Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists

Article abstract of DOI:10.1016/j.ejmech.2020.113013

The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC₅₀ = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC₅₀ = 7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.

Full text of DOI:10.1016/j.ejmech.2020.113013

Journal Pre-proof
Discovery of Tetrahydroquinolines and Benzomorpholines as Novel Potent RORγt
Agonists
Yuehan Xia, Mingcheng Yu, Yunpeng Zhao, Li Xia, Yafei Huang, Nannan Sun, Meiqi
Song, Huimin Guo, Yunyi Zhang, Di Zhu, Qiong Xie, Yonghui Wang
PII:
S0223-5234(20)30985-5
DOI:
https://doi.org/10.1016/j.ejmech.2020.113013
EJMECH 113013
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 1 September 2020
Revised Date: 24 October 2020
Accepted Date: 9 November 2020
Please cite this article as: Y. Xia, M. Yu, Y. Zhao, L. Xia, Y. Huang, N. Sun, M. Song, H. Guo, Y.
Zhang, D. Zhu, Q. Xie, Y. Wang, Discovery of Tetrahydroquinolines and Benzomorpholines as
Novel Potent RORγt Agonists, European Journal of Medicinal Chemistry, https://doi.org/10.1016/
j.ejmech.2020.113013.
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Graphical abstract

Discovery of Tetrahydroquinolines and Benzomorpholines as Novel Potent RORγt
Agonists
Yuehan Xiaa, Mingcheng Yua, Yunpeng Zhaoa, Li Xiaa, Yafei Huanga, Nannan Suna,c, Meiqi
Songa, Huimin Guoa, Yunyi Zhanga, Di Zhua, Qiong Xiea,b,* Yonghui Wanga,*
aDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, 826
ZhanghengRoad, Pudong, Shanghai 201203, China
bFudan Zhangjiang Institute, Shanghai 201203, China.
cKey Laboratory of Metabolism and Molecular Medicine, The Ministry of Education,
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan
University, Shanghai201203, China.
Abstract: The retinoic acid receptor-related orphan receptor γt (RORγt) is an important
nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin
17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential
approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt
agonist during in-house library screening. Changes in LHS core of 1 led to the identification
of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed
structure-activity relationship on substituent of the LHS core, amide linker and RHS
arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and
benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound
8g (EC50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC50 =
7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic
activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene
assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4%
activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt
inverse agonists accidentally discovered were also discussed.
Key words: tetrahydroquinolines, benzomorpholines, RORγt agonists, functional switch,
cancer immunotherapy
1. Introduction
T helper 17 (Th17) cells, one of the effector T-cell subsets differentiated from naive CD4+ T
cells, are characterized by unique transcription factors and production of the cytokine
interleukin 17 (IL-17) [1]. Recent studies have shown that Th17 cells and IL-17 expression
are widely distributed at human tumor sites [2, 3]. It has been demonstrated that Th17 cells
are actively involved in tumor immunology processes and have potential antitumor effect by
promoting a remarkable activation of tumor-specific CD8+ T cells and eliciting a protective
inflammation [4, 5]. Besides, there are also reports on modulators targeting the innate
immune system, like nucleotide-binding oligomerization domain (NOD), that could facilitate
the treatment of some cancers. [6, 7]

The retinoic acid receptor-related orphan receptor (ROR) subfamily consists of three
members: RORα, RORβ, and RORγ. RORγt is one of the two isoforms of RORγ present
mainly in the thymus [8]. Tissue specific expression of RORγt suggests its special role in the
regulation of the immune system. It has been implicated that RORγt is the key transcription
factor in the differentiation of Th17 cells [9]. RORγt agonists, which up-regulate RORγt gene
transcription, have shown increased basal activity of RORγt and the promotion of Th17 cell
differentiation and IL-17 production. Therefore, RORγt agonists could be developed as a
potential approach to cancer immunotherapy [10,11].
Increasing numbers of RORγt agonists have been reported in recent years [12], including
N-arylsulfonyl indolines by the Scripps research institute [13], N-benzyl indolines by Takeda
[14] and benzyloxytricyclic compounds by Bristol Myers Squibb [15] (Fig.1). LYC-55716
(Fig.1) developed by Lycera was the only RORγt agonist advanced into Phase 2a clinical
trials for the treatment of certain types of cancers [16]. A hybridization strategy based on
Lycera’s and Scripps' compounds led to the discovery of 6-aryl indole and indoline
derivatives as potent RORγt agonists (Fig.1) [17]. Besides, the binding modes of RORγt
agonists with RORγt ligand binding domain (LBD) were also reported and it was
well-accepted that RORγt agonists could stabilize activation function 2 (AF2) domain by
His479-Tyr502-Phe506 (HYF) cluster, including hydrogen bond interaction between His479
and Tyr502 and larger hydrophobic network among these residues, to recruit co-activators. On
the contrary, RORγt inverse agonists destroyed the formation of these interactions. In fact,
change on the ligand structure that may affect the stability of AF2 would cause a functional
switch between RORγt inverse agonists and RORγt agonists [13, 18-23]. A few of RORγt
agonists in the aryl sulfone chemical series bearing tertiary amine, thiazole ketone, and biaryl
groups were discovered through minor structure changes from the corresponding RORγt
inverse agonists [18, 19] (Fig.1).
To seek for more structurally distinct RORγt agonists, we have screened our in-house
compound library using RORγ dual FRET assay and identified a tetrahydroisoquinoline
compound 1 as a hit of RORγt agonist (15% activation at 3 µM). Using compound 1 as a
starting point, we carried out structural modification, trying to find potent RORγt agonists
comprising new scaffolds. In this paper, we described the design, synthesis, and
structure-activity relationship (SAR) of tetrahydroquinoline and benzomorpholine series as
novel RORγt agonists. Cell-based activity and binding modes of selected compounds were
also studied.

Fig. 1. Representative RORγt agonists.
2. Results and discussion
2.1 Compound design
First, analogs of the tetrahydroisoquinoline hit (1) with different benzo nitrogen-containing
heterocycle cores were designed, based on the principle of keeping a three-atom distance
between the two benzene rings on the left-hand side (LHS), to find new cores that could
improve RORγt agonistic activity. Consequently, a tetrahydroquinoline compound 6 was
identified with an EC50 of 21.5 nM, although the maximum activation percentage remained
low (39.3%). According to the docking study of 6 with RORγt LBD (PDB code: 4NIE)
(Fig.2), hydrogen bond interactions of the right-hand side (RHS) sulfone moiety with Arg367
and Leu287, and of the amide linker with Phe377 are observed. The LHS moiety occupies the
hydrophobic pocket of AF2 domain, forming two π−π stacking interactions: one between the
phenyl ring of tetrahydroquinoline and His479, and the other between the middle phenyl ring
and Phe378. Overlay of compound 6 with the original ligand in the PDB (code: 4NIE) (Fig.2)
shows that the LHS of 6 is not so close as the original ligand to AF2, which perhaps led to the
partial agonistic activity of 6. Therefore, we hypothesized that extending the length of the
molecule to increase AF2 stabilization would improve agonistic activity. In order to identify
the optimal position for substitution, we introduced a methyl group to four different positions
of the LHS tetrahydroquinoline phenyl ring. After the position exploration, we introduced
7-substituents with different sizes to the tetrahydroquinoline core. SARs of linker
(amide/urea/reverse amide) and RHS moiety (pyridinyl replacement) were investigated on
compounds of the tetrahydroquinoline series. The introduction of an oxygen atom on the
tetrahydroquinoline core led to benzomorpholine series with relatively lower CLogP. Then
benzomorpholine compounds were designed combining the optimal LHS 7-substituents,
linker (amide and reverse amide), and the RHS pyridinyl and methylsulfonyl groups based on
SAR knowledge learnt from other chemical series in our group [20] (Fig.3).

A
B
Fig. 2. A) Overlay of 6 (yellow stick) (a docking pose) with the original ligand (blue stick) (PDB:
4NIE) in RORγt LBD. Red dotted line represents hydrogen bond; B) The binding mode of 6 in 2D
graph.
LHS
RHS
core
new core
N
core
H
H
N
R
N
linker
core exploration
scaffold hopping
SAR
O
O
O
S
O
N
O
O
W
Z
S
O
S
O
N
n
X
Y
1
, hit
in-house library screening
dual FRET: % act. @ 3 μM = 15
6
tetrahydroquinoline,
tetrahydroquinolines and benzomorpholines
±
dual FRET: EC50 = 21.5 15.3 nM, % max. act. = 39.3
Detailed design:
R
N
W
N
N
N
LHS core=
N
N
X
O
H
F
Cl
Me
R=
O
CF3
CF3
CF3
F
HO
F3
N
O
O
O
O
O
F3
C
C
OH
H
N
H
N
H
N
H
N
O
linker=
N
H
O
O
O
O
X=CH2, O;
W=CH2,
;
Y=H, F, Cl;
Z=CH, N;
n=0,1
Fig. 3. Design of tetrahydroquinoline and benzomorpholine derivatives as RORγt agonists.
2.2 Chemistry
General synthetic route for the target amide compounds was outlined in Scheme 1. First, the
prepared lactam 10 was reduced to secondary amine intermediate 11 with borane. The
synthesis of lactam 10 was presented in supporting information. Nucleophilic substitution of
secondary amine 11 with p-nitrobenzyl bromide obtained tertiary amine intermediate 12.
Amide condensation of 2-(4-nitroaryl)acetic acid with 11 under the condition of HATU and
DIPEA afforded the amide intermediate 13. Subsequent reduction of the amide group and/or
nitro group of 12 and 13 afforded desired intermediate 15. Finally, the target compounds 1-3,

5, 6, 6a-6d, 7a-7i, 7k-7o, 8b, 9a-9c, 9h-9k were obtained via acylation of corresponding
amine intermediate 15 with 2-(4-(alkylsulfonyl)aryl)acetic acid.
General synthetic route for the target reverse amide compounds was outlined in Scheme 2.
Amide condensation of 2-(4-bromoaryl)acetic acid with prepared cyclic secondary amine 11
under the condition of HATU and DIPEA afforded amide intermediate 16. Subsequent
reduction of the amide group of 16 afforded desired intermediate 17. Cyanation of
bromobenzene gave benzonitrile compound 18 catalyzed by palladium complexes.
Subsequent hydrolysis by NaOH yielded the corresponding benzoic acid intermediate 19.
Finally, the desired target compounds 8d-8e, 8g-8j, 9d-9g were obtained by acylation of
corresponding alkylsulfonyl arylmethylamine with the carboxylic acid intermediate 19.
Synthetic procedures of compounds 4, 7j, 8a, 8c and 8f were described in the supporting
information.
Scheme 1. General synthetic procedures for the amide compounds. Reagents and conditions: a)
Borane-methyl sulfide complex, THF, 45oC; b) DIPEA, HATU, DCM, r.t.; c) DIPEA, DMF, r.t.; d)
SnCl2·2H2O, conc. HCl, EtOH, H2O, 95oC.

