General Synthetic Procedures
General procedure A: Benzanilide coupling using PCl3
The appropriate benzoic acid derivative (1 equiv.) and aniline derivative (1 equiv.) were dissolved in dry xylene (2 mL per mmol of reactants) and heated to reflux. PCl3 (0.4 equiv.) was added dropwise upon which a precipitate formed. Solution was refluxed for 4 h. The mixture was cooled to rt and filtered, after which the precipitate was washed with ethyl acetate.
General procedure B: LiOH Ester hydrolysis
The appropriate carboxylic acid was dissolved in a THF (5 mL per mmol) and MeOH (5 mL per mmol) mixture. A solution of 2M LiOH in water (10 mL per mmol) was added and the reaction was stirred at rt for 2 h. The reaction was neutralized with concentrated HCl at 0 °C upon which the product precipitated, was filtered and washed with water (3 × 10 mL).
General procedure C: Amide coupling using TBTU
The appropriate carboxylic acid (1 equiv.), N-methylmorpholine (3 equiv.), and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.1 equiv.) were dissolved in anhydrous DMF (3 mL per mmol of carboxylic acid) and stirred at rt for 15 min under N2. The appropriate amine (1.2 equiv.) was added and the reaction was stirred for 4 h at rt. Solution was concentrated in vacuo and the residue was collected in DCM, washed with 1M HCl (×3), saturated NaHCO3 (×3) and brine. The organic layer was concentrated and the product was purified using flash chromatography (0–10% MeOH in DCM).
General procedure D: Methoxy deprotection
The appropriate methoxy protected intermediate (1 equiv.) was dissolved in anhydrous DCM at 0 °C. A 1M solution of BBr3 in DCM (1.5 equiv. BBr3 per methoxy group) was added dropwise and the reaction was slowly warmed to rt. Solution was stirred overnight. The reaction was cooled to 0 °C and quenched with the careful addition of MeOH (5 mL per mmol) followed by stirring for 15 min. The reaction mixture was concentrated in vacuo and the product was purified using flash chromatography (0–10% MeOH in DCM).
General procedure E: Benzyl deprotection
The appropriate benzyl protected intermediate (1 equiv.) was dissolved in MeOH (3 mL per mmol) and THF (1 mL per mmol) Palladium on carbon (0.1 equiv.) was then added followed by H2 gas (balloon). The solution was stirred for 2 h at rt, filtered over celite and concentrated in vacuo. The product was purified using flash chromatography (0–10% MeOH in DCM).
General procedure F: Copper-assisted azide-alkyne cycloaddition (CuAAC)
The appropriate azide (1 equiv.) and alkyne (1 equiv.) and CuI·P(OEt)3 (0.3 equiv.) were dissolved in anhydrous DMF (3 mL) and treated with iPr2NEt (2 equiv.) The reaction was stirred under N2 at rt for 2 h. The reaction mixture was concentrated under vacuum, dissolved in water and extracted with DCM (× 3) The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. The product was purified using flash chromatography (0–10% MeOH in DCM).
(1) N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide
Niclosamide (1.435 g, 4.38 mmol) was suspended in 25 mL of 1:1 MeOH/THF, followed by the addition of 10 mL of saturated NH4Cl (aq). Zinc dust (3 g, 45.89 mmol) was slowly added into the solution at 0 °C. The reaction was warmed to RT and stirred for 4 h, after which TLC indicated that the starting material was completely consumed. The solution was filtered over celite to remove excess zinc and the resulting filtrate was concentrated in vacuo. The crude residue was dissolved in 30 mL ethyl acetate and washed with water (3 × 10 mL) and brine (3 × 5 mL). The organic layer was concentrated and purified by flash chromatography (0–10% MeOH in DCM) yielding 649.5 mg (2.19 mmol, 49.9%) of compound 1 as a pale yellow solid. 1H NMR (500 MHz, Methanol-d4) δ 8.64 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.41–7.37 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H). 13C NMR (126 MHz, Methanol-d4) δ 163.49, 155.16, 136.00, 133.39, 130.08, 126.86, 124.82, 124.55, 123.72, 123.19, 122.03, 119.42, 118.14. ESI-MS: M/Z [M+H]+ 297.0193.
