Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2017.12.001

The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.

Full text of DOI:10.1016/j.bmc.2017.12.001

Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and pharmacological evaluation of new acyl
sulfonamides as potent and selective Bcl-2 inhibitors
Xiaohua Liu a,d, Yu Zhang b,d, Wenjing Huang , Wenfu Tan , Ao Zhang a,c,
b
b,
⇑
⇑
a
CAS Key Laboratory of Receptor Research, and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of
Sciences, Shanghai 201203, China
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
b
c
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential
small molecule anticancer drug discovery. Herein, we report a different structural modification approach
on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of
novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-
Received 16 October 2017
Revised 30 November 2017
Accepted 1 December 2017
Available online xxxx
2
63. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55,
which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Bcl-2
Bcl-xL
Sulfonamide
Navitoclax
Apoptosis
1
. Introduction
The binding site on Bcl-2/Bcl-xL is a narrow and long groove
comprised by two large nearby pockets (P2 and P4) and three small
hydrophobic pockets (P1, P3 and P5). It is a challenge to design
7
The B-cell lymphoma-2 (Bcl-2) gene family encodes at least 20
proapoptotic and antiapoptotic proteins that are the key regulators
of apoptosis in the mitochondria-mediated death pathway. The
Bcl-2 inhibitors by targeting the interaction of Bcl-2/Bcl-xL pro-
teins with their proapoptotic binding partners including BAD and
BIM proteins. Nevertheless, during recent decades, a number of
small-molecule inhibitors targeting Bcl-2 proteins have been
developed and a few of them have been clinically investigated
either as single agents or as combinations with conventional anti-
1
antiapoptotic protein family includes Bcl-2, Bcl-xL, Bcl-w, Mcl-1
and A1 bearing four Bcl homology (BH) domains (BH1-4) and a
transmembrane domain. The proapoptotic proteins include Bax
and Bak and act as the essential apoptotic effectors containing
three BH domains (BH1-3). Interplay of the proapoptotic and the
8
cancer drugs to treat Bcl-2 dependent cancers. Among which, only
2
9
antiapoptotic proteins modulates cell survival and death. In nor-
compound 3 (ABT-199, venetocalx, Fig. 1) from AbbVie was suc-
mal healthy cell, antiapoptotic proteins sequester their apoptotic
counterparts through BH3 domain binding. To evade apoptosis,
tumor cells can upregulate antiapoptotic protein Bcl-2 and block
the normal apoptotic pathway.3 Therefore, a small molecule Bcl-
ceeded in the clinic and awarded the FDA’s approval in 2016 for
the treatment of relapsed or refractory chronic lymphoid leukemia
(CLL) with 17p deletion. Different from the dual Bcl-2/Bcl-xL non-
10,11
12,13
selective profile of the earlier inhibitors 1
(ABT-737) and 2
2
inhibitor designed to bind to the BH3 binding groove in the anti-
(ABT-263), 3 represents the first-in-class selective Bcl-2 inhibitor
sparing the on-target thrombocytopenia caused by Bcl-xL
inhibition.
apoptotic proteins may restore the normal apoptotic signaling and
overcome the apoptosis resistance of cancer cells.4
–6
The reported co-crystal structure of 2 (ABT-263, navitoclax)
with Bcl-2 (Fig. 2) indicated that this compound well occupied
the BH3 binding grove, especially the two high affinity interaction
⇑
Corresponding authors at: CAS Key Laboratory of Receptor Research, and the
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
(
14
P2 and P4 hot spots. The chlorophenyl cyclohexene component
was located in the P2 pocket and contributed to the activity of both
SIMM), University of Chinese Academy of Sciences, Shanghai 201203, China.
1
5
Bcl-2 and Bcl-xL. The phenyl thioether moiety was folded back
under the tri-substituted phenyl moiety to form interaction
and occupied the P4 pocket. The central N-(4-piperazinyl-phenyla-
E-mail addresses: wftan@fudan.edu.cn (W. Tan), aozhang@simm.ac.cn (A.
p-p
Zhang).
d
These authors contributed equally to this work.
https://doi.org/10.1016/j.bmc.2017.12.001
968-0896/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Fig. 1. Representative Bcl-2 family protein inhibitors.
Fig. 2. Key interactions of 2 (ABT-263, navitoclax) with Bcl-2 (PDB code: 4LVT)8 and our design (in red).
cyl) benzenesulfonamide component accreted the two components
and provided several key H-bonding interactions as well. With the
introduction of an azaindole as the new P4-binding moiety to cap-
ture the electrostatic interaction with Bcl-2 selective Asp103 moi-
ety, along with structural change in the P2-binding portion,
compound 3 showed high selectivity against Bcl-2 over Bcl-xL. To
gain more insights on the structural determinants of Bcl-2 selectiv-
ity in the acylsulfonamide class, here we report a different struc-
tural modification approach on compound 2 by merging the
piperazinyl-phenyl fragment into a bicyclic framework. Efforts to
downsize the P4 interaction moiety together with its connecting
bis(sulfonyl)aniline component were also conducted (Fig. 2).
amount of DMAP to yield acyl sulfonamide 8. N-Deprotection of 8
1
7
followed by nucleophilic substitution with 9 afforded the final
compound 10. Tetrahydroisoquinoline 13 was prepared by follow-
ing similar reaction procedures as that for preparation of 10 from
tetrahydroisoquinoline-6-carboxylic acid 11.
Thiophene and thiazole-fused bicyclic analogues 16 and 20
were prepared as shown in Scheme 2. 2-Ethyl 6,7-dihydrothieno
2
1
[3,2-c]pyridine-2,5(4H)-dicarboxylate 14 was deprotected and
treated with 9 to give ester 15. Hydrolysis of 15 followed by con-
densation with 7 provided acyl sulfonamide 16. 2-Ethyl 6,7-dihy-
drothiazolo[5,4-c] pyridine-2,5(4H)-dicarboxylate 1822 was
obtained by cyclization of 3-bromo-4-oxopiperidine-1-carboxylate
1
7 with ethyl 2-amino-2-thioxoacetate. By following similar reac-
tion procedures as that for preparation of 15, precursor 19 was pro-
duced in 31% yield. Hydrolysis of 19 with aqueous Na CO followed
by condensation with 7 provided acyl sulfonamide 20.
2
. Chemistry
2
3
As shown in Scheme 1, we first synthesized a small series of
Preparation of benzimidazoles 28 and 29 is outlined in
Scheme 3. tert-Butyl (1-(hydroxymethyl)cyclopropyl)carbamate
(21) was mesylated, and then substituted with NaI, followed by
treating with methyl 1H-benzo[d]imidazole-5-carboxylate led to
analogues of 2 by replacement of the phenylpiperazine component
with heterocycle-fused bicyclic frameworks. The benzazepine 10
was prepared from commercially available benzazepine 4, which
2
3
was first treated with TFAA followed by Friedel-Crafts acylation
22 as a pair of 6- and 7-isomers in about 1:1 ratio. Intermediate
with acetyl chloride to give 5.1
8,19
Oxidation of 5 with OXONE in
12
24 was obtained via N-deprotection of 22 followed by reductive
the presence of TFA delivered benzoic acid 6.20 Compound 7
was prepared via several steps according to literature procedures,
and then condensed with 6 in the presence of EDCI and a catalytic
16
12
amination with aldehyde 23. Suzuki cross-coupling of 24 with 4-
1
2
chlorophenylboronic acid afforded 25. Hydrolysis of 25 gener-
ated two separable isomers 26 and 27. Subsequent condensation
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X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
3
Scheme 1. Synthesis of compounds 10 and 13. Reagents and conditions: (a) TFAA, Et
,4-dioxane, 100 °C, 30%; (d) 7, EDCI, DMAP, CH Cl , rt, overnight, 60–73%; (e) K CO
reflux, 10 h, 57–64%.