Scheme 2. General synthetic procedures for the reverse amide compounds. Reagents and
conditions: a) DIPEA, HATU, DCM, rt; b) Borane-methyl sulfide complex, THF, 45oC; c)
Zn(CN)2, Pd(PPh3)4, DMF, 100oC; d) NaOH, EtOH/H2O,100oC.
2.3 Structure-activity relationship
The synthesized compounds were evaluated in RORγ dual FRET assay according to the basal
level activity changes, which was suitable for the activity and function assessment of both
agonists and inverse agonists. Compounds with good RORγt agonistic activities in each set
were subjected to cell-based Gal4 luciferase reporter gene assay.
The first set of compounds with different benzo nitrogen-containing heterocycle cores was
designed, synthesized and evaluated at 3 µM in RORγ dual FRET assay (Table 1). With the
strategies of changing the size or saturation of azaheterocycles and the position of nitrogen
atom,
we
replaced
tetrahydroisoquinoline
(1)
with
isoindoline
(5),
(2),
2,3,4,5-tetrahydro-1H-benzo[c]azepine
(3), 1H-indole
(4), indoline
and
tetrahydroquinoline (6). In view of the RORγt activity, compound 6 with six-membered ring
and nitrogen atom attached to the phenyl ring exhibited best RORγt efficacy. Therefore, we
chose tetrahydroquinoline as preferred core structure for the subsequent optimization.
Introduction of a substituent to the selected tetrahydroquinoline core was expected to improve
RORγt activity based on docking study (Fig. 2). We introduced methyl group tethered to four
positions (6a-6d) on the tetrahydroquinoline phenyl ring for purpose of exploring the effect of
substituent position on activity. Taking both RORγt agonistic potency and efficacy into
account, 7-substituted tetrahydroquinoline compound 6b (EC50 = 16.7 ± 0.3 nM, % max. act.
= 60.8) stood out among these four compounds, which was 2-fold more active than
5-substituted compound 6d in activating RORγt. In contrast, 8-substituted (6a) and
6-substituented (6c) tetrahydroquinolines were completely devoid of RORγt agonistic
efficacy in RORγ dual FRET assay. By analyzing the docking binding modes of 6 and 6c in
RORγt LBD, we found that 8-substituted methyl would collide with nearby amino acid
residues, including Leu396, Ile397, and Ile400, while 6-substituted methyl might block the
rotation of flexible residue Trp317 [14, 20] (see Fig. S1).
Subsequently, a series of compounds with different size and/or shape of 7-substituent (R
group) on the LHS phenyl ring was designed and synthesized (Table 2). As expected, the
compounds showed a range of maximum responses depending on the properties (size and
shape) of the 7-substituents. In dual FRET assay, maximum activation percentage improved
in an order of F < Cl ∼ t-Bu < Me ∼OMe ∼c-Pr < i-Pr < i-Bu. Concretely, the maximum
activation of compounds 7a−7f increased from 30.9% to 110.2% with the increase in size of
7-substituent. With a larger substituent than i-Bu (7f), such as t-Bu and neopentyl, compounds
7g and 7h showed reduced RORγt efficacy. As far as potency was concerned, compounds

7a−7h exhibited high RORγt agonistic potency with EC50 values between 7.8 nM and 46.4
nM.
Next, we designed a series of compounds with substituents which were similar in size as
isobutyl (7f), including cycloalkyl (7i), alkenyl (7j), amino (7k), and ether (7l-7o) groups.
Despite their similar size, potency and efficacy of these compounds (7i-7o) differed greatly.
Compound 7i with cyclopropylmethyl and compound 7l with isopropoxy outperformed other
analogs of 7f, showing a 4-fold increase in potency with EC50 values of ~10 nM relative to 7f
(EC50 = 46.4 ± 10.6 nM) but a slightly lower RORγt maximum response of 80-90%. Efficacy
trend of compound 7l vs. 7m was consistent with that of compound 7f vs. 7h, which indicated
that a tert-butyl end on LHS in 7h and 7m was a little too big in size which reduced the
potency and efficacy. Compound 7d, 7j, 7o with rigid cycloalkyl or alkenyl group had low
nanomolar (single-digit) EC50 in spite of a maximum activation of around 70%. Electronic
properties of the substituents may also affect the activity. Comparing the potency and efficacy
of 7f and 7k, it seemed that introducing a nitrogen on the beta position of the isobutyl group
was unfavorable. On basis of an overall consideration of both efficacy and potency, the
optimal R group was selected as isobutyl or isopropoxy.
With the 7-substituent R fixed to isobutyl as 7f, we explored SAR of the LHS N-methylene
(8a), middle phenyl ring (8b), linker (8c-8e) and RHS moiety (8f-8g) (Table 3). It was
interesting that replacing the N-methylene (W group) on tetrahydroquinoline with a carbonyl
(8a) resulted in a switch of function from agonist to inverse agonist. We explored the binding
mode difference between 7f and 8a in the section 2.4. Fluorine substituent on the middle
phenyl ring (8b) enhanced potency by 3-fold than 7f with partly reduced maximum response.
Replacing the amide linker with urea (8c), reverse amide (8d) or hydroxymethyl-tethered
reverse amide (8e) reduced efficacy by 23-32% in varying degrees. Replacing the RHS
phenyl ring with pyridinyl increased potency to low nanomolar level (8f-8g) and was
expected to reduce CLogP. Changing 7-substituent (R group) of the reverse amide 8g from
isobutyl to isopropoxy, cyclobutoxy, and oxetanoxy (8h-8j) produced little change in potency
despite a 30-43% decrease in RORγt agonistic efficacy. 7-Isobutyl-substituted compound 8g
comprising reverse amide linker and RHS pyridinyl group stood out with high RORγt
agonistic potency (EC50 = 8.9 ± 0.4 nM) and reached the highest maximum activation of
104.5% among the RHS pyridinyl series.

Table 1
SAR exploration of the LHS core structure.
RORγ dual FRETa
Compd.
LHS core
% act. @3 µMb
EC50 (nM)c
% max. act.d
e
e
1
2
15
-
-
5
-
-
-
-
3
4
10
27
24
30
-
-
5
-
-
7
6
5
8
6
21.5 ± 15.3
N/Af
39.3
N/Af
N
e
6a
-
6b
-
16.7 ± 0.3
60.8
6c
-
-
N/A
N/A
33.0
6d
34.3 ± 32.6
a YW-1 is a positive reference, EC50 = 2.6 ± 1.9 nM, % max. act. = 111.2%.
b Percent activation at 3 µM.
c EC50 value is expressed as Mean ± SD, n = 2.
d Percent maximum activation.
e
“-” means not determined.
f N/A means not applicable.

Table 2
SAR exploration of the 7-substituents on the
tetrahydroquinoline core.
RORγ dual FRETa
Compd.
R
EC50 (nM)b
% max. act.c
6b
7a
7b
Me
F
16.7 ± 0.3
60.8
11.5 ± 3.3
22.8 ± 9.8
30.9
43.4
Cl
7c
7d
7e
16.7 ± 1.7
7.8 ± 4.2
68.0
69.3
87.6
22.1 ± 12.3
7f
7g
7h
7i
46.4 ± 10.6
18.9 ± 6.9
30.3 ± 0.1
12.8 ± 0.4
5.3 ± 1.6
110.2
44.5
87.2
90.6
67.5
41.7
82.3
63.8
76.1
72.2
7j
7k
7l
99.4 ± 2.1
10.8 ± 0.9
16.4 ± 1.8
15.6 ± 0.8
6.6 ± 0.4
7m
7n
7o
a YW-1 is a positive reference, EC50 = 2.6 ± 1.9 nM, % max. act. = 111.2%.
b EC50 value is expressed as Mean ± SD, n = 2.
c Percent maximum activation.

Introduction of an oxygen atom on the tetrahydroquinoline core produced a new series of
benzomorpholine compounds (9a-9k) (Table 4). According to the SAR of LHS substituents,
isobutyl and isopropoxy were selected as the representative R groups. Considering the better
performance in maximum response of 7f (110.2%) vs. 8f (85.4%), and of 8g (104.5%) vs. 8d
(81.1%), we here designed benzomorpholine compounds 9a-9c with the combination of
amide linker and RHS phenyl group, and compounds 9d-9g with the combination of reverse
amide linker and RHS pyridinyl group. All the seven compounds (9a-9g) showed low
nanomolar EC50, although their efficacy varied depending on the LHS R substituent and the
middle Y substituent. Fluorine or chlorine substituent on the middle phenyl ring (9c, 9d)
maintained high potency in the benzomorpholine series, but reduced maximum response. To
our delight, the isopropoxy-substituted compound 9f showed excellent activity with an EC50
of 4.6 ± 0.9 nM and maximum activation of 102.5%. Compounds 9g, 9h with the replacement
of ethanesulfonyl in 9f, 9b with less lipophilic methanesulfonyl group maintained high
potency and strong efficacy. The EC50 of 9g was 7.5 ± 0.6 nM and it exhibited a maximum
activation of 105.8%.
Trifluoromethyl groups were furthered introduced to the LHS core substituent to evaluate
their effects on potency and efficacy. Compound 9i was as potent as its counterpart 9h with a
20% decrease of efficacy, while compound 9j was less potent than its tetrahydroquinoline
analog 7e. Interestingly, we observed the transition of another pair of compounds (9j vs. 9k)
from agonist to inverse agonist in dual FRET assay due to the replacement of
heptafluoroisopropyl by hexafluoroisopropanol.

Table 3
SAR exploration of LHS, linker and phenyl of RHS.
RORγ dual FRETb
% max.
Compd.
R
W
Y
linker
Z
CLogPa
EC50 (nM)c
46.4 ± 10.6
31.5 ± 13.1e
13.0 ± 6.8
25.9 ± 2.3
13.0 ± 1.8
20.9 ± 2.6
9.7 ± 0.3
act.d
7f
8a
8b
8c
8d
8e
8f
CH2
H
H
F
CH
CH
CH
CH
CH
CH
N
110.2
6.772
5.731
6.977
6.652
6.744
6.233
6.05
-80.8
81.3
78.4
81.1
87.3
85.4
104.5
70.2
66.5
55.9
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
H
H
H
H
H
H
H
H
8g
8h
8i
N
8.9 ± 0.4
5.809
4.868
5.088
3.858
N
8.9 ± 1.7
N
12.2 ± 2.8
7.7 ± 1.0
8j
N
a CLogP value is calculated by Discovery Studio 3.5.
b YW-1 is a positive reference, EC50 = 2.6 ± 1.9 nM, % max. act. = 111.2%.
c EC50 value is expressed as Mean ± SD, n = 2.
d Percent maximum activation.
e IC50.

