Quinoline carboxamide-type ABCG2 modulators: Indole and quinoline moieties as anilide replacements

Full text of DOI:10.1002/cmdc.201300319

Supporting Information
ꢀ
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2013
Quinoline Carboxamide-Type ABCG2 Modulators: Indole
and Quinoline Moieties as Anilide Replacements
[
a]
[b]
[b]
[b]
[a]
Stefanie Bauer, Cristian Ochoa-Puentes, Qiu Sun, Manuel Bause, Gꢀnther Bernhardt,
[b]
[a]
Burkhard Kçnig,* and Armin Buschauer*
cmdc_201300319_sm_miscellaneous_information.pdf

Contents
1
Synthesis of tetrahydroisoquinolines 20-23 ....................................................................................... 2
.1 Experimental details and analytical data .................................................................................... 2
1
1
13
1
.2 H and C NMR spectra............................................................................................................. 4
Synthesis of compounds 24a-h and 25a-h......................................................................................... 6
.1 Experimental details and analytical data .................................................................................... 6
2
2
1
13
2
.2 H and C NMR spectra........................................................................................................... 14
.3 HPLC analysis of compounds 24a-g and 25a-h....................................................................... 43
2
3
Synthesis of compounds 26-28 and further analogs........................................................................ 47
.1 Experimental details and analytical data .................................................................................. 47
3
1
13
3
.2 H and C NMR spectra........................................................................................................... 53
.3 HPLC analysis of compounds 26-28 ........................................................................................ 67
3
4
5
Assay protocol for the determination of ABCC1 inhibition ............................................................... 69
Chemical Stability in mouse plasma................................................................................................. 70
5
.1 Enzymatic cleavage of compound UR-COP78 ........................................................................ 71
.2 Enzymatic cleavage of compound 25a (UR-COP240)............................................................. 73
.3 Enzymatic cleavage of compound 25c (UR-COP251) ............................................................. 75
.4 Enzymatic cleavage of compound 25g (UR-COP269)............................................................. 77
.5 Enzymatic cleavage of compound 25h (UR-COP272)............................................................. 79
5
5
5
5
6
References ....................................................................................................................................... 81
1

Synthesis of tetrahydroisochinolines 20-23
1
Synthesis of tetrahydroisoquinolines 20-23
Chemicals and solvents were purchased from commercial suppliers and used without further
purification.
1.1
Experimental details and analytical data
[1]
Compound 20 and 21 are commercially available; the synthesis of 22 has already been reported.
Synthesis of compound 23:
Scheme 1: Synthesis of 23. Reagents and conditions: (a) HBr/CH COOH, reflux. (b) Boc O, Et N,
3
2
3
2 3 2
DCM 0 °C. (c) 31, K CO , THF, reflux. (d) TFA, DCM, rt. (e) TosCl, NaOH, H O/THF, rt.
1
,2,3,4-Tetrahydroisoquinoline-6,7-diol hydrobromide 29
[2]
Compound 29 has already been described. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (21.8
mmol) was refluxed in a mixture of HBr (24 mL, 48% in H O) and CH COOH (96 mL) for 8 h. The
2
3
solvent mixture was removed by distillation. The product was used without purification. Yield: 21.8
1
mmol (100%). H NMR (400 MHz, CD OD, δ): 2.95 (t, J = 6.3 Hz, 2 H, CH ), 3.31 (quint, J = 1.7 Hz, 1
3
2
H, NH), 3.42 (d, J = 6.4 Hz, 2 H, CH
2
), 4.18 (s, 2 H, CH
2
), 6.59 (s, 1 H, CHar), 6.62 (s, 1 H, CHar).
tert-Butyl 6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate 30
[2]
Compound 30 was prepared according to known procedures from 2 (21.8 mmol), Di-tert-
butyldicarbonate (0.95 eq, 20.7 mmol), and triethylamine (5 eq, 109 mmol). Flash column
chromatography (PE:EA 1:1) of the sticky brown crude product yielded a slightly yellow solid. Yield:
1
1
2.9 mmol (63 %). R (PE:EA 1:1): 0.58. H NMR (400 MHz, CDCl , δ): 1.48 (s, 9 H), 2.66 (t, J = 5.6
f
3
Hz, 2 H), 3.58 (s, 2 H), 4.41 (s, 2 H), 6.55 (s, 1 H), 6.58 (s, 1 H).
2
-(2-(2-Methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate 31
[3]
Compound 31 was prepared according to known procedures. It was obtained as colorless oil and
2

Synthesis of tetrahydroisochinolines 20-23
1
used without further purification. Yield: 88.1 mmol (76 %). H NMR (400 MHz, CDCl
3
, δ): 2.42 (s, 3 H),
3.34 (s, 3 H), 3.48-3.52 (m, 2 H), 3.55-3.60 (m, 6 H), 3.66 (t, J = 4.8, 3 H), 4.13 (t, J = 4.8, 3 H), 7.32
(d, J = 8.2, 2 H), 7.77 (d, J = 8.3, 2 H).
tert-Butyl 6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinoline-2(1H)-
carboxylate 32
Compound 30 (12.9 mmol), potassium hydroxide (2.4 eq, 31.0 mmol), and 31 (2.4 eq, 31.0 mmol)
were dissolved in tetrahydrofurane and refluxed overnight. The solvent was evaporated and the
residue was taken up in ethyl acetate, washed with water and brine, and concentrated. Flash column
chromatography (EA) of the crude product yielded 32 as yellow oil. Yield: 9.5 mmol (73 %). R (EA):
f
1
t
0
.26; R (CHCl :MeOH 19:1): 0.33. H NMR (400 MHz, CDCl , δ): 1.41 (s, 9 H, Bu), 2.65 (t, J = 5.3 Hz,
f
3
3
2
H, NCH
2
CH
2
C
q
), 3.30 (s, 6 H, OCH
3 2 2 q
), 3.46-3.49 (m, 4 H, PEG), 3.51-3.56 (m, 2 H, NCH CH C ),
3
4
.56-3.61 (m, 8 H, PEG), 3.65-3.68 (m, 4 H, PEG), 3.77 (t, J = 5.1 Hz, 4 H, PEG), 4.06 (t, J = 5.04 Hz,
13
H, PEG), 4.39 (s, 2 H, NCH C ), 6.57 (s, 1 H, NCH C CH ), 6.60 (s, 1 H, NCH CH C CH ).
C
2
q
2
q
ar
2
2
q
ar
t
NMR (101 MHz, CDCl
3
, δ): 28.42 (CH
2
), 28.49 (CH
3
Bu), 40.60 (CH
PEG), 69.61 (CH
2
), 41.90 (CH
PEG), 70.53 (CH
tBu), 112.74 (CHar), 115.07 (CHar), 126.24
2
), 44.86 (CH), 45.53
(
(
(
CH
CH
2
), 59.01 (CH
3
), 69.02 (CH
PEG), 71.92 (CH
2
PEG), 69.08 (CH
2
2
2
PEG), 70.67
2
PEG), 70.78 (CH
2
2
PEG), 79.72 (C
q
-
1
C ), 127.55 (C ), 147.49 (C ), 147.54 (C ), 154.89 (C=O). FTIR (cm ): ν 2933.7 (m, br), 2877.8 (m,
q
q
q
q
br), 1695.4 (m), 1516.0 (w), 1456.3 (w), 1415.7 (w), 1365.6 (w), 1259.5 (m), 1161.1 (m), 1101.4 (m),
+
6
32.7 (s), 536.2 (s), 495.7 (s), 403.1 (s). MS–ESI (m/z): [M + H] calcd. for C H NO 558.3; found
28 47 10
5
58.1.
,7-Bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-1,2,3,4-tetrahydroisoquinoline 2,2,2-
6
trifluoroacetate 23
Compound 31 (9.0 mmol) was dissolved in DCM and trifluoroacetic acid (10 eq, 90 mmol) and stirred
overnight at room temperature. The solvent was evaporated to yield 23 as a gray solid, which was
1
used without further purification. Yield: 9.0 mmol (100 %). H NMR (400 MHz, CD OD, δ): 3.00 (t, J =
3
6
.2 Hz, 2 H, NCH CH C ), 3.35 (s, 6 H, OCH ), 3.49 (t, J = 6.4 Hz, 2 H, NCH CH C ), 3.52-3.56 (m, 4
2 2 q 3 2 2 q
H, PEG), 3.63-3.68 (m, 8 H, PEG), 3.71-3.74 (m, 4 H, PEG), 3.82-3.85 (m, 4 H, PEG), 4.07-4.13 (m, 4
13
H, PEG), 4.25 (s, 2 H, NCH C ), 6.68 (s, 1 H, NCH C CH ), 6.73 (s, 1 H, NCH CH C CH ). C NMR
2
q
2
q
ar
2
2
q
ar
(
101 MHz, CD OD, δ): 25.64 (CH ), 43.05 (CH ), 45.59 (CH ), 59.17 (CH ), 70.23 (CH PEG), 70.34
3
2
2
2
3
2
(
CH
2
PEG), 70.92 (CH
2
PEG), 71.37 (CH
2
PEG), 71.67 (CH
2
PEG), 71.76 (CH
2
PEG), 72.96 (CH
2
q
-
1
PEG), 113.86 (CH ), 115.77 (CH ), 121.95 (C ), 125.73 (C ), 149.28 (C ), 150.02 (C ). FTIR (cm ): ν
ar
ar
q
q
q
3063.0 (w, br), 2935.7 (m, br), 2879.7 (m, br), 1776.4 (m), 1612.5 (w), 1525.7 (m), 1458.2 (w), 1352.1
(
(
w), 1263.4 (w), 1215.2 (m), 1168.9 (s), 1118.7 (s), 1051.2 (s), 962.5 (m), 858.3 (m), 790.8 (m), 700.2
+
s), 609.5 (w), 586.4 (w), 461.0 (m), 424.3 (m). HRMS–ESI (m/z): [M + H] calcd. for C H NO
23
40
8
458.2748; found 458.2757. MP: 46.7 °C (45.4 – 48.0 °C).
3

Synthesis of tetrahydroisochinolines 20-23
1
13
1.2
H and C NMR spectra
tert-Butyl 6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinoline-2(1H)-
carboxylate 32
4

Synthesis of tetrahydroisochinolines 20-23
6,7-Bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-1,2,3,4-tetrahydroisoquinoline 2,2,2-
trifluoroacetate 23
5