3
N, CH
2
Cl
2
, overnight; (b) acetyl chloride, AlCl
3
, CH
2
Cl
2
, 0 °C – rt, 2 h, 81%; (c) Oxone, TFA,
1
2
2
2
3
, MeOH/H O (2:1), rt, 3 h; (f) (i) 2 M HCl in MeOH, MeOH, rt, 2 h; (ii) 9, DIPEA, MeCN,
2
Scheme 2. Synthesis of compounds 16 and 20. Reagents and conditions: (a) (i) TFA, CH
2
Cl
2
, rt, 2 h; (ii) 9, DIPEA, MeCN, rt, 5 h, 31–55%; (b) LiOH, EtOH/H
2
O (3:2), rt, overnight;
(
c) 7, EDCI, DMAP, CH Cl , rt, overnight, 14–33%; (d) ethyl 2-amino-2-thioxoacetate, EtOH, reflux, overnight, 38%; (e) Na
2
2
2
CO , DME/H O/EtOH (7:3:2), 85 °C.
3
2
of 26 and 27 with 7 provided 28 and 29 in 40% and 36% yields,
respectively.
aromatic nucleophilic substitution provided intermediate 45.
Reduction of amide 45 with BH .DMS delivered sulfonamide
3
1
6
As shown in Scheme 4, ammonization of sulfonyl chlorides
46. In addition, etheric sulfonamides 49a–b were prepared from
ammonization of (3-(bromomethyl) oxetan-3-yl)methanol fol-
lowed by substitution with fluorobenzene 32 in the presence of
NaH. Treatment of acid 34 with precursor 42a–b, 45, 46, or 49a–
b provided corresponding acyl sulfonamides 50–55 in 35–50%
yields.
3
0a–c afforded sulfonamides 31a–c.24 Aromatic nucleophilic sub-
stitution of fluorobenzene 32 by appropriate amines gave corre-
24
sponding sulfonamides 33a–c. Condensation of benzoic acid
4
3
4 with sulfonamides 31a–c or 33a–c provided acyl sulfonamides
5–40 under aforementioned standard condensation conditions.
Similarly, Substitution of cyclopropyl methanol 21 with mor-
3
pholine or 3,3-difluoroazetidine hydrochloride produced 41a–b
Scheme 5). Subsequent N-deprotection followed by aromatic
nucleophilic substitution provided intermediates 42a–b. Amina-
tion of carboxylic acid 43 with morpholine followed by similar
3. Results and discussion
(
2
5
All the newly synthesized analogues of 2 were evaluated in a
fluorescence polarization assay (FPA) for their ability to displace
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4
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Scheme 3. Synthesis of compounds 28 and 29. Reagents and conditions: (a) (i) MsCl, Et
benzo[d]imidazole-5-carboxylate, Cs CO , MeCN, 50 °C, 1 h, 61%; (c) (i) TFA, CH Cl , rt, 0.5 h, (ii) 23, NaBH
M Na CO aq, PdCl (PPh , DME/H O/EtOH (7:3:2), 85 °C, 3 h, 84%; (e) LiOH, EtOH/H O (3:2), overnight; (f) 7, EDCI, DMAP, CH
3
N, CH
2
Cl
2
, 0 °C, 0.5 h, (ii) NaI, Me
CN, HOAc, EtOH, overnight, 96%; (d) 4-chlorophenylboronic acid, 2
Cl , rt, overnight, 36–40%.
2
CO, reflux, 1 h, 87% (two steps); (b) methyl 1H-
2
3
2
2
3
2
3
2
3
)
2
2
2
2
2
4 2 2
Scheme 4. Synthesis of compounds 35–40. Reagents and conditions: (a) NH OH, THF, rt, 5 h, 95–98%; (b) DIPEA, DMSO, 60 °C, 72–90%; (c) 34, EDCI, DMAP, DIPEA, CH Cl , rt,
overnight, 18–57%.
a Bax-derived peptide from Bcl-2, and a Bad-derived peptide from
Bcl-xL. Compound 2 (ABT-263, navitoclax) was used as a reference
for comparison, which showed nearly equal potency against Bcl-2
and Bcl-xL with IC50 values of 10.3 and 8.2 nM, respectively in our
assay (Table 1). Meanwhile, the approved drug 3 (ABT-199, veneto-
clax) was also tested and showed IC50 values of 7.39 and 52.7 nM
against Bcl-2 and Bcl-xL, respectively, confirming its high selectiv-
ity of Bcl-2/Bcl-xL. As shown in Table 1, the bicyclic subseries of
analogues generally retained moderate to good activity against
both Bcl-2 and Bcl-xL, with moderate preference to Bcl-xL. The
benzazepine 10 was 19-fold less potent than reference 2, whereas
the tetrahydroisoquinoline 13 was nearly equally potent to com-
pound 2 with IC50 values of 12.6 and 14.6 nM against Bcl-2 and
Bcl-xL, respectively. To explore the potential binding mode of 13
with Bcl-2, we used a surrogate ligand 13B (Fig. 3A) to avoid the
influence of F atom in Autodock. As expect, the binding mode of
13B (Fig. 3B) revealed it mimicked the interactions of inhibitor 2
with Bcl-2, and the two structures of 2 and 13B can be overlaid
to a large extent (Fig. 3C). The thiophen- and thiazole-fused bicy-
cles 16 and 20 retained good potency and showed increased selec-
tivity for Bcl-xL. The selectivity for Bcl-xL is further elevated in
benzoimidazole 28 that showed IC50 values of 107 and 29 nM
respectively against Bcl-2 and Bcl-xL. Interestingly, the regio-iso-
mer 29 was inactive against both Bcl-2 and Bcl-xL, indicating that
the steric repulsion caused by the regiochemistry in 29 likely inter-
feres the inhibitor-target interaction.
To validate the importance of the P4-interaction component, we
first evaluated a subseries of simplified analogues. As shown in
Table 2, removal of the P4-interaction moiety-connected aniline
with a simple alkyl or heterocycles led to compounds 35–37. These
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X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
5
Scheme 5. Synthesis of compounds 50–55. Reagents and conditions: (a) morpholine or 3,3-difluoroazetidine hydrochloride, K
2
CO
3
, MeCN, 50 °C, 3 h, 48–58%; (b) (i) TFA,
CH
MeCN, 75 °C, 6 h, 46–70%; (d) 32, NaH, THF, -10 °C, 0.5 h, 35–36%; (e) morpholine, PyBop, DIPEA, DMF, rt, 10 h; (f) 32, DIPEA, DMF, rt, 3d, 48% (two steps); (g) Borane (2M in
methyl sulfide), 50 °C, 75%; (h) 34, EDCI, DMAP, DIPEA, CH Cl , rt, overnight, 35–53%.
2 2 2 3
Cl , 2 h, (ii) 4-fluoro-3-((trifluoromethyl)sulfonyl) benzenesulfonamide, DIPEA, DMSO, 60 °C, 45–69%; (c) morpholine or 3,3-difluoroazetidine hydrochloride, K CO , KI,
2
2
compounds were inactive against Bcl-xL, whereas though reduced
but moderate potency was retained against Bcl-2. In this subseries,
pyrazole 37 showed high potency against Bcl-2 with an IC50 value
of 67 nM and the Bcl-2/Bcl-xL selectivity is >15-fold. This result
indicated that a simple heterocycle like the pyrazole moiety in
4. Summary
In conclusion, we conducted a structural modification on acyl
sulfonamide 2 (navitoclax), the precedent of the first-in-class Bcl-
2 inhibitor 3 (venetoclax) and evaluated the potency and selectiv-
ity of the resulting analogues against Bcl-2 and Bcl-xL. Merging the
arylpiperazine fragment of 2 into various bicyclic frameworks gen-
erally retained moderate to good activity against both Bcl-2 and
Bcl-xL, with moderate preference to Bcl-xL. Tetrahydroisoquinoline
13 is nearly equally potent against Bcl-2 as compound 2. Further
SAR in the P4-interaction pocket indicated that simply substituted
arylsulfonamide lacking the phenyl thioether-connected chiral
amino group retained good Bcl-2 activity with improved Bcl-2/
Bcl-xL selectivity. Compared to reference 2, the difluoroazetidine
substituted analogue 55 showed slightly less Bcl-2 potency (17.3
vs 10.3 nM), but the selectivity over Bcl-xL was improved (SF, 6.0
vs 0.8). Since the inhibition of Bcl-xL was relevant to the dose-lim-
iting toxicity of 2, the current result will provide useful insights to
design more potent and selective Bcl-2 inhibitors.