Table 4
SAR exploration of the benzomorpholine series.
RORγ dual FRETb
Compd.
R
Y
linker
Z
n
CLogPa
EC50 (nM)c
% max. act.d
9a
9b
9c
9d
9e
9f
H
H
F
CH
CH
CH
N
1
1
1
1
1
1
0
0
0
0
0
9.6 ± 1.0
7.3 ± 0.8
7.8 ± 1.4
5.1±1.3
89.7
6.043
5.103
5.308
4.804
5.08
73.8
65.6
71.5
74.9
102.5
105.8
97.5
77.4
75.0
-78.1
Cl
H
H
H
H
H
H
H
N
7.1 ± 1.6
4.6 ± 0.9
7.5 ± 0.6
4.4 ± 0.4
4.4 ± 1.3
46.0 ± 38.7
14.6 ± 0.5c
N
4.139
3.79
9g
9h
9i
N
CH
CH
CH
CH
4.754
5.413
6.279
5.339
CF3
O
9j
9k
a CLogP value is calculated by Discovery Studio 3.5.
b YW-1 is a positive reference, EC50 = 2.6 ± 1.9 nM, % max. act. = 111.2%.
c EC50 value is expressed as Mean ± SD, n = 2.
d Percent maximum activation.
e IC50.
2.4 Binding mode study
Binding modes of representative RORγt agonists, namely tetrahydroquinoline 8g and
benzomorpholine 9g, with RORγt-LBD were shown in Fig.4. The binding poses of 8g and 9g
within RORγt LBD are similar to that of 6. In addition to the above-mentioned conservative
hydrogen bonds and π-π stacking interactions, isobutyl of 8g and isopropoxy of 9g form

alkyl-π interactions with Trp317, which plays a critical role in the activation of RORγt by
stabilizing the HYF π-π cluster interactions [18].
During the study of SAR, two pairs of functional switch compounds 8a vs. 7f, 9k vs. 9j draw
our attention. According to previous reports on RORγt inverse agonists which contained
amide or hexafluoroisopropanol moiety facing AF2 region [25,26], we hypothesized that the
two groups of 8a and 9k interacted with the key residues of AF2 in a similar way. Therefore,
docking studies of 8a, 9k and 9j in RORγt LBD were carried out to understand their modes of
action. The binding pose of 8a (Fig.5A) shows a U-shaped conformation and the carbonyl of
LHS forms a hydrogen bond with His479, thereby breaking the hydrogen bond between
His479 and Tyr502 and weakening the stabilization of AF2. Similarly, the other inverse
agonist 9k also forms a hydrogen bond with His479 via the hydroxyl of
hexafluoroisopropanol (Fig.5C) and then prevents from the hydrogen bond interaction
between His479 and Tyr502. The counterpart agonist 9j, on the other hand, was unable to
form the hydrogen bond interaction because of no hydrogen bond donor or acceptor on the
heptafluoroisopropyl group [27] (Fig.5B).
A
B
Fig. 4. The binding modes of 8g (A, purple stick) and 9g (B, brown stick) in RORγt LBD
(PDB:4NIE) revealed by docking study. Red dotted line represents hydrogen bond. Orange dotted
line represents alky-π interaction.
8a, RORγt inverse agonist (green stick)
A

F
OH
F3C CF3
F3C
CF3
H
H
N
N
O
S
O
O
O
N
N
S
O
O
O
O
9j, RORγt agonist (orange stick)
9k, RORγt inverse agonist (pink stick)
B
C
Fig. 5. A) The binding mode of the agonist 8a (green stick) in RORγt LBD (PDB:4ZJR) revealed
by docking study and structure of 8a; The key residues in 4ZJR are represented in yellow as line;
B) The binding mode of the agonist 9j (orange stick) in RORγt LBD (PDB:4NIE) revealed by
docking study and structure of 9j; C) The binding mode of the inverse agonist 9k (pink stick) in
RORγt LBD (PDB:6BN6) revealed by docking study and structure of 9k. Red dotted line
represents hydrogen bond.
2.5. Cell-based activity and sub-type selectivity
We then evaluated the representative tetrahydroquinoline compounds 7f, 8a, 8g and
benzomorpholine compounds 9f, 9g in cell-based Gal4 luciferase reporter gene assay (Table
5). Compound 7f was evaluated towards other members of the ROR family for sub-type
selectivity over RORγ (see Table S1). 7f did not bind to RORα nor RORβ, showing excellent
RORγ sub-type selectivity. In RORγ Gal4 reporter gene assay, all the four agonists 7f, 8g, 9f,
9g performed good agonistic activity at cellular level. Particularly, tetrahydroquinoline
compound 8g showed good activity with an EC50 of 241.9 ± 9.1 nM and reached the highest
maximum effect of 73.8%. Meanwhile, benzomorpholine compound 9g with lower CLogP
showed the highest cellular potency with an EC50 of 107.0 ± 1.6 nM and a moderate
maximum effect of 54.4%. Then a mouse Th17 cell differentiation assay was performed to
evaluate the functional activity of 8g and 9g (Fig.6) in promoting IL-17 production. Both
compounds promoted the production of IL-17 well, and 8g reached a 104.5% agonistic
activity at 300 nM (Table 6). Besides, the inverse agonist 8a had good inhibitory activity in
the Gal4 cell-based assay with an IC50 of 151.0 ± 40.4 nM and maximum inhibition of
101.1%.

Table 5
Gal4 cell-based activity of selected compounds 7f, 8a, 8g, 9f, 9g.
RORγ-Gal4a
Compd.
CLogP
EC50 (nM)b
Emax. (%)
7f
8a
8g
9f
6.47
4.94
5.72
4.00
3.47
154.0 ± 27.2
151.0 ± 40.4c
241.9 ± 9.1
135.4 ± 33.3
107.0 ± 1.6
68.9
-101.1
73.8
61.2
9g
54.4
a LYC-55716 is a positive reference, EC50 = 153.0 nM, Emax. = 106.0%.
b EC50 value is expressed as Mean ± SD, n = 2.
c IC50.
Vehicle (DMSO)
8g (300 nM)
9g (300 nM)
CD4
A
30
20
10
0
****
***
Vehicle
8g
9g
B
Fig.6 Intracellular staining of IL-17A in Th17 cells. RORγt agonists 8g and 9g enhanced
Th17 differentiation. A) Representative flow graph; B) Histogram of the CD4+ IL-17A+ cells.
****, p＜0.0001, 8g Vs. Vehicle; ***, p＜0.001, 9g Vs. Vehicle. Data represent mean ± SD
of biological triplicates.

Table 6
Results in mouse Th17 cell differentiation assaya
Compd.
8g
% act. @30 nM b
% act. @300 nM b
104.5 ± 0.8
56.3 ± 5.5
45.2 ± 4.8
59.4 ± 8.5
9g
a LYC-55716 is a positive reference, % act. @100 nM =119.0 ± 9.1. DMSO is 0%.
b The value is expressed as Mean ± SD, n = 3.
3. Conclusion
In conclusion, we have discovered a series of tetrahydroquinoline and benzomorpholine
derivatives as novel potent RORγt agonists from the hit compound 1 by rational drug design
strategy. At the beginning of the exploration of LHS core, tetrahydroquinoline compound 6
was discovered. Step-by-step SAR explorations on the LHS, linker and the RHS arylsulfone
moiety of 6 led to the identification of potent RORγt agonists. The representative
tetrahydroquinoline compound 8g and benzomorpholine compound 9g were found to have
excellent RORγt activity in dual FRET assay as well as good cellular activity in Gal4 reporter
gene assay and Th17 cell differentiation assay. Further studies on mechanism of action of the
tetrahydroquinoline and benzomorpholine RORγt agonists and their potential applications for
cancer immunotherapy are ongoing and will be reported in due course.
4. Experimental
4.1 Materials and methods
All commercially available reagents were used without further purification unless
otherwise indicated. Melting point was recorded by WRS-1B digital instrument. The reactions
were monitored by thin-layer chromatography analysis. Silica gel (200-300 mesh) was used
for column chromatography. The purity of all test compounds was assessed by HPLC and
area % purity was measured at 254 nm. The HPLC analyses were performed using an Agilent
1260 instrument. Elution was done with a gradient of 5-90% solvent B (methanol) in solvent
A (water with 0.1% TFA) through an Agilent EC-C18(2) (4.6 mm × 50 mm, 2.7 µm) column
13
at 1.0 mL/min. 1H NMR spectra and C NMR spectra were recorded at 400 MHz. Chemical
1
shifts in H NMR spectra were reported in parts per million (ppm) using tetramethylsilane
(TMS) as an internal standard. Data are reported as follows: chemical shift (δ ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet, br= broad),
coupling constant in hertz (Hz), and integration. Mass spectroscopy was carried out on
electrospray ionization (ESI) instruments.

4.2 Chemical synthesis
4.2.1 General procedure A for the synthesis of compounds 1, 2, 3.
Step 1: To a solution of prepared lactam (1 eq) in THF, borane-dimethyl sulfide complex
2.0 mol/L in THF (3 eq) was slowly added at 0°C. The reaction mixture was stirred under N2
at 45°C for 3 h. The reaction mixture was cooled to room temperature and poured slowly into
methanol. After stirring at reflux for 30 minutes, solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica gel to afford the secondary
amine intermediate 10.
Step 2: To a stirred solution of 4-nitrobenzyl bromide (1 eq) in DMF was added DIPEA
(3 eq) and secondary amine (1.2 eq) (commercially available or intermediate 10). The mixture
was stirred at room temperature overnight. The reaction mixture was poured into saturated
ammonium chloride solution, and extracted by ethyl acetate three times. The combined
organic layers were washed with a saturated sodium chloride solution, dried over anhydrous
sodium sulfate, and concentrated under vacuo. The residue was purified by column
chromatography on silica gel to afford the p-nitrobenzylamine intermediate 12.
Step 3: To a stirred solution of p-nitrobenzylamine (1 eq), tin(II)dichloridedihydrate (2
eq) in ethanol, 3 drops concentrated hydrochloric acid was added and the mixture was
refluxed for 6 h. After the reaction completed, ethanol was removed under reduced pressure.
Then pH of the mixture was adjusted to 8 with saturated sodium bicarbonate solution, and the
mixture was extracted with ethyl acetate several times. Then the organic layers were
combined and the solvent was removed under reduced pressure. The residue was purified by
column chromatography on silica gel to afford the aniline intermediate 15.
Step 4: To a stirred solution of aniline 15 (1 eq) in DCM was added HATU (1.2 eq),
DIPEA (3 eq) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.2 eq). The mixture was stirred at
room temperature. After the reaction completed, solvent was removed under reduced pressure.
The residue was purified by column chromatography on silica gel to afford the target
compounds (1, 2, 3).
4.2.1.1 N-(4-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-2-(4-(ethylsulfonyl)
phenyl)acetamide (1). Yield: 45%, sticky white oil, purity: 93%. MS(ESI) m/z: 449.3 [M +
H]+, 447.1 [M - H]-. HRMS (ESI+) m/z calcd for C26H28N2O3S [M + H]+: 449.1893; found:
1
449.1894. H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.52 (d, J =
8.1 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.13 – 7.03 (m, 3H), 6.94 (d, J
= 7.1 Hz, 1H), 3.76 (s, 2H), 3.63 (s, 2H), 3.60 (s, 2H), 3.08 (q, J = 7.4 Hz, 1H), 2.87 (t, J =
5.8 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 1.25 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
167.79 (-C=O), 141.09 (-C, Ar), 137.48 (-C, Ar), 137.02 (-C, Ar), 133.77 (-C, Ar), 133.63 (-C,
Ar), 130.29 (-CH, Ar), 129.99 (-CH, Ar), 128.70 (-CH, Ar), 126.63 (-CH, Ar), 126.48 (-CH,
Ar), 125.87 (-CH, Ar), 119.96 (-CH, Ar), 61.64 (-CH2), 55.45 (-CH2), 50.65 (-CH2), 50.33
(-CH2), 44.18 (-CH2), 38.63 (-CH2), 7.41 (-CH3).

