, J ¼ 8.8,
J ¼ 7.9 Hz, 2H), 7.24e7.13 (m, 3H), 7.09e6.97 (m, 2H), 2.87 (t,
6.4 Hz, 2H), 2.49 (dd, J ¼ 8.7, 6.5 Hz, 2H), 1.91 (s, 3H) ppm. 13C NMR
J ¼ 7.7 Hz, 2H), 2.56 (t, J ¼ 7.7 Hz, 2H) ppm. 13C NMR (150 MHz,
(150 MHz, CDCl3)
d 170.36, 139.86, 129.01, 128.45, 126.79, 74.30,
CDCl3)
d
170.33, 139.48, 138.31, 133.91, 128.93, 128.52, 128.13,
45.26, 38.77, 31.26, 23.54 ppm. HRMS (ESþ) calculated for
126.32, 37.84, 30.18 ppm. HRMS (ESþ) calculated for C15H15NO3S
C
13H17NO3S [M þ Na]þ 290.0821, found 290.0821. IR (neat)
n
[M þ H]þ 290.0845, found 290.0846. IR (neat)
n
3107.25, 2886.93,
3298.61, 1647.68, 1540.27, 1455.85, 1358.84, 1315.32, 1301.07,
1682.94, 1460.06, 1452.37, 1344.62, 1170.12, 1089.75, 1072.22 cmꢀ1
.
1286.78, 1194.79, 1137.89, 1072.13, 1033.51 cmꢀ1
3-Phenethyloxetan-3-amine (42) and N-(3-phenethyloxetan-
3-yl)methanesulfonamide (15). To (S)-2-methyl-N-(3-
phenethyloxetan-3-yl)propane-2-sulfinamide 40 (0.150 g,
.
N-(Phenethylsulfonyl)acetamide (12). Synthesis of 12 followed
previously described procedures with some modifications [60]. To a
solution of 2-phenylethane-1-sulfonyl chloride (0.500 g,
2.44 mmol, 1.00 eq) in anh. CH2Cl2 (6.0 mL), NH3 (7.0 M in meth-
anol, 1.74 mL, 5.00 eq) was added dropwise at ꢀ78 ꢁC under N2. The
reaction mixture was slowly warmed to rt and stirred at this
temperature for 3 h. The resulting mixture was neutralized with
1.0 M HCl and extracted with EtOAc ( ꢂ 3). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated in
vacuo. The resulting material was used in the subsequent step
without further purification (0.452 g, 2.44 mmol, quantitative
0.533 mmol, 1.00 eq) in anh. CH3OH (4.0 mL), a solution of HCl
(2.13 mL, 1.25 M solution in CH3OH, 2.67 mmol, 5.00 eq) was added
dropwise at 0 ꢁC under N2. The mixture was stirred at rt overnight.
The mixture was concentrated in vacuo, and the resulting material
was used in the next step without purification. To 3-
phenethyloxetan-3-amine hydrochloride salt in anh. CH2Cl2
(4.0 mL), Et3N (0.150 mL, 1.07 mmol, 2.00 eq) was added at 0 ꢁC
under N2, followed by the addition of methanesulfonyl chloride
(0.083 mL, 1.07 mmol, 2.00 eq) dropwise at 0 ꢁC. The reaction
mixture was stirred at rt overnight. The reaction was then
quenched with H2O, and the resulting mixture was extracted with
EtOAc ( ꢂ 3). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel
column chromatography (up to 30% of EtOAc in hexane) provided
the title compound as a white solid (0.051 g, 0.197 mmol, 37% over
yield). 1H NMR (600 MHz, CDCl3)
d
7.33 (t, J ¼ 7.7 Hz, 2H), 7.27 (d,
J ¼ 7.2 Hz, 1H), 7.22 (d, J ¼ 7.2 Hz, 2H), 3.88 (s, 2H), 3.40e3.34 (m,
2H), 3.19e3.13 (m, 2H) ppm. To a solution of 2-phenylethane-1-
sulfonamide (0.100 g, 0.540 mmol, 1.00 eq), DMAP (0.007 g,
0.055 mmol, 0.10 eq), and Et3N (0.164 g, 1.62 mmol, 3.00 eq) in anh.
CH2Cl2 (5.0 mL), acetic anhydride (0.138 g, 1.35 mmol, 2.50 eq) was
added at ꢀ78 ꢁC under N2. The mixture was slowly warmed to rt
and stirred for 24 h. The resulting mixture was diluted with H2O
and extracted with EtOAc ( ꢂ 3). The combined organic extracts
were dried over Mg2SO4, filtered, and concentrated in vacuo. Pu-
rification by reverse phase HPLC (10%e90% CH3CN in H2O) provided
the title compound as an off-white solid (0.018 g, 0.079 mmol, 15%).
two steps). 1H NMR (600 MHz, CDCl3)
d
7.31 (t, J ¼ 7.6 Hz, 2H), 7.22
(d, J ¼ 7.9 Hz, 3H), 4.73 (d, J ¼ 7.0 Hz, 3H), 4.48 (d, J ¼ 7.0 Hz, 2H),
3.09 (s, 3H), 2.81e2.72 (m, 2H), 2.44e2.38 (m, 2H) ppm. 13C NMR
(150 MHz, CDCl3)
d 140.53, 128.90, 128.44, 126.61, 81.29, 59.60,
44.58, 38.54, 30.16, 24.91 ppm. HRMS (ESþ) calculated for
1H NMR (600 MHz, CDCl3)
d
7.33 (t, J ¼ 7.6 Hz, 2H), 7.27 (d,
C
12H17NO3S [M þ Na]þ 278.0821, found 278.0821. IR (neat)
n
J ¼ 7.9 Hz, 1H), 7.23 (d, J ¼ 7.5 Hz, 2H), 3.75 (t, J ¼ 7.7 Hz, 2H), 3.15 (t,
3142.48, 3029.94, 2954.18, 2931.24, 2886.46, 1682.06, 1601.77,
J ¼ 7.7 Hz, 2H),1.94 (s, 3H) ppm. 13C NMR (150 MHz, CDCl3)
d
169.05,
1469.16, 1453.11, 1348.08, 1308.44, 1154.59 cmꢀ1
N-(3-Phenethyloxetan-3-yl)benzenesulfonamide
Following the same procedure described for the synthesis of 15,
using (S)-2-methyl-N-(3-phenethyloxetan-3-yl)propane-2-
.