3
7 might mimic the role of the azaindole in the clinical drug 3 to
interact in the P4-pocket. Moderate potency was observed for com-
pounds 38–40 bearing downsized P4-interaction moieties. These
three compounds showed similar potency against both Bcl-2
(
46–65 nM) and Bcl-xL (116–217 nM), in spite of the different
amino substituents on the phenyl ring.
Next, we replaced the chiral dialkylamino moiety in reference 2,
with a small series of heterocycle-substituted alkylamino groups.
As shown in Table 3, the cyclopropane-substituted diamines 50
and 51 retained moderate potency against Bcl-2 with IC50 values
of 40.7 and 34.8 nM, respectively. The difluoroazetidine 51 also
displayed a 10-foldselectivity for Bcl-2 over Bcl-xL. Reducing the
basicity of the amino side chain by introducing an amido moiety
led to compound 52, showing slightly lower potency and reduced
selectivity with IC50 values of 68 and 59 nM respectively against
Bcl-2 and Bcl-xL. High potency was observed by reduction of amide
5
2, and the resulting compound 53 showed IC50 values of 20.7 nM
5
. Experimental section
against Bcl-2. Greater potency was obtained by introducing an oxe-
tane moiety in the linker, affording compounds 54 and 55. Both
compounds showed high Bcl-2 potency with IC50 values of 14.5
and 17.3 nM, respectively, only slightly less potency than reference
5
.1. General
All solvents and chemical reagents were obtained from com-
1
2. The latter compound, though slightly less potent than 2, showed
mercial sources and used without further purifications. H and
1
3
an improved Bcl-2/Bcl-xL selectivity of 6-fold, which is much
improved compared with that of 2.
C NMR spectra were recorded on a Varian Mercury 300, 400 or
00 NMR spectrometer. Low- and high-resolution mass spectra
5
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6
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Table 1
Inhibition of bicyclic analogues against Bcl-2 and Bcl-xL.
Compound
IC50, nM
SFa
Bcl-2
Bcl-xL
1
1
0
3
193 ± 96.3
25.6 ± 9.3
0.13
1.15
12.6 ± 6.0
14.6 ± 3.3
1
2
2
6
0
8
57.9 ± 11.1
38.1 ± 4.0
108 ± 32.5
26.6 ± 3.0
13.2 ± 5.0
29.3 ± 4.7
0.46
0.35
0.27
2
9
>1000
>1000
–
2
3
(ABT-263)
(ABT-199)
–
–
10.3 ± 1.7
7.39 ± 3.5
8.2 ± 2.1
52.7 ± 14.4
0.80
7.13
a
Selectivity Factor = IC50 (Bcl-xL)/IC50 (Bcl-2).
A
B
C
3 2
F CO S
O
3 2
H CO S
O
H
N
H
N
N
N
O
O
O
S
S
O
S
S
O
N
NH
Modification for
docking analysis
O
N
NH
Cl
Cl
13
13B
Fig. 3. (A) Structural modifications used to create surrogate ligand 13B for rigid protein docking with Bcl-2. (B) Binding mode of 13B (pink) with Bcl-2. (C) Overlay of binding
geometry of compound 2 (green) and 13B (pink) with Bcl-2.
was recorded in the ESI mode. Flash column chromatography on
silica gel (200–300 mesh) was used for the routine purification of
reaction products. The column output was monitored by TLC on sil-
ica gel (200–300 mesh) precoated on glass plates (15 mm ꢀ 50
mm), and spots were visualized by UV light at 254 or 365 nm.
NOE was used in the structural confirmation.
5.2. Synthetic procedures
5.2.1. 3-(2,2,2-Trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]
azepine-7-carboxylic acid (6)
1
7,18
To a solution of 5
(1.1 g, 3.8 mmol) in dioxane (30 mL) was
19
added OXONE (7 g, 11.4 mmol) and TFA (0.57 mL, 7.7 mmol).
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X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
7
Table 2
Inhibition of new acyl sulfonamides against Bcl-2 and Bcl-xL.
Compound
X =
IC50, nM
Bcl-2
SFa
Bcl-xL
>1000
3
3
5
6
495 ± 409
>2.02
>5.93
168 ± 63.7
>1000
3
3
7
8
67.4 ± 31.5
65.1 ± 26.1
>1000
>14.84
3.34
218 ± 9.9
3
4
9
0
46.6 ± 8.3
162 ± 72.4
116 ± 13.6
3.48
2.53
46.0 ± 15.3
2
(ABT-263)
–
10.3 ± 1.7
8.2 ± 2.1
0.80
a
Selectivity Factor = IC50 (Bcl-xL)/IC50 (Bcl-2).
0
0
The mixture was heated to reflux for 24 h and then cooled to room
temperature. H O was added and the mixture was extracted with
EtOAc. The combined organic layers were treated with aqueous
NaHCO solution and the aqueous layer was poured onto
5.2.3. (R)-3-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
2-yl)methyl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-
3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-
1H-benzo[d]azepine-7-carboxamide (10)
2
3
crushed ice and treated with 2 M HCl; a white solid precipitated
Compound 8 (100 mg, 0.12 mmol) was dissolved in MeOH (3
out. The precipitate was filtered off and dried in vacuo to give 6
2 2 3
mL) and H O (1 mL), and K CO (84 mg, 0.6 mmol) was added.
1
(
330 mg, 30%). H NMR (300 MHz, CD
3
OD) d 7.83 (d, J = 9.1 Hz,
The reaction was stirred at room temperature for 2 h and then con-
centrated to give the amine crude intermediate as pale oil (134
mg). Without purification, the amine intermediate (56 mg) was
2
H), 7.29 (d, J = 9.2 Hz, 1H), 3.77 (t, J = 9.5 Hz, 4H), 3.08 (t, J = 9.7
Hz, 4H).
1
6
dissolved in MeCN (1 mL), and compound 9 (14 mg, 0.05 mmol),
DIPEA (21 L, 0.65 mmol) was added. The mixture was stirred at
reflux for 10 h, then washed with water and extracted with EtOAc.
The combined organics were dried over Na SO , filtered, and con-
centrated under vacuo. The residue was prified by chromatography
l
5
(
2
.2.2. (R)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino) -3-
(trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-(2,2,2-trifluoroacetyl)-
,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carboxamide (8)
To a solution of 6 (60 mg, 0.2 mmol) in CH Cl (4 mL) were
2
4
1
(
CH
NMR (400 MHz, (CD
.2, 2.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.42–7.37 (m, 2H), 7.34–
7.26 (m, 4H), 7.21 (t, J = 7.3 Hz, 1H), 7.17–7.11 (m, 3H), 7.06 –
2
Cl
2
/CH
3
OH 40:1) to provide 10 (30 mg, 64%) as white solid. H
2
2
3 2
)
CO) d 8.33 (d, J = 2.2 Hz, 1H), 8.06 (dd, J =
added EDCI (58 mg, 0.3 mmol) and DMAP (4 mg, 0.03 mmol). The
solution was stirred at room temperature for 0.5 h and compound
9
1
5
7
(97 mg, 0.18 mmol) was added. The resulting mixture was stir-
red for another 8 h and water was added. The layers were sepa-
rated, and the aqueous layer was extracted with CH Cl . The
combined organic layers were dried over Na SO and concentrated
under vacuo. The residue was prified by chromatography (CH Cl
OH 40:1) to provide 8 as white solid (108 mg, 73%). H NMR
400 MHz, CDCl ) d 8.34 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.77–7.67
m, 2H), 7.41–7.35 (m, 2H), 7.33–7.22 (m, 3H), 7.17 (t, J = 8.7 Hz,
7.01 (m, 2H), 4.24–4.22 (mf, 1H), 3.59 (td, J = 6.0, 3.4 Hz, 4H),
3.36 (qd, J = 14.0, 6.1 Hz, 2H), 3.15 (s, 2H), 3.02 (s, 4H), 2.67 (s,
4H), 2.53–2.49 (m, 4H), 2.40–2.26 (m, 4H), 2.14 (s, 3H), 1.93–
1.85 (m, 1H), 1.47 (t, J = 6.5 Hz, 2H), 0.96 (s, 6H). HRMS (ESI) calcd
2
2
2
4
2
2
/
1
3 4 6 3
for C47H55ClF N O S , 959.2919; found, 959.291.
