Design, synthesis, and toward a side-ring optimization of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and their effect on melanin synthesis in murine B16 cells

Article abstract of DOI:10.1080/10426507.2018.1487968

Herein, we report the synthesis of 48 novel 3-sulfonylamides containing a tricyclic thieno[2,3-d]pyrimidin-4(3H)-one moiety, and their influence on melanin synthesis in murine B16 cells. All target sulfonylamides were synthesized through key intermediate 3-nitro-thieno[2,3-d]pyrimidin-4(3H)-ones using three types of ipso-nitration reactions. In this case, we converted the pyrido[1,2-a]- fragment of the thieno[2,3-d]pyrimidine moiety to pyrrolo[1,2-a]- and azepino[1,2-a]- side-rings in order to evaluate the bioactivities of the synthesized derivatives for a structure activity-relationships point of view. The obtained results suggest that some of the selected compounds revealed a promising influence on melanin synthesis in murine B16 cells and may serve as lead compounds for further drug discovery and development.

Full text of DOI:10.1080/10426507.2018.1487968

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Design, synthesis, and toward a
side-ring optimization of tricyclic
thieno[2,3-d]pyrimidin-4(3H)-ones and their effect
on melanin synthesis in murine B16 cells
Li Fei Nie, Khurshed Bozorov, Guozheng Huang, Jiangyu Zhao, Chao Niu &
Haji A. Aisa
To cite this article: Li Fei Nie, Khurshed Bozorov, Guozheng Huang, Jiangyu Zhao, Chao
Niu & Haji A. Aisa (2018): Design, synthesis, and toward a side-ring optimization of tricyclic
thieno[2,3-d]pyrimidin-4(3H)-ones and their effect on melanin synthesis in murine B16 cells,
Phosphorus, Sulfur, and Silicon and the Related Elements
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Design, synthesis, and toward a side-ring optimization of tricyclic thieno[2,3-
d]pyrimidin-4(3H)-ones and their effect on melanin synthesis in murine B16 cells
a,b
a,c
a
a
a
a,*
Li Fei Nie , Khurshed Bozorov , Guozheng Huang , Jiangyu Zhao , Chao Niu , Haji A. Aisa
a
Key Laboratory of Plant Resources and Chemistry in Arid Regions, State Key Laboratory Basis of
Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics
and Chemistry, Chinese Academy of Sciences, South Beijing Rd 40-1, Urumqi, 830011, P. R.
China
b
University of Chinese Academy of Sciences, Yuquan Rd 19 A, Beijing, 100049, P.R.China
c
Institute of the Chemistry of Plant Substances, Academy of Sciences of Uzbekistan, Mirzo
Ulugbekstr. 77, Tashkent, 100170, Uzbekistan
*
Corresponding author: Haji A. Aisa haji@ms.xjb.ac.cn
ABSTRACT
Herein, we report the synthesis of forty-eight novel 3-sulfonylamides containing a tricyclic
thieno[2,3-d]pyrimidin-4(3H)-one moiety, and their influence on melanin synthesis in murine
B16 cells. All target sulfonylamides were synthesized through key intermediate 3-nitro-
thieno[2,3-d]pyrimidin-4(3H)-ones using three types of ipso-nitration reactions. In this case, we
converted the pyrido[1,2-a]- fragment of the thieno[2,3-d]pyrimidine moiety to pyrrolo[1,2-a]-
and azepino[1,2-a]- side-rings in order to evaluate the bioactivities of the synthesized
derivatives for a structure activity-relationships point of view. The obtained results suggest that
some of the selected compounds revealed a promising influence on melanin synthesis in
murine B16 cells and may serve as lead compounds for further drug discovery and development.
Graphic Abstract

Keywords: Thieno[2,3-d]pyrimidin-4(3H)-ones; sulfonylamides; ipso-nitration; melanin
synthesis; murine B16 cells
Introduction
Human skin cancer types - such as cutaneous malignant melanoma (melanoma), basal cell and
squamous cell carcinomas of the skin (non-melanoma skin cancer) are now the most common
types of cancer in populations all over the world, and the incidence of skin cancer has reached
1
, 2
epidemic proportions. In humans, melanin production is important for the prevention of skin
3
, 4
cancers, such as melanoma. Melanogenesis
is a multistage process involving melanin
synthesis, melanin transport, and melanosome release. Additionally, melanin synthesis is
5
stimulated by various effectors, including α-melanocyte-stimulating hormone (α-MSH),
6
theophylline, cyclic AMP (cAMP)-elevating agents, and ultraviolet light. Thus, skin
pigmentation is the result of melanogenesis that occurs in melanocytes and/or melanoma cells.
Although melanogenesis is necessary for the prevention of DNA damage and cancer caused by
7
UV irradiation, excessive accumulation of melanin can also cause melanoma. It is known that
8
, 9
natural products are a good arsenal for treatment of the cancer-related diseases; however
1
0, 11
heterocyclic synthetic compounds also provide a special role in medicinal chemistry.
Therefore, treatment of skin cancer, melanoma or vitiligo on the basis of heterocyclic
compounds is becoming important approach in drug discovery.
1
2
It is known that structurally similar compounds do have similar biological activity. Recently,
1
3
we have reported novel pyrido[1,2-a]thieno[2,3-d]pyrimidine derivatives 1a-x (Chart 1) based
on their structural similarities with 8-methoxyposralen (8-MOP, a drug-candidate for vitiligo
treatment). The best results on melanin synthesis in murine B16 cells revealed that further
structural optimization could be perspective. Likewise, because of their excellent opportunities

thieno[2,3-d]pyrimidines (Fig. 1) have become attractive to researchers studying multiple
1
4-19
20
aspects of medicinal chemistry,
in particular for their anticancer properties.
˂
Figure 1>
Thus, continuing our systematic research, herein we present a cycloalkane side-ring
optimization of 3-sulfonylamide containing tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones 10a-x
and 11a-x (Chart 1) and their influence on melanin synthesis in murine B16 cells.
˂
Chart 1>
Results and discussion
Synthesis
General synthetic routes of the target thieno[2,3-d]pyrimidin-4(3H)-ones (10a-x and 11a-x) are
described in Scheme 1. 2,3-Dimethyl pyrrolo[1,2-a]- (2) and azepino[1,2-a]thieno[2,3-
d]pyrimidin-4(3H)-one (3) derivatives were selected as starting materials and obtained by the
condensation of 2-amino-4,5-dimethyl-3-carboxylate with appropriate lactams using
2
1, 22
phosphorus oxychloride.
If derivatives 2 and 3 interact with concentrated HNO /H SO ,
3
2
4
unexpected oxidation of the methyl substituent at position 3 was observed, which gave
2
3
selective 3-carboxy thieno[2,3-d]pyrimidin-4(3H)-ones (4 and 5). Selective nitro products 6
and 7 were synthesized from derivatives 4 and 5 using Cu(OAc) and AgNO as nitrate sources.
2
3
An intermediates 6 and 7 were subjected to the recovery reaction using SnCl · 2H O, and
2
2
afforded amino derivatives 8 and 9. Thus, the target sulfonylamides were synthesized from the
target intermediates 8 and 9 and appropriate benzensulfonyl chlorides, using dichloromethane
as the solvent.
˂
Scheme 1>
We decided that 3-nitro derivatives (6 and 7) are key intermediates for the synthesis of the
target compounds. Therefore, we tried to optimize and suggest more appropriate pathways via
2
4
ipso-nitration reactions.
The methyl 2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-
a]thieno[2,3-d]pyrimidine-3-carboxylate can be functionalized by the esterification reaction
from acid 4. Treatment of the methyl 2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-
a]thieno[2,3-d]pyrimidine-3-carboxylate with HNO /H SO gave the selective 3-nitro product 6.
3
2
4
(
Pathway 1, Scheme 2). In addition, this reaction demonstrates that ipso-nitration of the ester
substituents are possible without metal-catalyzed assistance.
Scheme 2>
Quinolone bearing acids were converted to selective nitro products using various nitrate
˂
2
5
sources, Lewis acids and metal salts. In our case, thieno[2,3-d]pyrimidin-4(3H)-one moiety has
π-excess electrons, therefore the reactivity of the thieno[2,3-d]pyrimidin-4(3H)-ones are higher
than quinolones in the ipso-nitration reactions. In order to convert 3-carboxy thieno[2,3-