Synthesis of compounds 24a-h and 25a-h
2
2
2
Synthesis of compounds 24a-h and 25a-h
Experimental details and analytical data
-(4-Amino-3-iodophenyl)ethanol 4
.1
[4]
Ethyl 2-(4-amino-3-iodophenyl)acetate 2 (100 mg, 0.32 mmol) was dissolved in anhydrous THF, the
solution was cooled in an ice bath and BH THF complex (0.97 mL, 0.97 mmol, 3 equiv) was added
3
.
dropwise. After the addition, the reaction was stirred at rt during 3 h and quenched with MeOH, diluted
with water and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4.
After evaporating the solvent, the compound was purified by recrystallization from PE:AcOEt 1:1. Yield
°
1
4
7
(
7%, white solid, mp. 81.4-82.0 C. H NMR (CD OD, 300 MHz): δ= 7.47 (d, J=1.9 Hz, 1H, ArH), 6.98
3
3 4 3 3
dd, J=8.1, J=2.0 Hz, 1H, ArH), 6.73 (d, J=8.1 Hz, 1H, ArH), 3.65 (t, J=7.0 Hz, 2H, CH
2
), 2.64 (t,
3
13
J=7.0 Hz, 2H, CH
2
). C NMR (CD
3
OD, 75 MHz): δ= 147.4 (Cquat,), 140.1 (+), 131.6 (Cquat,), 131.0 (+),
+
1
2
16.1 (+), 84.6 (Cquat,), 64.3 (–), 38.8 (–). HRMS (EI-MS) calcd. for C H10INO [MH] : 262.9807; found:
62.9809. IR (KBr) [cm ]: ν = 3372, 3267, 2947, 2860, 1601, 1495, 665, 584.
8
-
1
4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-iodoaniline 6
Imidazole (140 mg, 2.09 mmol, 1.1 equiv) was added to a mixture of 2-(4-amino-3-iodophenyl)ethanol
(500 mg, 1.9 mmol, 1 equiv) and TBDMS -Cl (310 mg, 2.09 mmol, 1.1 equiv) in 10 mL of anhydrous
4
DCM. The reaction was stirred at rt for 4 h, water was added and the organic phase was separated,
washed with brine and dried over MgSO . After evaporating the solvent, the compound was purified by
4
o
1
flash chromatography (PE:AcOEt 10:1, R = 0.22). Yield 99%, light yellow solid, mp. 81.4-82.0 C. H
f
4
3
4
NMR (CDCl
(
0
3
, 300 MHz): δ= 7.51 (d, J=1.7 Hz, 1H, ArH), 6.98 (dd, J=8.1, J=1.8 Hz, 1H, ArH), 6.67
3
3
3
d, J=8.1 Hz, 1H, ArH), 3.98 (s, 2H, NH ), 3.73 (t, J=6.9 Hz, 2H, CH ), 2.67 (t, J=6.9 Hz, 2H, CH ),
2
2
2
13
.89 (s, 9H, 3 CH ), -0.00 (s, 6H, 2 CH ). C NMR (CDCl , 75 MHz): δ= 144.9 (Cquat,), 139.3 (+), 131.0
3 3 3
(Cquat,), 130.1 (+), 114.5 (+), 84.1 (Cquat,), 64.5 (–), 38.0 (–), 25.9 (+), 18.3 (Cquat,), -5.3 (+). HRMS (EI-
+
-
1
MS) calcd. for C H INOSi [M+H] : 378.0745; found: 378.0750. IR (KBr) [cm ]: ν = 3448, 3207, 2951,
14
25
2856, 1616, 1498, 665.
General procedure for the preparation of the methanesulfonamides 7 and 8.
Methanesulfonyl chloride (0.36 mmol) was added dropwise to a solution of the aromatic amines 5
[5]
o
or 6 (0.36 mmol) in 5 mL of pyridine at 0 C. The mixture was stirred at room temperature overnight.
Water and AcOEt were added, the organic phase was separated, washed with 1 N HCl, 1 N NaHCO3
4
and dried over MgSO . After evaporating the solvent, the compound was recrystallized from PE:DCM
1
:1 (compound 8) or used without any further purification (compound 7).
N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-iodophenyl)methanesulfonamide 7
1
Yield 80%, white solid, mp. 100.3-101.8 °C, H NMR (CDCl , 300 MHz): δ= 7.81-7.78 (m, 1H, ArH),
3
3
3
4
7
.59 (d, J=8.3 Hz, 1H, ArH), 7.31 (dd, J=8.4, J=1.6 Hz, 1H, ArH), 6.57 (s, 1H, NH), 4.67 (s, 2H,
CH ), 2.99 (s, 3H, CH ), 0.94 (s, 9H, 3 CH ), 0.11 (s, 6H, 2 CH ). C NMR (CDCl , 75 MHz) δ 141.1
2 3 3 3 3
13
(
(
Cquat,), 136.8 (+), 136.1 (Cquat,), 127.5 (+), 122.6 (+), 92.4 (Cquat,), 63.4 (–), 40.0 (+), 25.9 (+), 18.4
+
C
3
quat,), -5.2 (+). HRMS (EI-MS) calcd. for C14H24INO SSi [MH] : 441.0291; found: 441.0290. IR (KBr)
-1
[cm ]: ν = 3273, 2953, 1327, 1149, 1089, 775.
N-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-iodophenyl)methanesulfonamide 8
1
4
Yield 83%, viscous orange oil. H NMR (CDCl , 300 MHz): δ= 7.75 (d, J=1.8 Hz, 1H, ArH), 7.58 (d,
3
3
3
4
3
J=8.3 Hz, 1H, ArH), 7.25 (dd, J=8.3, J=1.5 Hz, 1H, ArH), 6.62 (s, 1H, NH), 3.82 (t, J=6.4 Hz, 2H,
3
13
CH ), 3.01 (s, 3H, CH ), 2.78 (t, J=6.4 Hz, 2H, CH ), 0.89 (s, 9H, 3 CH ), -0.00 (s, 6H, 2 CH ).
C
2
3
2
3
3
NMR (CDCl
3
, 75 MHz) δ 140.0 (+), 139.5 (Cquat,), 135.6 (Cquat,), 130.7 (+), 122.8 (+), 92.5 (Cquat,), 63.7
+
(
–), 39.9 (+), 38.1 (–), 25.8 (+), 18.2 (Cqu-at,), -5.4 (+). HRMS (EI-MS) calcd. for C15
H
3
27INO SSi [M+H] :
1
456.0520; found: 456.0513. IR (KBr) [cm ]: ν =2926, 2856, 1332, 1161, 632.
Methyl 2-amino-4-((trimethylsilyl)ethynyl)benzoate 10
A mixture of methyl 2-amino-4-bromobenzoate 9 (100 mg, 0.43 mmol), trimethylsilylacetylene (73 µL,
0
.52 mmol, 1.2 equiv.), CuI (8.1 mg, 430 µmol, 10% mol) and Pd(PPh ) Cl (15 mg, 21.5 µmol,
3 2 2
o
5%mol) in 5 mL of THF/TEA 2/1 was stirred and heated at 60 C for 6 h. Water and DCM were added,
, brine and dried over MgSO . The
the organic layer separated and washed with 1N HCl, 1N NaHCO
3
4
solvent was evaporated and the compound was purified by flash chromatography PE:AcOEt 10:1.
6