4.2.1.2 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(isoindolin-2-ylmethyl)phenyl)acetamide (2). Yield:
1
18%, sticky white oil, purity: 93%. MS(ESI) m/z: 435.2 [M + H]+, 433.2 [M – H]-. H NMR
(400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.57
(d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.22 – 7.19 (m, 2H), 7.19 – 7.14 (m, 2H), 3.80 (s,
8H), 3.30 – 3.25 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.68
(-C=O), 141.02 (-C, Ar), 139.50 (-C, Ar), 137.49 (-C, Ar), 136.77 (-C, Ar), 134.78 (-C, Ar),
130.27 (-CH, Ar), 129.56 (-CH, Ar), 128.71 (-CH, Ar), 126.94 (-CH, Ar), 122.39 (-CH, Ar),
120.01 (-CH, Ar), 59.61 (-CH2), 58.81 (-CH2), 50.65 (-CH2), 44.20 (-CH2), 7.41 (-CH3).
4.2.1.3 2-(4-(Ethylsulfonyl)phenyl)-N-(4-((1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)meth
yl)phenyl)acetamide (3). Yield: 34%, sticky white oil, purity: 93%. MS(ESI) m/z: 463.2 [M +
H]+, 461.2 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2
Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.21 – 7.15 (m, 2H), 7.14 – 7.09
(m, 1H), 6.94 (d, J = 7.4 Hz, 1H), 3.96 (s, 2H), 3.85 (s, 2H), 3.56 (s, 2H), 3.15 (t, J = 5.2 Hz,
13
2H), 3.13 – 3.08 (m, 2H), 2.96 – 2.91 (m, 2H), 1.80 (s, 2H), 1.29 (t, J = 7.4 Hz, 3H). C
NMR (101 MHz, CDCl3) δ 167.78 (-C=O), 142.82 (-C, Ar), 141.08 (-C, Ar), 137.50 (-C, Ar),
130.43 (-C, Ar), 130.32 (-CH, Ar), 130.00 (-CH, Ar), 129.05 (-CH, Ar), 128.74 (-CH, Ar),
126.24 (-C, Ar), 119.86 (-CH, Ar), 58.75 (-CH2), 50.65 (-CH2), 44.24 (-CH2), 35.61 (-CH2),
24.39 (-CH2), 7.43 (-CH3).
4.2.2 General procedure B for the synthesis of amide compounds (5, 6, 6a-6d, 7a-7i, 7k-7o, 8b,
9a-9c, 9h-9k).
Step 1：To a stirred solution of 4-nitroarylacetic acid (1.2 eq) in DCM was added HATU
(1.2 eq), DIPEA (3 eq) and secondary amine (1 eq) (commercially available or intermediate
10). The mixture was stirred at room temperature. After the reaction completed, solvent was
removed under reduced pressure, and the residue was purified by column chromatography on
silica gel to afford the p-nitroarylacetamide intermediates 13.
Step 2: Reduction of p-nitroarylacetamide 13 to p-nitroarylethylamine intermediates 14
with borane dimethyl sulfide complex followed step 1 of general procedure A.
Step 3: Reduction of p-nitroarylethylamine 14 to aniline intermediates 15 with
tin(II)dichloridedihydrate followed step 3 of general procedure A.
Step 4: To a stirred solution of aniline 15 (1 eq) in DCM was added HATU (1.2 eq),
DIPEA (3 eq) and p-alkylsulfone aryl acetic acid (1.2 eq). The mixture was stirred at room
temperature. After the reaction completed, solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica gel to afford the target compound (5,
6, 6a-6d, 7a-7i, 7k-7o, 8b, 9a-9c, 9h-9k).
4.2.2.1 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(indolin-1-yl)ethyl)phenyl)acetamide (5) Yield:
71%, white solid, purity: 99%, mp 100.6-101.1oC. MS(ESI) m/z: 449.4 [M + H]+, 447.4 [M -
H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1
Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 7.6Hz, 1H), 6.96 (t, J
= 7.6 Hz, 1H), 6.52 (t, J = 7.7 Hz, 2H), 3.78 (s, 2H), 3.33 (t, J = 7.7 Hz, 2H), 3.28 (t, 2H),

3.24 (q, 7.3 Hz, 2H), 2.85 (s, 2H), 2.76 (s, 2H), 1.09 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 167.92 (-C=O), 152.06 (-C, Ar), 142.21 (-C, Ar), 137.07 (-C, Ar), 136.75 (-C,
Ar), 134.84 (-C, Ar), 130.14 (-C, Ar), 129.50 (-CH, Ar), 128.92 (-CH, Ar), 127.79 (-CH, Ar),
127.07 (-CH, Ar), 124.11 (-C, Ar), 119.18 (-CH, Ar), 116.93 (-CH, Ar), 106.72 (-CH, Ar),
52.30 (-CH2), 50.10 (-CH2), 49.19 (-CH2), 42.89 (-CH2), 38.22 (-CH2), 31.93 (-CH2), 27.93
(-CH2), 7.13 (-CH3).
4.2.2.2 N-(4-(2-(3,4-Dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-
(ethylsulfonyl)phenyl)acetamide (6) Yield: 68%, white solid, purity: 94%, mp 99.8-102.0oC.
MS(ESI) m/z: 463.2 [M + H]+, 461.3 [M - H]-. HRMS (ESI+) m/z calcd for C27H30N2O3S [M +
H]+: 463.2050; found:463.2056. 1H-NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.84 (d, J =
8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.97
(d, J = 7.8 Hz, 1H), 6.85 (d, J = 6.3 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 12.5, 6.3
Hz, 1H), 3.78 (s, 2H), 3.40 (q, 2H), 3.27 (dd, J = 14.6, 7.3 Hz, 2H), 3.17 (s, 2H), 2.73 (d, J =
7.3 Hz, 2H), 2.64 (d, J = 5.8 Hz, 2H), 1.78 (s, 2H), 1.10 (t, 3H). 13C NMR (101 MHz, CDCl3)
δ 167.57 (-C=O), 144.69 (-C, Ar), 141.02 (-C, Ar), 137.48 (-C, Ar), 136.52 (-C, Ar), 135.67
(-C, Ar), 130.27 (-C, Ar), 129.38 (-CH, Ar), 129.28 (-CH, Ar), 128.71 (-CH, Ar), 127.16 (-CH,
Ar), 122.48 (-C, Ar), 120.18 (-CH, Ar), 115.74 (-CH, Ar), 110.47 (-CH, Ar), 53.44 (-CH2),
50.66 (-CH2), 49.68 (-CH2), 44.18 (-CH2), 31.94 (-CH2), 28.10 (-CH2), 22.08 (-CH2), 7.41
(-CH3).
4.2.2.3 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(8-methyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)p
henyl)acetamide (6a). Yield: 58%, white solid, purity: 94%, mp 107.7-108.3oC. MS(ESI) m/z:
477.2 [M + H]+, 475.2 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.84 (d, J =
8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.92
(d, J = 7.2 Hz, 1H), 6.81 (d, J = 6.8 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 3.78 (s, 2H), 3.27 (q, J
= 7.4 Hz, 2H), 3.10 – 3.05 (m, 2H), 2.86 (s, 4H), 2.70 (t, J = 6.6 Hz, 2H), 2.17 (s, 3H), 1.75
(dd, J = 11.0, 5.9 Hz, 2H), 1.09 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 141.03 (-C,
Ar), 137.50 (-C, Ar), 130.33 (-CH, Ar), 129.24 (-CH, Ar), 128.73 (-C, Ar), 120.26 (-CH, Ar),
50.64 (-CH2), 44.21 (-CH2), 19.15 (-CH3), 7.43 (-CH3). 13C NMR (101 MHz, DMSO-d6) δ
167.84 (-C=O), 147.65 (-C, Ar), 142.11 (-C, Ar), 136.99 (-C, Ar), 136.67 (-C, Ar), 134.54 (-C,
Ar), 130.13 (-C, Ar), 128.88 (-CH, Ar), 128.55 (-CH, Ar), 128.25 (-CH, Ar), 127.71 (-C, Ar),
126.90 (-CH, Ar), 120.77 (-CH, Ar), 119.11 (-CH, Ar), 56.07 (-CH2), 49.11 (-CH2), 46.95
(-CH2), 42.80 (-CH2), 34.23 (-CH2), 27.27 (-CH2), 18.71 (-CH2), 17.07 (-CH3), 7.04 (-CH3).
4.2.2.4 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-methyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)p
henyl) acetamide (6b). Yield: 89%, white solid, purity: 98%, mp 118.8-120.2oC. MS(ESI) m/z:
477.3 [M + H]+, 475.2 [M - H]-. HRMS (ESI+) m/z calcd for C28H32N2O3S [M + H]+:
1
477.2206; found:477.2210. H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J = 8.2
Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.73 (d, J
= 7.4 Hz, 1H), 6.41 (s, 1H), 6.28 (d, J = 7.4 Hz, 1H), 3.78 (s, 2H), 3.39 (t, J = 7.5 Hz, 2H),
3.27 (q, J = 7.4 Hz, 2H), 3.18 – 3.10 (m, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H),
13
2.19 (s, 3H), 1.81 – 1.70 (m, 2H), 1.10 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ
167.61 (-C=O), 141.11 (-C, Ar), 137.43 (-C, Ar), 136.67 (-C, Ar), 135.76 (-C, Ar), 130.27