(2) N-(4-acetamido-2-chlorophenyl)-5-chloro-2-hydroxybenzamide
Compound 1 (88 mg, 0.3 mmol) was dissolved in 3 mL DCM followed by the addition of Et3N (125 µL, 0.9 mmol) and acetyl chloride (25 µL, 0.36 mmol). Solution was stirred at RT overnight and concentrated in vacuo. The crude residue was dissolved in 5 mL ethyl acetate and washed with saturated NaHCO3 (3 × 5 mL) and brine (3 × 3 mL). The organic layer was dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (0–10% MeOH in DCM) yielding 86.6 mg (0.25 mmol, 84.8%) 2 off-white powder.1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.76 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 9.0, 2.4 Hz, 1H), 7.47 (dd, J = 8.8, 2.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 2.07 (s, 3H). 13C NMR (126 MHz, DMSO- d6) δ 169.14, 163.02, 156.37, 137.21, 133.54, 130.32, 129.98, 123.99, 123.57, 123.51, 119.99, 119.75, 119.59, 118.44, 24.37. ESI-MS: M/Z [M+H]+ 339.0312.
(3) 3-chloro-4-(5-chloro-2-hydroxybenzamido)-N,N,N-trimethylanilinium
Compound 1 (250 mg, 0.85 mmol) was dissolved in 5 mL DMF. 2,6 lutidine (186 µL, 1.6 mmol) was added followed by iodomethane (211 µL, 3.4 mmol). Solution was stirred at RT overnight and 20 mL ethyl acetate was added to facilitate precipitation. Product was washed on-filter with ethyl acetate (3 × 5 mL), acetone (3 × 5 mL) and DCM (3 × 5 mL) yielding 142 mg (0.41 mmol, 49%) 3 as a dark brown solid. 1H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 11.17 (s, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.05–7.92 (m, 2H), 7.49 (d, J = 8.75 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.56 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 166.14, 155.73, 143.25, 136.31, 132.87, 130.21, 129.98, 123.99, 123.57, 123.62, 119.87, 118.92, 118.01, 56.87. ESI-MS: M/Z [M+H]+ 339.0661.
(4) N-(4-azidophenyl)-5-chloro-2-hydroxybenzamide
5-Chlorosalicylic acid (45 mg, 0.293 mmol) and EDC (112 mg, 0.586 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature and stirred for 15 min.
4-Azidoaniline (51 mg, 0.299 mmol) was added and the reaction mixture was stirred at rt for 5 h over which time the solution gradually turned from clear to yellow. The reaction was concentrated under vacuo and dissolved in 12 mL ethyl acetate, washed with 1 M HCl (3 × 5 mL), saturated sodium bicarbonate solution (3 × 5 mL) and brine (3 × 5 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified using flash chromatography using DCM as a solvent system to afford 4 as a brown solid (61 mg, 73%) 1H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.47 (s, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.0, 2.9 Hz, 2H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 7.16–7.13 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 177.32, 165.42, 157.41, 143.04, 135.53, 133.49, 128.77, 122.63, 122.60, 119.67, 119.63.
(5a) methyl 3-chloro-4-(5-chloro-2-hydroxybenzamido)benzoate
Compound 5a was synthesized following general procedure A starting from 5-Chlorosalicylic acid (928 mg, 5.38 mmol) and methyl 4-amino-3-chlorobenzoate (1 g, 5.38 mmol) and purified by flash chromatography (0–10% MeOH in DCM) resulting in 748 mg (2.2 mmol, 41%) 5a as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.14 (s, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.98–7.92 (m, 2H), 7.50 (dd, J = 8.7, 2.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.15, 162.85, 155.55, 139.79, 134.15, 130.46, 130.35, 129.55, 125.99, 124.14, 122.81, 121.53, 120.09, 119.53, 52.75. ESI-MS: M/Z [M+H]+ 340.0148.