Synthesis of compounds 24a-h and 25a-h
1
3
Yield 73%, Yellow solid, mp. 69-73.1 °C, R
f
= 0.27. H NMR (CDCl
3
, 300 MHz): δ= 7.72 (d, J=8.3 Hz,
4
3
4
1
H, ArH), 6.73 (d, J=1.4 Hz, 1H, ArH), 6.67 (dd, J=8.3, J=1.5 Hz, 1H, ArH), 5.68 (s, 2H, NH ), 3.80
2
13
(
(
(
s, 3H, OCH
3
), 0.20 (s, 9H, 3 CH
3
). C NMR (CDCl
3
, 75 MHz): δ= 168.2 (C=O
,
), 150.1 (Cquat,), 131.2
+), 128.6 (Cquat,), 119.9 (+), 119.7 (+), 110.6 (Cquat,), 104.5 (Cquat,), 96.5 (Cquat,), 51.7 (+), -0.01 (+). MS
CI-MS NH ): m/z (%)= 247.1 (75) [MH] ˙. IR (KBr) [cm ]: ν = 3460, 3354, 2949, 2160, 1689, 1244,
+
-1
3
837, 758.
Methyl 2-amino-4-ethynylbenzoate 11
A solution of methyl 2-amino-4-((trimethylsilyl)ethynyl)benzoate 10 (77 mg, 0.31 mmol) in 5 mL THF
was stirred and cooled in an ice bath. TBAF (0.31 mL, 0.31 mmol, 1M in THF) was added and the
reaction was stirred for 10 min. The solvent was evaporated, saturated NH Cl solution was added and
4
the compound was extracted with DCM. The organic layer was separated and dried over MgSO
4
. The
solvent was evaporated and the compound was purified by flash chromatography PE:AcOEt 10:1.
1
3
Yield 74%, Yellow solid, mp. 75.1-76.8 °C, R = 0.22. H NMR (CDCl , 300 MHz): δ= 7.82 (d, J=8.3
f
3
4
3
4
Hz, 1H, ArH), 6.81 (d, J=1.5 Hz, 1H, ArH), 6.76 (dd, J=8.2, J=1.5 Hz, 1H, ArH), 5.77 (s, 2H, NH
2
),
, 75 MHz): δ= 168.0 (C=O), 149.9 (Cquat,), 131.2 (+),
27.5 (Cquat,), 120.0 (+), 119.7 (+), 110.8 (Cquat,), 83.0 (Cquat,), 79.0 (+), 51.6 (+). MS (EI-MS): m/z (%)=
13
3
1
1
3 3
.88 (s, 3H, OCH ), 3.16 (s, 1H). C NMR (CDCl
+
-1
75.1 (100) [MH] ˙. IR (KBr) [cm ]: ν = 3479, 3375, 3244, 2949, 1689, 1244, 1099, 769.
General procedure for the synthesis of compounds 12 and 13
A mixture of methyl 2-amino-4-ethynylbenzoate 11 (0.57 mmol), Methanesulfonamides 7 or 8 (0.57
mmol), CuI (10.8 mg, 57 µmol, 10% mol) and Pd(PPh ) Cl (20 mg, 28.5 µmol, 5%mol) in 5 mL of
3
2
2
o
DMF/TEA 2/1 was stirred and heated at 90 C for 24 h. Water was added and the compound was
extracted with AcOEt. The organic layer was dried over MgSO and the solvent evaporated. The
4
compound was purified by flash chromatography PE:AcOEt 10:3.
Methyl 2-amino-4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(methylsulfonyl)-1H-indol-2-
yl)benzoate 12
1
3
Yield 69%, Yellow solid, mp. 112-114.8 °C, R = 0.29. H NMR (CDCl , 300 MHz): δ= 8.03 (d, J=8.6
Hz, 1H, ArH), 7.87 (d, J=8.2 Hz, 1H, ArH), 7.54 (d, J=0.8 Hz, 1H, ArH), 7.31 (dd, J=8.6, J=1.6 Hz,
f
3
3
4
3
4
1
OCH
H, ArH), 6.87-6.80 (m, 2H, ArH), 6.73 (s, 1H, ArH), 5.49 (bs, 2H, NH ), 4.83 (s, 2H, CH ), 3.86 (s, 3H,
2
2
13
3
), 2.69 (s, 3H, SO
2
CH
3
), 0.95 (s, 9H, 3 OCH
3 3 3
), 0.12 (s, 6H, 2 CH ). C NMR (CDCl , 75 MHz) δ
168.3 (C=O), 149.6 (Cquat,), 141.5 (Cquat,), 138.2 (Cquat,), 137.5 (Cquat,), 137.4 (Cquat,), 130.5 (+), 130.3
(
(
Cquat,), 123.9 (+), 118.6 (+), 118.2 (+), 117.9 (+), 115.7 (+), 113.9 (+), 110.7, 64.8 (–), 51.6 (+), 38.9
+
+
4
+), 26.0 (+), 18.4 (Cquat,), -5.1 (+). MS (EI-MS): m/z (%)= 530 (100) [M+NH ] , 489 (10) [MH] . IR (KBr)
-
1
[cm ]: ν = 3496, 3381, 2953, 2858, 1678 775.
Methyl 2-amino-4-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(methylsulfonyl)-1H-indol-2-
yl)benzoate 13
1
3
Yield 54%, Yellow solid, mp. 132-134 °C, R = 0.36. H NMR (CDCl , 300 MHz): δ= 8.01 (d, J=8.5 Hz,
f
3
3
4
3
4
1H, ArH), 7.90 (d, J=8.1 Hz, 1H, ArH), 7.44 (d, J=1.0 Hz, 1H, ArH), 7.26 (dd, J=8.9, J=1.9 Hz, 1H,
ArH), 6.91-6.84 (m, 2H, ArH), 6.73 (s, 1H, ArH), 5.83 (bs, 2H, NH ), 3.91-3.83 (m, 5H, OCH , CH ),
2
3
2
3
13
2
.94 (t, J=6.9 Hz, 2H, CH ), 2.70 (s, 3H, SO CH ), 0.89 (s, 9H, 3 CH ), 0.00 (s, 6H, 2 CH ). C NMR
2 2 3 3 3
(
3
CDCl , 75 MHz) δ: 168.3 (C=O), 149.7 (Cquat,), 141.4 (Cquat,), 137.5 (Cquat,), 137.0 (Cquat,), 136.0
(
(
C
Cquat,), 130.5 (+), 130.4 (Cquat,), 126.9 (+), 121.5 (+), 118.1 (+), 117.9 (+), 115.6 (+), 113.8 (+), 110.7
Cquat,), 64.6 (–), 51.6 (+), 39.3 (–), 38.7 (+), 25.9 (+), 18.3 (Cquat,), -5.3 (+). HRMS (EI-MS) calcd. for
H N O SSi [M+H] : 503.2030; found: 503.2035. IR (KBr) [cm ]: ν = 3495, 3379, 2951, 2854, 1689,
25 35 2 5
+
-1
7
73.
General procedure for the preparation of compounds 14 and 15
To a mixture of 12 or 13 (0.38 mmol) and TEA (1.66 mmol, 3 equiv.) in anhydrous DCM, quinoline-2-
o
carbonyl chloride (0.45 mmol, 1.2 equiv.) was added. The mixture was stirred and heated at 40 C
3
overnight. 1N HCl was added and the compound was extracted with DCM, washed with 1N NaHCO ,
brine and dried over MgSO . The solvent was evaporated and the compound was purified by flash
4
chromatography PE:AcOEt 10:3.
Methyl 4-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-
2
-carbonylamino)benzoate 15
1
Yield 92%, Yellow solid, mp. 81-83 °C, R = 0.45. H NMR (CDCl , 300 MHz): δ= 13.39 (s, 1H, NHCO),
f
3
4
3
3
9.30 (d, J=1.6 Hz, 1H, ArH), 8.38-8.33 (m, 3H, ArH), 8.17 (d, J=8.3 Hz, 1H, ArH), 8.02 (d, J=8.5 Hz,
7

Synthesis of compounds 24a-h and 25a-h
3
3
3
4
1
1
H, ArH), 7.90 (d, J=8.2 Hz, 1H, ArH), 7.83 (ddd, J=8.4, J=6.9, J=1.4 Hz, 1H, ArH), 7.69-7.62 (m,
4 3 4 3 4
H, ArH), 7.46 (d, J=1.1 Hz, 1H, ArH), 7.41 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.27 (dd, J=8.5, J=1.7
3
3
Hz, 1H, ArH), 6.89 (s, 1H, ArH), 4.08 (s, 3H, OCH
3
), 3.88 (t, J=6.8 Hz, 2H, CH
2
), 2.95 (t, J=6.8 Hz,
13
2
1
1
1
H, CH
2
), 2.84 (s, 3H, SO
2
CH
3
), 0.89 (s, 9H, 3 CH
3
), 0.00 (s, 6H, 2 CH
3
). C NMR (CDCl , 75 MHz): δ
3
67.7 (C=O), 163.8 (C=O), 149.9 (Cquat,), 146.6 (Cquat,), 141.0 (Cquat,), 140.4 (Cquat,), 138.0 (Cquat,),
37.7 (+), 137.1 (Cquat,), 136.0 (Cquat,), 130.4 (Cquat,), 130.3 (+), 130.3 (+), 130.2 (+), 129.4 (Cquat,),
28.3 (+), 127.6 (+), 127.1 (+), 125.3 (+), 121.6 (+), 120.6 (+), 118.8 (+), 116.1 (Cquat,), 115.5 (+), 114.5
(
C
+), 64.6 (–), 52.5 (+), 39.3 (–), 39.2 (+), 25.9 (+), 18.3 (C ), -5.3 (+). HRMS (EI-MS) calcd. for
H N O SSi [M+H] : 658.2402; found: 658.2402. IR (KBr) [cm ]: ν = 2953, 2856, 1685, 771.
35 40 3 6
quat,
-1
+
Methyl 4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-
-carbonylamino)benzoate 14
3
Yield 76%, Yellow solid, mp. 165-167 °C, R = 0.50. H NMR (CDCl , 300 MHz): δ= 13.34 (s, 1H,
3
2
1
f
4
NHCO), 9.25 (d, J=1.6 Hz, 1H, ArH), 8.34-8.29 (m, 3H, ArH), 8.13 (d, J=8.3 Hz, 1H, ArH), 8.01 (d,
3
3
3
3
4
J=8.6 Hz, 1H, ArH), 7.87 (d, J=8.1 Hz, 1H, ArH), 7.79 (ddd, J=8.4, J=6.9, J=1.3 Hz, 1H, ArH),
3
4
3
7
.65-7.59 (m, 1H, ArH), 7.54 (s, 1H, ArH), 7.37 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.31 (dd, J=8.6,
4
J=1.4 Hz, 1H, ArH), 6.87 (s, 1H, ArH), 4.82 (s, 2H, CH
2
), 4.03 (s, 3H, OCH
3 2 3
), 2.81 (s, 3H, SO CH ),
13
0
1
.93 (s, 9H, 3 CH ), 0.09 (s, 6H, 2 CH ). C NMR (CDCl , 75 MHz) δ: 167.7 (C=O), 163.8 (C=O),
49.9 (Cquat,), 146.6 (Cquat,), 141.1 (Cquat,), 140.4 (Cquat,), 138.2 (Cquat,), 137.9 (Cquat,), 137.7 (+), 137.5
3
3
3
(
(
(
(
Cquat,), 130.3 (+), 130.3 (+), 130.2 (+), 129.4 (Cquat,), 128.3 (+), 127.6 (+), 125.3 (+), 124.0 (+), 120.6
+), 118.8 (+), 118.7 (+), 116.2 (Cquat,), 115.6 (+), 114.7 (+), 64.9 (–), 52.5 (+), 39.4 (+), 26.0 (+), 18.4
+
Cquat,), -5.1 (+). HRMS (EI-MS) calcd. for C H N NaO SSi [M+Na] : 666.2065; found: 666.2066. IR
KBr) [cm ]: ν = 2949, 2852, 1705, 1676, 767.
34
37
3
6
-
1
Synthesis of compounds 16 and 17. General procedure.
A solution of 14 or 15 (0.15 mmol) in 5 mL THF was stirred and cooled in an ice bath. TBAF (0.15
mmol, 1M in THF) was added and the reaction was stirred for 10 min. The solvent was evaporated,
saturated NH Cl solution was added and the compound was extracted with DCM. The organic layer
4
4
was separated and dried over MgSO . The solvent was evaporated and the compound was purified by
flash chromatography PE:AcOEt 2:3.
Methyl 4-(5-(2-hydroxyethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)-
benzoate 17
1
Yield 61%, Yellow solid, mp. 198-200 °C, R = 0.32. H NMR (CDCl , 300 MHz): δ= 13.38 (s, 1H,
f
3
4
3
NHCO), 9.28 (d, J=1.6 Hz, 1H, ArH), 8.39-8.32 (m, 3H, ArH), 8.17 (d, J=8.3 Hz, 1H, ArH), 8.03 (d,
3
3
3
3
4
J=8.5 Hz, 1H, ArH), 7.91 (d, J=8.1 Hz, 1H, ArH), 7.83 (ddd, J=8.4, J=7.0, J=1.3 Hz, 1H, ArH),
3
4
7.70-7.62 (m, 1H, ArH), 7.47 (s, 1H, ArH), 7.39 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.29-7.24 (m, 1H,
3
3
3 2 2
ArH), 6.86 (s, 1H, ArH), 4.08 (s, 3H, OCH ), 3.93 (t, J=6.5 Hz, 2H, CH ), 2.99 (t, J=6.5 Hz, 2H, CH ),
13
2.89 (s, 3H, SO CH ). C NMR (CDCl , 75 MHz) δ: 167.7 (C=O), 163.8 (C=O), 149.9 (Cquat,), 146.6
2 3 3
(
C
quat,), 141.1 (Cquat,), 140.3 (Cquat,), 137.9 (Cquat,), 137.7 (+), 137.1 (Cquat,), 135.1 (Cquat,), 130.6 (Cquat,),
130.4 (+), 130.3 (+), 130.2 (+), 129.4 (Cquat,), 128.3 (+), 127.6 (+), 126.6 (+), 125.3 (+), 121.5 (+), 120.7
(
+), 118.8 (+), 116.2 (Cquat,), 115.8 (+), 114.2 (+), 63.8 (–), 52.5 (+), 39.7 (+), 39.0 (–). HRMS (EI-MS)
+
-
1
calcd. for C H N O S [M+H] : 544.1537; found: 544.1541. IR (KBr) [cm ]: ν = 2937, 2883, 1683,
29
26
3
6
7
69.
Methyl 4-(5-(hydroxymethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)-
benzoate 16
1
Yield 73%, Yellow solid, mp. 172.6-174 °C, R = 0.25. H NMR (DMSO, 300 MHz): δ= 13.12 (s, 1H,
f
4
3
3
NHCO), 9.12 (d, J=1.6 Hz, 1H, ArH), 8.62 (d, J=8.5 Hz, 1H, ArH), 8.25 (d, J=8.5 Hz, 1H, ArH), 8.18
3
3
4
(
d, J=8.4 Hz, 1H, ArH), 8.09 (m, 2H, ArH), 7.92 (m, 2H, ArH), 7.75 (td, J=7.1, J=0.8 Hz, 1H, ArH),
3 4
7
2
.67 (s, 1H, ArH), 7.43 (td, J=8.3, J=1.5 Hz, 2H, ArH), 7.05 (s, 1H, ArH), 5.32 (s, 1H, OH), 4.64 (s,
13
H, CH ), 4.03 (s, 3H, OCH ), 3.22 (s, 3H, SO CH ). C NMR (75 MHz, DMSO) δ: 166.8 (C=O), 162.7
2
3
2
3
(
C=O), 149.1 (Cquat,), 145.6 (Cquat,), 140.0 (Cquat,), 139.0 (Cquat,), 138.7 (Cquat,), 138.3 (+), 137.8 (Cquat,),
136.6 (Cquat,), 130.7 (+), 130.3 (+), 129.5 (Cquat,), 129.2 (+), 128.9 (Cquat,), 128.5 (+), 128.0 (+), 124.3
(
4
+), 124.1 (+), 120.5 (+), 119.0 (+), 118.4 (+), 115.6 (Cquat,), 114.7 (+), 113.6 (+), 62.6 (–), 52.6 (+),
0.1 (+). HRMS (EI-MS) calcd. for C H N O S [M+H] : 530.1380; found: 530.1382. IR (KBr) [cm ]: ν
28 24 3 6
+
-1
=
3267, 1681, 1249, 765.
8