d]pyrimidin-4(3H)-one to 3-nitro thieno[2,3-d]pyrimidin-4(3H)-one (Pathway 2, Table 1), we
have selected derivative 4 as the starting material, copper(II) acetate as Lewis acid (in a ratio of
5
0, 70 and 100 mol%), and metal salts such as AgNO , NaNO , Ca(NO ) as nitrating agents for
3
3
3 2
the ipso-nitration reaction. The best results were obtained with AgNO , (herein Cu(OAc) = 70
3
2
mol%; temperature = 80°C; solvent = ethanol), and were suggested as the method of choice for
synthesis of corresponding 3-nitro thieno[2,3-d]pyrimidin-4(3H)-ones (Table 1, entry 4).
˂
Table 1>
If substrate 2 interacts with HNO /H SO , no selective nitro product was formed (Table 2).
3
2
4
Nitrating mixtures HNO /CH COOH and HNO /(CH CO) O resulted very less yields (5 %), while
3
3
3
3
2
with Cu(NO ) /(CH CO) O mixture we have observed only trace of selective nitro product 6.
3
2
3
2
However, when HNO and substrate 2 interacted at -25 – 10 °C for 2 h, derivative 6 was
3
obtained in 15 % (Table 2, entry 5) (Pathway 3).
˂
Table 2>
Melanin synthesis evaluation in B16 cells
1
3,26
Previous screening
revealed that pyrido[1,2-a]thieno[2,3-d]pyrimidinone demonstrated
promising activity on melanin synthesis in murine B16 cells and may serve as lead compounds
for further drug discovery and treatment of vitiligo. Likewise, present results showed that
among the derivatives of pyrrolo[1,2-a]thieno[2,3-d]pyrimidinone, several compounds (10k,
3
29%; 10n, 367%; 10x, 329%) exhibited the best potency (Fig. S 2, Supplemental Materials).
After side-ring optimization (from pyrido- to pyrrolo- side-ring), substituents at the p-position
showed higher percentages on the melanin synthesis potency. For example, compound 10m
(with p- trifluoromethyl substituent) was more effective than compounds 10i (with o-
trifluoromethyl substituent) and 10j (with m- trifluoromethyl substituent) on melanin synthesis
evaluation in B16 cells. A similar case was observed among compounds with trifluromethoxy
group (10l-10n) substitution.
In case of the azepino[1,2-a]thieno[2,3-d]pyrimidinones, di-fluoro- substituents impacted
better activity. For example, derivative with 3,5-difluoro- substituent (11o, 369%) showed a
better activity than other difluoro derivatives 11p-11s. Conversely, the replacement of both
fluorine of 11o with chlorine dramatically decreased the activity (11w, 220%). The introduction
of methyl substituent (compound 11t, 400%), instead of inactive derivative with p-fluorine
substituent (11p, 75%), increased the activity by 5.3-fold. Results are summarized in Figure S 2
(Supplemental Materials).
Experimental
Chemistry

Materials and methods. Reagents and solvents were purchased from Sigma, and used without
further purification. Thin-layer chromatography (TLC) was carried out on glass plates coated
with silica gel (Qingdao Haiyang Chemical Co., G60F-254) and visualized by UV light (254 nm).
The products were purified by column chromatography over silica gel (Qingdao Haiyang
Chemical Co., 200–300 mesh). Melting points were determined on a Buchi B-540 apparatus and
uncorrected. All the NMR spectra were recorded with a Varian 400 MHz NMR spectrometer in
CDCl , using TMS as an internal standard. High-resolution mass spectra (HRMS) were recorded
3
on AB SCIEX QSTAR Elite quadrupole time-of-flight mass spectrometry.
General procedure of preparation of 4 and 5. To cooled H SO conc. (7.5 mL) was added
2
4(
)
compound 2 or 3 (42.73 mmol) at -10-15 °C. Next, a nitrating mixture (14.9 mL HNO and 14 mL
3
H SO ) was added drop wise for 30 min. The reaction mixture was stirred at room temperature
2
4
for 8 h. The reaction mixture was diluted with chloroform (2×100 mL). The organic layer was
washed with water, and dried over anhydrous MgSO . The crude product was purified by silica-
4
gel column chromatography to afford products 4 and 5.
2
-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidine-3-carboxylic acid (4).
1
Yield 92%, white solid, mp 257-259 ℃; H NMR (400 MHz, CDCl ) δ 4.29 (t, J = 7.6 Hz, 2H), 3.25
3
1
3
(t, J = 8.0 Hz, 2H), 2.90 (s, 3H), 2.46 – 2.35 (m, 2H). C NMR (100 MHz, CDCl ) δ 163.38, 162.31,
3
1
59.68, 159.58, 151.91, 122.53, 118.27, 47.45, 31.84, 19.66, 17.34. HRMS (ESI) calcd for
-
C H N O S [M-H] 249.0334, found 249.0339.
1
1 9 2 3
2
-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepine-3-carboxylic
1
acid (5). Yield 91%, white solid, mp 247-249 ℃; H NMR (400 MHz, CDCl ) δ 4.46 (t, J =6.8 Hz,
3
1
3
2
1
1
H), 3.11 (t, J = 7.1 Hz, 2H), 2.90 (s, 3H), 1.98 – 1.74 (m, 6H). C NMR (100 MHz, CDCl ) δ
3
62.45, 161.50, 160.73, 159.72, 152.12, 122.81, 118.18, 43.92, 37.06, 29.30, 27.23, 24.86,
-
7.41. HRMS (ESI) calcd for C H N O S [M-H] 277.0646, found 277.0652.
1
3 13 2 3
General procedure of preparation of 6 and 7. Compounds 6 and 7 were synthesized by a
2
3
previously reported methodology. Briefly, to a mixture of thieno[2,3-d]pyrimidin-4-one acids
4 and 5, 1 mmol), copper(II)acetate (70 mol%) and AgNO (1.2 mmol) was added ethanol (10
(
3
mL) and the reaction mixture was refluxed during 10 h. The reaction mixture was cooled and
diluted with EtOAc (3×10 mL). The organic layer was washed with an aqueous solution of
saturated NaHCO , water, brine, and dried over anhydrous MgSO . The crude product was
3
4
purified by silica-gel column chromatography to afford selective nitro products 6 and 7. The
Supplemental Materials contains sample 1H and 13C NMR spectra for the products 10 and 11
(Figures S 3 – S 88).
General procedure of preparation of 8 and 9. Into a three-necked flask added SnCl · 2H O (102
2
2
mmol), conc. HCl (31 mL, 36%) and was stirred 5 min. Next, added a suspension of 6 or 7 (34
mmol) (EtOH 48 mL and conc. HCl (16 mL), and stirred for another 10–15 min in ice bath.

Stirring was continued at room temperature (0.5 h). The reaction was continued with vigorous
stirring on a boiling water bath for 2 h. The mixture was diluted with water, and neutralized
with NaOH solution (10%) until the pH was 11. The resulting precipitate was filtered off,
washed with distilled water, dried and purified by silica gel chromatography to produce the
pure corresponding compounds (8 and 9).
3
-Amino-2-methyl-7,8-dihydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4(6H)-one (8). Yield 92%,
1
white solid, mp 178-180 ℃; H NMR (400 MHz, CDCl ) δ 5.16(s, 2H), 3.98(t, J = 7.5 Hz, 2H), 3.02
3
1
3
(t, J = 7.8 Hz, 2H), 2.15 (s, 3H), 1.98 – 1.82 (m, 2H). C NMR (100 MHz, CDCl ) δ 160.46, 159.77,
3
1
57.60, 136.99, 113.43, 101.25, 45.86, 31.42, 19.12, 10.88. HRMS (ESI) calcd for C H N OS [M-
1
0 11 3
-
H] 221.0618, found 221.0623.
3
-Amino-2-methyl-7,8,9,10-tetrahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-4(6H)-one (9).
1
Yield 91%, white solid, mp 184-186 ℃; H NMR (400 MHz, CDCl ) δ5.21(s, 2H), 4.21(t, J = 7.8 Hz,
3
1
3
2
1
H), 3.18 (t, J = 8.0 Hz, 2H), 2.75 (s, 3H), 1.98 – 1.74 (m, 6H). C NMR (100 MHz, CDCl ) δ
3
61.67, 160.34, 159.17, 137.52, 119.84, 108.67, 42.32, 36.91, 29.36, 26.73, 21.48, 15.611.
-
HRMS (ESI) calcd for C H N OS [M-H] 249.0931, found 249.0936.
1
2 15 3
General procedure of preparation of 10a-x and 11a-x. To a mixture of 3-amino-2-methyl-
thieno[2,3-d]pyrimidin-4(6H)-one (1.0 mmol) (8 and 9) and benzenesulfonyl chloride (1.1 mmol)
in DCM (10 mL) was added dropwise pyridine (1.2 mmol) in dichloromethane (2 mL). The
resulting mixture was stirred at room temperature for 12 h. The mixture was concentrated
under reduced pressure, and the residue was treated with water (30 mL). The aqueous mixture
was neutralized by the addition of aqueous 10% HCl solution and extracted with DCM (2 x 30
mL). The organic phase was washed with aqueous saturated NH Cl solution and brine. The
4
organic layer was separated and dried over anhydrous MgSO , filtered, and concentrated under
4
reduced pressure to give the crude product, which was purified by silica gel chromatography to
produce the pure corresponding compounds.
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10a). Yield 92%, light yellow solid, mp 149-150 ℃; H NMR (400 MHz,
CDCl ) δ 7.67 (d, J = 7.9 Hz, 3H), 7.44 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 3.89 (t, J = 7.4 Hz,
3
1
3
2
1
1
H), 3.07 (t, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.25 – 2.16 (m, 2H). C NMR (100 MHz, CDCl ) δ
3
60.79, 159.73, 156.76, 138.45, 132.63, 131.48, 128.30, 127.87, 124.75, 115.81, 45.95, 31.99,
-
1
9.57, 13.86. IR (KBr) v: 2920, 1668, 1543, 1444, 1171, 1086, 751 cm . HRMS (ESI) calcd for
-
C H N O S [M-H] 361.0565., found 361.0555.
1
6 15 3 3 2
4
-Methyl-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10b). Yield 87%, light yellow solid, mp 141-142 ℃; H NMR (400 MHz,
CDCl ) δ 7.72 (s, 1H), 7.58 – 7.47 (m, 2H), 7.10 (d, J = 7.9 Hz, 2H), 3.92 (t, J = 7.3 Hz, 2H), 3.07 (t,
3
1
3
J = 7.9 Hz, 2H), 2.64 – 2.54 (m, 3H), 2.32 (s, 3H), 2.27 – 2.16 (m, 2H). C NMR (100 MHz, CDCl )
3
δ 160.86, 159.75, 156.81, 143.41, 135.59, 131.01, 128.91, 127.82, 124.89, 115.86, 46.02, 32.03,