(5b) methyl 3-chloro-4-[(5-chloro-2-methoxybenzoyl)amino]benzoate
Compound 5b was synthesized following general procedure A starting from 5-Chloro-2-methoxybenzoic Acid (558 mg, 3 mmol) and methyl 4-amino-3-chlorobenzoate (516 g, 3 mmol) resulting in 840 mg (2.4 mmol, 82%) of 5b as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 10.80 (s, 1H), 8.81 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.05–7.94 (m, 1H), 7.50 (dd, J = 8.9, 2.8 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 4.12 (s, 3H), 3.94 (s, 3H). 13C NMR (75 MHz, Chloroform-d) δ 165.69, 162.19, 155.90, 139.56, 133.55, 132.37, 130.48, 129.49, 127.19, 125.90, 122.47, 120.84, 113.11, 56.77, 52.33. ESI-MS: M/Z [M+H]+ 354.0292.
(5c) methyl 4-{[2-(benzyloxy)-5-chlorobenzoyl]amino}-3-chlorobenzoate
Compound 5a (100 mg, 0.3 mmol) was dissolved in 3 mL anhydrous DMF under N2 at 0 °C. NaH (13 mg, 0.32 mmol) as a 60% dispersion in mineral oil was added and the solution was stirred at 0 °C for 15 min. Benzyl bromide (39 µL, 0.32 mmol) was added dropwise and the solution was warmed to RT and stirred for 4 h. The reaction was quenched with 10 mL 1M HCl (aq) at 0 °C which caused the product to precipitate. The precipitate was filtered and washed with 3 × 5 mL hexanes yielding 107 mg of 5c as a pale-yellow solid (0.25 mmol, 83%) which was used without further purification.
(6) 3-chloro-4-(5-chloro-2-hydroxybenzamido)benzoic acid
Compound 6 was obtained using general procedure B starting from 5a (708 mg, 2.1 mmol) in 98% (667 mg) yield as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.91–7.86 (m, 2H), 7.53–7.45 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 166.09, 163.06, 156.65, 139.29, 133.87, 130.44, 130.13, 129.57, 123.32, 122.61, 121.43, 120.09, 119.86. ESI-MS: M/Z [M+H]+ 327.1365.
(6b) 3-chloro-4-[(5-chloro-2-methoxybenzoyl)amino]benzoic acid
Compound 6b was obtained using general procedure B starting from 5b (820 mg, 2.3 mmol) in 96% (779 mg) yield as a white powder which was used without further purification.
(6c) 3-chloro-4-{[2-(benzyloxy)-5-chlorobenzoyl]amino}- benzoic acid
Compound 6c was obtained using general procedure B starting from 5c (107 mg, 0.25 mmol) in 96% (100 mg) yield as a white powder which was used without further purification.
(7) 5-chloro-N-[2-chloro-4-(methylcarbamoyl)phenyl]-2-hydroxybenzamide
Compound 7 was obtained using general procedure C starting from 6b (200 mg, 0.6 mmol) and methylamine HCl, followed by general procedure D resulting in 119 mg (0.35 mmol) of white powder (58% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ 12.33 (s, 1H), 11.05 (s, 1H), 8.54 (dd, J = 22.9, 7.1 Hz, 2H), 8.05–7.96 (m, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 8.7, 2.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 2.79 (d, J = 4.2 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.19, 162.96, 155.68, 137.82, 134.11, 131.29, 130.40, 128.56, 127.31, 124.11, 123.10, 121.85, 120.16, 119.59, 26.75. ESI-MS: M/Z [M+H]+ 339.0287.
(8) methyl [3-chloro-4-(5-chloro-2-hydroxybenzamido)benzamido]acetate
Compound 8 was obtained using general procedure C starting from 6b (200 mg, 0.6 mmol) and glycine methyl ester HCl, followed by general procedure D resulting in 132 mg (0.33 mmol) of white powder (55% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 11.10 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.03 (m, 2H), 7.92 (dd, J = 8.6, 2.1 Hz, 1H), 7.53 (dd, J = 8.7, 2.8 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 4.03 (s, 2H), 3.67 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 170.74, 165.25, 162.97, 155.67, 138.30, 134.14, 130.42, 130.26, 128.78, 127.61, 124.13, 123.09, 121.82, 120.15, 119.59, 52.25, 41.72. ESI-MS: M/Z [M+H]+ 397.0324.