Synthesis of compounds 24a-h and 25a-h
Synthesis of compounds 18 and 19. General procedure.
A mixture of 16 or 17 (0.18 mmol) and TEA (0.47 mmol, 2.5 equiv.) in 10 mL of anhydrous DCM was
stirred and cooled in an ice bath. Mesyl chloride (0.18 mmol) was added dropwise and the reaction
was stirred at rt overnight. Water was added, the organic layer separated and washed with 1N HCl, 1N
NaHCO , brine and dried over MgSO . The solvent was evaporated and the compound was purified by
3
4
flash chromatography (diethyl ether:PE 10:1). Compound 18 was used in the next step without any
further purification.
Methyl 4-(1-(methylsulfonyl)-5-(2-((methylsulfonyl)oxy)ethyl)-1H-indol-2-yl)-2-(quinoline-2-
carbonylamino)benzoate 19
1
Yield 81%, Yellow solid, mp. 220-222 °C, R = 0.40. H NMR (CDCl , 300 MHz)= δ: 13.39 (s, 1H,
f
3
4
3
NHCO), 9.28 (d, J=1.6 Hz, 1H, ArH), 8.40-8.32 (m, 3H, ArH), 8.18 (d, J=8.3 Hz, 1H, ArH), 8.06 (d,
J=8.6 Hz, 1H, ArH), 7.92 (d, J=8.2 Hz, 1H, ArH), 7.84 (ddd, J=8.4, J=7.0, J=1.3 Hz, 1H, ArH),
.71-7.64 (m, 1H, ArH), 7.49 (d, J=1.2 Hz, 1H, ArH), 7.39 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.27 (dd,
3
3
3
3
4
4
3
4
7
3
4
3
J=8.6, J=1.7, 1H, ArH), 6.86 (s, 1H, ArH), 4.49 (t, J=6.8 Hz, 2H, CH
2
), 4.09 (s, 3H, OCH
). C NMR (CDCl , 75 MHz) δ: 167.7
C=O), 163.8 (C=O), 149.9 (Cquat,), 146.6 (Cquat,), 141.3 (Cquat,), 140.4 (Cquat,), 137.7 (Cquat,), 137.7 (+),
3
), 3.19 (t,
3
13
J=6.8 Hz, 2H, CH
2
), 2.93 (s, 3H, SO
2
CH
3
), 2.92 (s, 3H, SO
2
CH
3
3
(
137.3 (Cquat,), 132.8 (Cquat,), 130.5 (Cquat,), 130.5 (+), 130.3 (+), 130.2 (+), 129.4 (Cquat,), 128.3 (+),
1
27.6 (+), 126.4 (+), 125.2 (+), 121.6 (+), 120.8 (+), 118.8 (+), 116.3 (Cquat,), 115.9 (+), 113.8 (+), 70.2
+
(–), 52.5 (+), 40.0 (+), 37.5 (+), 35.5 (–). HRMS (EI-MS) calcd. for C H N O S [M+H] : 622.1312;
30
28
3
8
2
-
1
found: 622.1315. IR (KBr) [cm ]: ν = 2949, 1683, 769.
General procedure for the synthesis of indole derivatives 24a-h
A mixture 18 or 19 (56 µmol), DIPEA (67µmol, 1.2 equiv.) and the tetrahydroisoquinolines 20-23 in
CH CN was refluxed overnight. The solvent was evaporated, 1N HCl was added and the compound
3
3
was extracted with AcOEt. The organic layer was washed with 1N NaHCO , brine and dried over
MgSO . The solvent was evaporated and the compound was purified by flash chromatography.
4
Methyl 4-(5-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-
(
quinoline-2-carbonylamino)benzoate 24e
1
Yield 62%, yellow solid, mp. 121-123 °C, R = 0.21 (DCM/MeOH 100/3). H NMR (CDCl , 600 MHz):
δ= 13.38 (s, 1H, NHCO), 9.29 (d, J=1.6 Hz, 1H, ArH), 8.38-8.34 (m, 3H, ArH), 8.17 (d, J=8.2 Hz, 1H,
ArH), 8.02 (d, J=8.5 Hz, 1H, ArH), 7.91 (d, J=7.7 Hz, 1H, ArH), 7.85-7.82 (m, 1H, ArH), 7.67-7.65 (m,
f
3
4
3
3
3
4
3
4
3
4
1
H, ArH), 7.49 (d, J=0.9 Hz, 1H, ArH), 7.40 (dd, J=8.2, J=1.7 Hz, 1H, ArH), 7.30 (dd, J=8.5, J=1.6
Hz, 1H, ArH), 7.16-7.10 (m, 3H, ArH), 7.07-7.04 (m, 1H, ArH), 6.87 (s, 1H, ArH), 4.08 (s, 3H, OCH ),
.77 (s, 2H, CH ), 3.05 (dd, J=9.5, J=6.6 Hz, 2H, CH ), 2.96 (t, J=5.8 Hz, 2H, CH ), 2.88 (s, 3H,
3
3
3
3
3
2
2
2
13
SO CH ), 2.86-284 (m, 4H, 2 CH ). C NMR (CDCl , 151 MHz) δ: 167.7 (C=O), 163.7 (C=O), 149.9
2
3
2
3
(
C
q
), 146.6 (C
q q
), 140.9 (C ), 140.3 (C
q
), 137.9 (C
q q q q
), 137.6 (+), 137.0 (C ), 136.9 (C ), 134.2 (C ), 130.5
(
+), 130.3 (+), 130.3 (+), 130.2 (C ), 129.3 (C ), 128.6 (+), 128.2 (+), 127.6 (+), 126.5 (+), 126.5 (+),
q q
q q
126.1 (+), 125.6 (+), 125.3 (+), 121.0 (+), 120.6 (C ), 118.7 (+), 116.1 (C ), 115.6 (+), 114.3 (+), 77.2
(
–), 77.0 (–), 76.7 (–), 60.4 (–), 56.1 (–), 52.4 (+), 50.9 (–), 39.5 (+), 33.7 (–), 29.0 (–). HRMS (EI-
+
-
1
MS) calcd. for C H N O S [M+H] : 659.2323; found: 659.2329. IR (KBr) [cm ]: ν = 2931, 1685, 1519,
38
35
4
5
7
73. HPLC: t 14.89 min, purity 94%.
R
Methyl 4-(5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-
quinoline-2-carbonylamino)benzoate 24a
Yield 79%, yellow solid, mp. 135-137 °C, R = 0.23 (DCM/MeOH 100/4). H NMR (CDCl , 600 MHz):
(
1
f
3
4
3
δ= 13.37 (s, 1H, NHCO), 9.29 (d, J=1.6 Hz, 1H, ArH), 8.37-8.34 (m, 3H, ArH), 8.18 (d, J=8.2 Hz, 1H,
ArH), 8.06 (d, J=8.5 Hz, 1H, ArH), 7.91 (d, J=8.1 Hz, 1H, ArH), 7.83 (ddd, J=8.3, J=6.9, J=1.3 Hz,
3
3
3
3
4
3
4
3
4
1
1
3
H, ArH), 7.68-7.64 (m, 2H, ArH), 7.47 (dd, J=8.6, J=1.6 Hz, 1H, ArH), 7.40 (dd, J=8.2, J=1.7 Hz,
H, ArH), 7.15-7.09 (m, 3H, ArH), 7.00 (d, J=6.9 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 4.08 (s, 3H, OCH ),
.82 (s, 2H, CH ), 3.70 (s, 2H, CH ), 2.96-2.92 (m, 5H, SO CH , CH ), 2.81 (t, J = 5.9 Hz, 2H, CH ).
3
3
3
2
2
2
3
2
2
1
3
C NMR (CDCl
3
, 151 MHz) δ: 167.6 (C=O), 163.7 (C=O), 149.8 (C
q
), 146.5 (C
q
), 140.9 (C
q
), 140.3
(
(
C ), 137.9 (C ), 137.6 (+), 137.5 (C ), 134.8 (C ), 134.6 (C ), 134.2 (C ), 130.3 (+), 130.2 (+), 130.2
q
q
q
q
q
q
C
q q
), 130.2 (+), 129.3 (C ), 128.6 (+), 128.2 (+), 127.6 (+), 126.7 (+), 126.5 (+), 126.1 (+), 125.5 (+),
1
5
6
25.2 (+), 121.6 (+), 120.7 (+), 118.7 (+), 116.1 (C ), 115.4 (+), 114.1 (+), 62.4 (–), 56.0 (–), 52.4 (+),
q
+
0.6 (–), 39.8 (+), 29.0 (–). HRMS (EI-MS) calcd. for C H N O S [M+H] : 645.2166; found:
3
7
33
4
5
-
1
R
45.2161. IR (KBr) [cm ]: ν = 1683, 1504, 775. HPLC: t 27.60 min, purity 95%.
9