-
1
2
1.49, 19.63, 13.82. IR (KBr) v: 2921, 1667, 1544, 1438, 1167, 1087, 703 cm . HRMS (ESI) calcd
-
for C H N O S [M-H] 375.0728, found 375.0711.
1
7 17 3 3 2
2
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10c). Yield 81%, light yellow solid, mp 162-163 ℃; H NMR (400 MHz,
CDCl ) δ 7.76 (s, 1H), 7.73 – 7.65 (m, 1H), 7.52 – 7.42 (m, 1H), 7.16 – 7.05 (m, 2H), 3.95 (t, J = 7.4
3
1
3
Hz, 2H), 3.09 (t, J = 8.0 Hz, 2H), 2.56 (s, 3H), 2.27 – 2.17 (m, 2H). C NMR (100 MHz, CDCl ) δ
3
1
60.81, 160.27 (d, J = 101.3 Hz), 158.24, 156.80, 134.95 (d, J = 8.4 Hz), 132.27, 130.50, 127.13
(
d, J = 14.1 Hz), 123.86 (d, J = 3.7 Hz), 123.80, 116.90 (d, J = 21.5 Hz), 115.93, 46.06, 32.02,
-
1
1
9.56, 13.90. IR (KBr) v: 29218, 1666, 1544, 1439, 1173, 1106, 877 cm . HRMS (ESI) calcd for
C H FN O S [M-H]- 379.0453, found 379.0461.
1
6
14
3 3 2
3
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10d). Yield 84%, light yellow solid, mp 172-173 ℃; H NMR (400 MHz,
CDCl ) δ 7.72 (s, 1H), 7.42 (ddd, J = 11.5, 8.2, 4.8 Hz, 2H), 7.30 (td, J = 8.0, 5.3 Hz, 1H), 7.14 (td, J
3
=
8.3, 2.5 Hz, 1H), 3.94 (t, J = 7.4 Hz, 2H), 3.09 (t, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.27 – 2.18 (m, 2H).
1
3
C NMR (100 MHz, CDCl ) δ 162.08 (d, J = 209.8 Hz), 160.63, 159.88, 156.83, 140.49 (d, J = 6.8
3
Hz), 131.81, 130.03 (d, J = 7.6 Hz), 124.25, 123.70 (d, J = 3.5 Hz), 119.80 (d, J = 21.2 Hz), 115.66,
1
1
15.26 (d, J = 20.9 Hz), 46.01, 32.02, 19.57, 13.86. IR (KBr) v: 2921, 1666, 1543, 1463, 1166,
-1
-
085, 739 cm . HRMS (ESI) calcd for C H FN O S [M-H] 379.0450, found 379.0461.
1
6
14
3 3 2
4
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10e). Yield 85%, light yellow solid, mp 179-180 ℃; H NMR (400 MHz,
CDCl ) δ 7.73 – 7.64 (m, 2H), 7.62 (s, 1H), 7.05 – 6.93 (m, 2H), 3.92 (t, J = 7.4 Hz, 2H), 3.09 (t, J =
3
1
3
8
.0 Hz, 2H), 2.62 (s, 3H), 2.27 – 2.18 (m, 2H). C NMR (100 MHz, CDCl ) δ165.19 (d, J = 254.6
3
Hz), 161.10, 159.87, 156.80, 134.45 (d, J = 2.9 Hz), 131.92, 130.70 (d, J = 9.4 Hz), 124.48, 115.63
(
d, J = 10.8 Hz), 115.35, 46.01, 32.02, 19.55, 13.85. IR (KBr) v: 29210, 1660, 1547, 1464, 1170,
-1
-
1
048, 708 cm . HRMS (ESI) calcd for C H FN O S [M-H] 379.0472, found 379.0461.
1
6
14
3 3 2
4
-Bromo-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10f). Yield 89%, white solid, mp 174-175 ℃; H NMR (400 MHz, CDCl )
3
δ 7.58 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 7.2 Hz, 2H), 3.10 (t, J =
1
3
7
1
.9 Hz, 2H), 2.62 (s, 3H), 2.31 – 2.19 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.07, 159.94,
3
56.70, 137.29, 132.26, 131.49, 129.55, 127.69, 124.28, 115.75, 46.08, 32.06, 19.63, 13.82. IR
-
1
(
KBr) v: 2936, 1669, 1542, 1451, 1176, 1087, 742 cm . HRMS (ESI) calcd for C H BrN O S [M-
1
6
14
3 3 2
-
H] 438.9654, found 438.9660.
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-4-
1
nitrobenzenesulfonamide (10g). Yield 74%, light yellow solid, mp 225-226 ℃; H NMR (400
MHz, CDCl ) δ 8.18 – 8.10 (m, 2H), 7.89 – 7.81 (m, 2H), 7.70 (s, 1H), 3.87 (t, J = 7.4 Hz, 2H), 3.08
3
1
3
(
t, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.28-2.19 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.37, 160.11,
3
1
56.73, 150.11, 144.12, 132.76, 129.23, 123.53, 123.45, 115.33, 46.06, 32.03, 19.42, 13.89. IR

-
1
-
(
KBr) v: 2922, 1666, 1545, 1338, 1164, 1091, 684 cm . HRMS (ESI) calcd for C H N O S [M-H]
1
6 14 4 5 2
4
06.0412, found 406.0406.
4
-Methoxy-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10h). Yield 82%, light yellow solid, mp 248-249 ℃; H NMR (400 MHz,
CDCl ) δ 7.65 (s, 1H), 7.63 – 7.56 (m, 2H), 6.81 – 6.72 (m, 2H), 3.93 (t, J = 7.4 Hz, 2H), 3.79 (s, 3H),
3
1
3
3
1
1
.06 (d, J = 8.0 Hz, 2H), 2.60 (s, 3H), 2.27 – 2.15 (m, 2H). C NMR (100 MHz, CDCl ) δ 162.96,
3
60.73, 159.68, 156.85, 131.24, 130.28, 130.05, 125.08, 115.95, 113.46, 55.55, 46.05, 32.01,
-
1
9.65, 13.76. IR (KBr) v: 2929, 1665, 1547, 1421, 1175, 1089, 757 cm . HRMS (ESI) calcd for
-
C H N O S [M-H] 391.0671, found 391.0660.
1
7 17 3 4 2
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-2-
trifluoromethyl)benzenesulfonamide (10i). Yield 83%, light yellow solid, mp 203-204 ℃; H
NMR (400 MHz, CDCl ) δ 7.86 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.65 – 7.54 (m, 2H),
1
(
3
7
2
1
4
.47 (t, J = 7.4 Hz, 1H), 3.86 (t, J = 7.4 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 2.53 (s, 3H), 2.23 – 2.14 (m,
1
3
H). C NMR (100 MHz, CDCl ) δ 160.62, 159.86, 156.30, 138.03, 133.29, 132.45, 131.53,
3
31.15, 128.83 (d, J = 35.4 Hz), 128.06 (q, J = 6.3 Hz), 124.01 (q, J = 3.5 Hz), 121.40, 115.94,
-
1
6.01, 32.01, 19.59, 13.89. IR (KBr) v: 2932, 1659, 1547, 1431, 1161, 1083, 789 cm . HRMS (ESI)
-
calcd for C H F N O S [M-H] 429.0416, found 429.0429.
1
7 14 3 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-3-
trifluoromethyl)benzenesulfonamide (10j). Yield 79%, light yellow solid, mp 191-192 ℃; H
NMR (400 MHz, CDCl ) δ 7.91 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (s,
1
(
3
1
2
1
1
H), 7.49 (t, J = 7.9 Hz, 1H), 3.85(t, J = 7.4 Hz, 2H), 3.06 (t, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.24 –
1
3
.15 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.22, 159.99, 156.63, 139.52, 132.77, 131.28,
3
30.77 (d, J = 33.5 Hz), 129.20, 129.10 (q, J = 3.7 Hz), 125.01 (q, J = 4.0 Hz), 124.51, 123.98,
-
1
15.54, 45.88, 31.98, 19.60, 13.74. IR (KBr) v: 2933, 1678, 1541, 1436, 1159, 1067, 743 cm .
-
HRMS (ESI) calcd for C H F N O S [M-H] 429.0435, found 429.0429.
1
7 14 3 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-4-
1
(
trifluoromethyl)benzenesulfonamide (10k). Yield 80%, white solid, mp 216-217 ℃; H NMR
(
400 MHz, CDCl ) δ 7.76 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.51 (s, 1H), 3.82 (t, J = 7.4 Hz,
3
1
3
2
1
1
1
H), 3.06 (t, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.23 – 2.15 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.13,
3
60.02, 156.53, 141.71, 134.23 (q, J = 32.8 Hz), 132.92, 128.57, 125.27 (q, J = 3.6 Hz), 123.94,
22.92 (d, J = 33 Hz) 115.64, 45.95, 32.01, 19.52, 13.81. IR (KBr) v: 2923, 1662, 1547, 1407, 1165,
-1
-
061, 713 cm . HRMS (ESI) calcd for C H F N O S [M-H] 429.0422, found 429.0429.
1
7 14 3 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-2-
trifluoromethoxy)benzenesulfonamide (10l). Yield 81%, light yellow solid, mp 158-159 ℃; H
NMR (400 MHz, CDCl ) δ 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (s, 1H), 7.53 (td, J = 8.2, 1.7 Hz, 1H),
1
(
3
7
2
1
.34 – 7.22 (m, 2H), 3.93(t, J = 7.4 Hz, 2H), 3.09 (t, J = 8.0 Hz, 2H), 2.51 (s, 3H), 2.26 – 2.16 (m,
1
3
H). C NMR (100 MHz, CDCl ) δ 160.95, 159.76, 156.84, 146.64 (d, J = 1.8 Hz), 134.28, 131.82,
3
31.04, 126.13, 123.91, 121.35, 120.05, 118.76, 115.98, 46.02, 32.07, 19.59, 13.77. IR (KBr) v:

-1
-
2
4
933, 1663, 1545, 1240, 1156, 1047, 717 cm . HRMS (ESI) calcd for C H F N O S [M-H]
1
7 14 3 3 4 2
45.0384, found 445.0378.
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-3-
trifluoromethoxy)benzenesulfonamide (10m). Yield 83%, light yellow solid, mp 153-154 ℃; H
NMR (400 MHz, CDCl ) δ 7.71 (d, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.42 (dd, J = 9.8, 6.2 Hz, 2H), 7.30
1
(
3
(
d, J = 8.3 Hz, 1H), 3.86 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 8.0 Hz, 2H), 2.63 (s, 3H), 2.25 – 2.15 (m,
1
3
2
1
2
4
H). C NMR (100 MHz, CDCl ) δ 161.19, 159.86, 156.65, 148.53 (d, J = 3.7 Hz), 140.38, 132.45,
3
29.99, 126.55, 125.32, 123.98, 120.64, 118.77, 115.48, 45.83, 31.94, 19.57, 13.76. IR (KBr) v:
-1
-
921, 1667, 1544, 1438, 1167, 1087, 703 cm . HRMS (ESI) calcd for C H F N O S [M-H]
1
7 14 3 3 4 2
45.0380, found 4445.0378.
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-4-
trifluoromethoxy)benzenesulfonamide (10n). Yield 88%, light yellow solid, mp 181-182 ℃; H
NMR (400 MHz, CDCl ) δ 7.72 – 7.65 (m, 2H), 7.53 (s, 1H), 7.13 (d, J = 8.2 Hz, 2H), 3.87 (t, J = 7.4
1
(
3
1
3
Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 2.63 (s, 3H), 2.25 – 2.15 (m, 2H). C NMR (100 MHz, CDCl ) δ
3
1
61.07, 159.89, 156.64, 152.14 (q, J = 1.4 Hz), 136.67, 132.62, 130.16, 120.33, 120.16 (q, J = 258
Hz), 115.66, 110.03, 45.94, 31.97, 19.46, 13.78. IR (KBr) v: 2928, 1652, 1544, 1,342, 1155, 1090,
-
1
-
7
84 cm . HRMS (ESI) calcd for C H F N O S [M-H] 445.0375, found 445.0378.
1
7 14 3 3 4 2
3
,5-Difluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10o). Yield 81%, light yellow solid, mp 201-202 ℃; H NMR (400 MHz,
CDCl ) δ 7.77 (s, 1H), 7.23 (dd, J = 6.4, 2.2 Hz, 2H), 6.89 (tt, J = 8.4, 2.3 Hz, 1H), 3.97 (t, J = 7.4 Hz,
3
1
3
2
H), 3.11 (t, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.30 – 2.21 (m, 2H). C NMR (100 MHz, CDCl ) δ 162.19
3
(dd, J = 254.0, 11.4 Hz), 161.31, 160.06, 156.91, 141.84 (t, J = 8.5 Hz), 132.31, 123.74, 115.54,
1
1
3
11.46 (q, J = 27.9 Hz), 108.17 (t, J = 25.0 Hz), 46.10, 32.06, 19.59, 13.87. IR (KBr) v: 2926, 1667,
-1
-
545, 1435, 1166, 1089, 782 cm . HRMS (ESI) calcd for C H F N O S [M-H] 397.0361, found
1
6 13 2 3 3 2
97.0366.
3
,4-Difluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10p). Yield 85%, light yellow solid, mp 219-220 ℃; H NMR (400 MHz,
CDCl ) δ 7.67 (s, 1H), 7.59 – 7.51 (m, 1H), 7.48 – 7.41 (m, 1H), 7.11 (dd, J = 16.9, 8.8 Hz, 1H),
3
1
3
3
.96 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 7.9 Hz, 2H), 2.61 (s, 3H), 2.30 – 2.21 (m, 2H). C NMR (100
MHz, CDCl ) δ 161.24, 160.04, 156.87, 153.14 (dd, J = 256.2, 11.7 Hz), 149.53 (dd, J = 253.0, 14.1
3
Hz), 135.24 (t, J = 3.9 Hz), 132.26, 125.15 (dd, J = 7.6, 4.0 Hz), 124.01, 117.94 (d, J = 19.3 Hz),
1
1
17.34 (d, J = 18.2 Hz), 115.58, 46.17, 32.13, 19.59, 13.82. IR (KBr) v: 2921, 1655, 1547, 1437,
-
1
-
164, 1087, 688 cm . HRMS (ESI) calcd for C H F N O S [M-H] 397.0361, found 397.0366.
1
6 13 2 3 3 2
2
,6-Difluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10q). Yield 89%, light yellow solid, mp 179-180 ℃; H NMR (400 MHz,
CDCl ) δ 7.88 (s, 1H), 7.41 (t, J = 6.9 Hz, 1H), 6.89 (t, J = 8.7 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.11
3
1
3
(
t, J = 7.4 Hz, 2H), 2.59 (s, 3H), 2.28 – 2.18 (m, 2H). C NMR (100 MHz, CDCl ) δ 159.99 (dd, J =
3

2
60.9, 3.6 Hz), 160.97, 159.80, 156.81, 134.43 (t, J = 9.1 Hz), 132.95, 123.15, 117.06 (d, J = 15.7
Hz), 115.81, 159.99 (dd, J = 260.9, 3.6 Hz), 46.18, 32.14, 19.61, 13.94. IR (KBr) v: 2926, 1668,
-
1
-
1
651, 1544, 1463, 1179, 1000, 771 cm . HRMS (ESI) calcd for C H F N O S [M-H] 397.0359,
1
6 13 2 3 3 2
found 397.0366.
2
,5-Difluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10r). Yield 82%, light yellow solid, mp 162-163 ℃; H NMR (400 MHz,
CDCl ) δ 7.79 (s, 1H), 7.43 – 7.35 (m, 1H), 7.16 (ddd, J = 12.2, 7.0, 3.3 Hz, 1H), 7.08 (td, J = 8.9,
3
1
3
4
.0 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.12 (t, J = 8.0 Hz, 2H), 2.56 (s, 3H), 2.29 – 2.19 (m, 2H). C
NMR (100 MHz, CDCl ) δ 161.14, 159.90, 157.71 (dd, J = 171.3, 2.4 Hz), 156.95，155.22 (dd, J =
3
1
78.3, 2.6 Hz), 132.92, 128.38 (dd, J = 16.6, 6.8 Hz), 123.34, 121.45 (dd, J = 23.8, 8.5 Hz), 118.20
(
dd, J = 24.6, 7.7 Hz), 117.08 (d, J = 27.0 Hz), 115.84, 46.11, 32.06, 19.55, 13.91. IR (KBr) v: 2927,
-1
-
1
3
662, 1545, 1488, 1170, 833 cm . HRMS (ESI) calcd for C H F N O S [M-H] 397.0364, found
1
6 13 2 3 3 2
97.0366.
2
,4-Difluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10s). Yield 77%, light yellow solid, mp 176-177 ℃; H NMR (400 MHz,
CDCl ) δ 7.69 (s, 1H), 7.75 – 7.61 (m, 1H), 6.83 (t, J = 8.5 Hz, 2H), 3.96 (t, J = 7.4 Hz, 2H), 3.11 (t, J
3
1
3
=
2
1
8.0 Hz, 2H), 2.57 (s, 3H), 2.29 – 2.19 (m, 2H). C NMR (100 MHz, CDCl ) δ 165.80 (dd, J =
3
57.9, 12.1 Hz), 161.12, 160.46 (dd, J = 265.0, 16.8 Hz), 159.88, 156.83, 132.96, 132.27 (dd, J =
6.5, 6.87Hz), 123.56, 123.54 (dd, J = 14.2, 3.9 Hz), 115.82, 111.26 (dd, J = 21.8, 3.9 Hz), 105.30
(
t, J = 25.6 Hz), 46.12, 32.03 – 31.83 (m), 19.62, 14.03. IR (KBr) v: 2919, 1658, 1598, 1426, 1174,
-
1
-
9
71, 740 cm . HRMS (ESI) calcd for C H F N O S [M-H] 397.0369, found 397.0366.
1
6 13 2 3 3 2
3
3
-Fluoro-4-methyl-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-
1
-yl)benzenesulfonamide (10t). Yield 79%, light yellow solid, mp 184-185 ℃; H NMR (400 MHz,
CDCl ) δ 7.73 (s, 1H), 7.41 – 7.31 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 3.95 (t, J = 7.3 Hz, 2H), 3.10 (t, J
3
1
3
=
7.9 Hz, 2H), 2.59 (s, 3H), 2.29 – 2.18 (m, 5H). C NMR (100 MHz, CDCl ) δ 161.23 (d, J = 55.2
3
Hz), 159.79, 159.03, 156.90, 137.71 (d, J = 7.0 Hz), 131.38, 131.33 (d, J = 4.8 Hz), 130.48 (d, J =
1
1
7.3 Hz), 124.50, 123.43 (d, J = 3.9 Hz), 115.74, 114.80 (d, J = 25.7 Hz), 46.04, 32.04, 19.64,
-
1
4.75 (d, J = 3.7 Hz), 13.89. IR (KBr) v: 2922, 1663, 1544, 1402, 1154, 709 cm . HRMS (ESI) calcd
-
for C H FN O S [M-H] 393.0610, found 393.0617.
1
7
16
3 3 2
2
3
-Methyl-4-fluoro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-
1
-yl)benzenesulfonamide (10u). Yield 85%, white solid, mp 193-194 ℃; H NMR (400 MHz,
CDCl ) δ 7.74 (dd, J = 8.8, 5.8 Hz, 1H), 7.65 (s, 1H), 6.88 (d, J = 9.5 Hz, 1H), 6.83 (t, J = 8.3 Hz, 1H),
3
1
3
3
.97 (t, J = 7.3 Hz, 2H), 3.11 (t, J = 8.0 Hz, 2H), 2.58 (s, 3H), 2.49 (s, 3H), 2.30 – 2.19 (m, 2H). C
NMR (100 MHz, CDCl ) δ 164.76 (d, J = 254.2 Hz), 160.97, 159.87, 156.94, 142.17 (d, J = 9.1 Hz),
3
1
33.27, 132.84 (d, J = 9.5 Hz), 131.35, 124.55, 118.84 (d, J = 21.9 Hz), 115.98, 112.74 (d, J = 21.8
-
1
Hz), 46.07, 32.04, 21.15, 19.59, 13.81. IR (KBr) v: 2925, 1664, 1540, 1456, 1160, 935, 707 cm .
-
HRMS (ESI) calcd for C H FN O S [M-H] 393.0613, found 393.0617.
1
7
16
3 3 2