136.93, 129.12, 128.67, 127.34, 53.95, 29.65, 23.60 ppm. HRMS (ESþ)
(16).
calculated for C10H14NO3S [M þ Na]þ 250.0508, found 250.0509. IR
(neat)
1135.20 cmꢀ1
N-(3-Methyloxetan-3-yl)-2-phenylethane-1-sulfonamide
(13). To solution of 3-methyloxetan-3-amine (0.050 g,
n 3238.70, 2925.23, 1722.07, 1404.68, 1326.17, 1146.20,
.
sulfinamide 40 (0.173 g, 1.95 mmol, 1.00 eq), benzenesulfonyl
chloride (0.345 g, 1.95 mmol, 2.00 eq), and Et3N (0.198 g, 1.95 mmol,
2.00 eq). Purification by silica gel column chromatography (up to
20% EtOAc in hexane) provided the title compound (0.210 g,
a
0.570 mmol, 1.00 eq) in anh. CH2Cl2 (5.0 mL), Et3N (0.170 g,
1.70 mmol, 3.00 eq) was added at 0 ꢁC under N2, followed by 2-
phenylethane-1-sulfonyl chloride (0.350 g, 1.70 mmol, 3.00 eq).
0.662 mmol, 68%). 1H NMR (600 MHz, CDCl3)
d
7.93 (d, J ¼ 8.1 Hz,
2H), 7.67e7.60 (m, 1H), 7.55 (t, J ¼ 7.8 Hz, 2H), 7.24 (t, J ¼ 7.3 Hz, 2H),
11

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
7.21e7.15 (m, 1H), 7.00e6.91 (m, 2H), 5.01 (s, 1H), 4.61 (d, J ¼ 7.0 Hz,
2H), 4.35 (d, J ¼ 7.0 Hz, 2H), 2.47e2.40 (m, 2H), 2.36e2.29 (m, 2H)
38.00, 37.68, 29.70 ppm. HRMS (ESþ) calculated for C13H20N2O2S2
[M þ Na]þ 323.0858, found 323.0861. IR (neat)
n 2923.28, 2853.49,
ppm. 13C NMR (150 MHz, CDCl3)
d
142.02, 140.70, 133.13, 129.51,
1453.49, 1323.19, 1143.97, 1033.10, 1054.35 cmꢀ1
.
129.48, 128.38, 127.01, 126.28, 81.28, 59.25, 38.37, 29.85 ppm. HRMS
cis-N-(1-Oxido-3-phenethylthietan-3-yl)meth-
(ESþ) calculated for C17H19NO3S [M þ Na]þ 340.0978, found
anesulfonamide (21). Following the same procedure described for
the synthesis of 18, using of cis-3-amino-3-phenethylthietane 1-
oxide 38 (0.030 g, 0.140 mmol, 1.00 eq), Et3N (0.04 g,
0.430 mmol, 3.00 eq) and methanesulfonyl chloride (0.049 g,
0.043 mmol, 3.00 eq). Purification by reverse phase HPLC (10%e90%
CH3CN in H2O) provided the title compound (0.028 g, 0.097 mmol,
340.0975. IR (neat)
n 3115.92, 2981.87, 1444.04, 1320.06, 1147.53,
1092.66 cmꢀ1
.
N,N-Dimethyl-[3-(2-phenylethyl)oxetane-3-yl]sulfamoyl-
amine (17). Following the same procedure described for the syn-
thesis of 15, using (S)-2-methyl-N-(3-phenethyloxetan-3-yl)pro-
pane-2-sulfinamide 40 (0.173 g, 0.976 mmol, 1.00 eq),
dimethylsulfamoyl chloride (0.280 g, 1.95 mmol, 2.00 eq), and Et3N
(0.198 g, 1.95 mmol, 2.00 eq). Purification by silica gel column
chromatography (up to 20% EtOAc in hexane) provided the title
compound (0.098 g, 0.340 mmol, 35%). 1H NMR (600 MHz, CDCl3)
68%). 1H NMR (600 MHz, CDCl3)
d
7.31 (t, J ¼ 7.5 Hz, 2H), 7.23 (t,
J ¼ 7.3 Hz, 1H), 7.19 (d, J ¼ 7.5 Hz, 2H), 5.44 (s, 1H), 3.97e3.88 (m,
2H), 3.70e3.59 (m, 2H), 3.08 (s, 3H), 2.77e2.68 (m, 2H), 2.07 (dd,
J ¼ 10.1, 6.4 Hz, 2H) ppm. 13C NMR (150 MHz, CDCl3)
d 139.77,
128.97, 128.39, 126.78, 62.78, 51.54, 44.75, 42.53, 29.97 ppm. HRMS
d
7.31 (t, J ¼ 7.7 Hz, 2H), 7.22 (d, J ¼ 6.8 Hz, 3H), 4.74 (d, J ¼ 7.0 Hz,
2H), 4.45 (d, J ¼ 6.8 Hz, 2H), 4.38 (s, 1H), 2.86 (s, 6H), 2.75e2.70 (m,
2H), 2.43e2.35 (m, 2H) ppm. 13C NMR (150 MHz, CDCl3)
140.98,
(ESþ) calculated for C12H17NO3S2 [M þ Na]þ 310.0542, found
310.0542. IR (neat)
n 3125.00, 2862.28, 1465.89, 1310.97, 1033.39,
d
1022.67 cmꢀ1
.
128.78, 128.46, 126.41, 81.08, 59.23, 38.43, 38.01, 30.01 ppm. HRMS
cis-N-(1-Oxido-3-phenethylthietan-3-yl)benzenesulfona-
mide (22). Following the same procedure described for the syn-
thesis of 18, using of cis-3-amino-3-phenethylthietane 1-oxide 38
(0.030 g, 0.133 mmol, 1.00 eq), Et3N (0.040 g, 0.400 mmol, 3.00 eq)
and benzenesulfonyl chloride (0.071 g, 0.400 mmol, 3.00 eq). Pu-
rification by reverse phase HPLC (10%e90% CH3CN in H2O) provided
the title compound (0.034 g, 0.093 mmol, 70%). 1H NMR (600 MHz,
(ESþ) calculated for C13H20N2O3S [M þ H]þ 285.1267, found
285.1268. IR (neat)
n 2923.70, 1455.67, 1326.43, 1144.23, 1050.98,
1033.09 cmꢀ1
.