Synthesis of compounds 24a-h and 25a-h
Methyl 4-(5-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(methylsulfonyl)-1H-
indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24f
1
Yield 86%, yellow solid, mp. 124-126 °C, R = 0.24 (DCM/MeOH 100/4). H NMR (CDCl , 300 MHz):
f
3
4
3
δ= 13.38 (s, 1H, NHCO), 9.28 (d, J=1.5 Hz, 1H, ArH), 8.40-8.31 (m, 3H, ArH), 8.17 (d, J=8.3 Hz, 1H,
3
3
ArH), 8.02 (d, J=8.5 Hz, 1H, ArH), 7.91 (d, J=8.1 Hz, 1H, ArH), 7.86-7.80 (m, 1H, ArH), 7.68-7.63 (m,
1
3
4
3
4
H, ArH), 7.48 (s, 1H, ArH), 7.40 (dd, J=8.3, J=1.6 Hz, 1H, ArH), 7.29 (dd, J=8.6, J=1.5 Hz, 1H,
ArH), 6.87 (s, 1H, ArH), 6.62 (s, 1H, ArH), 6.56 (s, 1H, ArH), 4.08 (s, 3H, OCH ), 3.85 (s, 3H, OCH ),
3
3
3
3
3
SO
.84 (s, 3H, OCH ), 3.70 (s, 2H, CH ), 3.04 (dd, J=9.7, J=6.0 Hz, 2H, CH ), 2.88-2.82 (m, 9H,
3
2
2
13
2
CH
), 146.6 (C
3
, 6 CH
2
). C NMR (75 MHz, CDCl
), 141.0 (C ), 140.4 (C
3
) δ: 167.7 (C=O), 163.8 (C=O), 149.9 (C
q
), 147.5 (C ), 147.2
q
), 130.5 (C ), 130.4
q
(
C
q
q
q
q
), 137.9 (C
q
), 137.7 (C
q
), 137.0 (+), 136.9 (C
q
(
+), 130.3 (+), 130.2 (+), 129.4 (C ), 128.3 (+), 127.6 (+), 126.6 (+), 126.3 (C ), 126.1 (C ), 125.3 (+),
q
q
q
1
5
q
21.1 (+), 120.6 (+), 118.8 (+), 116.2 (C ), 115.7 (+), 114.3 (+), 111.3 (+), 109.4 (+), 60.3 (–)55.9 (+),
39 4 7
5.9 (+), 55.7 (–), 52.5 (+), 51.0 (–), 39.6 (+), 33.8 (–), 28.6 (–). HRMS (EI-MS) calcd. for C40H N O S
+
-1
[M+H] : 719.2534; found: 719.2532. IR (KBr) [cm ]: ν = 2931, 1683, 1518, 773. HPLC: t 14.56 min,
R
purity 98%.
Methyl 4-(5-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1-(methylsulfonyl)-1H-
indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24b
1
Yield 52%, light yellow solid, mp. 140-142 °C, R
f
= 0.29 (CHCl
3
/MeOH 100/3). H NMR (CDCl
3
, 600
4
3
MHz): δ= 13.38 (s, 1H, NHCO), 9.28 (d, J=1.5 Hz, 1H, ArH), 8.39-8.32 (m, 3H, ArH), 8.18 (d, J=8.2
3
3
Hz, 1H, ArH), 8.06 (d, J=8.5 Hz, 1H, ArH), 7.91 (d, J=7.9 Hz, 1H, ArH), 7.86-7.81 (m, 1H, ArH), 7.69-
3
4
3
4
7.64 (m, 2H, ArH), 7.46 (dd, J=8.5, J=1.1 Hz, 1H, ArH), 7.40 (dd, J=8.2, J=1.6 Hz, 1H, ArH), 6.87
(
s, 1H, ArH), 6.61 (s, 1H, ArH), 6.50 (s, 1H, ArH), 4.08 (s, 3H, OCH ), 3.84 (s, 3H, OCH ), 3.83-3.80
3
3
(
m, 5H, OCH , CH ), 3.61 (s, 2H, CH ), 2.94 (s, 3H, SO CH ), 2.88-2.84 (m, 2H, CH ), 2.83-2.79 (m,
3
2
2
2
3
2
13
2
1
1
H, CH ). C NMR (CDCl , 151 MHz) δ: 167.7 (C=O), 163.8 (C=O), 149.9 (C ), 147.5 (C ), 147.2 (C ),
2
3
q
q
q
46.6 (C
q
), 140.9 (C
q
), 140.3 (C
q
), 137.9 (C
q
), 137.6 (+), 137.5 (C
q
), 130.4 (+), 130.3 (+), 130.2 (C
q
),
30.2 (+), 129.3 (C ), 128.3 (+), 127.6 (+), 126.8 (+), 126.0 (C ), 125.2 (+), 121.7 (+), 120.7 (+), 118.7
q
q
(
2
+), 116.2 (C ), 115.5 (+), 114.1 (+), 111.4 (+), 109.4 (+), 62.4 (–), 55.8 (+), 52.4 (+), 50.7 (–), 39.9 (+),
q
+
9.6 (–), 28.5 (–). HRMS (EI-MS) calcd. for C39
H
37
N
4
O
7
S [M+H] : 705.2377; found: 705.2376. IR (KBr)
-
1
[cm ]: ν = 1687, 1518, 769. HPLC: t 14.60 min, purity 99%.
R
Methyl 4-(5-(2-(6-methoxy-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-
(1H)-yl)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24g
2
1
Yield 82%, yellow solid, mp. 93-96 °C, R = 0.22 (DCM/MeOH 100/4). H NMR (CDCl , 600 MHz): δ=
f
3
4
3
13.36 (s, 1H, NHCO), 9.27 (d, J=1.6 Hz, 1H, ArH), 8.35-8.33 (m, 3H, ArH), 8.16 (d, J=8.2 Hz, 1H,
3
3
ArH), 8.01 (d, J=8.5 Hz, 1H, ArH), 7.90 (d, J=7.4 Hz, 1H, ArH), 7.83-7.81 (m, 1H, ArH), 7.67-7.64 (m,
4
3
4
3
1
H, ArH), 7.48 (d, J=0.6 Hz, 1H, ArH), 7.39 (dd, J=8.2, J=1.7 Hz, 1H, ArH), 7.29 (dd, J = 8.6,
4
3
2
J=1.6 Hz, 1H, ArH), 6.86 (s, 1H, ArH), 6.61 (s, 2H, ArH), 4.13 (t, J=5.0 Hz, 2H, CH ), 4.07 (s, 3H,
3
OCH ), 3.85 (t, J=5.3 Hz, 2H, CH ), 3.81 (s, 3H, OCH ), 3.73 (m, 2H, CH ), 3.69-3.63 (m, 6H, 3 CH ),
3
2
3
2
2
3
.55-3.53 (m, 2H, CH
2
2
), 3.37 (s, 3H, OCH
3
3
), 3.06-3.03 (m, 2H, CH
2
2 3
), 2.89-2.84 (m, 9H, SO CH , 3
13
CH ). C NMR (CDCl , 151 MHz) δ: 167.7 (C=O), 163.7 (C=O), 149.8 (C ), 148.2 (C ), 146.5 (C ),
q
q
q
1
46.4 (C ), 140.9 (C ), 140.3 (C ), 137.9 (C ), 137.6 (+), 136.9 (C ), 136.7 (C ), 130.4 (+), 130.3 (+),
q q q q q q
1
30.2 (+), 130.2 (C ), 129.3 (C ), 128.2 (+), 127.6 (+), 126.7 (C ), 126.5 (+), 125.2 (+), 121.0 (+), 120.6
q
q
q
(
+), 118.7 (+), 116.1 (C
q
), 115.6 (+), 114.2 (+), 112.2 (+), 111.9 (+), 71.8 (–), 70.7 (–), 70.5 (–), 70.4 (–
)
, 69.6 (–), 68.6 (–), 60.1 (–), 58.9 (+), 55.9 (+), 55.4 (–), 52.4 (+), 50.8 (–), 39.5 (+), 33.5 (–), 28.4 (–).
+
-1
HRMS (EI-MS) calcd. for C H N O S [M+H] : 851.3320; found: 851.3326. IR (KBr) [cm ]: ν = 2922,
46
51
4
10
R
1685, 1518, 771. HPLC: t 24.22 min, purity 95%.
Methyl 4-(5-((6-methoxy-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24c
1
Yield 63%, yellow solid, mp. 115-117 °C, R = 0.16 (DCM/MeOH 100/3). H NMR (CDCl , 600 MHz):
f
3
4
3
δ= 13.35 (s, 1H, NHCO), 9.28 (d, J=1.7 Hz, 1H, ArH), 8.36-8.31 (m, 3H, ArH), 8.16 (d, J=8.2 Hz, 1H,
ArH), 8.05 (d, J=8.6 Hz, 1H, ArH), 7.88 (d, J=8.2 Hz, 1H, ArH), 7.81 (ddd, J=8.4, J=6.9, J=1.3 Hz,
H, ArH), 7.66-7.62 (m, 2H, ArH), 7.44 (dd, J=8.6, J=1.5 Hz, 1H, ArH), 7.39 (dd, J=8.2, J=1.7 Hz,
H, ArH), 6.86 (s, 1H, ArH), 6.60 (s, 1H, ArH), 6.55 (s, 1H, ArH), 4.10 (t, J=5.4 Hz, 2H, CH
3
3
3
3
4
3
4
3
4
1
1
3
3
2
), 4.06 (s,
3
3
H, OCH ), 3.83 (t, J=5.1 Hz, 2H, CH ), 3.80 (s, 3H, OCH ), 3.78 (s, 2H, CH ), 3.71 (dd, J=5.9,
3
2
3
2
3
J=3.7 Hz, 2H, CH
2
), 3.66-3.61 (m, 4H, 2 CH
2
), 3.57 (s, 2H, CH
2
), 3.54-3.51 (m, 2H, CH
2
), 3.35 (s, 3H,
3
3
13
OCH
3
), 2.93 (s, 3H, SO
CDCl
C ), 140.2 (C ), 137.8 (C ), 137.5 (+), 137.4 (C ), 134.8 (C ), 130.3 (+), 130.2 (+), 130.1 (C ), 130.1
2
CH
3
), 2.83 (t, J=5.6 Hz, 2H, CH
2
), 2.76 (t, J=5.7 Hz, 2H, CH
2
). C NMR
(
(
3
, 151 MHz) δ: 167.6 (C=O), 163.6 (C=O), 149.8 (C
q
), 148.1 (C
q
q
), 146.5 (C
q
), 146.3 (C ), 140.8
q
q
q
q
q
q
1
0