CH
3
(
(
3
5.2.4. (R)-Tert-butyl 6-(((4-((4-morpholino-1-(phenylthio)butan-2-
yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)-
3,4-dihydroisoquinoline-2(1H)-carboxylate (12)
Compound 12 was obtained according to the procedure of
preparing 8 using compound 7 and 2-(tert-butoxycarbonyl)-
1H), 7.01 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 9.3 Hz, 1H), 4.01–3.99 (m,
1H), 3.82 (t, J = 4.7 Hz, 4H), 3.78–3.61 (d, J = 28.5 Hz, 4H), 3.18–
3.04 (m, 2H), 3.00–2.98 (m, 4H), 2.77–2.65 (m, 6H), 2.27–2.15
(
m, 1H), 1.92–1.86 (m, 1H).
Please cite this article in press as: Liu X., et al. Bioorg. Med. Chem. (2017), https://doi.org/10.1016/j.bmc.2017.12.001

8
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Table 3
Inhibition of new acyl sulfonamides against Bcl-2 and Bcl-xL.
Compound
Y =
IC50, nM
Bcl-2
SFa
Bcl-xL
5
5
0
1
40.7 ± 7.2
55.3 ± 12.1
1.36
34.8 ± 5.9
342 ± 73.1
9.83
5
5
2
3
68.2 ± 12.3
20.7 ± 3.4
59.3 ± 18.1
33.5 ± 5.6
0.87
1.62
5
5
4
5
14.5 ± 5.4
17.3 ± 4.8
49.3 ± 7.2
105 ± 11.9
3.40
6.06
2
(ABT-263)
–
10.3 ± 1.7
8.2 ± 2.1
0.80
a
Selectivity Factor = IC50 (Bcl-xL)/IC50 (Bcl-2).
1
234-tetrahydroisoquinoline-6-carboxylic acid. White solid; 60%;
128.78, 128.47, 126.99, 126.15, 125.21, 121.14, 118.54, 112.51,
107.91, 66.45, 59.36, 54.20, 53.97, 53.28, 50.11, 49.73, 40.69,
38.77, 34.83, 31.00, 29.86, 28.79, 27.51, 26.61. HRMS (ESI) calcd
1
H NMR (400 MHz, CDCl
.71–7.64 (s, 2H), 7.39 (d, J = 7.4 Hz, 2H), 7.34–7.28 (m, 3H), 7.17
d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 9.3 Hz, 1H),
3
) d 8.39 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H),
7
(
for C46
3
H51ClF N
4
O
S
6 3
, 943.2617; found, 943.2617.
4
2
2
.60 (s, 2H), 4.06–3.95 (m, 1H), 3.81 (s, 4H), 3.65 (t, J = 6.0 Hz,
H), 3.11 (qd, J = 13.9, 5.9 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 2.68–
.61 (m, 6H), 2.30–2.16 (m, 1H), 1.88–1.82 (m, 1H), 1.51 (s, 9H).
0
0
5
.2.6. Ethyl 5-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -bip-
henyl]-2-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxy-
late (15)
Compound 15 was obtained according to the procedure of
preparing 13 using compound 9 and 5-tert-butyl 2-ethyl 6,7-dihy-
drothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate. White solid; 55%;
3
H NMR (300 MHz, CDCl ) d 7.33 (s, 1H), 7.24–7.18 (m, 2H),
0
0
5.2.5. (R)-2-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
2
3
-yl)methyl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-
-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquino-
line-6-carboxamide (13)
1
To a solution of compound 12 (30 mg, 0.04 mmol) dissolved in
MeOH (1 mL) was added 2 M HCl in MeOH (0.5 mL). The mixture
was allowed to stir at room temperature until the starting material
was consumed completely. The reaction was concertrated to give
crude precursor which was used for the next step without further
purification.
6
2
.98–6.91 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.26 (s, 2H), 2.89 (s,
H), 2.75 (t, J = 5.7 Hz, 2H), 2.50 (t, J = 5.7 Hz, 2H), 2.20 (d, J = 6.9
Hz, 2H), 1.96 (s, 2H), 1.41 (t, J = 6.5 Hz, 2H), 1.28 (t, J = 7.1 Hz,
4
H), 0.92 (s, 6H).
0
0
Compound 13 was obtained according to the procedure of
5.2.7. (R)-5-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -bip-
henyl]-2-yl)methyl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)
amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridine-2-carboxamide (16)
preparing 10 using the crude precursor and compound 9. White
1
solid; 59%; H NMR (400 MHz, (CD
3
)
2
CO) d 8.32 (s, 1H), 8.03 (d, J
=
9.2 Hz, 1H), 7.71–7.61 (m, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.35 (d,
J = 6.6 Hz, 2H), 7.32–7.26 (m, 2H), 7.25–7.19 (m, 3H), 7.16–7.02
m, 3H), 4.29–4.25 (m, 1H), 3.73–3.66 (m, 6H), 3.39 (qd, J = 13.9,
.8 Hz, 2H), 3.23 (s, 2H), 2.92 (s, 2H), 2.80–2.53 (m, 8H), 2.34 (t,
J = 7.2 Hz, 2H), 2.23 (m, 1H), 2.12 (s, 2H), 1.97 (m, 1H), 1.50 (t, J
To a solution of compound 15 (22 mg, 0.05 mmol) dissolved in
(
5
2
EtOH (1.5 mL) and H O (1 mL) was added LiOH (84 mg, 0.6 mmol).
The reaction was stirred at room temperature for 2 h and then con-
centrated. The residue was dissolved in water and treated with 1 M
HCl; a white solid precipitated out. The precipitate was filtered off
and dried in vacuo to give crude acid.
=
1
7.2 Hz, 2H), 0.98 (s, 6H). 13C NMR (126 MHz, CDCl
39.93, 136.25, 134.45, 133.01, 132.73, 130.79, 128.96, 128.89,
3
) d 150.39,
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X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
9
0
0
Compound 16 was obtained according to the procedure of
preparing 8 using the crude acid and compound 7. White solid;
5.2.11. 1-((1-(((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -bip-
henyl]-2-yl)methyl)amino)cyclopropyl)methyl)-1H-benzo[d]imidazole-
3%; 1H NMR (400 MHz, (CD
5-carboxylic acid (26) and 1-((1-(((4 -chloro-4,4-dimethyl-3,4,5,6-
tetrahydro-[1,1 -biphenyl]-2-yl)methyl)amino)cyclopropyl)methyl)-
0
3
3
)
2
CO) d 8.22 (d, J = 2.2 Hz, 1H), 7.90
0
(
d, J = 9.1 Hz, 1H), 7.39–7.35 (m, 5H), 7.29–7.25 (m, 2H), 7.22–
7
3
2
2
6
9
.19 (m, 3H), 6.94 (dd, J = 15.6, 9.1 Hz, 2H), 4.31–4.17 (m, 1H),
.69–3.62 (m, 6H), 3.47–3.20 (m, 4H), 2.94–2.85 (m, 4H), 2.68–
.56 (m, 6H), 2.32 (t, J = 6.5 Hz, 2H), 2.24–2.16 (m, 1H), 2.11 (s,
H), 2.00–1.88 (m, 1H), 1.48 (t, J = 6.5 Hz, 2H), 0.96 (d, J = 4.6 Hz,
1H-benzo[d]imidazole-6-carboxylic acid (27)
1
1
Compounds 25 were prepared according to corresponding
literature procedures by Suzuki cross-coupling of 24 with 4-
chlorophenylboronic acid. The hydrolysis of 25 provided com-
pound 26 and 27 according to the above method using LiOH. The
H). HRMS (ESI) calcd for C44
H
49ClF
3
N
4
O
6
4
S , 949.2181; found,
49.2205.