N-(3-Phenethylthietan-3-yl)methanesulfonamide (18). To a
solution of 3-phenethylthietan-3-amine 43 (0.245 g, 1.27 mmol,
1.00 eq) in anh. CH2Cl2 (5.0 mL), Et3N (0.256 g, 2.53 mmol, 2.00 eq)
was added, followed by methanesulfonyl chloride (0.290 g,
2.53 mmol, 2.00 eq) at 0 ꢁC under N2. The reaction mixture was
stirred at rt overnight. H2O was added, and the crude was extracted
with EtOAc ( ꢂ 3). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel
column chromatography (up to 30% of EtOAc in hexane) provided
the title compound (0.118 g, 0.435 mmol, 34%). 1H NMR (600 MHz,
CDCl3)
d
7.93 (d, J ¼ 7.9 Hz, 2H), 7.64 (t, J ¼ 7.5, 1H), 7.56 (t, J ¼ 7.7 Hz,
2H), 7.28 (s, 1H), 7.20 (t, J ¼ 7.4 Hz, 2H), 7.02 (d, J ¼ 7.7 Hz, 2H), 5.02
(s, 1H), 3.78e3.70 (m, 2H), 3.39e3.33 (m, 2H), 2.60e2.54 (m, 2H),
2.00e1.94 (m, 2H) ppm. 13C NMR (150 MHz, CDCl3)
d 141.73, 139.79,
133.53, 129.71, 128.85, 128.39, 127.22, 126.67, 62.90, 51.09, 42.57,
29.78 ppm. HRMS (ESe) calculated for C17H19NO3S2 [M þ Na]þ
372.0699, found 372.0700.
CDCl3)
d
7.32 (t, J ¼ 7.6 Hz, 2H), 7.24 (d, J ¼ 7.2 Hz, 3H), 4.66 (s, 1H),
cis-3-[(Dimethylsulfamoyl)amino]-3-(2-phenylethyl)-
1lambda4-thietan-1-one (23). Following the same procedure
described for the synthesis of 18, using of cis-3-amino-3-
phenethylthietane 1-oxide 38 (0.060 g, 0.290 mmol, 1.00 eq),
Et3N (0.087 g, 0.860 mmol, 3.00 eq) and dimethylsulfamoyl chlo-
ride (0.120 g, 0.860 mmol, 3.00 eq). Purification by reverse phase
HPLC (10%e90% CH3CN in H2O) provided the title compound
3.66 (d, J ¼ 9.9 Hz, 2H), 3.14 (d, J ¼ 10.1 Hz, 2H), 3.08 (s, 3H), 2.76
(dd, J ¼ 10.4, 6.5 Hz, 2H), 2.49 (dd, J ¼ 10.3, 6.6 Hz, 2H) ppm. 13
C
NMR (150 MHz, CDCl3)
d 140.75, 128.86, 128.48, 126.49, 63.28,
44.79, 39.95, 38.16, 29.85 ppm. HRMS (ESþ) calculated for
C
12H17NO2S2 [M þ Na]þ 294.0593, found 294.0592. IR (neat)
n
3234.79, 2967.55, 1732.48, 1442.63, 1307.46, 1153.47, 1130.11 cmꢀ1
.
N-(3-Phenethylthietan-3-yl)benzenesulfonamide
(19).
(0.014 g, 0.44 mmol, 15%). 1H NMR (600 MHz, CDCl3)
d 7.31 (t,
Following the same procedure described for the synthesis of 18,
using of 3-phenethylthietan-3-amine 43 (0.200 g, 1.03 mmol, 1.00
eq), Et3N (0.209 g, 2.07 mmol, 2.00 eq) and benzenesulfonyl chlo-
ride (0.365 g, 2.07 mmol, 2.00 eq). Purification by silica gel column
chromatography (up to 20% EtOAc in hexane) provided the title
compound (0.270 g, 0.810 mmol, 78%). 1H NMR (600 MHz, CDCl3)
J ¼ 7.5 Hz, 2H), 7.22 (td, J ¼ 7.2, 1.5 Hz,1H), 7.21e7.17 (m, 2H), 4.65 (s,
1H), 3.90e3.82 (m, 2H), 3.64e3.57 (m, 2H), 2.86 (s, 6H), 2.75e2.67
(m, 2H), 2.06e1.99 (m, 2H) ppm. 13C NMR (150 MHz, CDCl3) 140.13,
128.89, 128.44, 126.63, 62.43, 50.98, 42.53, 38.02, 29.83 ppm. HRMS
(ESþ) calculated for C13H20N2O3S2 [M þ Na]þ 339.0808, found
339.0801.
d
7.96e7.90 (m, 2H), 7.64e7.58 (m, 1H), 7.57e7.49 (m, 2H), 7.27 (d,
N-(1,1-Dioxido-3-phenethylthietan-3-yl)meth-
J ¼ 2.0 Hz, 1H), 7.24 (d, J ¼ 2.0 Hz, 1H), 7.22e7.15 (m, 1H), 7.06e6.99
(m, 2H), 4.89 (s, 1H), 3.54e3.48 (m, 2H), 3.02e2.95 (m, 2H),
2.54e2.48 (m, 2H), 2.45e2.40 (m, 2H) ppm. 13C NMR (150 MHz,
anesulfonamide (24). Following the same procedure described for
the synthesis of 18, using of 3-amino-3-phenethylthietane 1,1-
dioxide 46 (0.050 g, 0.220 mmol, 1.00 eq), Et3N (0.067 g,
0.670 mmol, 3.00 eq) and methanesulfonyl chloride (0.076 g,
0.670 mmol, 3.00 eq). Purification by reverse phase HPLC (10%e90%
CH3CN in H2O) provided the title compound (0.043 g, 0.014 mmol,
CDCl3)
d 142.48, 140.93, 133.02, 129.43, 128.56, 126.98, 126.16,
63.00, 39.63, 38.08, 29.60 ppm. HRMS (ESþ) calculated for
C
17H19NO2S2 [M þ Na]þ 356.0749, found 356.0749. IR (neat)
n
3276.99, 2948.31, 1448.03, 1320.15, 1154.08, 1090.87, 1063.51 cmꢀ1
.