Synthesis of compounds 24a-h and 25a-h
(
+), 129.2 (C
q q q
), 128.2 (+), 127.5 (+), 126.8 (C ), 126.7 (+), 126.5 (C ), 125.1 (+), 121.5 (+), 120.6 (+),
1
18.6 (+), 116.1 (C ), 115.3 (+), 114.1 (+), 112.2 (+), 111.9 (+), 71.8 (–), 70.6 (–), 70.5 (–), 70.4 (–),
q
6
9.5 (–), 68.6 (–), 62.4 (–), 58.9 (+), 55.9 (+), 55.5 (–), 52.4 (+), 50.6 (–), 39.7 (+), 28.6 (–). HRMS (EI-
+
-
1
49 4
MS) calcd. for C45H N O10S [M+H] : 837.3164; found: 837.3174. IR (KBr) [cm ]: ν = 2931, 1681,
1
518, 767. HPLC: t 23.82 min, purity 99%.
R
Methyl 4-(5-(2-(6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24h
1
Yield 38%, sticky yellow solid, R = 0.27 (DCM/MeOH 100/5). H NMR (CDCl , 300 MHz): δ= 13.35 (s,
1
f
3
4
3
H, NHCO), 9.26 (d, J=1.6 Hz, 1H, ArH), 8.35-8.29 (m, 3H, ArH), 8.14 (d, J=8.3 Hz, 1H, ArH), 8.00
3 3 3 3 4
(
7
d, J=8.6 Hz, 1H, ArH), 7.88 (d, J=8.2 Hz, 1H, ArH), 7.80 (ddd, J=8.4, J=7.0, J=1.3 Hz, 1H, ArH),
3
4
.67-7.59 (m, 1H, ArH), 7.46 (s, 1H, ArH), 7.37 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.30-7.25 (m, 1H,
3
2
ArH), 6.85 (s, 1H, ArH), 6.65 (s, 1H, ArH), 6.60 (s, 1H, ArH), 4.11 (t, J=5.0 Hz, 4H, 2 CH ), 4.05 (s,
H, OCH ), 3.82 (t, J=5.1 Hz, 4H, 2 CH ), 3.75-3.70 (m, 4H, 2 CH ), 3.66-3.62 (m, 10H, 5 CH ), 3.53
3
3
(
3
2
2
2
3
3
dd, J=5.9, J=3.3 Hz, 4H, 2 CH
SO CH ), 2.88-2.75 (m, 6H, 3 CH
), 147.5 (C ), 147.1 (C ), 146.6 (C
2
), 3.36 (s, 6H, 2 OCH
). C NMR (CDCl
3
2
), 3.03-2.98 (m, 2H, CH ), 2.86 (s, 3H,
, 75 MHz) δ: 167.7 (C=O), 163.7 (C=O), 149.9
), 137.9 (C ), 137.7 (+), 137.0 (C ), 136.9
1
3
2
3
2
3
(
C
q
q
q
q
), 141.0 (C ), 140.3 (C
q
q
q
q
(
C ), 130.5 (C ), 130.4 (+), 130.3 (+), 130.2 (+), 129.3 (C ), 128.3 (+), 127.6 (+), 127.5 (+), 127.2 (C ),
q
q
q
q
1
26.5 (+), 125.2 (+), 121.1 (+), 120.6 (+), 118.8 (+), 116.1 (C
q
), 115.6 (+), 115.0 (+), 114.3 (+), 113.3
(
(
+), 71.9 (–), 70.7 (–), 70.6 (–), 70.5 (–), 69.7 (–), 69.1 (–), 69.0 (–), 60.4 (–), 59.0 (+), 55.7 (–), 52.5
+
+), 51.0 (–), 39.5 (+), 33.8 (–), 28.6 (–). HRMS (EI-MS) calcd. for C H N O S [M+H] : 983.4107;
5
2
63
4
13
-
1
found: 983.4109. IR (KBr) [cm ]: ν = 2926, 2879, 1683, 1518. HPLC: t 24.13 min, purity 95%.
R
Methyl 4-(5-((6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24d
1
Yield 80%, sticky yellow solid, R = 0.27 (CHCl /MeOH 100/4). H NMR (CDCl , 300 MHz): δ= 13.37 (s,
1
f
3
3
4
3
H, NHCO), 9.28 (d, J=1.6 Hz, 1H, ArH), 8.38-8.32 (m, 3H, ArH), 8.17 (d, J=8.3 Hz, 1H, ArH), 8.05
3 3 3 3 4
(
7
d, J=8.6 Hz, 1H, ArH), 7.90 (d, J=8.2 Hz, 1H, ArH), 7.82 (ddd, J=8.4, J=6.9, J=1.3 Hz, 1H, ArH),
3
4
3
4
.67-7.62 (m, 2H, ArH), 7.44 (dd, J=8.6, J=1.5 Hz, 1H, ArH), 7.39 (dd, J=8.3, J=1.7 Hz, 1H, ArH),
6
.87 (s, 1H, ArH), 6.66 (s, 1H, ArH), 6.55 (s, 1H, ArH), 4.15-4.05 (m, 7H, OCH , 2 CH ), 3.86-3.76 (m,
3
2
6
OCH
H, 3 CH ), 3.75-3.69 (m, 4H, 2 CH ), 3.68-3.61 (m, 8H, 4 CH ), 3.56-3.51 (m, 6H, 3 CH ), 3.36 (s, 3H,
2
2
2
2
13
3
), 3.35 (s, 3H, OCH
3
), 2.93 (s, 3H, SO
2
CH
3 2 3
), 2.81-2.75 (m, 4H, 2 CH ). C NMR (CDCl , 75
MHz) δ: 167.7 (C=O), 163.8 (C=O), 149.9 (C ), 147.5 (C ), 147.1 (C ), 146.6 (C ), 140.9 (C ), 140.3
q
q
q
q
q
(
(
C ), 138.0 (C ), 137.7 (+), 137.5 (C ), 135.0 (C ), 130.4 (+), 130.3 (+), 130.3 (C ), 130.2 (+), 129.4
q
q
q
q
q
C
q q q
), 128.3 (+), 127.6 (+), 127.2 (C ), 126.8 (+), 125.2 (+), 121.6 (+), 120.7 (+), 118.8 (+), 116.2 (C ),
1
15.5 (+), 115.1 (+), 114.2 (+), 113.2 (+), 71.9 (-), 70.7 (–), 70.6 (–), 70.5 (–), 69.7 (–), 69.7 (–), 69.0 (–
)
, 69.0 (–), 62.6 (–), 59.0 (+), 55.7 (–), 52.5 (+), 50.7 (–), 39.8 (+), 28.6 (–). HRMS (EI-MS) calcd. for
+
-1
C H N O S [M+H] : 969.395; found: 969.3954. IR (KBr) [cm ]: ν = 2877, 1685, 1518, 769. HPLC: t
51
61
4
13
R
23.74 min, purity 95%.
General procedure for the synthesis of indole derivatives 25a-h.
A solution of 24 (0.15 mmol) in 5 mL THF was stirred and cooled in an ice bath. TBAF (0.15 mmol, 1M
in THF) was added and the reaction was stirred for 72 h at room temperature. The solvent was
evaporated, saturated NH Cl solution was added and the compound was extracted with DCM. The
4
organic layer was separated and dried over MgSO . The solvent was evaporated and the compound
4
was purified by flash chromatography.
Methyl 4-(5-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1H-indol-2-yl)-2-(quinoline-2-
carbonylamino)benzoate 25e
1
Yield 57%, yellow solid, mp. 116-118 °C R = 0.29 (DCM/MeOH 100/4). H NMR (CDCl , 5% CD OD,
3
f
3
3
4
00 MHz): δ= 13.39 (s, 1H, NHCO), 9.99 (s, 1H, NH), 9.19 (d, J=1.5 Hz, 1H, ArH), 8.36-8.29 (m, 3H,
3 3 3 3 4
ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.89 (d, J=8.2 Hz, 1H, ArH), 7.81 (ddd, J=8.4, J=7.0, J=1.3 Hz,
3
4
1
H, ArH), 7.67-7.61 (m, 1H, ArH), 7.51 (dd, J=8.4, J=1.7 Hz, 1H, ArH), 7.46 (s, 1H, ArH), 7.42-7.31
(
2
m, 2H, ArH), 7.13-7.02 (m, 4H, ArH), 6.92 (s, 1H, ArH), 4.05 (s, 3H, OCH ), 3.79 (s, 2H, CH ), 3.06-
3
2
13
.93 (m, 4H, 2 CH
2 2 3 3
), 2.91-2.76 (m, 4H, 2 CH ). C NMR (CDCl , 5% CD OD, 75 MHz) δ: 167.7 (C=O),
1
63.9 (C=O), 149.9 (C ), 146.6 (C ), 141.4 (C ), 137.8 (C ), 137.7 (+), 136.6 (C ), 136.1 (C ), 134.2
q
q
q
q
q
q
(
C ), 132.2 (C ), 131.9 (+), 130.2 (+), 129.4 (C ), 128.6 (+), 128.3 (+), 128.0 (C ), 127.6 (+), 127.2 (C ),
q
q
q
q
q
1
26.6 (+), 126.1 (+), 125.6 (+), 124.5 (+), 120.5 (+), 119.6 (+), 118.8 (+), 115.6 (+), 114.8 (C
q
), 111.2
(+), 101.9 (+), 56.1 (–), 52.4 (+), 51.0 (–), 40.3 (–), 34.0 (–), 28.3 (–). HRMS (EI-MS) calcd. for
1
1