4
-Chloro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-3-
1
nitrobenzenesulfonamide (10v). Yield 72%, light yellow solid, mp 191-192 ℃; H NMR (400
MHz, CDCl ) δ 7.87 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 8.3
3
1
3
Hz, 1H), 3.68 (t, J = 6.1 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.65 (s, 3H), 1.97 – 1.80 (m, 2H). C NMR
100 MHz, CDCl ) δ 160.84, 158.67, 156.73, 148.98, 139.88, 134.17, 131.93, 131.51, 129.13,
(
3
1
1
25.55, 124.09, 116.63, 41.70, 32.77, 18.81, 13.69. IR (KBr) v: 2924, 1662, 1540, 1343, 1170,
-1
-
046, 776 cm . HRMS (ESI) calcd for C H ClN O S [M-H] 440.0023, found 440.0016.
1
6
13
4 5 2
3
,5-Dichloro-N-(2-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-
1
yl)benzenesulfonamide (10w). Yield 76%, light yellow solid, mp 202-203 ℃; H NMR (400 MHz,
CDCl ) δ 7.67 (s, 1H), 7.55 (d, J = 1.8 Hz, 2H), 7.41 (t, J = 1.7 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.11
3
1
3
(
t, J = 7.9 Hz, 2H), 2.61 (s, 3H), 2.32 – 2.19 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.30, 160.07,
3
1
56.81, 141.19, 135.16, 132.71, 132.43, 126.42, 123.70, 115.60, 46.09, 32.10, 19.71, 13.79. IR
-
1
(KBr) v: 2930, 1658, 1548, 1342, 1172, 937, 780 cm . HRMS (ESI) calcd for C H Cl N O S [M-
1
6
13
2 3 3 2
-
H] 428.9780, found 428.9775.
N-(2-Methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-3-yl)-[1,1'-
1
biphenyl]-4-sulfonamide (10x). Yield 82%, light yellow solid, mp 167-168 ℃; H NMR (400 MHz,
CDCl ) δ 7.68 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.50 (d, J = 7.5 Hz, 4H), 7.44 (t, J = 7.3 Hz, 2H), 7.41
3
1
3
–
7.35 (m, 1H), 3.82 (t, J = 7.1 Hz, 2H), 2.99 (t, J = 7.7 Hz, 2H), 2.62 (s, 3H), 2.09-2.03 (m, 2H). C
NMR (100 MHz, CDCl ) δ 160.89, 159.70, 156.73, 145.36, 139.17, 136.86, 131.71, 129.07,
3
1
28.53, 128.50, 127.04, 126.69, 124.79, 115.93, 45.95, 31.96, 19.43, 13.84. IR (KBr) v: 2929,
-
1
-
1
651, 1549, 1456, 1166, 1090, 765 cm . HRMS (ESI) calcd for C H N O S [M-H] 437.0683,
2
2 19 3 3 2
found 437.0688
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11a). Yield 91%, light yellow solid, mp 173-174 ℃; H NMR (400 MHz,
CDCl ) δ 7.72 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 4.06
3
1
3
(
t, J = 4.8Hz, 2H), 2.93 (t, J = 4Hz, 2H), 2.62 (s, 3H), 1.82-1.71 (m, 4H), 1.61-150 (m, 2H). C NMR
(
100 MHz, CDCl ) δ 159.86, 159.02, 157.59, 138.35, 132.55, 131.76, 128.19, 127.93, 125.02,
3
1
6
15.42, 41.83, 37.21, 29.30, 27.49, 24.93, 13.79. IR (KBr) v: 2926, 1654, 1576, 1410, 1165, 1090,
-
1
+
24 cm . HRMS (ESI) calcd for C H N O S [M-H] 389.0861, found 389.0868.
1
8 19 3 3 2
4
-Methyl-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11b). Yield 85%, white solid, mp 179-180 ℃; H NMR (400 MHz, CDCl )
3
δ 7.69 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.07 (t, J = 4.8 Hz, 2H), 2.94 (t, J =
1
3
4
Hz, 2H), 2.61 (s, 3H), 2.30 (s, 3H), 1.83 – 1.71 (m, 4H), 1.60-1.52(m, 2H). C NMR (100 MHz,
CDCl ) δ 159.82, 158.70, 157.52, 143.28, 135.51, 131.70, 128.79, 127.95, 125.23, 115.55, 41.81,
3
-
3
7.08, 29.34, 27.42, 24.96, 21.47, 13.78. IR (KBr) v: 2921, 1663, 1573, 1488, 1159, 1088, 671cm
1
-
.
HRMS (ESI) calcd for C H N O S [M-H] 403.1030, found 403.1024.
19 21 3 3 2