(9) methyl (4S)-5-amino-4-[3-chloro-4-(5-chloro-2-hydroxybenzamido)benzamido]-5-oxopentanoate
Compound 9 was obtained using general procedure C starting from 6b (200 mg, 0.6 mmol) and L-Glutamic Acid γ-Methyl Ester α-Amide Hydrochloride followed by general procedure D resulting in 146 mg (0.31 mmol) of white powder (52% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ. 12.42 (s, 1H), 11.09 (s, 1H), 8.51 (m, 2H), 8.09 (s, 1H), 7.92 (m, 2H), 7.42 (m, 2H), 6.09 (m, 2H) 4.32 (m, 1H), 3.52 (s, 1H), 2.23 (m, 2H), 1.98 (m, 1H), 1.78 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 173.61, 173.32, 165.05, 163.04, 155.90, 138.07, 134.11, 130.78, 130.39, 129.03, 124.94, 123.98, 122.90, 121.66, 120.15, 119.65, 53.18, 51.80, 30.77, 27.28. ESI-MS: M/Z [M+H]+ 468.0712.
(10) (4S)-5-amino-4-[3-chloro-4-(5-chloro-2-hydroxybenzamido)benzamido]-5-oxopentanoic acid
Compound 10 was obtained using general procedure B starting from 9 (100 mg, 0.21 mmol) resulting in 78 mg (0.17 mmol) of off-white powder (81%). 1H NMR (500 MHz, Methanol-d4) δ 8.65 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.7, 2.0 Hz, 1H), 7.41 (dd, J = 8.7, 2.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.58 (dd, J = 9.2, 5.0 Hz, 1H), 2.48 (t, J = 7.4 Hz, 2H), 2.26–2.20 (m, 1H), 2.12–2.05 (m, 1H). 13C NMR (126 MHz, Methanol-d4) δ 175.29, 175.07, 166.73, 163.32, 155.04, 138.27, 133.35, 130.22, 129.86, 128.44, 126.60, 124.87, 123.16, 121.17, 119.70, 118.10, 53.27, 30.06, 26.79. ESI-MS: M/Z [M+H]+ 454.0515.
(11) 5-chloro-N-(4-{[(2S)-1,4-diamino-1-oxobutan-2-yl]carbamoyl}phenyl)-2-hydroxybenzamide
Compound 11 was obtained using general procedure C starting from 6c (100 mg, 0.3 mmol) and L-diaminobutyric acid γ- Carbobenzoxy-α-Amide hydrochloride followed by general procedure E resulting in 43 mg (0.10 mmol) of brown powder (34% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ 12.52–12.43 (m, 1H), 11.12 (s, 1H), 8.71 (d, J = 7.8 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.77–7.69 (m, 3H), 7.57–7.50 (m, 2H,), 7.23 (s, 1H, 12-b), 7.12 (d, J = 8.6 Hz, 1H), 4.51–4.46 (m, 1H), 2.92–2.85 (m, 2H), 2.11 (dd, J = 14.1, 6.8 Hz, 1H), 1.96 (dd, J = 14.6, 7.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 173.09, 165.18, 163.00, 155.72, 138.15, 134.17, 130.62, 130.38, 129.09, 128.02, 124.09, 122.87, 121.64, 120.12, 119.62, 51.44, 36.97, 29.97 ESI-MS: M/Z [M+H]+ 425.0761.
(12) (2S)-2-[3-chloro-4-(5-chloro-2-hydroxybenzamido)benzamido]pentanedioic acid
Compound 12 was obtained using general procedure C starting from 6c (100 mg, 0.3 mmol) and Di-tert-butyl (S)-2-Aminopentanedioate hydrochloride followed by general procedure E and then general procedure B resulting in 22 mg (0.05 mmol) of white powder (15% over 3 steps). 1H NMR (500 MHz, Methanol-d4) δ 8.73 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.86–7.79 (m, 2H), 7.08 (dd, J = 8.8, 3.1 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 4.39 (dd, J = 8.3, 4.4 Hz, 1H), 2.35–2.21 (m, 3H), 2.13–2.08 (m, 1H). 13C NMR (126 MHz, Methanol-d4) δ 180.97, 177.83, 168.80, 167.48, 166.23, 139.73, 132.64, 129.31, 128.45, 128.32, 128.25, 125.99, 123.53, 120.97, 119.21, 116.99, 56.06, 34.39, 29.03. ESI-MS: M/Z [M+Na]+ 477.0291.