64%). 1H NMR (600 MHz, CDCl3)
d
7.31 (t, J ¼ 7.6 Hz, 2H), 7.22 (dd,
N,N-Dimethyl-[3-(2-phenylethyl)thietan-3-yl]sulfamoyl-
amine (20). Following the same procedure described for the syn-
thesis of 18, using of 3-phenethylthietan-3-amine 43 (0.050 g,
0.260 mmol, 1.00 eq), Et3N (0.052 g, 0.520 mmol, 2.00 eq) and
dimethylsulfamoyl chloride (0.074 g, 0.520 mmol, 2.00 eq). Purifi-
cation by silica gel column chromatography (up to 20% EtOAc in
hexane) provided the title compound (0.024 g, 0.080 mmol, 24%).
J ¼ 27.3, 7.3 Hz, 3H), 5.50 (s, 1H), 4.36e4.28 (m, 2H), 4.13e4.07 (m,
2H), 3.13 (s, 3H), 2.84e2.73 (m, 2H), 2.49e2.37 (m, 2H) ppm. 13C
NMR (150 MHz, CDCl3)
d 139.29, 129.06, 128.45, 126.94, 74.73,
48.35, 44.75, 41.64, 30.86 ppm. HRMS (ESe) calculated for
C
12H17NO4S2 [M ꢀ H]e 302.0526, found 302.0526. IR (neat)
n
3275.93, 3028.34, 2924.35, 1455.59, 1315.13, 1232.45, 1143.38,
1090.29 cmꢀ1
.
1H NMR (600 MHz, CDCl3)
d
7.31 (t, J ¼ 7.6 Hz, 2H), 7.25e7.20 (m,
N-(1,1-Dioxido-3-phenethylthietan-3-yl)benzenesulfona-
mide (25). Following the same procedure described for the syn-
thesis of 18, using of 3-amino-3-phenethylthietane 1,1-dioxide 46
(0.030 g, 0.133 mmol, 1.00 eq), Et3N (0.040 g, 0.399 mmol, 3.00 eq)
3H), 4.38 (s, 1H), 3.69 (d, J ¼ 9.9 Hz, 2H), 3.09 (d, J ¼ 10.3 Hz, 2H),
2.84 (s, 6H), 2.74e2.72 (m, 2H), 2.47e2.45 (m, 2H) ppm. 13C NMR
(150 MHz, CDCl3)
d 141.15, 128.73, 128.51, 126.31, 62.92, 39.76,
12

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
and benzenesulfonyl chloride (0.071 g, 0.399 mmol, 3.00 eq). Pu-
rification by reverse phase HPLC (10%e90% CH3CN in H2O) provided
the title compound (0.034 g, 0.093 mmol, 70%). 1H NMR (600 MHz,
CDCl3 d 8.71 (s, 1H), 7.85e7.80 (m, 2H), 7.65e7.61 (m, 1H), 7.57 (td,
J ¼ 8.0, 7.5, 2.1 Hz, 2H), 7.13e7.09 (m, 2H), 7.05 (dd, J ¼ 8.5, 6.3 Hz,
1H), 6.74e6.70 (m, 2H), 4.34e4.29 (m, 2H), 4.23 (d, J ¼ 14.8 Hz, 2H),
2.21e2.15 (m, 2H), 1.98e1.92 (m, 2H) ppm. 13C NMR (150 MHz,
[M þ H]þ 268.0750, found 268.0753. IR (neat)
n 2918.50, 1621.68,
1596.55, 1577.84, 1470.33, 1417.05, 1399.21, 1355.58, 1166.61,
1035.13 cmꢀ1
.
N-(1-Phenyl-1H-1,2,3-triazol-4-yl)methanesulfonamide (30).
Following the same procedure described for the synthesis of 18, 1-
phenyl-1H-1,2,3-triazol-4-amine (0.030 g, 0.190 mmol, 1.00 eq),
methanesulfonyl chloride (0.024 g, 0.210 mmol, 1.10 eq), and Et3N
(0.021 g, 0.210 mmol, 1.10 eq). Purification by silica gel column
chromatography (up to 30% EtOAc in hexane) provided the desired
product (0.012 g, 0.050 mmol, 27%). 1H NMR (600 MHz, CDCl3)
DMSO‑d6)
d 142.50, 140.49, 132.99, 129.63, 128.29, 128.19, 126.50,
126.00, 74.13, 46.86, 40.97, 29.75 ppm. HRMS (ESe) calculated for
C
17H19NO4S2 [M ꢀ H]e 364.0683, found 364.0685. IR (neat)
n
3235.00, 2919.23, 1449.08, 1342.17, 1302.06, 1243.77, 1161.36 cmꢀ1
.
d
8.04 (d, J ¼ 2.4 Hz, 1H), 7.77e7.73 (m, 2H), 7.56 (td, J ¼ 7.8, 2.2 Hz,
3-[(Dimethylsulfamoyl)amino]-3-(2-phenylethyl)-
2H), 7.48 (dd, J ¼ 8.6, 6.4 Hz, 1H), 6.74 (s, 1H), 3.12 (s, 3H) ppm. 13
C
1lambda6-thietane-1,1-dione (26). Following the same procedure
described for the synthesis of 18, using of 3-amino-3-
phenethylthietane 1,1-dioxide 46 (0.080 g, 0.355 mmol, 1.00 eq),
Et3N (0.108 g, 1.07 mmol, 3.00 eq) and dimethylsulfamoyl chloride
(0.153 g, 1.07 mmol, 3.00 eq). Purification by reverse phase HPLC
(10%e90% CH3CN in H2O) provided the title compound (0.018 g,
NMR (150 MHz, CDCl3) d 142.83, 136.91, 130.04, 129.46, 120.54,
114.88, 40.30 ppm. HRMS (ESþ) calculated for C9H11N4O2S [M þ H]þ
239.0597, found 239.0599. IR (neat)
n 2919.65, 1597.66, 1573.98,
1498.02, 1411.81, 1345.55, 1330.76, 1215.67, 1153.87, 1053.08 cmꢀ1
.