2
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11c). Yield 83%, light yellow solid, mp 158-159 ℃; H NMR (400 MHz,
CDCl ) δ 7.80 (s, 1H), 7.71 – 7.64 (m, 1H), 7.49 – 7.42 (m, 1H), 7.13 – 7.03 (m, 2H),4.09 (t, J = 4.8
3
1
3
Hz, 2H), 2.95 (t, J = 4.1 Hz, 2H), 2.57 (s, 3H), 1.82 – 1.72 (m, 4H), 1.63-1.54(m, 2H). C NMR (100
MHz, CDCl ) δ 159.88, 159.58 (d, J = 258.3 Hz), 159.07, 157.67, 134.86 (d, J = 8.3 Hz), 132.51,
3
1
30.64, 126.95 (d, J = 13.9 Hz), 124.12, 123.76 (d, J = 3.9 Hz), 116.81 (d, J = 21.6 Hz), 115.39,
-
4
1.88, 37.25, 29.36, 27.52, 24.94, 13.85. IR (KBr) v: 2923, 1656, 1578, 1478, 1157, 1073, 717 cm
1
-
.
HRMS (ESI) calcd for C H FN O S [M-H] 407.0767, found 407.0774.
18
18
3 3 2
3
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11d). Yield 86%, light yellow solid, mp 175-176 ℃; H NMR (400 MHz,
CDCl ) δ 7.74 (s, 1H), 7.45 – 7.41 (m, 1H), 7.41 – 7.37 (m, 1H), 7.31 – 7.24 (m, 1H), 7.17 – 7.08
3
(
m, 1H), 4.10 (t, J = 4.8 Hz, 2H), 2.95 (t, J = 4Hz, 2H), 2.62 (s, 3H), 1.82-1.71 (d, J = 2.5 Hz, 4H),
1
3
1
1
4
1
4
.64-1.56 (m, 2H). C NMR (100 MHz, CDCl ) δ 161.83 (d, J = 250.6 Hz), 160.06, 159.03, 157.62,
3
40.37 (d, J = 6.9 Hz), 132.18, 129.89 (d, J = 7.6 Hz), 124.54, 123.74 (d, J = 3.2 Hz), 119.72 (d, J =
4 Hz), 115.32 (d, J = 44 Hz), 115.27, 41.93, 37.18, 29.31, 27.44, 24.90, 13.79. IR (KBr) v: 2923,
-
1
-
653, 1507, 1477, 1164, 698 cm . HRMS (ESI) calcd for C H FN O S [M-H] 407.0770, found
1
8
18
3 3 2
07.0774.
4
-Fluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11e). Yield 87%, light yellow solid, mp 169-170 ℃; H NMR (400 MHz,
CDCl ) δ 7.68 (s, 1H), 7.65 – 7.60 (m, 2H), 7.02 – 6.91 (m, 2H), 4.09 (t, J = 4.8 Hz, 2H), 2.95 (t, J =
3
1
3
4
1
Hz, 2H), 2.62 (s, 3H), 1.84 – 1.72 (m, 4H), 1.62-1.53(m, 2H). C NMR (100 MHz, CDCl ) δ
3
65.16 (d, J = 254.7 Hz), 160.07, 159.21, 157.56, 134.34 (d, J = 2.9 Hz), 132.32, 130.74 (d, J = 9.4
Hz), 124.75, 115.34, 115.31 (d, J = 9.4 Hz), 41.92, 37.22, 29.26, 27.46, 24.92, 13.74. IR (KBr) v:
-
1
-
2
4
4
926, 1659, 1577, 1490, 1164, 1087, 836 cm . HRMS (ESI) calcd for C H FN O S [M-H]
1
8
18
3 3 2
07.0765, found 407.0774.
-Bromo-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)benzenesulfonamide (11f). Yield 90%, light yellow solid, mp 168-169 ℃; H NMR (400 MHz,
CDCl ) δ 7.62 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.07 (t, J = 4.8 Hz, 2H), 2.95
3
1
3
(
t, J = 4 Hz, 2H), 2.63 (s, 3H), 1.85-1.73 (m 4H), 1.65-1.56(m, 2H). C NMR (100 MHz, CDCl ) δ
3
1
3
62.90, 159.82, 158.95, 157.58, 131.74, 130.08, 130.05, 125.35, 115.60, 113.28, 55.43, 41.80,
-1
7.18, 29.28, 27.42, 24.96, 13.75. IR (KBr) v: 2921 1660, 1581, 1337, 1161, 1064, 739cm .
-
HRMS (ESI) calcd for C H BrN O S [M-H] 466.9965, found 466.9973.
1
8
18
3 3 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-4-
1
nitrobenzenesulfonamide (11g). Yield 73%, white solid, mp 224-225 ℃; H NMR (400 MHz,
CDCl ) δ 8.17 – 8.09 (m, 2H), 7.87 – 7.80 (m, 2H), 7.69 (s, 1H), 4.01 (t, J = 4.8 Hz, 2H), 2.94 (t, J =
3
1
3
4
1
Hz, 2H), 2.65 (s, 3H), 1.79 – 1.70 (m, 4H), 1.50(m, 2H). C NMR (100 MHz, CDCl ) δ 160.29,
3
59.17, 157.47, 150.10, 144.02, 133.15, 129.31, 123.65, 123.31, 114.96, 41.88, 37.07, 29.12,

-
1
2
7.32, 24.82, 13.78. IR (KBr) v: 2921, 1654, 1577, 1416, 1341, 1169, 1088, 781 cm . HRMS (ESI)
-
calcd for C H N O S [M-H] 434.0712, found 434.0719.
1
8 18 4 5 2
4
3
-Methoxy-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11h). Yield 77%, light yellow solid, mp 150-151 ℃; H NMR (400
MHz, CDCl ) δ 7.66 (s, 1H), 7.59 – 7.51 (m, 2H), 6.79 – 6.70 (m, 2H), 4.09 (t, J = 4.8 Hz, 2H), 3.77
3
1
3
(
s, 3H), 2.94 (t, J = 4Hz, 2H), 2.61 (s, 3H), 1.83-1.72 (m, 4H), 1.61-1.52(m, 2H). C NMR (100
MHz, CDCl ) δ 162.87, 159.78, 158.92, 157.55, 131.68, 130.08, 130.04, 125.31, 115.57, 113.24,
3
5
1
5.40, 41.76, 37.14, 29.24, 27.39, 24.92, 13.71. IR (KBr) v: 2925, 1661, 1580, 1415, 1335, 1167,
-1
-
079, 739 cm . HRMS (ESI) calcd for C H N O S [M-H] 419.0967, found 419.0973.
1
9 21 3 4 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-2-
trifluoromethyl)benzenesulfonamide (11i). Yield 73%, light yellow solid, mp 136-137 ℃; H
NMR (400 MHz, CDCl ) δ 7.85 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J =
1
(
3
7
1
1
1
1
.7 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 3.67 (t, J = 6.1 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H),
1
3
.96-1.83 (m, 6H). C NMR (100 MHz, CDCl ) δ 160.07, 158.85, 156.79, 139.09, 133.28, 132.96,
3
31.85, 131.58, 129.51 (d, J = 33.6 Hz), 128.39 (q, J = 6.3 Hz), 125.73 (q, J = 3.7 Hz), 124.34,
15.92, 41.76, 37.27, 29.58, 27.61, 24.83, 13.69. IR (KBr) v: 2928, 1653, 1575, 1413, 1346, 1169,
-1
-
081, 762 cm . HRMS (ESI) calcd for C H F N O S [M-H] 457.0749, found 457.0742.
1
9 18 3 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-3-
trifluoromethyl)benzenesulfonamide (11j). Yield 84%, light yellow solid, mp 170-171 ℃; H
NMR (400 MHz, CDCl ) δ 7.87 (d, J = 7.9 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 6.6 Hz, 2H), 7.47 (t, J =
1
(
3
7
.8 Hz, 1H), 4.02 (t, J = 4.8 Hz, 2H), 2.93(t, J = 4Hz, 2H), 2.64 (s, 3H), 1.81-1.70 (m, 4H), 1.60-1.51
1
3
(m, 2H). C NMR (100 MHz, CDCl ) δ 160.20, 159.29, 157.44, 139.39, 132.95, 131.24, 130.79 (d,
3
J = 33.3 Hz), 129.05, 129.01 (d, J = 6.4, Hz), 125.08 (q, J = 3.9 Hz), 124.23, 115.11, 41.84, 37.21,
-
1
2
9.35, 27.43, 24.83, 13.73. IR (KBr) v: 2927, 1655, 1575, 1327, 1125, 724 cm . HRMS (ESI) calcd
-
for C H F N O S [M-H] 457.0737, found 457.0742.
1
9 18 3 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-4-
trifluoromethyl)benzenesulfonamide (11k). Yield 82%, light yellow solid, mp 167-168 ℃; H
NMR (400 MHz, CDCl ) δ 7.74 (d, J = 3.2 Hz, 2H),, 7.68 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 4.00 (t, J =
1
(
3
1
3
4
.8Hz, 2H), 2.93 (t, J = 4Hz, 2H), 2.64 (s, 3H), 1.80 – 1.69 (m, 4H), 1.56-1.43(m, 2H). C NMR
(
100 MHz, CDCl ) δ 160.20, 159.33, 157.46, 141.71, 134.24 (q, J = 32.9 Hz), 132.92, 125.20 (q, J =
3
3
.7 Hz), 124.58, 124.21, 121.85, 115.18, 41.85, 37.18, 29.23, 27.34, 24.83, 13.81. IR (KBr) v:
-
1
-
2
924, 1671, 1577, 1319, 1160, 780 cm . HRMS (ESI) calcd for C H F N O S [M-H] 457.0734,
1
9 18 3 3 3 2
found 457.0742.
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-2-
trifluoromethoxy)benzenesulfonamide (11l). Yield 79%, light yellow solid, mp 161-162 ℃; H
NMR (400 MHz, CDCl ) δ 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.85 (s, 1H), 7.57 (td, J = 8.1, 1.7 Hz, 1H),
1
(
3
7
.35 – 7.27 (m, 2H), 3.81 (t, J = 6.3 Hz, 2H), 2.89 (t, J = 6.5 Hz, 1H), 2.64 (s, 3H), 1.92 – 1.85 (m,