(13) 5-chloro-N-{2-chloro-4-[(prop-2-yn-1-yl)carbamoyl]phenyl}-2-hydroxybenzamide
Compound 13 was obtained using general procedure C starting from 6b 500 mg, 1.5 mmol) and propargylamine followed by general procedure D resulting in 267 mg (0.74 mmol) of white powder (49% over 2 steps) which was used without further purification.
(14) methyl {4-[({3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]benzoyl}amino)ethyl]-1H-1,2,3-triazol-1-yl}acetate
Compound 14 was obtained using general procedure F starting from 13 (55 mg, 0.15 mmol) and ethyl 2-azidoacetate resulting in 23 mg (0.05 mmol) of off-white powder (33%).1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 11.08 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.00–7.88 (m, 3H), 7.53 (dd, J = 8.7, 2.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 5.35 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.22–1.18 (m, 3H). 13C NMR (126 MHz, DMSO-d6) δ 167.72, 164.75, 162.95, 155.66, 145.45, 138.06, 134.13, 130.81, 130.40, 128.77, 127.59, 124.93, 124.11, 123.04, 121.76, 120.14, 119.58, 61.88, 50.74, 35.33, 14.44. ESI-MS: M/Z [M+H]+ 492.0779.
(15) {4-[({3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]benzoyl}amino)methyl]-1H-1,2,3-triazol-1-yl}acetic acid
Compound 15 was obtained using general procedure B starting from 13 (15 mg, 0.03 mmol) resulting in 12 mg (0.025 mmol) of off-white powder (86%).1H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.17 (t, J = 5.8 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 3.1 Hz, 2H), 7.92 (dd, J = 8.6, 2.0 Hz, 1H), 7.50 (dd, J = 8.7, 2.9 Hz, 1H), 7.11 (dd, J = 9.2, 5.0 Hz, 1H), 5.21 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.81, 163.13, 156.33, 145.34, 138.19, 134.03, 130.68, 130.31, 128.77, 127.57, 124.86, 123.63, 122.97, 121.68, 119.79, 53.08, 35.33. ESI-MS: M/Z [M+H]+ 464.0523.
(16) {4-[({3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]benzoyl}amino)methyl]-1H-1,2,3-triazol-1-yl}benzoic acid
Compound 16 was obtained using general procedure F starting from 13 (55 mg, 0.15 mmol) and 4-azido benzoic acid resulting in 42 mg (0.08 mmol) of off-white powder (53%). 1H NMR (500 MHz, DMSO-d6) δ 13.20 (s, 1H), 12.52 (s, 1H), 11.12 (s, 1H), 9.23 (s, 1H), 8.82 (d, J = 7.1 Hz, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.16–8.06 (m, 5H), 8.03–7.93 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.83, 164.96, 164.87, 138.09, 134.09, 131.55, 131.52, 130.94, 130.35, 128.87, 127.72, 124.00, 122.96, 121.85, 121.69, 121.19, 120.13, 35.38. ESI-MS: M/Z [M+H]+ 526.0617.
(17) 3-{4-[({3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]benzoyl}amino)methyl]-1H-1,2,3-triazol-1-yl-phenyl}propionic acid
Compound 17 was obtained using general procedure F starting from 13 (55 mg, 0.15 mmol) and 3-(4-Azidophenyl)propanoic acid resulting in 51 mg (0.09 mmol) of off-white powder (61%). 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 12.17 (s, 1H), 11.09 (s, 1H), 9.17 (t, J = 5.6 Hz, 1H), 8.66 (s, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 8.02–7.93 (m, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.53 (dd, J = 8.9, 2.8 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.7 Hz, 1H), 4.62 (d, J = 5.4 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 174.07, 164.81, 162.96, 155.67, 146.37, 141.97, 138.04, 135.33, 134.12, 130.86, 130.39, 130.07, 130.07, 128.85, 127.69, 124.10, 123.02, 121.74, 121.61, 120.38, 120.37, 120.14, 119.58, 35.40, 35.36, 30.24. ESI-MS: M/Z [M+H]+ 554.0965.