(-CH, Ar), 129.35 (-CH, Ar), 129.17 (-C, Ar), 128.67 (-CH, Ar), 120.17 (-CH, Ar), 50.66
(-CH2), 49.70 (-CH2), 44.17 (-CH2), 32.01 (-CH2), 27.65 (-CH2), 21.72 (-CH3), 7.41 (-CH3).
4.2.2.5 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(6-methyl-3,4-dihydroquinolin-1(2H)-yl)
ethyl)phenyl)acetamide (6c). Yield: 11%, sticky white oil, purity: 95%. MS(ESI) m/z: 477.3
1
[M + H]+, 475.3 [M - H]-. H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.84 (d, J = 8.3 Hz,
2H), 7.60 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.79 (d, J =
8.2 Hz, 1H), 6.69 (s, 1H), 6.53 (d, J = 8.3 Hz, 1H), 3.78 (s, 2H), 3.44 – 3.34 (m, 2H), 3.27 (q,
J = 7.4 Hz, 2H), 3.16 – 3.10 (m, 2H), 2.75 – 2.68 (m, 2H), 2.61 (t, J = 6.3 Hz, 2H), 2.12 (s,
1
3
2H), 1.82 – 1.74 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 167.67
(-C=O), 141.22 (-C, Ar), 137.43 (-C, Ar), 136.53 (-C, Ar), 135.82 (-C, Ar), 130.57 (-CH, Ar),
130.34 (-CH, Ar), 130.06 (-CH, Ar), 129.32 (-C, Ar), 128.77 (-CH, Ar), 128.67 (-CH, Ar),
127.54 (-CH, Ar), 120.14 (-CH, Ar), 53.63 (-CH2), 50.65 (-CH2), 49.64 (-CH2), 44.18 (-CH2),
31.84 (-CH2), 28.04 (-CH2), 22.28 (-CH2), 20.19 (-CH3), 7.41 (-CH3).
4.2.2.6 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(5-methyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)p
henyl) acetamide (6d). Yield: 28%, sticky white oil, purity: 95%. MS(ESI) m/z: 477.3 [M +
H]+, 475.3 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H),
7.61 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.88 (t, J = 7.8 Hz,
1H), 6.53 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.3 Hz, 1H), 3.78 (s, 2H), 3.43 – 3.36 (m, 2H), 3.27
(q, J = 7.4 Hz, 2H), 3.18 – 3.07 (m, 2H), 2.78 – 2.68 (m, 2H), 2.55 – 2.51 (m, 2H), 2.09 (s,
3H), 1.87 – 1.77 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 167.84
(-C=O), 144.72 (-C, Ar), 142.11 (-C, Ar), 136.98 (-C, Ar), 136.68 (-C, Ar), 135.71 (-C, Ar),
134.71 (-C, Ar), 130.08 (-CH, Ar), 128.91 (-CH, Ar), 127.71 (-CH, Ar), 126.06 (-C, Ar),
120.24 (-CH, Ar), 119.13 (-CH, Ar), 117.30 (-CH, Ar), 108.69 (-CH, Ar), 53.10 (-CH2), 49.12
(-CH2), 48.28 (-CH2), 42.81 (-CH2), 30.84 (-CH2), 24.17 (-CH2), 21.64 (-CH2), 19.52 (-CH3),
7.05 (-CH3).
4.2.2.7 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl)ph
enyl)acetamide (7a). Yield: 69%, white solid, purity: 99%, mp 157.8-159.1oC. MS(ESI) m/z:
481.1 [M + H]+, 479.3 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.64 (d, J =
8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.63
(t, J = 7.7 Hz, 1H), 6.17 (d, J = 13.0 Hz, 1H), 6.01 (t, J = 8.1 Hz, 1H), 3.58 (s, 2H), 3.20 (d, J
= 7.0 Hz, 2H), 3.07 (dd, J = 14.6, 7.3 Hz, 2H), 2.93 (s, 2H), 2.53 (d, J = 7.3 Hz, 2H), 2.38 (s,
2H), 1.52 (d, J = 13.4 Hz, 2H), 1.06 (d, J = 26.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 167.93 (-C=O), 142.19 (-C, Ar), 137.14 (-C, Ar), 136.76 (-C, Ar),
134.49 (-C, Ar), 130.17 (-C, Ar), 129.66 (-C, Ar), 129.08 (-CH, Ar), 127.79 (-C, Ar), 119.18
(-CH, Ar), 117.56 (-CH, Ar), 100.72 (-CH, Ar), 100.51 (-CH, Ar), 96.88 (-CH, Ar), 96.62
(-CH, Ar), 52.40 (-CH2), 49.20 (-CH2), 48.44 (-CH2), 42.88 (-CH2), 30.90 (-CH2), 26.85
(-CH2), 21.39 (-CH2), 7.13 (-CH3).
4.2.2.8 N-(4-(2-(7-Chloro-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(ethylsulfonyl)p
henyl) acetamide (7b). Yield: 36%, sticky white oil, purity: 99%. MS(ESI) m/z: 497.1 [M +
H]+, 495.3 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H),

7.60 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.2 Hz,
1H), 6.69 (s, 1H), 6.53 (d, J = 8.3 Hz, 1H), 3.78 (s, 2H), 3.44 – 3.34 (m, 2H), 3.27 (q, J = 7.4
Hz, 2H), 3.16 – 3.10 (m, 2H), 2.75 – 2.68 (m, 2H), 2.59 (t, J = 6.3 Hz, 2H), 1.82 – 1.74 (m,
2H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 167.93 (-C=O), 164.57 (-C,
Ar), 145.74 (-C, Ar), 142.18 (-C, Ar), 136.76 (-C, Ar), 134.47 (-C, Ar), 131.39 (-C, Ar),
130.16 (-CH, Ar), 129.98 (-CH, Ar), 129.04 (-CH, Ar), 127.79 (-CH, Ar), 120.55 (-C, Ar),
119.20 (-CH, Ar), 114.20 (-CH, Ar), 109.30 (-CH, Ar), 52.25 (-CH2), 49.20 (-CH2), 48.57
(-CH2), 42.88 (-CH2), 30.90 (-CH2), 26.99 (-CH2), 21.17 (-CH2), 7.13 (-CH3).
4.2.2.9 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-methoxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)
phenyl) acetamide (7c). Yield: 21%, white solid, purity: 99%, mp 139.1-141.4oC. MS(ESI)
m/z: 493.0 [M + H]+, 491.2 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d,
J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H),
6.75 (d, J = 8.1 Hz, 1H), 6.11 (d, J = 2.1 Hz, 1H), 6.06 (dd, J = 8.1, 2.2 Hz, 1H), 3.78 (s, 2H),
3.66 (s, 3H), 3.39 (t, J = 7.4 Hz, 2H), 3.27 (q, J = 7.3 Hz, 2H), 3.18 – 3.10 (m, 2H), 2.74 (t, J
= 7.4 Hz, 2H), 2.56 (t, J = 6.2 Hz, 2H), 1.76 (dd, J = 11.2, 5.7 Hz, 2H), 1.10 (t, J = 7.3 Hz,
13
3H). C NMR (101 MHz, DMSO-d6) δ 167.92 (-C=O), 158.81 (-C, Ar), 145.36 (-C, Ar),
142.19 (-C, Ar), 137.09 (-C, Ar), 136.76 (-C, Ar), 134.72 (-C, Ar), 130.16 (-CH, Ar), 129.25
(-CH, Ar), 129.00 (-C, Ar), 127.79 (-CH, Ar), 119.24 (-CH, Ar), 114.40 (-CH, Ar), 100.06
(-CH, Ar), 96.62 (-CH, Ar), 54.64 (-CH3), 52.62 (-CH2), 49.20 (-CH2), 48.69 (-CH2), 42.88
(-CH2), 30.99 (-CH2), 26.84 (-CH2), 21.87 (-CH2), 7.13 (-CH3).
4.2.2.10 N-(4-(2-(7-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(ethylsulfo
nyl) phenyl)acetamide (7d). Yield: 10%, sticky white oil, purity: 98%. MS(ESI) m/z: 502.8
[M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.60 (d, J
= 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 7.6 Hz, 1H),
6.27 (s, 1H), 6.16 (d, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.40 (t, J = 7.4 Hz, 2H), 3.27 (q, J = 7.4
Hz, 2H), 3.20 – 3.11 (m, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H), 1.83 – 1.71 (m,
3H), 1.10 (t, J = 7.4 Hz, 3H), 0.88 – 0.77 (m, 2H), 0.58 – 0.49 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 167.50 (-C=O), 140.92 (-C, Ar), 137.59 (-C, Ar), 130.30 (-C, Ar), 129.37 (-C, Ar),
129.29 (-CH, Ar), 128.78 (-CH, Ar), 120.19 (-CH, Ar), 50.65 (-CH2), 49.63 (-CH2), 44.27
(-CH2), 31.96 (-CH2), 29.71 (-CH2), 29.33 (-CH2), 19.19 (-CH), 15.56 (-CH2), 8.82 (-CH2),
7.43 (-CH3).
4.2.2.11 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-isopropyl-3,4-dihydroquinolin-1(2H)-yl)ethyl
)phenyl) acetamide (7e). Yield: 34%, colorless semi-solid, purity: 90%. MS(ESI) m/z: 504.9
1
[M + 1]+, 502.9 [M - H]-. H NMR (400 MHz, CDCl3) δ 7.89 (s, 2H), 7.56 (s, 2H), 7.43 (s,
2H), 7.18 (s, 2H), 6.90 (s, 1H), 6.49 (s, 2H), 3.81 (s, 2H), 3.45 (s, 2H), 3.19 (s, 2H), 3.12 (s,
2H), 2.83 (s, 2H), 2.71 (s, 2H), 2.43 (s, 1H), 1.89 (s, 2H), 1.29 (d, J = 3.1 Hz, 3H), 1.24 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 167.46 (-C=O), 140.87 (-C, Ar), 137.62 (-C, Ar), 130.30
(-C, Ar), 129.39 (-C, Ar), 129.29 (-CH, Ar), 129.18 (-CH, Ar), 128.82 (-CH, Ar), 120.19 (-CH,
Ar), 50.66 (-CH2), 49.69 (-CH2), 44.29 (-CH2), 34.29(-CH), 31.94 (-CH2), 29.72 (-CH2),
24.18 (-CH3), 22.71 (-CH2), 14.14 (-CH2), 7.44 (-CH3).

4.2.2.12 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-isobutyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)
phenyl) acetamide (7f). Yield: 35%, white solid, purity: 95%, mp 122.8-124.4oC. MS(ESI)
m/z: 519.1 [M + H]+, 517.2 [M - H]-. HRMS (ESI+) m/z calcd for C31H38N2O3S [M + H]+:
519.2676; found:519.2683. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.9 Hz, 2H), 7.53 (d, J
= 7.7 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.87 (d, J = 6.8 Hz, 1H),
6.43 (s, 2H), 3.78 (s, 2H), 3.43 (d, J = 7.2 Hz, 2H), 3.18 (s, 2H), 3.11 (d, J = 7.3 Hz, 2H), 2.82
(d, J = 8.0 Hz, 2H), 2.71 (s, 2H), 2.38 (d, J = 6.7 Hz, 2H), 1.88 (s, 2H), 1.83 (d, J = 6.5 Hz,
1H), 1.28 (t, J = 7.3 Hz, 3H), 0.92 (d, J = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.49
(-C=O), 140.91 (-C, Ar), 137.59 (-C, Ar), 130.30 (-C, Ar), 129.37 (-CH, Ar), 129.08 (-CH, Ar),
128.78 (-CH, Ar), 120.17 (-CH, Ar), 50.65 (-CH2), 49.62 (-CH2), 45.73 (-CH2), 44.27 (-CH2),
31.82 (-CH2), 30.24 (-CH), 29.70 (-CH2), 22.56 (-CH3), 7.43 (-CH3).
4.2.2.13 N-(4-(2-(7-(tert-Butyl)-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(ethylsulfon
yl)phenyl) acetamide (7g). Yield: 98%, sticky white oil, purity: 95%. MS(ESI) m/z: 519.1 [M
+ H]+, 517.2 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.9
Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.89 (s, 1H), 6.67 (s, 2H), 3.77 (s,
2H), 3.42 (s, 2H), 3.20 (s, 2H), 3.08 (q, J = 7.2 Hz, 2H), 2.83 (s, 2H), 2.70 (s, 2H), 1.89 (s,
13
2H), 1.27 (s, 9H), 1.24 (d, J = 7.7 Hz, 3H). C NMR (101 MHz, CDCl3) δ 141.10 (-C, Ar),
130.32 (-C, Ar), 129.31 (-C, Ar), 128.72 (-CH, Ar), 122.47 (-CH, Ar), 120.44 (-CH, Ar),
120.28 (-CH, Ar), 50.65 (-CH2), 44.22 (-CH2), 34.63 (-C), 31.94 (-CH2), 31.41 (-CH3), 29.70
(-CH2), 26.72 (-CH2), 7.43 (-CH3).
4.2.2.14 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-neopentyl-3,4-dihydroquinolin-1(2H)-yl)ethy
l)phenyl) acetamide (7h). Yield: 73%, colorless semi-solid, purity: 96%. MS(ESI) m/z: 533.9
[M + H]+, 531.9 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 4.0 Hz, 2H), 7.54 (d, J =
4.3 Hz, 2H), 7.43 (d, J = 4.2 Hz, 2H), 7.14 (d, J = 4.4 Hz, 2H), 6.86 (s, 1H), 6.41 (s, 2H), 3.79
(d, J = 3.2 Hz, 2H), 3.43 (s, 2H), 3.19 (s, 2H), 3.11 (dd, J = 7.2, 4.1 Hz, 2H), 2.83 (s, 2H),
13
2.71 (s, 2H), 2.41 (d, J = 3.3 Hz, 2H), 1.89 (s, 2H), 1.29 – 1.27 (m, 3H), 0.92 (s, 9H). C
NMR (101 MHz, CDCl3) δ 156.18 (-C=O), 156.07 (-C, Ar), 149.05 (-C, Ar), 141.38 (-C, Ar),
140.91 (-C, Ar), 137.61 (-CH, Ar), 137.01 (-C, Ar), 130.31 (-CH, Ar), 129.36 (-C, Ar), 128.79
(-CH, Ar), 120.20 (-CH, Ar), 50.65 (-CH2), 49.65 (-CH2), 44.27 (-CH2), 31.94 (-CH2), 31.81
(-CH2), 29.71 (-CH2), 29.59 (-CH2), 29.37 (-CH2), 22.70 (-C), 14.13 (-CH3), 7.42 (-CH3).
4.2.2.15 N-(4-(2-(7-(Cyclopropylmethyl)-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(et
hylsulfonyl) phenyl)acetamide (7i). Yield: 31%, sticky white oil, purity: 99%. MS(ESI) m/z:
516.8 [M + H]+, 514.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.7 Hz, 2H), 7.55
(d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 7.3 Hz, 1H),
6.59 (s, 1H), 6.54 (s, 1H), 3.81 (s, 2H), 3.46 (t, J = 7.5 Hz, 2H), 3.20 (s, 2H), 3.13 (q, J = 7.3
Hz, 2H), 2.86 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.48 (d, J = 6.8 Hz, 2H), 1.90 (s,
2H), 1.30 (d, J = 7.4 Hz, 3H), 1.05 – 0.93 (m, 1H), 0.53 (q, J = 4.4 Hz, 2H), 0.22 (d, J = 4.7
13
Hz, 2H). C NMR (101 MHz, CDCl3) δ 167.48 (-C=O), 140.88 (-C, Ar), 137.62 (-C, Ar),
130.31 (-C, Ar), 129.37 (-CH, Ar), 129.26 (-CH, Ar), 128.80 (-CH, Ar), 120.18 (-CH, Ar),
50.66 (-CH2), 44.28 (-CH2), 40.62 (-CH2), 36.91 (-CH2), 31.92 (-CH2), 29.72 (-CH2), 29.33
(-CH2), 11.99 (-CH), 7.43 (-CH3), 4.74 (-CH2).