1
3
6
1
2
H). C NMR (100 MHz, CDCl ) δ 160.09, 159.21, 156.02, 147.39, 134.91, 132.15, 132.55,
3
31.72, 126.85, 124.22, 120.57 (d, J = 260.0 Hz), 119.67 (q, J = 5.8Hz), 115.21, 41.83, 37.24,
-
1
9.48, 27.25, 24.27, 13.70. IR (KBr) v: 2925, 1655, 1581, 1215, 1151, 1073, 738 cm . HRMS (ESI)
-
calcd for C H F N O S [M-H] 473.0695, found 473.0691.
1
9 18 3 3 4 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-3-
1
(
(
(
trifluoromethoxy)benzenesulfonamide (11m). Yield 81%, white solid, mp 142-143 ℃; H NMR
400 MHz, CDCl ) δ 7.68 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.27
3
1
3
d, J = 17.8 Hz, 1H), 4.05 – 4.00 (m, 2H), 2.95 – 2.89 (m, 2H), 2.61 (s, 3H), 1.75 – 1.53 (s, 6H). C
NMR (100 MHz, CDCl ) δ 160.03, 159.26, 157.50, 148.55 (q, J =2.8 Hz), 140.25, 132.55, 129.81,
3
1
2
26.46, 125.11, 124.27, 120.64, 120.09 (q, J = 258.8 Hz), 115.06, 41.78, 37.17, 29.31, 27.39,
-
1
4.78, 13.73. IR (KBr) v: 2922, 1663, 1580, 1488, 1254, 1161, 725 cm . HRMS (ESI) calcd for
-
C H F N O S [M-H] 473.0688, found 473.0691.
1
9 18 3 3 4 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-4-
trifluoromethoxy)benzenesulfonamide (11n). Yield 85%, light yellow solid, mp 124-125 ℃; H
NMR (400 MHz, CDCl ) δ 7.74 (d, J = 3.2 Hz, 2H),, 7.68 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 4.00 (t, J =
1
(
3
1
3
4
.8Hz, 2H), 2.93 (t, J = 4Hz, 2H), 2.64 (s, 3H), 1.80 – 1.69 (m, 4H), 1.56-1.43(m, 2H). C NMR
(
100 MHz, CDCl ) δ 160.20, 159.33, 157.46, 152.12 (q, J = 2.0 Hz), 136.57, 132.59, 130.14,
3
1
24.48, 119.4, 120.10 (q, J = 259.2 Hz), 115.18, 41.85, 37.18, 29.23, 27.34, 24.83, 13.81. IR (KBr)
-1
-
v: 2923, 1655, 1578, 1488, 1250, 1151, 629 cm . HRMS (ESI) calcd for C H F N O S [M-H]
1
9 18 3 3 4 2
4
73.0684, found 473.0691.
3
3
,5-Difluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11o). Yield 80%, light yellow solid, mp 205-206 ℃; H NMR (400
MHz, CDCl ) δ 7.76 (s, 1H), 7.21 (dt, J = 6.0, 3.7 Hz, 2H), 6.88 (tt, J = 8.4, 2.3 Hz, 1H), 4.13 (t, J =
3
1
3
4
.8Hz, 2H), 2.97 (t, J = 4Hz, 2H), 2.61 (s, 3H), 1.84-1.73 (m, 4H), 1.67-1.59(m, 2H). C NMR (100
MHz, CDCl ) δ 161.31 (dd, J = 254.0, 11.4 Hz), 160.11, 158.46., 156.03, 138.84 (t, J = 8.5 Hz),
3
1
2
32.79, 125.14, 115.54, 113.45 (q, J = 27.9 Hz), 109.38 (t, J = 25.0 Hz), 41.84, 37.31, 29.37,
-
1
7.51, 24.89, 13.71. IR (KBr) v: 2924, 1655, 1578, 1487, 1251, 1160, 631 cm . HRMS (ESI) calcd
-
for C H F N O S [M-H] 425.0675, found 425.0679.
1
8 17 2 3 3 2
3
3
,4-Difluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11p). Yield 83%, light yellow solid, mp 177-178 ℃; H NMR (400
MHz, CDCl ) δ 7.73 (s, 1H), 7.51 (ddd, J = 9.5, 7.3, 2.2 Hz, 1H), 7.42 – 7.30 (m, 1H), 7.15 – 6.95
3
(
m, 1H), 4.12 (t, J = 4.8Hz, 2H), 2.97 (t, J = 4Hz, 2H), 2.61 (s, 3H), 1.84-1.73 ( m, 4H), 1.65-1.58(m,
1
3
2
H). C NMR (100 MHz, CDCl ) δ 160.20, 159.41, 157.64, 153.07 (dd, J = 256.4, 12.1 Hz), 149.43
3
(
dd, J = 255.3, 12.3 Hz), 135.12 (d, J = 24.0 Hz), 132.68, 125.21 (d, J = 21.3 Hz), 124.27, 117.95
d, J = 20.0 Hz), 117.11 (d, J = 17.8 Hz), 115.20, 41.94, 37.24, 29.27, 27.41, 24.91, 13.75. IR (KBr)
(
-1
-
v: 2924, 1668, 1579, 1483, 1161, 1090, 623 cm . HRMS (ESI) calcd for C H F N O S [M-H]
1
8 17 2 3 3 2
4
25.0671, found 425.0679.

2
3
,6-Difluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11q). Yield 89%, light yellow solid, mp 204-205 ℃; H NMR (400
MHz, CDCl ) δ 7.93 (s, 1H), 7.39 (tt, J = 8.4, 5.8 Hz, 1H), 6.87 (t, J = 8.6 Hz, 2H), 4.10 (t, J = 4.8Hz,
3
1
3
2
H), 2.96 (t, J = 4Hz, 2H), 2.59 (s, 3H), 1.83-1.72(m, 4H), 1.62-1.53 (m, 2H). C NMR (100 MHz,
CDCl ) δ 160.05 (dd, J = 261.1, 3.7 Hz), 159.92, 159.25, 157.69, 134.36 (t, J = 10.9 Hz), 133.21,
3
1
2
23.33, 117.01 (t, J = 15.2 Hz), 115.28, 112.58 (dd, J = 23.5, 3.7 Hz), 41.89, 37.26, 29.36, 27.58,
-
1
4.93, 13.80. IR (KBr) v: 2923, 1656, 1575, 1470, 1166, 1000, 790 cm . HRMS (ESI) calcd for
-
C H F N O S [M-H] 425.0682, found 425.0679.
1
8 17 2 3 3 2
2
3
,5-Difluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11r). Yield 82%, white solid, mp 148-149 ℃; H NMR (400 MHz,
CDCl ) δ 7.86 (s, 1H), 7.40 – 7.31 (m, 1H), 7.15 (ddt, J = 9.2, 7.0, 3.4 Hz, 1H), 7.04 (td, J = 8.9, 4.0
3
Hz, 1H), 4.13(t, J = 4.8Hz, 2H), 2.97 (t, J = 4Hz, 2H), 2.57 (s, 3H), 1.84-1.73 (m, 4H), 1.65-1.56 (m,
1
3
2
H). C NMR (100 MHz, CDCl ) δ 160.08, 159.26, 157.67, 157.29 (dd, J = 247.2, 2.7 Hz), 155.60
3
(dd, J = 254.5, 2.8 Hz), 133.14, 128.16 (dd, J = 16.9, 6.9 Hz), 123.58, 121.36 (dd, J = 23.9, 8.5 Hz),
1
1
18.09 (dd, J = 24.6, 7.7 Hz), 117.17 (d, J = 27 Hz), 115.38, 41.95, 37.25, 29.34, 27.51, 24.90,
-1
3.90. IR (KBr) v: 2927, 1662, 1578, 1475, 1163, 1007, 725 cm . HRMS (ESI) calcd for
-
C H F N O S [M-H] 425.0686, found 425.0679.
1
8 17 2 3 3 2
2
3
,4-Difluoro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11s). Yield 79%, light yellow solid, mp 169-170 ℃; H NMR (400
MHz, CDCl ) δ 7.69 (s, 1H), 7.67 – 7.61 (m, 1H), 6.80 (ddd, J = 9.5, 4.4, 2.6 Hz, 2H), 4.11(t, J =
3
1
3
4
.8Hz, 2H), 2.96 (t, J = 4Hz, 2H), 2.58 (s, 3H), 1.83 – 1.75 (m, 4H), 1.65-1.58(m, 2H). C NMR
(
100 MHz, CDCl ) δ 165.80 (dd, J = 257.7, 12.0 Hz), 160.52 (dd, J = 262.9, 14.6 Hz), 160.02,
3
1
1
59.19, 157.63, 133.35, 132.46 (dd, J = 6.8, 5.4 Hz), 123.81, 123.33 (dd, J = 10.3, 7.9 Hz), 115.36,
11.13 (dd, J = 18.6, 7.2 Hz), 105.17 (d, J = 25.2Hz), 41.90, 37.24, 29.32, 27.50, 24.93, 13.81. IR
-
1
(KBr) v: 2929, 1670, 1564, 1482, 1168, 1071, 738 cm . HRMS (ESI) calcd for C H F N O S [M-
1
8 17 2 3 3 2
-
H] 425.0683, found 425.0679.
3
-Fluoro-4-methyl-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-
1
a]azepin-3-yl)benzenesulfonamide (11t). Yield 77%, light yellow solid, mp 200-201 ℃; H NMR
(
400 MHz, CDCl ) δ 7.74 (s, 1H), 7.35 – 7.27 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H), 4.10(t, J = 4.8Hz,
3
2
2
7
1
H), 2.96 (t, J = 4Hz, 2H), 2.61 (s, 3H), 2.23 (d, J = 1.8 Hz, 3H), 1.84-1.75 (m, 4H), 1.63-1.55(m,
1
3
H). C NMR (100 MHz, CDCl ) δ 161.42, 159.96, 158.99 (d, J = 8.7 Hz), 157.64, 137.59 (d, J =
3
.0 Hz), 131.91, 131.14 (d, J = 4.9 Hz), 130.37 (d, J = 17.1 Hz), 124.77, 123.50 (d, J = 3.7 Hz),
15.37, 114.86 (d, J = 24.6Hz), 41.87, 37.15, 29.26, 27.40, 24.95, 14.70 (d, J = 3.6 Hz), 13.78. IR
-
1
-
(KBr) v: 2923, 1673, 1576, 1409, 1157, 673 cm . HRMS (ESI) calcd for C H FN O S [M-H]
1
9
20
3 3 2
4
21.0921, found 421.0930.
4
-Fluoro-2-methyl-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-
1
a]azepin-3-yl)benzenesulfonamide (11u). Yield 79%, light yellow solid, mp 125-126 ℃; H NMR
(
400 MHz, CDCl ) δ 7.71 (s, 1H)7.73 – 7.66 (m, 1H), 6.85 (dd, J = 9.5, 2.5 Hz, 1H), 6.79 (td, J = 8.4,
3