two isomers were separated by chromatography (CH
Cl
2 2
/CH
3
OH
H
1
5
0:1) and diagnosed by NOE. Compound 26, white solid; 42%;
3
NMR (500 MHz, CDCl ) d 8.74 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 8.5
Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.98 (d, J
= 8.4 Hz, 2H), 4.02 (s, 2H), 3.05 (s, 2H), 2.17 (t, J = 6.6 Hz, 2H),
0
0
5
2
(
.2.8. Ethyl 5-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
-yl)methyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate
19)
Compound 19 was obtained according to the procedure of
preparing 15. White solid; 31%; 1H NMR (300 MHz, CDCl
) d 7.26
d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 4.44 (q, J = 7.3 Hz, 2H),
.56 (s, 2H), 2.99 (s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 6.0 Hz,
H), 2.26 (t, J = 6.8 Hz, 2H), 2.02 (s, 2H), 1.52–1.44 (m, 2H), 1.41
1
4
.79 (s, 2H), 1.37 (t, J = 6.6 Hz, 2H), 0.89 (s, 6H), 0.77–0.66 (m,
H). Compound 27, white solid; 35%; H NMR (500 MHz, CDCl )
3
1
3
d 8.22 (s, 1H), 8.18 (s, 1H), 8.13 (dd, J = 8.5, 1.3 Hz, 1H), 7.94 (d, J
8.5 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.07
s, 2H), 3.03 (s, 2H), 2.21–2.13 (m, 2H), 1.78 (t, J = 2.2 Hz, 2H),
(
3
2
=
(
1
.36 (t, J = 6.4 Hz, 2H), 0.88 (s, 6H), 0.72 (s, 4H).
(
t, J = 6.8 Hz, 3H), 0.98 (s, 6H).
0
0
5
.2.12. (R)-1-((1-(((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -
0
0
5
2
3
.2.9. (R)-5-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
biphenyl]-2-yl)methyl)amino)cyclopropyl)methyl)-N-((4-((4-mor-
pholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sul-
fonyl)phenyl)sulfonyl)-1H-benzo[d]imidazole-5-carboxamide (28)
-yl)methyl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-
-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo
5,4-c]pyridine-2-carboxamide (20)
Compound 19 (40 mg, 0.09 mmol) was dissolved in DME (0.7
2 2 3
O (0.3 mL), and EtOH (0.2 mL), and 2 M aqueous Na CO
90 L) was added. The reaction was stirred at 85 °C for 2 h and
then concentrated. The residue was dissolved in water and treated
with 1 M HCl; a white solid precipitated out. The precipitate was
filtered off and dried in vacuo to give crude acid.
Compound 20 was obtained according to the procedure of
preparing 8 using the crude acid and compound 7. White solid;
4%; H NMR (400 MHz, CDCl
H), 7.37 (d, J = 7.3 Hz, 2H), 7.33–7.27 (m, 4H), 7.25 (m, 1H), 7.07
d, J = 9.1 Hz, 1H), 6.99 (d, J = 7.3 Hz, 2H), 6.60 (d, J = 8.7 Hz, 1H),
[
Compound 28 were obtained according to the procedure of
preparing 8 from compound 26 and 7. White solid; 40%; 1H NMR
mL), H
(
(
400 MHz, CDCl
3
) d 8.79 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.40 (s,
H), 8.21 (d, J = 9.1 Hz, 1H), 7.89 (dd, J = 9.0, 2.2 Hz, 1H), 7.41–
.36 (m, 2H), 7.33–7.28 (m, 3H), 7.25–7.24 (m, 1H), 7.08–7.06
m, 3H), 6.87 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 9.0 Hz, 1H), 3.96–3.91
m, 3H), 3.73–3.61 (m, 4H), 3.08 (qd, J = 13.9, 5.8 Hz, 2H), 2.98 (s,
H), 2.52–2.31 (m, 6H), 2.20–2.08 (m, 3H), 1.77 (s, 2H), 1.71–1.68
m, 1H), 1.34 (t, J = 6.4 Hz, 2H), 0.84 (s, 6H), 0.69 (d, J = 13.4 Hz,
H). HRMS (ESI) calcd for C48
99.2962.
l
1
7
(
(
4
(
4
9
1
1
1
(
3
) d 8.37 (s, 1H), 8.00 (d, J = 8.7 Hz,
3
H55ClF N
6
O
S
6 3
, 999.298; found,
3
2
2
2
9
.92 (s, 1H), 3.69 (s, 4H), 3.58 (s, 2H), 3.14–3.01 (m, 4H), 2.80 (s,
H), 2.69 (s, 2H), 2.58–2.36 (m, 6H), 2.27 (t, J = 7.3 Hz, 2H), 2.16–
.13 (m, 1H), 2.01 (s, 2H), 1.75–1.71 (m, 1H), 1.47 (t, J = 7.3 Hz,
0
0
5
.2.13. (R)-1-((1-(((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -
biphenyl]-2-yl)methyl)amino)cyclopropyl)methyl)-N-((4-((4-mor-
pholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)
phenyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide (29)
H), 0.97 (s, 6H). HRMS (ESI) calcd for
50.2134; found, 950.2119.
43 3 5 6 4
C H48ClF N O S ,
Compound 29 were obtained according to the procedure of
preparing 8 from compound 27 and 7. White solid; 36%; 1H NMR
5
.2.10. Methyl 1-((1-(((2-bromo-5,5-dimethylcyclohex-1-en-1-yl) methyl)-
amino)cyclopropyl)methyl)-1H-benzo[d]imidazole-5 and 6-carboxylates
24)
To a solution of isomers 2222 (535 mg, 1.55 mmol) dissolved in
Cl (15 mL) was added TFA (2.3 mL). The mixture was allowed
(
3
400 MHz, CDCl ) d 8.43 (s, 1H), 8.07–7.97 (m, 3H), 7.78–7.68 (m,
2
7
1
2
6
H), 7.38–7.36 (m, 2H), 7.32–7.28 (m, 2H), 7.25–7.23 (m, 1H),
(
.08 (d, J = 8.2 Hz, 3H), 6.90 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 9.3 Hz,
H), 3.97–3.94 (m, 3H), 3.71 (s, 4H), 3.17–2.94 (m, 4H), 2.54–
.46 (m, 6H), 2.14–2.13 (m, 3H), 1.78–1.74 (m, 3H), 1.36 (t, J =
.4 Hz, 2H), 0.87 (s, 6H), 0.68–0.67 (d, J = 5.2 Hz, 4H). HRMS (ESI)
CH
2
2
to stir at room temperature until the starting material was con-
sumed completely. The reaction was concertrated to give crude
amide salt.
calcd for C48
3 6 6 3
H55ClF N O S , 999.298; found, 999.2964.
Without further purification, the crude amide salt was dissolved
in EtOH, and compound 2311 (293 mg, 1.35 mmol) was added. The
mixture was allowed to stir at room temperature until the imine
0
0
5.2.14. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
2-yl)methyl)piperazin-1-yl)-N-(methylsulfonyl)benzamide (35)
Compound 31a was prepared according to literature proce-
3
intermediate was observed completely. NaBH CN (110 mg, 1.76
mmol) was added and the mixture was stirred at rt overnight.