4.2.2.16 N-(4-(2-(7-((Dimethylamino)methyl)-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(
4-(ethylsulfonyl)phenyl)acetamide (7k). Yield: 21%, sticky white oil, purity: 92%. MS(ESI)
m/z: 519.9 [M + H]+, 517.9 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H),
7.56 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 7.2 Hz,
1H), 6.40 (s, 2H), 3.81 (s, 2H), 3.48 – 3.41 (m, 2H), 3.19 (s, 2H), 3.12 (q, J = 7.4 Hz, 2H),
13
2.84 (s, 2H), 2.72 (t, J = 6.1 Hz, 2H), 2.41 (s, 2H), 1.31 – 1.29 (m, 3H), 0.93 (s, 6H). C
NMR (101 MHz, CDCl3) δ 167.45 (-C=O), 140.88 (-C, Ar), 138.59 (-C, Ar), 137.64 (-C, Ar),
130.29 (-C, Ar), 129.36 (-CH, Ar), 128.80 (-CH, Ar), 128.54 (-CH, Ar), 120.18 (-CH, Ar),
50.66 (-CH2), 50.59 (-CH2), 49.71 (-CH2), 44.28 (-CH2), 31.94 (-CH2), 31.80 (-CH2), 29.71
(-CH2), 29.63 (-CH3), 14.12 (-CH2), 7.42 (-CH3).
4.2.2.17 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-isopropoxy-3,4-dihydroquinolin-1(2H)-yl)eth
yl)phenyl) acetamide (7l). Yield: 21%, sticky white oil, purity: 96%. MS(ESI) m/z: 520.9 [M
+ H]+, 518.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1
Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.34 (s, 1H), 7.16 (d, J = 8.2 Hz, 2H), 6.83 (d, J = 8.1 Hz,
1H), 6.17 (s, 2H), 4.52 – 4.43 (m, 1H), 3.80 (s, 2H), 3.44 – 3.39 (m, 1H), 3.14 (d, J = 7.4 Hz,
2H), 3.13 – 3.08 (m, 2H), 2.87 – 2.81 (m, 2H), 2.66 (t, J = 6.2 Hz, 2H), 1.89 – 1.81 (m, 2H),
13
1.59 (s, 4H), 1.32 (d, J = 6.1 Hz, 6H), 1.31 – 1.27 (m, 3H). C NMR (101 MHz, CDCl3) δ
167.43 (-C=O), 157.49 (-C, Ar), 140.88 (-C, Ar), 137.62 (-C, Ar), 135.64 (-C, Ar), 130.29
(-CH, Ar), 129.66 (-CH, Ar), 129.54 (-CH, Ar), 129.43 (-C, Ar), 128.79 (-CH, Ar), 128.75
(-CH, Ar), 120.10 (-CH, Ar), 69.81(-CH), 50.66 (-CH2), 49.60 (-CH2), 44.27(-CH3), 32.02
(-CH2), 22.29 (-CH2), 7.43 (-CH3).
4.2.2.18 N-(4-(2-(7-(tert-Butoxy)-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(ethylsulfo
nyl)phenyl) acetamide (7m). Yield: 21%, colorless semi-solid, purity: 99%. MS(ESI) m/z:
1
534.7 [M + H]+, 532.7 [M - H]-. H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J =
8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.74
(d, J = 8.0 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 6.09 (dd, J = 7.9, 2.1 Hz, 1H), 3.78 (s, 2H), 3.40
– 3.34 (m, 2H), 3.27 (q, J = 14.7, 7.3 Hz, 2H), 3.18 – 3.13 (m, 2H), 2.72 (t, J = 7.4 Hz, 2H),
2.59 (t, J = 6.2 Hz, 2H), 1.82 – 1.73 (m, 2H), 1.25 (s, 9H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 167.56 (-C=O), 154.54 (-C, Ar), 141.03 (-C, Ar), 137.52 (-C, Ar),
135.77 (-C, Ar), 130.29 (-C, Ar), 130.26 (-CH, Ar), 129.34 (-CH, Ar), 129.04 (-CH, Ar),
128.72 (-CH, Ar), 128.49 (-CH, Ar), 120.17 (-CH, Ar), 61.33(-C), 50.65 (-CH2), 49.45 (-CH2),
44.20 (-CH2), 41.16 (-CH2), 31.84 (-CH2), 29.70 (-CH2), 29.02 (-CH3), 14.15 (-CH2),
7.42(-CH3).
4.2.2.19 N-(4-(2-(7-Cyclobutoxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)phenyl)-2-(4-(ethylsulfo
nyl)phenyl) acetamide (7n). Yield: 36%, sticky white oil, purity: 100%, mp 121.7-122.5oC.
1
MS(ESI) m/z: 532.9 [M + H]+, 530.8 [M - H]-. H NMR (400 MHz, DMSO-d6) δ 10.19 (s,
1H), 7.84 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.18 (d, J =
8.4 Hz, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 6.53 (d, J = 8.3 Hz, 1H), 3.78 (s, 2H), 3.44
– 3.34 (m, 2H), 3.27 (q, J = 7.4 Hz, 2H), 3.16 – 3.10 (m, 2H), 2.75 – 2.68 (m, 2H), 2.61 (t, J =
6.3 Hz, 2H), 2.12 (s, 2H), 1.82 – 1.74 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,

CDCl3) δ 167.49 (-C=O), 157.18 (-C, Ar), 140.91 (-C, Ar), 137.63 (-C, Ar), 130.31 (-C, Ar),
129.70 (-C, Ar), 129.41 (-CH, Ar), 128.79 (-CH, Ar), 120.14 (-CH, Ar and -C, Ar), 115.66
(-CH, Ar), 93.38 (-CH, Ar), 71.43 (-CH), 50.66 (-CH2), 49.54 (-CH2), 44.27 (-CH2), 31.90
(-CH2), 30.92 (-CH2), 29.71 (-CH2), 13.33 (-CH2), 7.42(-CH3).
4.2.2.20 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(7-(oxetan-3-yloxy)-3,4-dihydroquinolin-1(2H)-
yl)ethyl) phenyl)acetamide (7o). Yield: 36%, white solid, purity: 97%, mp 127.6-129.3oC.
1
MS(ESI) m/z: 534.9 [M + H]+, 532.8 [M - H]-. H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H),
7.81 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz,
2H), 6.80 (d, J = 8.0 Hz, 1H), 6.05 (s, 1H), 5.79 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 11.1, 5.5 Hz,
1H), 4.93 (t, J = 6.6 Hz, 2H), 4.80 – 4.70 (m, 2H), 3.74 (s, 2H), 3.39 (t, J = 7.3 Hz, 2H), 3.16
– 3.11 (m, 2H), 3.11 – 3.06 (m, 2H), 2.82 – 2.79 (m, 2H), 2.63 (t, J = 6.0 Hz, 2H), 1.88 – 1.77
(m, 2H), 1.25 (d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.75 (-C=O), 156.24 (-C,
Ar), 145.74 (-C, Ar), 141.2 (-C, Ar)5, 137.30 (-C, Ar), 136.09 (-C, Ar), 135.99 (-C, Ar),
130.27 (-CH, Ar), 129.66 (-CH, Ar), 129.33 (-CH, Ar), 128.60 (-CH, Ar), 120.23 (-CH, Ar),
116.29 (-CH, Ar), 97.89 (-CH, Ar), 78.29 (-CH2), 70.00 (-CH), 53.51 (-CH2), 50.65 (-CH2),
49.51 (-CH2), 44.07 (-CH2), 31.94 (-CH2), 27.29 (-CH2), 22.04 (-CH2), 7.40(-CH3).
4.2.2.21 2-(4-(Ethylsulfonyl)phenyl)-N-(3-fluoro-4-(2-(7-isobutyl-3,4-dihydroquinolin-1(2H)-
yl)ethyl) phenyl)acetamide (8b). Yield: 20%, white solid, purity: 98%, mp 159.2-161.3oC.
1
MS(ESI) m/z: 536.8 [M + H]+, 534.8 [M - H]-. H NMR (400 MHz, DMSO-d6) δ 10.41 (s,
1H), 7.85 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 13.1 Hz, 1H), 7.24 (d, J =
4.6 Hz, 2H), 6.74 (d, J = 7.4 Hz, 1H), 6.36 (s, 1H), 6.26 (d, J = 7.5 Hz, 1H), 3.80 (s, 2H), 3.39
(t, J = 7.4 Hz, 2H), 3.27 (q, J = 7.3 Hz, 2H), 3.21 – 3.17 (m, 2H), 2.77 (t, J = 7.4 Hz, 2H),
2.61 (t, J = 6.2 Hz, 2H), 2.29 (d, J = 7.1 Hz, 2H), 1.80 (dd, J = 12.6, 6.5 Hz, 2H), 1.76 – 1.70
(m, 1H), 1.10 (t, J = 7.4 Hz, 3H), 0.84 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ
168.25 (-C=O), 159.12 (-C, Ar), 144.08 (-C, Ar), 141.79 (-C, Ar), 139.40 (-C, Ar), 136.76 (-C,
Ar), 131.22 (-C, Ar), 130.13 (-C, Ar), 128.50 (-CH, Ar), 127.73 (-CH, Ar), 120.82 (-C, Ar),
119.08 (-CH, Ar), 116.00 (-CH, Ar), 114.78 (-CH, Ar), 111.01 (-CH, Ar), 106.00 (-CH, Ar),
105.73 (-CH, Ar), 51.09 (-CH2), 49.11 (-CH2), 48.62 (-CH2), 45.05 (-CH2), 42.76 (-CH2),
29.52 (-CH2), 27.14 (-CH2), 24.64 (-CH), 22.17 (-CH3), 21.72 (-CH2), 7.05 (-CH3).
4.2.2.22 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(6-isobutyl-2,3-dihydro-4H-benzo[b][1,4]oxazi
n-4-yl)ethyl) phenyl)acetamide (9a). Yield: 35%, sticky white oil, purity: 95%. MS(ESI) m/z:
520.9 [M + H]+. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.52 (d,
J = 8.0 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 7.9 Hz, 1H),
6.45 (s, 1H), 6.39 (d, J = 7.9 Hz, 1H), 4.13 (s, 2H), 3.78 (s, 2H), 3.45 (t, J = 7.3 Hz, 2H), 3.22
(s, 2H), 3.12 (q, J = 7.4 Hz, 2H), 2.85 – 2.80 (m, 3H), 2.36 (d, J = 7.1 Hz, 2H), 1.82 – 1.76 (m,
1H), 1.28 (t, J = 7.5 Hz, 5H), 0.91 (d, J = 6.5 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.58
(-C=O), 140.99 (-C, Ar), 137.53 (-C, Ar), 135.93 (-C, Ar), 135.05 (-C, Ar), 130.28 (-C, Ar),
129.34 (-CH, Ar), 128.74 (-CH, Ar), 120.24 (-CH, Ar), 116.14 (-CH, Ar), 64.03 (-CH2), 50.66
(-CH2), 47.49 (-CH2), 45.28 (-CH2), 44.21 (-CH2), 31.72 (-CH2), 30.37 (-CH), 29.70 (-CH2),
22.46 (-CH3), 7.42 (-CH3).