(18) N-(2-chloro-4-nitrophenyl)-2,4-dihydroxybenzamide
Compound 18 was obtained using general procedure A starting from 2,4-Dimethoxybenzoic acid (182mg, 1 mmol) and 2-chloro-4-nitro aniline (172 mg, 1 mmol) followed by general procedure D, resulting in 120 mg (0.39 mmol) pale orange powder (39% over 2 steps)1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.21 (s, 1H), 10.31 (s, 1H), 8.86 (d, J = 9.2 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.28 (dd, J = 9.3, 2.6 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 6.49–6.43 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.27, 163.42, 158.44, 142.44, 142.38, 133.45, 125.23, 124.35, 122.32, 120.77, 110.04, 109.17, 103.10. ESI-MS (negative mode): M/Z [M−H]− 307.0388.
(19) N-(2-chloro-4-nitrophenyl)-2,4,5-trihydroxybenzamide
Compound 19 was obtained using general procedure A starting from 2,4,5-Trimethoxybenzoic acid (212 mg, 1 mmol) and 2-chloro-4-nitro aniline (172 mg, 1 mmol) followed by general procedure D, resulting in 175 mg (0.54 mmol) pale yellow powder (54% over 2 steps) 1H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 2H), 9.88 (s, 1H), 8.83–8.80 (m, 2H), 8.35 (d, J = 2.6 Hz, 1H), 8.21 (dd, J = 9.3, 2.7 Hz, 1H), 7.36 (s, 1H), 6.45 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 164.25, 152.17, 150.86, 142.52, 142.24, 139.69, 125.21, 124.33, 122.04, 120.49, 116.63, 108.86, 104.09 ESI-MS (negative mode): M/Z [M−H]− 323.0201.
(20) 3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]-N-(3,4-dihydroxybenzyl)benzamide
Compound 20 was obtained using general procedure C starting from 6b (100 mg, 0.3 mmol) and 1-(3,4-dimethoxyphenyl)methanamine followed by general procedure D resulting in 52 mg (0.12 mmol) of white powder (39% over 2 steps).1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.11 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.14–8.06 (m, 1H), 7.99 (d, J = 2.9 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.8, 2.9 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.73 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.50, 162.98, 155.77, 145.54, 144.64, 137.93, 134.11, 131.20, 130.70, 130.38, 128.71, 127.54, 124.03, 123.06, 121.80, 120.14, 119.61, 118.76, 115.77, 115.38, 42.83. ESI-MS: M/Z [M+H]+ 447.0510.
(21) 3-chloro-4-[(5-chloro-2-hydroxybenzoyl)amino]-N-[2-(3,4-dihydroxyphenyl)ethyl]benzamide
Compound 21 was obtained using general procedure C starting from 6b (100 mg, 0.3 mmol) and 2-(3,4-dimethoxyphenyl)ethan-1-amine followed by general procedure D resulting in 67 mg (0.15 mmol) of white powder (50% over 2 steps).1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.09 (s, 1H), 8.76 (s, 1H), 8.70–8.53 (m, 3H), 8.00 (d, J = 14.3 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.70–6.58 (m, 2H), 6.48 (d, J = 8.0 Hz, 1H), 3.41 (s, 2H), 2.66 (t, J = 7.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.62, 162.96, 155.76, 145.53, 144.00, 137.84, 134.08, 131.37, 130.66, 130.38, 128.61, 127.39, 124.04, 123.04, 121.78, 120.14, 119.70, 119.59, 116.46, 115.96, 41.85, 35.03. ESI-MS: M/Z [M+H]+ 461.0597.