2
4
.6 Hz, 1H), 4.11(t, J = 4.8Hz, 2H), 2.96 (t, J = 4Hz, 2H), 2.55 (s, 3H), 2.52 (s, 3H), 1.84-1.74 (m,
1
3
H), 1.67-1.58(m, 2H). C NMR (100 MHz, CDCl ) δ 160.02, 159.11, 157.72, 142.25 (d, J = 9.2
3
Hz), 133.01 (dd, J = 20.4, 6.2 Hz), 131.73, 124.81, 118.81, 118.60, 115.54, 112.70, 112.49, 41.90,
-
3
7.25, 29.32, 27.46, 24.93, 21.16, 13.77. IR (KBr) v: 2928, 1667, 1579, 1410, 1163, 950, 686 cm
1
-
.
HRMS (ESI) calcd for C H FN O S [M-H] 421.0925, found 421.0930.
19
20
3 3 2
4
-Chloro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-
1
yl)-3-nitrobenzenesulfonamide (11v). Yield 75%, light yellow solid, mp 211-212 ℃; H NMR
(
400 MHz, CDCl ) δ 7.95 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J =
3
8
.4 Hz, 1H),4.07(t, J = 4.8Hz, 2H), 2.97 (t, J = 4Hz, 2H), 2.63 (s, 3H), 1.85-1.74(m, 4H), 1.63-1.54
1
3
(m, 2H). C NMR (100 MHz, CDCl ) δ 160.53, 159.62, 157.50, 147.41, 138.44, 134.08, 131.93,
3
1
31.74, 130.96, 124.94, 123.46, 114.98, 42.06, 37.26, 29.35, 27.38, 24.83, 13.71. IR (KBr) v:
-
1
-
2
927, 1664, 1577, 1423, 1160, 760 cm . HRMS (ESI) calcd for C H ClN O S [M-H] 468.0334,
1
8
17
4 5 2
found 468.0329.
3
3
,5-Dichloro-N-(2-methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-
1
-yl)benzenesulfonamide (11w). Yield 81%, light yellow solid, mp 184-185 ℃; H NMR (400
MHz, CDCl ) δ 7.68 (s, 1H), 7.51 (d, J = 1.8 Hz, 2H), 7.39 (t, J = 1.8 Hz, 1H), 4.13(t, J = 4.8Hz, 2H),
3
1
3
2
.98 (t, J = 4Hz, 2H), 2.62 (s, 3H), 1.87-1.79 (m, 4H), 1.69-1.61 (m, 2H). C NMR (100 MHz, CDCl )
3
δ 160.24, 159.36, 157.61, 141.05, 135.11, 132.99, 132.36, 126.39, 123.98, 115.15, 42.02, 37.28,
-
1
2
9.38, 27.49, 24.89, 13.76. IR (KBr) v: 2922, 1664, 1584, 1342, 1171, 799 cm . HRMS (ESI) calcd
-
for C H Cl N O S [M-H] 457.0082, found 457.0088.
1
8
17
2 3 3 2
N-(2-Methyl-4-oxo-4,6,7,8,9,10-hexahydrothieno[2',3':4,5]pyrimido[1,2-a]azepin-3-yl)-[1,1'-
1
biphenyl]-4-sulfonamide (11x). Yield 85%, white solid, mp 170-171 ℃; H NMR (400 MHz,
CDCl ) δ 7.73 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 7.4 Hz, 4H), 7.41 (m, 3H), 3.99 (t, J =
3
1
3
4
.8Hz, 2H), 2.87 (t, J = 4Hz, 2H), 2.65 (s, 3H), 1.68 – 1.54 (m, 4H), 1.45-1.36 (m, 2H). C NMR
(
100 MHz, CDCl ) δ 159.92, 158.91, 157.52, 145.28, 138.97, 136.79, 132.03, 129.02, 128.52,
3
1
28.43, 127.00, 126.52, 125.06, 115.53, 41.77, 37.05, 29.10, 27.31, 24.83, 13.77. IR (KBr) v:
-
1
-
2
931, 1670, 1575, 1424, 1180, 781 cm . HRMS (ESI) calcd for C H N O S . [M-H] 465.1174,
2
4 23 3 3 2
found 465.1181
Biology
Materials and methods. Murine B16 melanoma cell lines (B16F10) were obtained from CAS
Chinese Academy of Sciences, China). The B16F10 cells were grown in DMEM medium (GIBICO,
(
USA) supplemented with 10% heat-inactivated fetal bovine serum (GIBICO, USA), 100 U/mL
penicillin and 100 mg/mL streptomycin (GIBCO, USA) in a humidified atmosphere with 5% CO2
at 37 °C.
Melanin contents assay

5
Exponentially growing cells were seeded into 6-well plates at a concentration of 5 x 10 cells per
well. After 24 h incubation at 37 °C, the culture medium was removed and replaced with fresh
medium containing the candidate compounds in different concentrations. The cells were
incubated for another 48 h, washed with ice cold PBS, followed by lysis with RIPA buffer for 40
min on ice, and the lysates were centrifuged at 10,000 g for 20 min. Supernatants containing
protein were subject to the protein assay and the pellets with intracellular melanin were
solubilized in 200 µl of 1 M NaOH for 2 h at 60 °C. Melanin amount was determined
spectrophotometrically at 405 nm by a multi-plate reader. The melanin amount was calculated
by normalizing the total melanin values with protein content (abs melanin/lg protein).
Conclusion
In summary, herein we have reported the synthesis and evaluation of two novel series of 3-
sulfonylamide containing pyrrolo- and azepino[1,2-a]thieno[2,3-d]pyrimidinone derivatives on
melanin synthesis in murine B16 cells. Likewise, cycloalkane side-ring influences and various
versions of ipso-nitration reactions toward a produce target sulfonamide derivatives were also
developed. In general, some of synthesized tricyclic thieno[2,3-d]pyrimidinones showed
promising potency. These results suggest that by the increasing of the thieno[2,3-
d]pyrimidinone side-ring, the activity of the prepared samples were also increased, when
substituents were at m- or o- positions (for example: from pyrrolo-, pyrido- and azepino- side-
rings, compounds activity increased by following regularity: p-CF <m-CF , o-CF . Thus, the
3
3
3
obtained results suggest that side-ring optimization influenced on melanin synthesis in murine
B16 cells and further biological evaluation of other novel tricyclic thieno[2,3-d]pyrimidinone
derivatives is ongoing and will be reported in due course.
Funding
This work was funded by grants from the Chinese Academy of Sciences President’s
International Fellowship Initiative (Grant No. 2016PT014) and National Natural Science
Foundation of China (NSFC) (Grant No. 21550110495).
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Figure 1. Biologically relevant thieno[2,3-d]pyrimidine scaffolds.
Chart 1

Scheme 1. Reagents and conditions: (a) appropriate lactams, POCl ; (b) HNO /H SO ; (c)
3
3
2
4
Cu(OAc) and AgNO , EtOH; (d) SnCl · 2H O, HCl, EtOH; (e) appropriate benzensulfonyl
2
3
2
2
chlorides, dichloromethane, pyridine.
Scheme 2. Pathway 1. Reagents and conditions: (a) H SO , MeOH, reflux; (b) HNO /H SO , -10 –
2
4
3
2
4
0
°C.

Table 1. Optimization of ipso-nitration reaction for the substrate 4.
Entry
Catalyst/
mol%)
Nitrate sources
Time
Yeild
(%)
65
(h)
(
1
Cu(OAc) /50
AgNO3
NaNO3
Ca(NO3)2
AgNO3
5
5
2
2
3
4
5
6
7
8
9
1
Cu(OAc) /50
45
2
Cu(OAc) /50
10
10
10
10
15
15
15
20
48
2
Cu(OAc) /70
85
2
Cu(OAc) /70
NaNO3
Ca(NO3)2
AgNO3
65
2
Cu(OAc) /70
62
2
Cu(OAc) /100
85
2
Cu(OAc) /100
NaNO3
Ca(NO3)2
AgNO3
68
2
Cu(OAc) /100
66
2
0
Cu(OAc) /60
82
2

Table 2. Optimization of ipso-nitration reaction for the substrate 2.
Entry
Nitrating mixture
HNO /H SO
Temperature (°C)/ Yield
(%)
Time (h)
-10 – 0/5
-10 – 0/5
-10 – 0/5
-10 – 0/5
-25 – 10/2
1
―
5
3
2
4
2
3
4
5
HNO /CH COOH
3
3
Cu(NO ) / (CH CO) O
trace
5
3
2
3
2
HNO /(CH CO) O
3
3
2
HNO3
15