4.2.2.23 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(2-(6-isopropoxy-2,3-dihydro-4H-benzo[b][1,4]ox
azin-4-yl) ethyl)phenyl)acetamide (9b). Yield: 52%, white solid, purity: 98%, mp
148.4-149.7oC. MS(ESI) m/z: 522.7 [M + H]+, 520.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ
8.11 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.12
(d, J = 8.1 Hz, 2H), 6.67 (d, J = 8.5 Hz, 1H), 6.26 (s, 1H), 6.15 (d, J = 8.4 Hz, 1H), 4.41 (dt, J
= 12.0, 6.0 Hz, 1H), 4.06 (s, 2H), 3.73 (s, 2H), 3.41 (t, J = 7.0 Hz, 2H), 3.18 (s, 2H), 3.13 –
3.07 (m, 2H), 2.81 (t, J = 7.1 Hz, 2H), 1.31 (d, J = 6.0 Hz, 6H), 1.26 (t, J = 7.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 167.62 (-C=O), 152.90 (-C, Ar), 141.05 (-C, Ar), 138.49 (-C, Ar),
137.46 (-C, Ar), 135.96 (-C, Ar), 135.82 (-C, Ar), 134.57 (-C, Ar), 130.28 (-CH, Ar), 129.36
(-CH, Ar), 128.69 (-CH, Ar), 120.20 (-CH, Ar), 116.42 (-CH, Ar), 104.34 (-CH, Ar), 101.73
(-CH, Ar), 70.67 (-CH), 63.97 (-CH2), 53.15 (-CH2), 50.66 (-CH2), 47.52 (-CH2), 44.17
(-CH3), 31.87 (-CH2), 22.25 (-CH2), 7.41 (-CH3).
4.2.2.24 2-(4-(Ethylsulfonyl)phenyl)-N-(3-fluoro-4-(2-(6-isopropoxy-2,3-dihydro-4H-benzo[b
][1,4]oxazin-4-yl)ethyl)phenyl)acetamide (9c). Yield: 41%, colorless semi-solid, purity: 98%.
MS(ESI) m/z: 540.7 [M + H]+, 538.7 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.1
Hz, 2H), 7.75 (s, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.48 (s, 1H), 7.12 – 7.03 (m, 2H), 6.67 (d, J =
8.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 6.16 (dd, J = 8.6, 2.6 Hz, 1H), 4.45 – 4.37 (m, 1H),
4.12 – 4.07 (m, 2H), 3.77 (s, 2H), 3.43 (t, J = 7.4 Hz, 2H), 3.27 – 3.23 (m, 2H), 3.12 (q, J =
7.4 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 1.32 – 1.30 (m, 6H), 1.28 (d, J = 7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 167.73 (-C=O), 162.37 (-C, Ar), 159.94 (-C, Ar), 152.94 (-C, Ar),
140.85 (-C, Ar), 138.27 (-C, Ar), 137.43 (-C, Ar), 135.00 (-C, Ar), 131.30 (-C, Ar), 131.24
(-CH, Ar), 130.25 (-CH, Ar), 128.67 (-CH, Ar), 122.36 (-CH, Ar), 116.34 (-CH, Ar), 115.21
(-CH, Ar), 107.65 (-CH, Ar), 107.38 (-CH, Ar), 104.15 (-CH, Ar), 101.21 (-CH, Ar), 70.75
(-CH), 64.17 (-CH2), 51.23 (-CH2), 50.67 (-CH2), 47.41 (-CH2), 44.08 (-CH3), 25.88 (-CH2),
22.27 (-CH2), 7.40 (-CH3).
4.2.2.25 N-(4-(2-(6-Isopropoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)phenyl)-2-(4-
(methylsulfonyl)phenyl)acetamide (9h). Yield: 36%, white solid, purity: 98%, mp
144.7-146.0oC. MS(ESI) m/z: 508.8 [M + H]+, 506.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ
7.92 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.47 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.15
(d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 6.24 – 6.17 (m, 1H),
4.41 (dt, J = 12.1, 6.1 Hz, 1H), 4.13 – 4.07 (m, 2H), 3.79 (s, 2H), 3.44 (t, J = 7.4 Hz, 2H),
13
3.22 (s, 2H), 3.05 (s, 3H), 2.86 (t, J = 7.3 Hz, 2H), 1.31 (d, J = 6.1 Hz, 6H). C NMR (101
MHz, CDCl3) δ 167.53 (-C=O), 152.90 (-C, Ar), 140.96 (-C, Ar), 139.57 (-C, Ar), 138.58 (-C,
Ar), 135.90 (-C, Ar), 135.80 (-C, Ar), 130.41 (-CH, Ar), 129.39 (-CH, Ar), 127.93 (-CH, Ar),
120.20 (-CH, Ar), 116.49 (-CH, Ar), 104.66 (-CH, Ar), 101.91 (-CH, Ar), 70.68 (-CH), 63.88
(-CH2), 53.28 (-CH2), 47.52 (-CH2), 44.55 (-CH3), 44.19 (-CH2), 31.83 (-CH2), 22.25 (-CH3).
4.2.2.26 2-(4-(Methylsulfonyl)phenyl)-N-(4-(2-(6-((1,1,1-trifluoropropan-2-yl)oxy)-2,3-dihyd
ro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)phenyl)acetamide (9i). Yield: 26%, white solid, purity:
1
98%, mp 163.1-165.0oC. MS(ESI) m/z:562.8 [M + H]+, 560.7 [M - H]-. H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.7 Hz, 2H), 7.42 (d, J = 7.7 Hz, 2H), 7.16 (d,
J = 7.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 6.20 (dd, J = 8.6, 2.6 Hz,

1H), 4.50 – 4.39 (m, 1H), 4.09 (s, 2H), 3.80 (s, 2H), 3.44 (t, J = 7.1 Hz, 2H), 3.22 (s, 2H),
3.06 (s, 3H), 2.85 (t, J = 7.1 Hz, 2H), 1.46 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
167.42 (-C=O), 152.42 (-C, Ar), 140.80 (-C, Ar), 139.70 (-C, Ar), 139.63 (-C, Ar), 135.96
(-CF3), 135.82 (-C, Ar), 135.22 (-C, Ar), 130.43 (-CH, Ar), 129.44 (-CH, Ar), 128.01 (-CH,
Ar), 120.24 (-CH, Ar), 116.41 (-CH, Ar), 104.18 (-CH, Ar), 101.97 (-CH, Ar), 73.82 (-CH),
64.06 (-CH2), 52.96 (-CH2), 47.38 (-CH2), 44.56 (-CH3), 44.28 (-CH2), 31.98 (-CH2), 14.19
(-CH3).
4.2.2.27 2-(4-(Methylsulfonyl)phenyl)-N-(4-(2-(6-(perfluoropropan-2-yl)-2,3-dihydro-4H-ben
zo[b][1,4] oxazin-4-yl)ethyl)phenyl)acetamide (9j). Yield: 53%, white solid, purity: 98%, mp
182.8-184.7oC. MS(ESI) m/z: 618.7 [M + H]+, 616.6 [M - H]-. HRMS (ESI+) m/z calcd for
1
C28H25F7N2O4S [M + H]+: 619.1496; found:619.1509. H NMR (400 MHz, DMSO-d6) δ
10.22 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.14
(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 6.74 (s, 1H), 4.19 – 4.15 (m, 2H),
3.77 (s, 2H), 3.49 (t, J = 7.4 Hz, 2H), 3.19 (s, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.51 – 2.50 (m,
13
3H). C NMR (101 MHz, DMSO-d6) δ 167.98 (-C=O), 145.71 (-C, Ar), 142.02 (-C, Ar),
139.10 (-C, Ar), 137.32 (-C, Ar), 135.27 (-C, Ar), 134.03 (-C, Ar), 130.09 (-CH, Ar), 128.83
(-CH, Ar), 126.94 (-CH, Ar), 119.26 (-CH, Ar), 116.35 (-CF3), 64.00 (-CH2), 51.77 (-CH2),
45.96 (-CH2), 43.58 (-CH2), 42.90 (-CH2), 30.55 (-CH3).
4.2.2.28 N-(4-(2-(6-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-2,3-dihydro-4H-benzo[b]
[1,4]oxazin-4-yl)ethyl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide (9k). Yield: 34%,
white solid, purity: 98%, mp 111.5-113.9oC. MS(ESI) m/z: 616.7 [M + H]+, 614.7 [M - H]-.
1
HRMS (ESI+) m/z calcd for C28H26F6N2O5S [M + H]+: 617.1539; found:617.1541. H NMR
(400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.44 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.3
Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.82 – 6.75 (m, 2H),
4.18 – 4.12 (m, 2H), 3.78 (s, 2H), 3.48 – 3.40 (m, 2H), 3.32 – 3.27 (m, 2H), 3.20 (s, 3H), 2.79
– 2.73 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 167.99 (-C=O), 144.69 (-C, Ar), 142.01
(-C, Ar), 139.11 (-C, Ar), 137.27 (-C, Ar), 134.35 (-C, Ar), 134.17 (-C, Ar), 130.11 (-C, Ar),
128.82 (-CH, Ar), 126.95 (-CH, Ar), 123.22 (-CF3), 119.31 (-CH, Ar), 115.61 (-CH, Ar),
115.05 (-CH, Ar), 110.13 (-C), 64.07 (-CH2), 51.96 (-CH2), 46.14 (-CH2), 43.58 (-CH2), 42.89
(-CH2), 30.38 (-CH3).
4.2.3 General procedure C for the synthesis of compounds 8d-8e, 8g-8j, 9d-9g.
Step 1: To a stirred solution of 4-bromoarylacetic acid (1.2 eq) in DCM was added
HATU (1.2 eq), DIPEA (3 eq) and secondary amine 11 (1 eq). The mixture was stirred at
room temperature for 1 h. After the reaction completed, solvent was removed under reduced
pressure, and the residue was purified by column chromatography on silica gel to afford
intermediate 16.
Step 2: Reduction of prepared amide intermediate 16 to tertiary amine intermediate 17
with borane dimethyl sulfide complex followed step 1 of general procedure A.
Step 3: To a vial was added intermediate 17 (1 eq), zinc cyanide (3 eq), Pd(PPh3)4 (0.06
eq), and DMF. Then the reaction mixture was stirred under N2 atmosphere at 100oC for 12 h.
The reaction mixture was poured into water, and extracted by ethyl acetate three times. The