N-(1-Phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide (31).
Following the same procedure described for the synthesis of 18,
using 1-phenyl-1H-1,2,3-triazol-4-amine (0.030 g, 0.190 mmol,1.00
eq), benzenesulfonyl chloride (0.033 g, 0.19 mmol, 1.00 eq), and
Et3N (0.019 g, 0.190 mmol, 1.00 eq). Purification by reverse phase
HPLC (10%e90% CH3CN in H2O) provided the desired compound
0.054 mmol, 15%). 1H NMR (600 MHz, CDCl3)
d
7.31 (t, J ¼ 7.6 Hz,
2H), 7.25e7.18 (m, 3H), 4.68 (s, 1H), 4.36e4.29 (m, 2H), 4.07e4.02
(m, 2H), 2.88 (s, 6H), 2.78 (dd, J ¼ 6.8, 4.0 Hz, 2H), 2.46e2.40 (m, 2H)
ppm. 13C NMR (150 MHz, CDCl3)
d 139.54, 129.02, 128.53, 126.87,
74.27, 48.00, 41.35, 38.06, 30.86 ppm. HRMS (ESþ) calculated for
(0.012 g, 0.040 mmol, 21%). 1H NMR (600 MHz, CDCl3)
d 8.07 (d,
C
12H17NO4S2 [M þ Na]þ 355.0747, found 355.0760. IR (neat)
n
J ¼ 2.4 Hz, 1H), 7.83 (d, J ¼ 7.7 Hz, 2H), 7.73 (dd, J ¼ 6.3, 4.3 Hz, 2H),
3258.71, 1453.15, 1341.72, 1310.12, 1249.77, 1153.23 cmꢀ1
.
7.57e7.51 (m, 3H), 7.49e7.44 (m, 3H) ppm. 13C NMR (150 MHz,
N-(5-Phenylisoxazol-3-yl)methanesulfonamide (27). To a so-
lution of 5-phenylisoxazol-3-amine 48 (0.030 g, 0.190 mmol, 1.00
eq) in anh. CH2Cl2 (1.8 mL), Et3N (0.038 g, 0.370 mmol, 2.00 eq) and
methanesulfonyl chloride (0.026 g, 0.220 mmol, 1.20 eq) were
added at 0 ꢁC under N2. The reaction mixture was slowly warmed to
rt and stirred at this temperature overnight. After 16 h, solvent was
removed in vacuo. Purification by silica gel column chromatog-
raphy (up to 30% EtOAc in hexane) provided the desired product
CDCl3) d 143.19, 139.07, 136.95, 133.57, 130.00, 129.40, 129.32,
127.21, 120.43, 113.40 ppm. HRMS (ESþ) calculated for C12H13N4O2S
[M þ H]þ 301.0754, found 301.0755. IR (neat)
n 2922.24, 1567.23,
1492.90, 1449.21, 1414.92, 1353.95, 1333.27, 1164.36, 1093.35,
1053.00 cmꢀ1
.
N-(1-Phenyl-1H-1,2,3-triazol-4-yl)-N,N-dimethylaminesulfo-
namide (32). Following the same procedure described for the
synthesis of 15, using 1-phenyl-1H-1,2,3-triazol-4-amine (0.030 g,
0.190 mmol, 1.00 eq), dimethylsulfamoyl chloride (0.027 g,
0.19 mmol, 1.00 eq), and Et3N (0.019 g, 0.190 mmol, 1.00 eq). Puri-
fication by reverse phase HPLC (10%e90% CH3CN in H2O) provided
the desired compound (0.013 g, 0.049 mmol, 26%). 1H NMR
(0.025 g, 0.10 mmol, 56%). 1H NMR (600 MHz, CD3OD)
J ¼ 7.7, 2.0 Hz, 2H), 7.55e7.49 (m, 3H), 6.74 (s, 1H), 3.21 (s, 3H) ppm.
13C NMR (150 MHz, CD3OD)
171.63, 159.90, 131.62, 130.08, 126.60,
d 7.84 (dd,
d
93.83, 49.00, 40.70 ppm. HRMS (ESþ) calculated for C10H10N2O3S
[M þ Na]þ 261.0310, found 261.0305. IR (neat)
n
2919.22, 2850.47,
(600 MHz, CDCl3)
d
7.99 (s, 1H), 7.77e7.72 (m, 2H), 7.54 (dd, J ¼ 8.8,
1623.00, 1578.33, 1470.58, 1332.46, 1152.41, 1042.94 cmꢀ1
.
7.3 Hz, 2H), 7.48e7.45 (m, 1H), 2.89 (s, 6H) ppm. 13C NMR (150 MHz,
N-(5-Phenylisoxazol-3-yl)benzenesulfonamide (28). Synthe-
sis of 28 was previously described [61]. To a solution of 5-
phenylisoxazol-3-amine 48 (0.030 g, 0.190 mmol, 1.00 eq) in anh.
pyridine (1.8 mL), benzenesulfonyl chloride (0.043 g, 0.240 mmol,
1.30 eq) was added at 0 ꢁC under N2. The reaction mixture was
slowly warmed to rt and stirred at this temperature overnight. The
solvent was then removed in vacuo. Purification by silica gel col-
umn chromatography (up to 30% EtOAc in hexane) provided the
desired product (0.042 g, 0.140 mmol, 75%). 1H NMR (600 MHz,
CDCl3) d 143.99, 137.02, 129.99, 129.28, 120.46, 113.65, 38.60 ppm.
HRMS (ESþ) calculated for C10H14N5O2S [M þ H]þ 268.0863, found
268.0864. IR (neat)
n 2917.46, 1597.33, 1576.48, 1494.69, 1426.58,
1364.30, 1232.86, 1164.11, 1148.06 cmꢀ1
.