The reaction was concentrated under vacuo and prified by chro-
matography (petroleum ether/EtOAc 2:1) to provide 24 (600 mg,
2
3
dures. Compound 35 were obtained according to the procedure
of preparing 8 using compound 31a and 34. White solid; 57%; 1
NMR (300 MHz, CDCl ) d 7.70 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.0
Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.43–3.23
(m, 7H), 2.87–2.84 (m, 2H), 2.39 (s, 4H), 2.26 (t, J = 6.5 Hz, 2H),
2.04 (s, 2H), 1.47 (t, J = 6.5 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) calcd
H
9
8
6%) as colorless oil. 1H NMR (300 MHz, CDCl
3
) d 8.52 (s, 0.5H),
.34–8.16 (m, 1.5H), 8.00 (dd, J = 13.0, 8.6 Hz, 1H), 7.81 (d, J = 8.6
3
Hz, 0.5H), 7.47 (d, J = 8.6 Hz, 0.5H), 4.22 (d, J = 7.8 Hz, 2H), 3.94
d, J = 2.6 Hz, 3H), 3.31 (d, J = 3.1 Hz, 2H), 2.41 (s, 2H), 1.78 (s,
H), 1.33 (t, J = 5.6 Hz, 2H), 0.88–0.74 (m, 10H).
(
2
3 3
for C27H35ClN O S, 516.2082; found, 516.2093.
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1
0
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
0
0
5
2
.2.15. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
5.2.20. 4-((1-(Morpholinomethyl)cyclopropyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide (42a)
-yl)methyl)piperazin-1-yl)-N-((4-methylpiperazin-1-yl)sulfonyl)benza-
mide (36)
Compound 31b was prepared according to literature proce-
Compounds 42a were prepared according to corresponding lit-
erature procedures. Colorless oil; 69%; H NMR (400 MHz, CDCl )
3
d 8.32 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 9.2, 2.2 Hz, 1H), 7.31 (d, J =
9.2 Hz, 1H), 7.26 (s, 1H), 4.89 (s, 2H), 3.64 (t, J = 11.9 Hz, 4H),
2.76 (s, 2H), 1.60 (s, 3H), 1.01–0.85 (m, 4H).
2
3
1
2
3
dures. Compound 36 were obtained according to the procedure
1
of preparing 8 using compound 31b and 34. White solid; 18%; H
3
NMR (400 MHz, CDCl ) d 7.71 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.4
Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.51 (t, J
=
2
6
5
5.2 Hz, 4H), 3.27 (t, J = 5.2 Hz, 4H), 2.85 (s, 2H), 2.59 (s, 4H),
.39–2.36 (m, 7H), 2.27 (t, J = 6.5 Hz, 2H), 2.04 (s, 2H), 1.49 (t, J =
5
3
.2.21. 4-((1-((3,3-Difluoroazetidin-1-yl)methyl)cyclopropyl) amino)-
-((trifluoromethyl)sulfonyl)benzenesulfonamide (42b)
.5 Hz, 2H), 1.01 (s, 6H). HRMS (ESI) calcd for C31
98.2624; found, 598.2637.
5 3
H41ClN O S,
Compounds 42b were prepared according to corresponding lit-
23
1
erature procedures. White foam; 45%; H NMR (400 MHz, Chlo-
roform-d) d 8.29 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 9.2, 2.2 Hz, 1H),
7.29–7.26 (m, 2H), 5.02 (s, 2H), 3.67 (s, 4H), 2.51 (s, 6H), 0.91 (s,
4H).
0
0
5.2.16. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
-yl)methyl)piperazin-1-yl)-N-((1-methyl-1H-pyrazol-3-yl)sulfonyl)
2
benzamide (37)
Compound 31c was prepared according to literature proce-
5
.2.22. 4-((3-(Morpholinomethyl)oxetan-3-yl)methoxy)-3-
2
3
dures. Compound 37 were obtained according to the procedure
(
(trifluoromethyl)sulfonyl)benzenesulfonamide (49a)
1
of preparing 8 using compound 31c and 34. White solid; 36%;
NMR (400 MHz, (CD CO) d 7.90 (d, J = 8.6 Hz, 2H), 7.72 (d, J =
.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.83
d, J = 8.6 Hz, 2H), 6.65 (s, 1H), 3.81 (s, 3H), 3.31–3.19 (m, 4H),
H
To a stirred solution of 48a (110 g, 0.57 mmol)in anhydrous THF
3 2
)
(
50 mL), NaH (30 mg, 0.76 mmol) was added under N
2
at ꢁ10 °C
2
(
and stirred for 10 min. Compound 32 was added and stirred for
another 1 h. Water was added to quenching the reaction and the
2
2
H
.85 (s, 2H), 2.40 (t, J = 4.9 Hz, 4H), 2.31 (t, J = 6.5 Hz, 2H), 2.09 (s,
H), 1.50 (t, J = 6.5 Hz, 2H), 1.01 (s, 6H). HRMS (ESI) calcd for C30
aqueous layer was extracted with CH
layers were dried over Na SO and concentrated under vacuo.
The residue was prified by chromatography (CH Cl /CH OH 50:1)
to provide 49a as colorless oil (66 mg, 36%). H NMR (400 MHz,
CDCl ) d 8.58 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.9, 2.4 Hz, 1H), 7.40
2 2
Cl . The combined organic
-
2
4
5
35ClN O
3
S, 580.2155; found, 580.217.
2
2
3
1
0
0
5
2
.2.17. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
-yl)methyl)piperazin-1-yl)-N-((4-(dimethylamino)-3-((trifluoro-
3
(d, J = 8.9 Hz, 1H), 5.13 (s, 2H), 4.62 (d, J = 6.7 Hz, 4H), 4.51 (s,
methyl)sulfonyl)phenyl)sulfonyl)benzamide (38)
2H), 3.63 (s, 4H), 2.87 (s, 2H), 2.37 (s, 4H).
Compound 33a was prepared according to literature proce-
2
4
dures. Compound 38 were obtained according to the procedure
5.2.23. 4-((3-((3,3-Difluoroazetidin-1-yl)methyl)oxetan-3-yl)
methoxy)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (49b)
Compound 49b was obtained according to the procedure of
preparing 49a using the crude acid and compound 7. Colorless
1
of preparing 8 using compound 33a and 34. White solid; 39%;
NMR (400 MHz, CDCl ) d 8.62 (d, J = 2.2 Hz, 1H), 8.36 (dd, J = 8.7,
.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.34–7.29 (m, 3H), 7.00 (d, J
8.2 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.54 (s, 1H), 3.43–3.17 (m,
H), 2.89 (s, 6H), 2.72 (s, 4H), 2.28 (t, J = 6.4 Hz, 2H), 2.09 (s, 2H),
H
3
2
=
6
1
1
oil; 35%; H NMR (400 MHz, CDCl ) d 8.56 (d, J = 2.4 Hz, 1H), 8.32
3
(dd, J = 9.0, 2.4 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 5.05 (s, 2H), 4.54–
4.52 (m, 4H), 4.46 (d, J = 6.7 Hz, 2H), 3.64 (t, J = 11.8 Hz, 4H), 3.13
(s, 2H).
41
.46 (t, J = 6.4 Hz, 2H), 0.93 (s, 6H). HRMS (ESI) calcd for C35H -
3
ClF N
4
O
S
5 2
, 753.2154; found, 753.2132.