combined organic layers were washed with a saturated sodium chloride solution, dried over
anhydrous sodium sulfate, and concentrated under vacuo. The crude mixture was further
purified by column chromatography on silica gel to afford intermediate 18.
Step 4: To a stirred solution of intermediate 18 (1 eq) in EtOH/H2O (4:1) was added
NaOH aq. (2 N, 3 eq). After that the reaction mixture was stirred at 100oC for 5 h. After
cooled to room temperature, the pH of solution was adjusted to about 3 by 2 N HCl. The
reaction mixture was poured into water, and extracted by ethyl acetate three times. The
combined organic layers were washed with a saturated sodium chloride solution, dried over
anhydrous sodium sulfate, and concentrated under vacuo. The crude mixture was purified by
column chromatography on silica gel to afford the desired intermediate 19.
Step 5: To a stirred solution of 19 (1 eq) in DCM was added HATU (1.2 eq), DIPEA (3
eq) and benzylamine (1.2 eq). The mixture was stirred at room temperature. After the reaction
completed, solvent was removed under reduced pressure. The residue was purified by column
chromatography on silica gel to afford the target compounds (8d-8e, 8g-8j, 9d-9g).
4.2.3.1 N-(4-(Ethylsulfonyl)benzyl)-4-(2-(7-isobutyl-3,4-dihydroquinolin-1(2H)-yl)ethyl)ben
zamide (8d). Yield: 54%, white solid, purity: 96%, mp 109.2-111.3oC. MS(ESI) m/z: 518.9 [M
+ H]+, 516.8 [M - H]-. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (t, J = 5.9 Hz, 1H), 7.85 (dd, J
= 8.1, 5.4 Hz, 4H), 7.58 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 7.4 Hz, 1H),
6.37 (s, 1H), 6.27 (d, J = 7.3 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 3.47 (t, J = 7.4 Hz, 2H), 3.26
(q, J = 7.4 Hz, 2H), 3.21 – 3.16 (m, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H),
2.31 (d, J = 7.1 Hz, 2H), 1.82 – 1.78 (m, 2H), 1.76 (d, J = 6.8 Hz, 1H), 1.09 (t, J = 7.4 Hz,
3H), 0.85 (d, J = 6.6 Hz, 6H). 3C NMR (101 MHz, CDCl3) δ 167.63 (-C=O), 141.12 (-C, Ar),
137.44 (-C, Ar), 136.34 (-C, Ar), 130.27 (-C, Ar), 129.51 (-CH, Ar and -C, Ar), 128.68 (-CH,
Ar), 128.20 (-CH, Ar), 125.30 (-CH, Ar), 120.07 (-CH, Ar), 50.66 (-CH), 45.04 (-CH2), 44.14
(-CH2), 30.27 (-CH2), 26.18 (-CH2), 24.07 (-CH3), 22.36 (-CH2), 7.42 (-CH3).
4.2.3.2 N-(1-(4-(Ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-(7-isobutyl-3,4-dihydroquinolin
-1(2H)-yl)ethyl)benzamide (8e). Yield: 7%, colorless semi-solid, purity: 98%. MS(ESI) m/z:
548.8 [M + H]+, 546.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.80
(d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 7.4 Hz, 1H),
6.45 (s, 2H), 5.32 – 5.26 (m, 1H), 4.09 – 3.95 (m, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.19 (s, 2H),
3.09 (q, J = 7.4 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 6.2 Hz, 2H), 2.39 (d, J = 7.1 Hz,
2H), 1.94 – 1.86 (m, 2H), 1.85 – 1.78 (m, 1H), 1.27 (t, J = 7.4 Hz, 5H), 0.92 (d, J = 6.6 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 167.34 (-C=O), 146.18 (-C, Ar), 140.63 (-C, Ar), 137.71
(-C, Ar), 131.60 (-C, Ar), 129.20 (-CH, Ar and -C, Ar), 129.10 (-CH, Ar), 128.62 (-CH, Ar),
127.76 (-CH, Ar), 127.44 (-CH, Ar), 65.49 (-CH2), 55.41 (-CH), 50.64 (-CH2), 49.75 (-CH2),
45.79 (-CH2), 32.51 (-CH2), 30.25 (-CH), 22.58 (-CH3), 7.37 (-CH3).
4.2.3.3 N-((5-(Ethylsulfonyl)pyridin-2-yl)methyl)-4-(2-(7-isobutyl-3,4-dihydroquinolin-1(2H
)-yl)ethyl) benzamide (8g). Yield: 76%, white solid, purity: 99%, mp 122.1-124.2oC. MS(ESI)
m/z: 519.9 [M + H]+, 517.8 [M - H]-. HRMS (ESI+) m/z calcd for C30H37N3O3S [M + H]+:
1
520.2628; found:520.2626. H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.18 (t, J = 5.8
Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 8.3, 2.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H),

7.59 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 7.5 Hz, 1H), 6.38 (s, 1H), 6.28
(d, J = 7.1 Hz, 1H), 4.67 (d, J = 5.7 Hz, 2H), 3.48 (t, J = 7.3 Hz, 2H), 3.39 (q, J = 7.3 Hz, 2H),
3.22 – 3.14 (m, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.61 (t, J = 6.1 Hz, 2H), 2.32 (d, J = 7.0 Hz, 2H),
1.80 (d, J = 6.1 Hz, 2H), 1.76 (s, 1H), 1.14 (d, J = 7.3 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H). 13C
NMR (101 MHz, CDCl3) δ 167.36 (-C=O), 162.35 (-C, Ar), 148.84 (-CH, Ar and -C, Ar),
136.78 (-CH, Ar and -C, Ar), 133.86 (-C, Ar), 129.18 (-CH, Ar and -C, Ar), 129.00 (-CH, Ar),
127.34 (-CH, Ar), 122.2 (-CH, Ar), 116.83 (-CH, Ar), 111.53 (-CH, Ar),53.19（-CH2), 51.06
(-CH2), 49.80 (-CH2), 45.84 (-CH2), 44.92 (-CH2), 32.57 (-CH2), 30.26 (-CH), 27.72 (-CH2),
22.59 (-CH3), 22.26(-CH2), 7.36 (-CH3).
4.2.3.4 N-((5-(Ethylsulfonyl)pyridin-2-yl)methyl)-4-(2-(7-isopropoxy-3,4-dihydroquinolin-1
(2H)-yl) ethyl)benzamide (8h). Yield: 59%, colorless semi-solid, purity: 96%. MS(ESI) m/z:
521.8 [M + H]+, 519.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.13 (dd, J = 8.2,
1.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.0
Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.21 – 6.08 (m, 2H), 4.85 (d, J = 5.1 Hz, 2H), 4.54 – 4.43
(m, 1H), 3.48 (t, J = 7.3 Hz, 2H), 3.19 – 3.14 (m, 2H), 3.11 (d, J = 6.0 Hz, 2H), 2.93 (t, J =
7.3 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 1.87 – 1.81 (m, 2H), 1.33 (d, J = 6.0 Hz, 6H), 1.32 –
1.27 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 167.45 (-C=O), 162.61 (-C, Ar), 157.50 (-C, Ar),
148.83 (-CH, Ar), 145.56 (-C, Ar), 144.40 (-C, Ar), 136.79 (-C, Ar), 133.73 (-C, Ar), 131.72
(-C, Ar), 129.58 (-CH, Ar and -C, Ar)), 129.21 (-CH, Ar), 127.34 (-CH, Ar), 122.23 (-CH, Ar),
115.28 (-CH, Ar), 102.31 (-CH, Ar), 99.48 (-CH, Ar), 69.79 (-CH), 53.20 (-CH2), 51.06
(-CH2), 49.71 (-CH2), 44.94 (-CH3), 32.66 (-CH2), 29.70 (-CH2), 27.31 (-CH2), 22.30 (-CH2),
7.36 (-CH3).
4.2.3.5 4-(2-(7-Cyclobutoxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)-N-((5-(ethylsulfonyl)pyridi
n-2-yl) methyl)benzamide (8i). Yield: 51%, colorless semi-solid, purity: 90%. MS(ESI) m/z:
1
533.8 [M + H]+, 531.7 [M - H]-. H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 5.9 Hz, 1H),
8.96 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 8.3, 2.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.59 (d, J =
8.3 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 5.97
(dd, J = 8.1, 2.3 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 4.57 (p, J = 7.1 Hz, 1H), 3.46 (t, J = 7.4 Hz,
2H), 3.39 (q, J = 7.3 Hz, 2H), 3.20 – 3.12 (m, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 6.2 Hz,
2H), 2.41 – 2.30 (m, 2H), 2.06 – 1.94 (m, 2H), 1.77 (dd, J = 10.8, 6.7 Hz, 2H), 1.74 – 1.55 (m,
2H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.33 (-C=O), 164.60 (-C,
Ar), 156.61 (-C, Ar), 147.99 (-CH, Ar), 145.38 (-C, Ar), 143.70 (-C, Ar), 136.69 (-C, Ar),
133.21 (-C, Ar), 131.65 (-C, Ar), 129.36 (-CH, Ar), 128.78 (-CH, Ar), 127.44 (-CH, Ar),
121.29 (-CH, Ar), 114.43 (-CH, Ar), 101.50 (-CH, Ar), 97.42 (-CH, Ar), 70.44 (-CH), 52.26
(-CH2), 49.41 (-CH2), 48.70 (-CH2), 44.76 (-CH2), 31.57 (-CH2), 30.38 (-CH2), 26.83 (-CH2),
21.85 (-CH2), 12.84 (-CH2), 6.94 (-CH3).
4.2.3.6 N-((5-(Ethylsulfonyl)pyridin-2-yl)methyl)-4-(2-(7-(oxetan-3-yloxy)-3,4-dihydroquino
lin-1(2H)-yl) ethyl)benzamide (8j). Yield: 14%, colorless semi-solid, purity: 96%. MS(ESI)
m/z: 535.9 [M + H]+, 533.8 [M - H]-. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.16 (d, J =
8.1 Hz, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.33 (d, J = 7.8
Hz, 2H), 6.83 (d, J = 8.1 Hz, 1H), 6.10 (s, 1H), 5.81 (d, J = 7.7 Hz, 1H), 5.20 – 5.11 (m, 1H),