(S)-2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide
(36). Synthesis of 36 closely followed previously described pro-
cedures.42, 43 1H NMR (600 MHz, CDCl3)
d
5.80 (ddd, J ¼ 15.4, 4.5,
2.1 Hz, 1H), 5.67 (ddd, J ¼ 15.4, 4.4, 2.0 Hz, 1H), 5.53e5.41 (m, 2H),
1.27 (s, 9H) ppm. 13C NMR (150 MHz, CDCl3)
d 175.98, 85.45, 85.34,
CDCl3)
7.62e7.56 (m, 1H), 7.52e7.45 (m, 5H), 6.80 (s, 1H) ppm. 13C NMR
(150 MHz, CDCl3) 171.25, 157.96, 139.01, 133.83, 130.96, 129.55,
d
7.89 (dd, J ¼ 8.5, 2.3 Hz, 2H), 7.76 (dd, J ¼ 6.7, 3.2 Hz, 2H),
57.40, 21.77 ppm. HRMS (ESþ) calculated for C7H14NO2S [M þ H]þ
176.0740, found 176.0741. IR (neat)
n 2961.88, 2926.46, 1696.95,
d
1626.13, 1456.15, 1362.66, 1264.92, 1131.77, 1079.36 cmꢀ1
.
129.20, 127.19, 126.98, 125.99, 93.27 ppm. HRMS (ESþ) calculated
(S)-2-Methyl-N-(thietan-3-ylidene)propane-2-sulfinamide
(37). Synthesis of 37 closely followed previously described pro-
cedures [42,43], using 3-thietanone (5.00 g, 56.7 mmol, 1.00 eq),
(S)-(ꢀ)-2-methylpropane-2-sulfinamide (8.25 g, 68.1 mmol, 1.20
eq), and titanium (IV) isopropoxide (32.3 g, 113 mmol, 2.00 eq).
Purification by silica gel column chromatography (up to 10% of
EtOAc in hexane) provided the title compound as a light brown
for C15H12N2O3S [M þ H]þ 301.0639, found 301.0639. IR (neat)
n
2963.47, 1616.6, 1578.49, 1470.68, 1398.46, 1317.67, 1165.18,
1082.67 cmꢀ1
.
N-(5-Phenylisoxazol-3-yl)-N,N-dimethylaminesulfonamide
(29). Following the same procedure described for the synthesis of
28, using 5-phenylisoxazol-3-amine 48 (0.030 g, 0.190 mmol, 1.00
eq) and dimethylsulfamoyl chloride (0.035 g, 0.240 mmol, 1.30 eq).
Purification by reverse phase HPLC (10%e90% CH3CN in H2O) pro-
vided the desired product (0.009 g, 0.034 mmol, 18%). 1H NMR
liquid (8.40 g, 44.0 mmol, 77%). 1H NMR (600 MHz, CDCl3)
d 4.74
(dd, J ¼ 17.2, 4.5 Hz, 1H), 4.50 (dd, J ¼ 17.1, 4.2 Hz, 1H), 4.24 (dd,
J ¼ 16.1, 4.5 Hz, 1H), 4.14 (dd, J ¼ 15.9, 4.3 Hz, 1H), 1.20 (s, 9H) ppm.
(600 MHz, CDCl3)
d
8.49 (s, 1H), 7.77 (dd, J ¼ 6.6, 3.3 Hz, 2H),
13C NMR (150 MHz, CDCl3)
d 175.05, 57.87, 46.48, 45.10, 22.39 ppm.
7.52e7.45 (m, 3H), 6.73 (d, J ¼ 3.3 Hz, 1H), 2.93 (s, 6H) ppm. 13C
HRMS (ESþ) calculated for C7H14NOS2 [M þ H]þ 192.0511, found
NMR (150 MHz, CDCl3)
d
170.88, 159.01, 130.89, 129.18, 127.05,
192.0513. IR (neat) n 2959.04, 2944.88, 2869.80, 1784.77, 1657.29,
125.97, 93.24, 38.48 ppm. HRMS (ESþ) calculated for C11H13N3O3S
1456.15, 1395.24, 1362.66, 1264.92, 1164.35, 1077.95 cmꢀ1
.
13

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
(S)-1-(tert-Butylsulfinyl)-5-oxa-1-azaspiro[2.3]hexane (38).
Synthesis of 38 closely followed previously described procedure.43
(0.670 g, 2.25 mmol, 1.00 eq) in anh. CH3OH (11.0 mL), a solution of
HCl (9.01 mL, 1.25 M solution in CH3OH, 2.67 mmol, 5.00 eq) was
added dropwise at 0 ꢁC under N2. The mixture was stirred at rt
overnight. The mixture was concentrated in vacuo, and the
resulting salt was dissolved in minimal H2O and the pH of the so-
lution was brought to 9. The mixture was then extracted with EtOAc
( ꢂ 3), and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by silica gel column
chromatography (up to 20% EtOAc in hexane) provided the title
compound (0.270 g, 1.40 mmol, 62%). 1H NMR (600 MHz, CDCl3)
1H NMR (600 MHz, CDCl3)
d
5.04 (d, J ¼ 7.9 Hz, 1H), 5.00e4.88 (m,
1H), 4.82 (d, J ¼ 7.9 Hz, 1H), 4.78 (d, J ¼ 7.2 Hz, 1H), 2.67 (s, 1H), 1.98
(s, 1H), 1.22 (s, 9H) ppm. 13C NMR (150 MHz, CDCl3)
78.35, 75.66,
d
56.94, 40.92, 22.51 ppm. HRMS (ESþ) calculated for C8H16NO2S
[M þ H]þ 190.0896, found 190.0897. IR (neat)
n 2954.79, 2872.64,
1456.15, 1393.82, 1362.66, 1301.72, 1150.19, 1066.62 cmꢀ1
.
(S)-1-(tert-Butylsulfinyl)-5-thia-1-azaspiro[2.3]hexane (39).
Synthesis of 39 closely followed previously described procedure
[43], using of NaH (1.84 g, 46.0 mmol, 1.10 eq), trimethylsulfoxo-
nium iodide (10.1 g, 46.0 mmol, 1.10 eq), and (S)-2-methyl-N-
(thietan-3-ylidene)propane-2-sulfinamide 37 (8.00 g, 41.8 mmol,
1.00 eq). Purification by silica gel column chromatography (up to
10% of EtOAc in hexane) provided the title compound (3.35 g,
d
7.30 (t, J ¼ 7.7 Hz, 2H), 7.25e7.17 (m, 3H), 3.23e3.10 (m, 4H),
2.74e2.66 (m, 2H), 2.15e2.08 (m, 2H), 1.98 (d, J ¼ 14.3 Hz, 2H) ppm.