Synthesis of compounds 24a-h and 25a-h
+
-1
C
37
H
33
N
O
4 3
[M+H] : 581.2547; found: 581.2545. IR (KBr) [cm ]: ν = 1681, 1519, 771, 740. HPLC: t
R
14.60 min, purity 85%.
Methyl 4-(5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-indol-2-yl)-2-(quinoline-2-carbonyl-
amino)benzoate 25a
1
Yield 34%, yellow solid, mp. 204-206 °C R = 0.20 (CHCl /MeOH 100/4). H NMR (CDCl , 300 MHz):
f
3
3
4
δ= 13.40 (s, 1H, NHCO), 9.36 (d, J=1.6 Hz, 1H, ArH), 8.95 (s, 1H, NH), 8.39-8.30 (m, 3H, ArH), 8.13
3
3
3
3
4
(
d, J=8.3 Hz, 1H, ArH), 7.91 (d, J=8.1 Hz, 1H, ArH), 7.82 (ddd, J=8.4, J=6.9, J=1.3 Hz, 1H, ArH),
3
4
3
7
.70-7.64 (m, 1H, ArH), 7.63 (s, 1H, ArH), 7.48 (dd, J=8.4, J=1.7 Hz, 1H, ArH), 7.39 (d, J=8.3 Hz,
3 4
1H, ArH), 7.29 (dd, J=8.3, J=1.3 Hz, 1H, ArH), 7.10-7.07 (m, 3H, ArH), 7.02-6.94 (m, 2H, ArH), 4.07
3
3
(
s, 3H, OCH ), 3.79 (s, 2H, CH ), 3.69 (s, 2H, CH ), 2.92 (t, J=5.5 Hz, 2H, CH ), 2.80 (t, J=5.7 Hz,
3
2
2
2
13
2
1
1
H, CH
2
). C NMR (75 MHz, CDCl
3
) δ 167.7 (C=O), 163.9 (C=O), 146.6 (C
q q q q
q
), 137.7 (+), 136.8 (C
q
),
),
36.6 (C
q
), 134.9 (C ), 134.4 (C ), 131.9 (+), 131.6 (C ), 130.2 (+), 129.4 (C ), 129.3 (C ), 128.9 (C
q
q
28.7 (+), 128.3 (+), 127.6 (+), 126.6 (+), 126.0 (+), 125.5 (+), 125.0 (+), 121.5 (+), 119.7 (+), 118.8
(
+), 115.7 (+), 114.9 (+), 111.1 (+), 102.1 (+), 63.2 (–), 56.0 (–), 52.4 (+), 50.5 (–), 29.1 (–). HRMS (EI-
+
-
1
MS) calcd. for C H N O [M+H] : 567.2391; found: 567.240. IR (KBr) [cm ]: ν = 3408, 1683, 1514,
36
31
4
3
R
773. HPLC: t 25.47 min, purity 95%.
Methyl 4-(5-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1H-indol-2-yl)-2-(quinoline-
-carbonylamino)benzoate 25f
Yield 70%, yellow solid, mp. 118-120 C R = 0.24 (DCM/MeOH 100/4). H NMR (CDCl , 5% CD OD,
2
o
1
f
3
3
4
300 MHz): δ= 13.35 (s, 1H, NHCO), 10.18 (s, 1H, NH), 9.14 (d, J=1.4 Hz, 1H, ArH), 8.30-8.27 (m, 3H,
3
3
ArH), 8.06 (d, J=8.4 Hz, 1H, ArH), 7.85 (d, J=8.1 Hz, 1H, ArH), 7.81-7.75 (m, 1H, ArH), 7.61 (t,
3
3
3
4
J=7.5 Hz, 1H, ArH), 7.51-7.43 (m, 2H, ArH), 7.36 (d, J=8.3 Hz, 1H, ArH), 7.07 (dd, J=8.3, J=1.2 Hz,
1
H, ArH), 6.90 (s, 1H, ArH), 6.59 (s, 1H, ArH), 6.54 (s, 1H, ArH), 4.02 (s, 3H, OCH ), 3.82 (s, 6H, 2
3
3 3 13
3 2 2 2
OCH ), 3.70 (s, 2H, CH ), 3.00 (dd, J=10.6, J=5.4 Hz, 2H, CH ), 2.85-2.80 (m, 6H, 3 CH ). C NMR
(
(
(
CDCl , 5% CD OD, 75 MHz) δ 167.6 (C=O), 163.7 (C=O), 149.6 (C ), 147.5 (C ), 147.2 (C ), 146.5
3
3
q
q
q
C ), 140.8 (C ), 138.1 (C ), 137.6 (+), 136.6 (C ), 136.3 (C ), 131.8 (+), 131.5 (C ), 130.2 (+), 130.2
q
q
q
q
q
q
+), 129.3 (C
q
), 129.1 (C
q q
), 128.3 (+), 127.6 (+), 126.1 (C ), 125.9 (C
q
), 124.2 (+), 120.3 (+), 120.0 (+),
1
5
18.7 (+), 115.5 (+), 114.7 (C ), 111.3 (+), 111.3 (+), 109.4 (+), 101.4 (+), 60.8 (–), 55.9 (+), 55.8 (+),
q
+
5.5 (–), 52.4 (+), 50.9 (–), 33.8 (–), 28.3 (–). HRMS (EI-MS) calcd. for C H N O [M+H] : 641.2758;
39
37
4
5
-
1
R
found: 641.2763. IR (KBr) [cm ]: ν = 3520, 1668, 1518, 775. HPLC: t 14.99 min, purity 98%.
Methyl 4-(5-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-indol-2-yl)-2-(quinoline-
-carbonylamino)benzoate 25b
Yield 75%, yellow solid, mp. 168-170 °C R = 0.23 (CHCl /MeOH 100/5). H NMR (CDCl , 300 MHz):
2
1
f
3
3
4
δ= 13.31 (s, 1H, NHCO), 9.31 (d, J=1.6 Hz, 1H, ArH), 9.13 (s, 1H, NH), 8.30-8.25 (m, 3H, ArH), 8.04
3
3
(d, J=8.4 Hz, 1H, ArH), 7.84 (d, J=8.1 Hz, 1H, ArH), 7.80-7.73 (m, 1H, ArH), 7.64-7.57 (m, 2H, ArH),
3
4
3
3
4
7.39 (dd, J=8.4, J=1.6 Hz, 1H, ArH), 7.32 (d, J=8.3 Hz, 1H, ArH), 7.25 (dd, J=8.4, J=1.2 Hz, 1H,
4
ArH), 6.92 (d, J=1.5 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 6.47 (s, 1H, ArH), 4.03 (s, 3H, OCH ), 3.82 (s,
3
13
3H, OCH ), 3.77 (s, 3H, OCH ), 3.76 (s, 2H, CH ), 3.57 (s, 2H, CH ), 2.81 (m, 4H, 2 CH ). C NMR
3 3 2 2 2
(
(
(
CDCl , 75 MHz) δ: 167.6 (C=O), 163.8 (C=O), 149.8 (C ), 147.4 (C ), 147.1 (C ), 146.5 (C ), 141.3
3
q
q
q
q
C ), 137.7 (C ), 137.6 (+), 136.8 (C ), 136.7 (C ), 131.8 (+), 130.2 (+), 130.1 (+), 130.0 (C ), 129.3
q
q
q
q
q
C
q
), 128.9 (C
q q
), 128.2 (+), 127.6 (+), 126.8 (C ), 126.3 (C
q
), 124.9 (+), 121.5 (+), 119.6 (+), 118.7 (+),
1
15.7 (+), 114.8 (C ), 111.4 (+), 111.2 (+), 109.5 (+), 102.0 (+), 63.2 (–), 55.9 (+), 55.8 (+), 55.6 (–),
q
+
52.4 (+), 50.7 (–), 28.7 (–). HRMS (EI-MS) calcd. for C H N O [M+H] : 627.2602; found: 627.2608.
38
35
4
5
-
1
R
IR (KBr) [cm ]: ν = 3408, 1683, 1516, 771. HPLC: t 14.64 min, purity 97%.
Methyl 4-(5-(2-(6-methoxy-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-
(1H)-yl)ethyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 25g
2
1
Yield 65%, yellow solid, mp. 128-130 °C R = 0.20 (DCM/MeOH 100/5). H NMR (CDCl , 5% CD OD,
f
3
3
4
300 MHz): δ= 13.35 (s, 1H, NHCO), 9.96 (s, 1H, NH), 9.18 (d, J=1.2 Hz, 1H, ArH), 8.30-8.27 (m, 3H,
3
3
ArH), 8.06 (d, J=8.4 Hz, 1H, ArH), 7.86 (d, J=8.2 Hz, 1H, ArH), 7.82-7.75 (m, 1H, ArH), 7.62 (t,
3
3
3
4
J=7.5 Hz, 1H, ArH), 7.48-7.44 (m, 2H, ArH), 7.35 (d, J=8.3 Hz, 1H, ArH), 7.07 (dd, J=8.3, J=1.2 Hz,
3
1H, ArH), 6.90 (s, 1H, ArH), 6.59 (s, 2H, ArH), 4.12 (t, J=5.2 Hz, 2H, CH
2
), 4.03 (s, 3H, OCH
3
), 3.85
3
(t, J=5.1 Hz, 2H, CH ), 3.80 (s, 3H, OCH ), 3.74-3.70 (m, 2H, CH ), 3.67-3.62 (m, 6H, 3 CH ), 3.54
2
3
2
2
3
3
3
3
(
dd, J=5.8, J=3.3 Hz, 2H, CH ), 3.36 (s, 3H, OCH ), 2.99 (dd, J=10.5, J=5.4 Hz, 2H, CH ), 2.82 (dd,
2
3
2
3
3
13
J=9.9, J=6.0 Hz, 6H, 3 CH
2
). C NMR (CDCl
), 146.5 (C ), 146.4 (C
31.8 (+), 131.7 (C ), 130.2 (+), 129.3 (C ), 129.1 (C ), 128.3 (+), 127.6 (+), 126.8 (C ), 126.4 (C ),
3
, 5% CD
3
OD, 75 MHz,) δ: 167.7 (C=O), 163.8 (C=O),
), 141.0 (C ), 138.1 (C ), 137.6 (+), 136.7 (C ), 136.4 (C ),
q q q q q
1
1
49.7 (C
q
), 148.1 (C
q
q
q
q
q
q
q
1
2