0
0
0
0
5
2
.2.18. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
5.2.24. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
2-yl)methyl)piperazin-1-yl)-N-((4-((1-(morpholinomethyl)cyclopropyl)
amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (50)
Compound 50 were obtained according to the procedure of
-yl)methyl)piperazin-1-yl)-N-((4-(3,3-difluoroazetidin-1-yl)-3-((trifluo-
romethyl)sulfonyl)phenyl)sulfonyl)benzamide (39)
Compound 33b was prepared according to literature proce-
dures. Compound 39 were obtained according to the procedure
2
4
preparing 8 from compound 42a and 34. White solid; 35%; 1
NMR (400 MHz, CDCl ) d 8.41 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.65
H
1
of preparing 8 using compound 33b and 34. White solid; 42%; H
3
NMR (400 MHz, (CD
7
2
3
)
2
CO) d 8.54 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H),
.82 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz,
H), 6.96–6.89 (m, 3H), 4.85 (t, J = 12.2 Hz, 4H), 3.48 (s, 4H), 3.12
(d, J = 8.6 Hz, 2H), 7.30 (d, J = 14.8 Hz, 2H), 7.24 (d, J = 8.9 Hz, 1H),
6.99 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 3.65 (t, J = 4.6 Hz,
4H), 3.37–3.25 (m, 4H), 2.88 (s, 2H), 2.50–2.41 (m, 10H), 2.26 (t,
J = 6.4 Hz, 2H), 2.03 (s, 2H), 1.46 (t, J = 6.4 Hz, 2H), 0.98 (s, 6H),
0.89 (s, 4H). HRMS (ESI) calcd for C41H48ClF N O S , 862.2692;
(
s, 2H), 2.65 (s, 4H), 2.33 (t, J = 6.4 Hz, 2H), 2.20 (s, 2H), 1.51 (t, J
=
8
6.4 Hz, 2H), 1.02 (s, 6H). HRMS (ESI) calcd for C36
01.1965; found, 801.1972.
5 4 5 2
H39ClF N O S ,
3
5 6 2
found, 862.2668.
0
0
0
0
5
2
(
.2.19. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
5.2.25. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
2-yl)methyl)piperazin-1-yl)-N-((4-((1-((3,3-difluoroazetidin-1-yl)methyl)
cyclopropyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)
benzamide (51)
-yl)methyl)piperazin-1-yl)-N-((4-((2-hydroxyethyl)(methyl)amino)-3-
(trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (40)
Compound 33c was prepared according to literature proce-
dures. Compound 40 were obtained according to the procedure
of preparing 8 using compound 33c and 34. White solid; 43%;
2
4
Compound 51 were obtained according to the procedure of
1
preparing 8 from compound 42b and 34. White solid; 45%; 1
H
H
NMR (400 MHz, (CD CO) d 8.61 (d, J = 2.2 Hz, 1H), 8.35 (dd, J =
3
)
2
3
NMR (400 MHz, CDCl ) d 8.41 (d, J = 2.2 Hz, 1H), 8.31 (dd, J = 9.2,
8
7
2
.9, 2.2 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.9 Hz, 1H),
.37 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.7 Hz,
H), 3.81 (t, J = 5.8 Hz, 2H), 3.47 (t, J = 5.8 Hz, 2H), 3.37 (t, J = 5.0
2.2 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.22
(d, J = 9.2 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H),
3.61 (t, J = 11.9 Hz, 4H), 3.30 (s, 4H), 2.89 (s, 2H), 2.72 (s, 2H),
2.41 (s, 4H), 2.25 (t, J = 6.5 Hz, 2H), 2.03 (s, 2H), 1.46 (t, J = 6.5 Hz,
2H), 0.97 (s, 6H), 0.94–0.89 (m, 2H), 0.88–0.82 (m, 2H). HRMS
Hz, 4H), 3.06 (s, 3H), 2.98 (s, 2H), 2.52 (s, 4H), 2.32 (t, J = 6.5 Hz,
H), 2.11 (s, 2H), 1.50 (t, J = 6.5 Hz, 2H), 1.00 (s, 6H). HRMS (ESI)
calcd for C36 41ClF , 781.2114; found, 781.2121.
2
H
3
4
N O
S
6 2
5 5 5 2
(ESI) calcd for C40H44ClF N O S , 868.2398; found, 868.2401.
Please cite this article in press as: Liu X., et al. Bioorg. Med. Chem. (2017), https://doi.org/10.1016/j.bmc.2017.12.001

X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
11
0
0
5
.2.26. (S)-4-(4-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -
31.10, 28.94, 27.88. HRMS (ESI) calcd for C41
899.2344; found, 899.2353.
5 4 7 2
H45ClF N O S ,
biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((3-cyclopropyl-1-
morpholino-1-oxopropan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)
phenyl)sulfonyl)benzamide (52)
Acknowledgments
Compound 52 were obtained according to the procedure of
preparing 8 from compound 4515 and 34. White solid; 36%;
1
H
This work was supported by grants from Chinese NSF (Grants
81773565, 81773767, 81430080). Supporting grants from the
National Program on Key Basic Research Project of China (Grant
2015CB910603-004), the International Cooperative Program
(Grant GJHZ1622) and Key Program of the Frontier Science (Grant
160621) of the Chinese Academy of Sciences, the Shanghai Com-
mission of Science and Technology (Grants 16XD1404600,
14431900400), and CAS Key Laboratory of Receptor Research of
SIMM (Grants SIMM1606YKF-08, SIMM1606YZZ-06) are also
highly appreciated.
NMR (400 MHz, CDCl
Hz, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.28 (d, J
8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 9.1 Hz, 1H), 6.67
d, J = 8.5 Hz, 2H), 4.65–4.55 (m, 1H), 3.75 (q, J = 6.4 Hz, 1H),
.61–3.53 (m, 4H), 3.28 (s, 4H), 2.97 (s, 2H), 2.48 (s, 4H), 2.26 (t,
J = 6.4 Hz, 2H), 2.03 (s, 2H), 1.81–1.63 (m, 2H), 1.46 (t, J = 6.4 Hz,
H), 0.96 (s, 6H), 0.74–0.65 (m, 1H), 0.51 (q, J = 5.1 Hz, 2H), 0.09
q, J = 5.1 Hz, 2H). HRMS (ESI) calcd for 52ClF
3
) d 8.39 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 9.1
=
(
3
2
(
C
43
H
3 5 7 2
N O S ,
9
06.2943; found, 906.2968.
0
0
5
.2.27. (S)-4-(4-((4 -chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -
A. Supplementary data
biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropyl-3-
morpholinopropan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)
phenyl)sulfonyl)benzamide (53)
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmc.2017.12.001.
Compound 53 were obtained according to the procedure of
preparing 8 from compound 4615 and 34. White solid; 53%;
NMR (400 MHz, CDCl ) d 8.40 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 9.2,
.2 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 6.8 Hz, 1H), 7.27
d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.2 Hz, 1H),
1
H
References
3
1
2
3
4
.
.
.
.
Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell..
004;116:2005–2019.
Opferman JT. Attacking cancer’s achilles heel: antagonism of antiapoptotic BCL-
2 family members. FEBS J.. 2016;283:2661–2675.
Wang S, Yang D, Lippman ME. Targeting Bcl-2 and Bcl-xL with nonpeptidic
small-molecule antagonists. Semin Oncol.. 2003;30:133–142.
Delbridge AR, Grabow S, Strasser A, et al. Thirty years of BCL-2: translating cell
death discoveries into novel cancer therapies. Nat Rev Cancer.. 2016;16:99–109.
2
(
2
6.76 (d, J = 8.7 Hz, 2H), 3.75 (q, J = 6.4 Hz, 1H), 3.67 (t, J = 4.4 Hz,
4H), 3.30 (t, J = 5.1 Hz, 4H), 2.90 (s, 2H), 2.59 (d, J = 6.4 Hz, 2H),
2.53–2.37 (m, 8H), 2.26 (t, J = 6.4 Hz, 2H), 2.02 (s, 2H), 1.54 (td, J
= 6.6, 4.3 Hz, 2H), 1.46 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H), 0.67 (dt, J =
13.3, 7.1 Hz, 1H), 0.51 (d, J = 7.7 Hz, 2H), 0.11 (dq, J = 9.3, 4.8, 4.1
5. Hennessy EJ. Selective inhibitors of Bcl-2 and Bcl-xL: balancing antitumor
activity with on-target toxicity. Bioorg Med Chem Lett.. 2016;26:2015–2114.