13C NMR (150 MHz, CDCl3)
d 141.85, 128.64, 128.49, 60.55, 42.45,
41.50, 29.89 ppm. HRMS (ESþ) calculated for C11H15NS [M þ H]þ
194.0998, found 194.1002. IR (neat)
n
3349.61, 2972.83, 2924.02,
16.3 mmol, 39%). 1H NMR (600 MHz, CDCl3)
d
3.98 (d, J ¼ 10.1 Hz,
2843.43, 1602.51, 1490.12, 1448.10 cmꢀ1
.
1H), 3.80 (d, J ¼ 9.7 Hz, 1H), 3.23 (d, J ¼ 10.1 Hz, 1H), 3.17 (d,
trans-3-Amino-3-phenethylthietane 1-oxide (44) and cis-3-
amino-3-phenethylthietane 1-oxide (45). To a solution of 3-
phenethylthietan-3-amine 43 (0.100 g, 0.517 mmol, 1.00 eq) in
anh. CH2Cl2 (2.5 mL), a solution of m-CPBA (0.136 g, 0.569 mmol,
1.10 eq) in anh. CH2Cl2 (1.5 mL) was added dropwise at ꢀ78 ꢁC
under N2. The reaction was stirred at this temperature for 2 h, and
then the reaction was quenched with H2O and satd. NaHCO3. The
mixture was extracted with CH2Cl2 ( ꢂ 3) and washed with brine.
The combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by silica gel column chro-
matography (up to 30% of EtOAc in hexane) led to the separation of
product 44 (0.011 g, 0.053 mmol, 10%) and product 45 (0.076 g,
0.360 mmol, 70%). trans-3-Amino-3-phenethylthietane 1-oxide
J ¼ 9.7 Hz, 1H), 2.71 (s, 1H), 2.03 (s, 1H), 1.21 (s, 9H) ppm. 13C NMR
(150 MHz, CDCl3)
d 57.17, 42.89, 36.33, 33.72, 22.65 ppm. HRMS
(ESþ) calculated for C8H16NOS2 [M
206.0668. IR (neat) 2853.38, 2927.88, 1514.22, 1454.73, 1357.00,
1263.51, 1170.03, 1124.69, 1055.28 cmꢀ1
þ
H]þ 206.0668, found
n
.
(S)-2-Methyl-N-(3-phenethyloxetan-3-yl)propane-2-
sulfinamide (40). To a solution of copper (I) iodide (0.101 g,
0.528 mmol, 0.10 eq) in anh. THF (35 mL), benzylmagnesium
chloride (11.0 mL, 1.40 M solution in THF-Me, 15.9 mmol, 3.00 eq)
was added at rt under N2. The mixture was cooled to ꢀ30 ꢁC using
an CH3CN/dry ice bath. 1-(tert-Butylsulfinyl)-5-oxa-1-azaspiro[2.3]
hexane 38 (1.00 g, 5.28 mmol, 1.00 eq) in anh. THF (5.0 mL) was
added dropwise at ꢀ30 ꢁC. The reaction was stirred at this tem-
perature for 10 min, after which it was warmed to 0 ꢁC and stirred
for 1 h. Satd. aq. NaCl was added and the reaction was warmed to rt.
The resulting crude was extracted with EtOAc ( ꢂ 3), and the
combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by silica gel column chroma-
tography (up to 50% EtOAc in hexane) provided the title compound
(44): 1H NMR (600 MHz, CDCl3)
d
7.30 (t, J ¼ 7.7 Hz, 2H), 7.20
(dd, J ¼ 26.5, 7.5 Hz, 3H), 3.47 (dd, J ¼ 8.8, 3.1 Hz, 2H), 3.03 (dd,
J ¼ 8.8, 3.1 Hz, 2H), 2.71e2.61 (m, 2H), 2.03e1.93 (m, 2H), 1.25 (s,
2H) ppm. 13C NMR (150 MHz, CDCl3)
d 140.52, 128.83, 128.40, 63.91,
51.44, 47.21, 29.86 ppm. HRMS (ESþ) calculated for C11H15NOS [M þ
Na]þ 232.0767, found 232.0768. IR (neat)
n 3362.74, 2923.99,
1602.64, 1373.96, 1224.97, 1051.38, 1033.11 cm-1 cis-3-Amino-3-
(1.34 g, 4.75 mmol, 90%). 1H NMR (600 MHz, CDCl3)
d 7.29 (t,
phenethylthietane 1-oxide (45). 1H NMR (600 MHz, CDCl3)
J ¼ 7.6 Hz, 2H), 7.20 (dd, J ¼ 8.1, 5.9 Hz, 3H), 4.74 (d, J ¼ 6.8 Hz, 1H),
4.69 (d, J ¼ 7.0 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.47 (d, J ¼ 6.6 Hz,
1H), 3.72 (s, 1H), 2.68 (t, J ¼ 8.1 Hz, 2H), 2.45e2.30 (m, 2H), 1.25 (d,
d
77.30 (t, J ¼ 7.6 Hz, 2H), 7.24e7.12 (m, 3H), 3.92e3.79 (m, 2H),
3.21e3.02 (m, 2H), 2.75e2.58 (m, 2H), 1.87 (s, 2H), 1.83e1.72 (m,
2H) ppm. 13C NMR (150 MHz, CDCl3)
140.74, 128.78, 128.34, 65.78,
d
J ¼ 2.2 Hz, 9H) ppm. 13C NMR (150 MHz, CDCl3)
d
141.04, 128.76,
48.82, 43.89, 30.03 ppm. HRMS (ESþ) calculated for C11H15NOS
128.49, 126.38, 82.52, 82.33, 59.99, 56.11, 38.96, 29.91, 22.63 ppm.
[M þ Na]þ 232.0767, found 232.0767. IR (neat)
n 3372.63, 2913.66,
HRMS (ESþ) calculated for C15H24NO2S [M þ H]þ 282.1522, found
1602.52, 1492.51, 1453.07, 1044.94, 1028.83, 1018.41 cmꢀ1
.