Synthesis of compounds 24a-h and 25a-h
1
q
24.2 (+), 120.3 (+), 119.9 (+), 118.7 (+), 115.6 (+), 114.7 (C ), 112.2 (+), 111.9 (+), 111.4 (+), 101.5
(
+), 71.9 (–), 70.7 (–), 70.6 (–), 70.5 (–), 69.6 (–), 68.6 (–), 60.9 (–), 59.0 (+), 55.9 (+), 55.6 (–), 52.4
+
(+), 51.0 (–), 33.9 (–), 28.5 (–). HRMS (EI-MS) calcd. for C H N O [M+H] : 773.3545; found:
45
49
4
8
-
1
7
R
73.3544. IR (KBr) [cm ]: ν = 3533, 2916, 2833, 1681, 1516, 771. HPLC: t 14.87 min, purity 90%.
Methyl 4-(5-((6-methoxy-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)methyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 25c
1
Yield 18%, light yellow solid, mp. 110-112 °C R = 0.15 (CHCl /MeOH 100/4). H NMR (CDCl , 600
f
3
3
4
MHz): δ= 13.34 (s, 1H, NHCO), 9.32 (d, J=1.7 Hz, 1H, ArH), 9.18 (s, 1H, NH), 8.31-8.29 (m, 3H,
ArH), 8.08 (d, J=8.3 Hz, 1H, ArH), 7.87 (d, J=8.1 Hz, 1H, ArH), 7.79 (ddd, J=8.3, J=6.9, J=1.3 Hz,
H, ArH), 7.65-7.61 (m, 1H, ArH), 7.59 (s, 1H, ArH), 7.44 (dd, J=8.3, J=1.7 Hz, 1H, ArH), 7.36 (d,
J=8.3 Hz, 1H, ArH), 7.27-7.25 (m, 1H, ArH), 6.95 (d, J=1.5 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 6.52 (s,
), 3.81 (t, J=5.1 Hz, 2H, CH
OCH ), 3.76 (s, 2H, CH ), 3.70 (dd, J=5.9, J=3.7 Hz, 2H, CH ), 3.65-3.61 (m, 4H, 2 CH ), 3.56 (s,
3
3
3
3
4
3
4
1
3
4
3
3
1
H, ArH), 4.07 (t, J=5.4 Hz, 2H, CH
2
), 4.05 (s, 3H, OCH
3
2
), 3.79 (s, 3H,
3
3
3
2
2
2
3
3
2
2
1
1
1
7
H, CH
2
), 3.53-3.50 (m, 2H, CH
). C NMR (CDCl
), 141.2 (C ), 137.7 (C
2
), 3.35 (s, 3H, OCH
3
), 2.82 (t, J=5.5 Hz, 2H, CH
), 148.0 (C
), 131.8 (+), 130.1 (+), 130.1 (+),
29.9 (C ), 129.3 (C ), 128.8 (C ), 128.2 (+), 127.5 (+), 127.0 (C ), 126.8 (C ), 124.8 (+), 121.4 (+),
2
), 2.76 (t, J=5.6 Hz,
13
H, CH
2
3
, 151 MHz) δ: 167.6 (C=O), 163.7 (C=O), 149.8 (C
), 137.6 (+), 136.8 (C ), 136.6 (C
q
q
), 146.5 (C ),
q
46.3 (C
q
q
q
q
q
q
q
q
q
q
19.5 (+), 118.7 (+), 115.7 (+), 114.7 (C
q
), 112.2 (+), 111.9 (+), 111.1 (+), 101.9 (+), 71.8 (–), 70.7 (–),
0.5 (–), 70.4 (–), 69.5 (–), 68.5 (–), 63.1 (–), 58.9 (+), 55.9 (+), 55.5 (–), 52.3 (+), 50.5 (–), 28.6 (–).
HRMS (EI-MS) calcd. for C H N O [M+H] : 759.3394; found: 759.3408. IR (KBr) [cm ]: ν = 2900,
+
-1
44
47
4
8
2
875, 1681, 1516, 771. HPLC: t 14.63 min, purity 98%.
R
Methyl 4-(5-(2-(6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)ethyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 25h
1
Yield 53%, sticky light yellow oil, R = 0.23 (DCM/MeOH 100/5). H NMR (CDCl , 300 MHz): δ= 13.33
f
3
4
3
(
s, 1H, NHCO), 9.31 (d, J=1.5 Hz, 1H, ArH), 9.25 (s, 1H, NH), 8.33-8.26 (m, 3H, ArH), 8.07 (d, J=8.4
Hz, 1H, ArH), 7.87 (d, J=8.1 Hz, 1H, ArH), 7.82-7.75 (m, 1H, ArH), 7.66-7.59 (m, 1H, ArH), 7.46-7.43
m, 2H, ArH), 7.33 (d, J=8.3 Hz, 1H, ArH), 7.07 (dd, J=8.4, J=1.3 Hz, 1H, ArH), 6.92 (s, 1H, ArH),
3
3
3
4
(
6
3
3
.63 (s, 1H, ArH), 6.58 (s, 1H, ArH), 4.11 (t, J=5.0 Hz, 4H, 2 CH ), 4.04 (s, 3H, OCH ), 3.82 (t, J=5.1
2
3
3
3
Hz, 4H, 2 CH ), 3.75-3.70 (m, 4H, 2 CH ), 3.69-3.61 (m, 10H, 5 CH ), 3.54 (dd, J=5.9, J=3.3 Hz, 4H,
), 3.36 (s, 3H, OCH ), 2.99 (dd, J=10.1, J=5.6 Hz, 2H, CH ), 2.83-2.77 (m,
3 2
H, 3 CH ). C NMR (CDCl , 75 MHz) δ 167.7 (C=O), 163.8 (C=O), 149.8 (C ), 147.4 (C ), 147.0 (C ),
46.5 (C ), 141.3 (C ), 137.9 (C ), 137.6 (+), 136.6 (C ), 136.2 (C ), 132.0 (C ), 131.8 (+), 130.2 (+),
q q q
29.3 (C ), 129.2 (C ), 128.2 (+), 127.6 (+), 127.2 (C ), 124.3 (+), 120.4 (+), 119.5 (+), 118.7 (+), 115.7
2
2
2
3
3
2
6
1
1
CH
2
), 3.36 (s, 3H, OCH
3
1
3
2
3
q
q
q
q
q
q
q
q
q
(
+), 114.9 (+), 114.7 (C ), 113.2 (+), 111.3 (+), 101.7 (+), 71.9 (–), 70.7 (–), 70.6 (–), 70.5 (–), 69.7 (–),
q
6
9.0 (–), 68.9 (–), 61.0 (–), 59.0 (+), 55.7 (–), 52.4 (+), 51.0 (–), 34.1 (–), 28.6 (–). HRMS (EI-MS)
+ -1
calcd. for C H N O [M+H] : 905.4331; found: 905.4333. IR (KBr) [cm ]: ν = 2870, 1683, 1516, 771.
51
61
4
11
HPLC: t 24.75 min, purity 94%.
R
Methyl 4-(5-((6,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-
yl)methyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 25d
1
Yield 55%, light yellow oil, R = 0.18 (CHCl /MeOH 100/6). H NMR (CDCl , 300 MHz): δ= 13.37 (s,
f
3
3
4
3
1
H, NHCO), 9.34 (d, J=1.5 Hz, 1H, ArH), 9.15 (s, 1H, NH), 8.36-8.28 (m, 3H, ArH), 8.11 (d, J=8.4
Hz, 1H, ArH), 7.89 (d, J=8.1 Hz, 1H, ArH), 7.84-7.76 (m, 1H, ArH), 7.66-7.59 (m, 2H, ArH), 7.48 (dd,
J=8.4, J=1.5 Hz, 1H, ArH), 7.38 (d, J=8.3 Hz, 1H, ArH), 7.26 (dd, J=8.3, J=1.1 Hz, 1H, ArH), 6.96
s, 1H, ArH), 6.63 (s, 1H, ArH), 6.51 (s, 1H, ArH), 4.12-4.05 (m, 5H, OCH , CH ), 3.82-3.60 (m, 20H,
3
3
4
3
3
4
(
3
2
1
0 CH ), 3.55-3.49 (m, 6H, 3 CH ), 3.36 (s, 3H, OCH ), 3.34 (s, 3H, OCH ), 2.82-2.71 (m, 4H, 2 CH ).
2
2
3
3
2
q
q
13
C NMR (CDCl
3
, 75 MHz) δ: 167.7 (C=O), 163.8 (C=O), 149.9 (C
q
), 147.3 (C
q
), 147.0 (C
q
), 146.6 (C
),
),
1
1
41.4 (C
q
), 137.8 (C
q
), 137.7 (+), 136.8 (C ), 136.7 (C ), 131.9 (+), 130.2 (+), 130.0 (+), 129.4 (C
q
q
28.9 (C ), 128.3 (+), 127.9 (C ), 127.6 (+), 127.3 (C ), 124.9 (+), 121.4 (+), 119.6 (+), 118.8 (+), 115.7
q
q
q
(
+), 115.1 (+), 114.8 (C ), 113.1 (+), 111.2 (+), 102.0 (+), 77.2 (–), 71.9 (–), 70.7 (–), 70.7 (–), 70.6 (–),
q
7
2
=
0.6 (–), 70.5 (–), 70.5 (–), 69.7 (–), 69.7 (–), 68.9 (–), 63.2 (–), 59.0 (+), 55.6 (–), 52.4 (+), 50.6 (–),
+
-
1
8.6 (–). HRMS (EI-MS) calcd. for C H N O [M+H] : 891.4175; found: 891.4178. IR (KBr) [cm ]: ν
50
59
4
11
R
2872, 1685, 1516, 771. HPLC: t 14.46 min, purity 97%.
1
3

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
1
13
2.2
H and C NMR spectra
2-(4-Amino-3-iodophenyl)ethanol 4
1
4

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-iodoaniline 6
1
5

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
N-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-iodophenyl)methanesulfonamide 8
1
6

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-iodophenyl) methane sulfonamide 7.
1
7

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 2-amino-4-((trimethylsilyl)ethynyl)benzoate 10
1
8

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 2-amino-4-ethynylbenzoate 11
1
9

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 2-amino-4-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(methylsulfonyl)-1H-indol-2-
yl)benzoate 13
2
0

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 2-amino-4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(methylsulfonyl)-1H-indol-2-
yl)benzoate 12
2
1

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-
2
-carbonylamino)benzoate 15
2
2

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-
2
-carbonylamino)benzoate 14
2
3

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(2-hydroxyethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)-
benzoate 17
2
4

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(hydroxymethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-(quinoline-2-carbonylamino)-
benzoate 16
OH
N
Ms
O
O
HN
N
O
2
5

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(1-(methylsulfonyl)-5-(2-((methylsulfonyl)oxy)ethyl)-1H-indol-2-yl)-2-(quinoline-2-
carbonylamino)benzoate 19
2
6

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-
(quinoline-2-carbonylamino)benzoate 24e
N
N
Ms
O
O
HN
N
O
2
7

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1-(methylsulfonyl)-1H-indol-2-yl)-2-
(quinoline-2-carbonylamino)benzoate 24a
2
8

1
13
Synthesis of compounds 24a-h and 25a-h - H and C NMR spectra
Methyl 4-(5-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(methylsulfonyl)-1H-
indol-2-yl)-2-(quinoline-2-carbonylamino)benzoate 24f
O
O
N
N
Ms
O
O
HN
N
O
2
9