Hz, 2H). HRMS (ESI) calcd for C43
3
H54ClF N
5
O
S
7 2
, 892.3151; found,
6.
7.
8.
Ashkenazi A, Fairbrother WJ, Leverson JD, et al. From basic apoptosis
discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug
Discov.. 2017;16:273–284.
8
92.3129.
Zheng CH, Zhou YJ, Zhu J, et al. Construction of
a three-dimensional
0
0
5
.2.28. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -
pharmacophore for Bcl-2 inhibitors by flexible docking and the multiple copy
simultaneous search method. Bioorg Med Chem.. 2007;15:6407–6417.
Fletcher S, Yap JL, Chen L, et al. Expanding the cancer arsenal with targeted
therapies: disarmament of the antiapoptotic Bcl-2 proteins by small molecules.
J Med Chem.. 2017;60:821–838.
biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(morpholinomethyl)
oxetan-3-yl)methoxy)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)
benzamide (54)
Compound 54 were obtained according to the procedure of
9. Elmore SW, Souers AJ, Leverson JD, et al. ABT-199, a potent and selective BCL-2
inhibitor, achieves antitumor activity while sparing platelets. Nat Med..
1
preparing 8 from compound 49a and 34. White solid; 50%;
NMR (400 MHz, CDCl
J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H),
.60 (s, 2H), 4.62–4.45 (m, 6H), 3.59 (t, J = 4.6 Hz, 4H), 3.33–3.23
m, 6H), 2.81–2.68 (m, 6H), 2.36–2.29 (m, 6H), 2.07 (s, 2H), 1.46
t, J = 6.6 Hz, 2H), 0.93 (s, 6H). 13C NMR (126 MHz, CDCl
) d
61.19, 152.93, 140.56, 136.50, 135.26, 132.40, 132.34, 129.91,
H
2013;19:2020–2208.
3
) d 8.60 (s, 1H), 8.55–8.46 (m, 1H), 7.71 (d,
1
1
1
0. Bruncko M, Oost TK, Elmore SW, et al. Studies leading to potent, dual inhibitors
of Bcl-2 and Bcl-xL. J Med Chem.. 2007;50:641–662.
1. Oltersdorf T, Elmore SW, Rosenberg SH, et al. An inhibitor of Bcl-2 family
proteins induces regression of solid tumours. Nature.. 2005;435:677–681.
2. Elmore SW, Park CM, Bruncko M, et al. Discovery of an orally bioavailable small
molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem..
6
(
(
1
1
7
3
8
3
2
008;51:6902–6915.
3. Elmore SW, Tse C, Shoemaker AR, et al. ABT-263:
bioavailable Bcl-2 family inhibitor. Cancer Res.. 2008;68:3421–3428.
1
a potent and orally
29.17, 128.39, 120.73, 119.27, 118.13, 114.05, 113.51, 77.38,
1.50, 71.30, 66.44, 60.04, 53.65, 51.92, 45.92, 42.69, 40.87,
14. Petros AM, Olejniczak ET, Fesik SW. Structural biology of the Bcl-2 family of
proteins. Biochim Biophys Acta.. 2004;1644:83–94.
4.98, 30.76, 28.64, 27.60. HRMS (ESI) calcd for C42
95.2783; found, 895.2783.
3 4 8 2
H51ClF N O S ,
1
1
1
5. Lee EF, Czabotar PE, Smith BJ, et al. Crystal structure of ABT-737 complexed
with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family. Cell
Death Differ.. 2007;14:1711–1713.
6. Ghosh I, Porter JR, Helmers MR, et al. Profiling small molecule inhibitors against
helix–receptor interactions: the Bcl-2 family inhibitor BH3I-1 potently inhibits
p53/hDM2. Chem Commun.. 2010;46:8020–8022.
0
0
5
2
.2.29. 4-(4-((4 -Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1 -biphenyl]-
-yl)methyl)piperazin-1-yl)-N-((4-((3-((3,3-difluoroazetidin-1-yl)methyl)
oxetan-3-yl)methoxy)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)
benzamide (55)
7. Weissleder R, Giedt RJ, Sprachman MM, et al. Imaging cellular distribution of
Bcl inhibitors using small molecule drug conjugates. Bioconjugate Chem..
2
014;25:2081–2085.
18. Kasai S, Kamaura M, Kamata M, et al. Melanin-concentrating hormone receptor
antagonists: synthesis, structure-activity relationship, docking studies, and
Compound 55 were obtained according to the procedure of
1
1
preparing 8 from compound 49b and 34. White solid; 51%;
NMR (400 MHz, CDCl ) d 8.58 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 7.71
d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H),
H
biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
Bioorg Med Chem.. 2011;19:6261–6273.
3
(
19. Drakuli c´ BJ, Supuran CT, Cvijeti c´ IN, et al. 5-Aryl-1H-pyrazole-3- carboxylic
acids as selective inhibitors of human carbonic anhydrases IX and XII. Bioorg
Med Chem.. 2015;23:4649–4659.
7
=
6
.00 (d, J = 8.0 Hz, 2H), 6.55 (s, 2H), 4.56–4.29 (m, 6H), 3.60 (t, J
11.9 Hz, 4H), 3.33 (s, 6H), 3.07 (s, 2H), 2.75 (s, 4H), 2.29 (t, J =
2
0. Sawant SD, Kumar KAA, Venkateswarlu V, et al. A metal-free approach to
carboxylic acids by oxidation of alkyl, aryl, or heteroaryl alkyl ketones or
arylalkynes. Synthesis.. 2015;47:3161–3168.
1
3
.4 Hz, 2H), 2.06 (s, 2H), 1.45 (t, J = 6.5 Hz, 2H), 0.91 (s, 6H).
) d 160.86, 152.96, 140.75, 138.29, 133.06,
32.80, 130.33, 129.47, 128.76, 123.64, 121.04, 119.51, 118.61,
18.44, 116.42, 114.23, 113.87, 113.65, 77.28, 76.77, 71.46, 66.31
C
NMR (126 MHz, CDCl
3
2
1. Venkatesan AM, Agarwal A, Abe T, et al. Structure-activity relationship of 6-
methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum b-
lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R
stereochemistry by computational methods. J Med Chem.. 2006;49:4623–4637.
1
1
(
t, J = 23.0 Hz), 60.65, 60.28, 52.20, 46.10, 43.58, 41.12, 35.24,
Please cite this article in press as: Liu X., et al. Bioorg. Med. Chem. (2017), https://doi.org/10.1016/j.bmc.2017.12.001

1
2
X. Liu et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
2
2. Staben ST, Castanedo GM, Blaquiere N, et al. Structure-based design of tricyclic
NF- inducing kinase (NIK) inhibitors that have high selectivity over
phosphoinositide-3-kinase (PI3K). J Med Chem.. 2017;60:627–640.
3. Waldmann H, Zimmermann G, Schultz-Fademrecht C, et al. Structure guided
design and kinetic analysis of highly potent benzimidazole inhibitors targeting
the PDEd prenyl binding site. J Med Chem.. 2014;57:5435–5448.
24. Vivas JM, Díaz JA, Morante ME, et al. Synthesis and anti-inflammatory
evaluation of new sulfamoylheterocarboxylic derivatives. Arch Pharm..
1996;329:229–238.
25. Lawhorn BG, Philp J, Zhao Y, et al. Identification of purines and 7-deazapurines
as potent and selective Type I inhibitors of troponin I-interacting kinase
(TNNI3K). J Med Chem.. 2015;58:7431–7448.
jB
2
Please cite this article in press as: Liu X., et al. Bioorg. Med. Chem. (2017), https://doi.org/10.1016/j.bmc.2017.12.001