282.1520. IR (neat)
n
3413.74, 3138.94, 2959.96, 2875.47, 1492.98,
3-Amino-3-phenethylthietane 1,1-dioxide (46). To a solution
of 3-phenethylthietan-3-amine 43 (0.100 g, 0.517 mmol, 1.00 eq) in
acetone (2.5 mL), a solution of Oxone® (0.477 g,1.55 mmol, 3.00 eq)
in H2O (2.5 mL) was added dropwise at 0 ꢁC. The mixture was
stirred at this temperature for 10 min, then warmed to rt and
stirred overnight. The reaction mixture was then cooled to 0 ꢁC and
a solution of Na2SO3 (1.0 M, 5.0 mL) was added. The resulting
mixture was extracted with EtOAc ( ꢂ 3) and washed with brine.
The combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by silica gel column chro-
matography (up to 25% of EtOAc in hexane) provided the title
compound (0.055 g, 0.240 mmol, 47%). 1H NMR (600 MHz, CDCl3)
1356.15, 1368.33, 1338.58, 1263.51, 1164.35, 1114.14, 1083.61,
1004.29 cmꢀ1
.
(S)-2-Methyl-N-(3-phenethylthietan-3-yl)propane-2-
sulfinamide (41). Following the same procedure described for the
synthesis of 40 using 1-(tert-butylsulfinyl)-5-thia-1-azaspiro[2.3]
hexane 39 (1.00 g, 4.87 mmol, 1.00 eq), benzylmagnesium chloride
(14.6 mL, 1.0 M solution in THF-Me, 15.9 mmol, 3.00 eq), and copper
(I) iodide (0.093 g, 0.487 mmol, 0.10 eq). Purification by silica gel
column chromatography (up to 25% EtOAc in hexane) provided the
title compound (0.696 g, 2.34 mmol, 48%). 1H NMR (600 MHz,
CDCl3)
d 7.33e7.29 (m, 2H), 7.24e7.19 (m, 3H), 3.67 (s, 1H), 3.60 (d,
J ¼ 9.7 Hz, 1H), 3.54 (d, J ¼ 10.1 Hz, 1H), 3.19 (dd, J ¼ 9.9, 1.5 Hz, 1H),
3.13 (dd, J ¼ 9.8, 1.4 Hz, 1H), 2.68 (ddd, J ¼ 9.0, 6.5, 1.9 Hz, 2H),
2.49e2.43 (m, 1H), 2.42e2.35 (m, 1H), 1.24 (s, 9H) ppm. 13C NMR
d
7.31 (t, J ¼ 7.6 Hz, 2H), 7.25e7.17 (m, 3H), 4.09e4.03 (m, 2H),
3.85e3.80 (m, 2H), 2.75 (dd, J ¼ 9.6, 6.6 Hz, 2H), 2.19e2.11 (m, 2H),
1.80 (s, 2H) ppm. 13C NMR (150 MHz, CDCl3)
140.17,128.90, 128.46,
d
(150 MHz, CDCl3)
d
141.26, 128.75, 128.52, 126.31, 63.68, 56.19,
76.55, 44.58, 43.71, 31.18, 24.25, 24.05 ppm. HRMS (ESþ) calculated
40.82, 39.25, 29.50, 22.66 ppm. HRMS (ESþ) calculated for
for C11H16NO2S [M þ H]þ 226.0896, found 226.0897. IR (neat)
n
C
15H24NOS2 [M þ H]þ 298.1294, found 298.1296. IR (neat)
n
3385.41, 3313.17, 3017.12, 2920.80, 2852.81, 1494.39, 1389.57,
3199.85, 2943.46, 1495.81, 1453.32, 1362.66, 1263.51, 1218.18,
1303.17, 1229.51, 1179.94, 1041.69, 1077.95 cmꢀ1
.
1162.94, 1051.03 cmꢀ1
3-Phenethylthietan-3-amine (43). To a solution of (S)-2-
methyl-N-(3-phenethylthietan-3-yl)propane-2-sulfinamide 41
.
5-Phenylisoxazol-3-amine (48). Synthesis of 48 closely fol-
lowed previously described procedures [46,62]. 1H NMR (600 MHz,
CDCl3)
d
7.72 (d, J ¼ 7.7 Hz, 2H), 7.43 (dt, J ¼ 8.8, 6.4 Hz, 3H), 6.09 (s,
14

K.R. Francisco, C. Varricchio, T.J. Paniak et al.
European Journal of Medicinal Chemistry 218 (2021) 113399
1H), 3.99 (s, 2H) ppm. 13C NMR (150 MHz, CDCl3)
d
169.64, 163.84,
List of Nonstandard Abbreviations
m-CPBA meta-chloroperbenzoic acid
130.17, 128.96, 127.77, 125.76, 92.04 ppm. HRMS (ESþ) calculated for
C6H9N2O [M þ H]þ 161.0709, found 161.0710. IR (neat)
n 3444.90,
3324.50, 1621.88, 1517.06, 1488.73, 1342.83, 1264.92, 1051.03 cmꢀ1
.
TMSOI
EDC
trimethylsulfoxonium iodide;
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
Stability Studies. Stock solutions (5 mM) were prepared in DMSO.
From the stock solution, test compounds solutions (100 M final
m
concentration) were prepared and stirred in BICCA® Simulated
intestinal fluid (without pancreatin, pH 7.40e7.60) at rt. Percent-
ages of compound left after 5 h of incubation were determined by
assessing relative change in peak area of the analytical LC/MS
chromatograms. LC/MS conditions employed gradients of CH3CN in
H2O (from 10% to 90% CH3CN) over 4 min and flow rate of 2 mL/min.
Determination of Physicochemical Properties. Determinations of
pKa values were obtained via automated potentiometric titrations
using a Sirius T3 instrument (Pion, Inc) according to manufacturer
instructions. Three or more titrations were performed from pH 1.8
to pH 12.2 using ionic strength adjusted water (0.15 M KCl), acid
(0.5 M HCl) and base (0.5 M KOH). For compounds with relatively
low aqueous solubility (16 and 25), the pKa determinations were
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