3.1. Chemistry
Reagents were obtained from commercial sources and were used without further purification. Characterization of all compounds was carried out with 1H and 13C NMR and mass spectrometry. 1H and 13C NMR spectra were recorded on a 400 MHz Bruker Avance III Nanobay spectrometer with Ultrashield working at 400 and 100 MHz, respectively, and analyzed by use of MestReNova analytical chemistry software version 14.1.1-24571. Chemical shifts are in ppm, and coupling constants are in hertz (Hz). Splitting patterns are designated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), brs (broad singlet), and dd (double of doublets). The UPLC (ultraperformance liquid chromatography) used to quantify the purity of the products was an ACQUITY UPLC H-Class system with a TUV detector Waters coupled to an MS detector Waters QDa. An Acquity UPLC BEH C18 1.7 μm (2.1 mm × 50 mm) column was used and as eluent with a mixture of 0.1% FA in H2O, 0.1% FA in ACN, H2O, and ACN. The wavelengths for UV detection were 254 and 214 nm. When necessary, flash column chromatography was performed on a Biotage ISOLERA One flash system equipped with an internal variable dual-wavelength diode array detector (200–400 nm). For normal phase purifications, Biotage Sfär cartridges (5–100 g, flow rate of 10–100 mL/min) were used, and reverse phase purifications were performed, making use of Büchi C18 cartridges (4–30 g, flow rate of 10–50 mL/min). Dry sample loading was carried out by self-packing sample cartridges using Celite 545. The gradients used varied for each purification.
The following sections comprise the synthetic procedures and analytical data for all compounds reported in this manuscript. Several synthetic procedures that were used in the preparation of intermediates and final products are summarized here as ‘General Procedures’. Target compounds were obtained with a purity of >95%. Most of the compounds described in this paper have been synthesized according to general procedures A–H.
General procedure A. General procedure A describes the synthesis of aldehyde derivatives 1–5 (
Scheme 1). A solution of acetophenone (a1–a4) (1 equiv.) in EtOH (70 mL) was treated with acetic acid (1.2 equiv.) and hydrazine (b1–b2) (1.2 equiv.). The reaction was left to stir until the consumption of the starting materials (TLC/UPLC monitoring). The obtained precipitates were filtered off and washed with cold EtOH (3 × 20 mL) to afford hydrazones (c2–c4), or the solvents were removed under reduced pressure to obtain the hydrazones (c1, c5) to use without further purification. In a round-bottom flask, phosphorus oxychloride (3.0 equiv.) was cooled to 0 °C; then, previously cooled (0–5 °C) DMF (3.0 equiv.) was added dropwise and left to stir for 15–20 min to form so-called Vilsmeier reagent (chloroiminium ion). A solution of hydrazone (c1–c5) (0.01 mol, 1 equiv.) in DMF (15–20 mL) was added dropwise to the reaction mixture using an addition funnel and heated at 80 °C for 3 h. After the consumption of the starting materials (TLC monitoring), the mixture was cooled to 0 °C, quenched with slush, and neutralized with NaOH. The precipitate was filtered off, washed with water (3 × 30 mL) to afford aldehydes (1–5), and used without any further purification.
General Procedure B. General Procedure B outlines the reductive amination reactions in
Scheme 2 to afford compounds 15–17, 19–21, 23–29, 55–59, 61–67 and 69. A solution of aldehyde (1–5) (0.25 g, 1.0 equiv.) in 5 mL dry EtOH was treated with the appropriate primary or secondary aliphatic amine (1.1 equiv.) at the room temperature. The reaction was stirred for four hours, then cooled-down to 0 °C and sodium borohydride (4.0 equiv.) was added portion-wise, and allowed to reach rt. The consumption of the starting materials was monitored by UPLC and then quenched with slush and basified by saturated solution of sodium bicarbonate. The solvents were removed under reduced pressure and the obtained residue extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (3 × 30 mL) and dried over Na
2SO
4, and the solvents were removed under reduced pressure to give a residue that was then purified by silica gel/reverse-phase flash column chromatography. The combined pure fractions were evaporated under vacuum to give the products, which were converted into their corresponding hydrochloride (15–17, 19–21, 24–29, 55–59, 61–64, 66–67, and 69) or oxalate salts (23, 65). Subsequentely, they were dried in a vacuum oven (40 °C) to obtain the titled products as amorphous solids.
General Procedure C. General procedure C outlines the reductive amination reactions in
Scheme 2 to afford amine derivatives 13–14, 18, 22, and 60. A mixture of aldehyde 1–2 (0.25 g, 1.0 equiv.) and appropriate aniline derivative (1.0 equiv.) in 5 mL dry THF was treated with acetic acid (0.1 equiv.) and then cooled down to 0 °C, followed by addition of sodium cyanoborohydride (2.5 equiv.). The reaction was allowed to stir at rt until the consumption of the starting materials (UPLC monitoring) and then quenched with slush, pH was basified by adding 5 mL of aqueous sodium bicarbonate saturated solution, extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (2 × 15 mL), brine (1 × 15 mL) and dried over Na
2SO
4, and solvents removed under reduced pressure to give a residue which was purified by silica gel/reverse-phase flash column chromatography. The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to to give titled compounds 13–14, 18, 22, 60 as amorphous solids.
General Procedure D. General procedure D outlines the synthesis of amide derivatives 30–44 reported in
Scheme 2. A solution of carboxylic acid derivative 6 (1.0 equv.) in dry DMF at 0 °C was treated with
N-hydroxy succinimide (1.2 equiv.) and EDCl (1.2 equiv.) (for the aliphatic amine derivatives) or HATU (1.2 equiv.) (for the aniline derivatives 30–31 and 38) and stirred for 30 min, followed by the addition of an appropriate amine (1.0 equiv.), DIPEA (2.5 equiv.) and allowed to warm to rt. The reaction was continued until the consumption of the starting materials (UPLC monitoring), then quenched with water, and extracted with ethyl acetate (3 × 10 mL); the combined organic layers were washed with water (2 × 15 mL) and brine (1 × 15 mL) and dried over Na
2SO
4, and solvents were removed under reduced pressure to give a residue that was purified by silica gel/reverse-phase flash column chromatography. The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to afford the titled compounds 30–44 as amorphous solids.
General Procedure E. General procedure E outlines the preparation of ether derivatives 9, 45, and 68 reported in
Scheme 3. A solution of the aldehyde derivative 1, 4 (1.0 equiv.) in MeOH was treated with sodium borohydride (4.0 equiv.) and warmed to rt. The reaction was quenched with slush after the consumption of the starting materials (UPLC monitoring). Excess solvents were removed under reduced pressure and extracted with ethyl acetate (3 × 10 mL); the combined organic layers were washed with water (2 × 15 mL) and brine (1 × 15 mL) and dried over Na
2SO
4, and solvents were removed under reduced pressure to give the alcohol derivatives 7–8. A solution of alcohol derivative 7–8 (1.0 equiv.) in 5 mL of dry THF was cooled down to −10 °C, treated with sodium hydride (5.0 equiv.), and left to stir for 30 min, followed by the addition of alkyl bromide (1.2 equiv.), and then warmed to rt. The reaction was continued until the consumption of the starting materials (UPLC monitoring), quenched with slush, and extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were washed with water (2 × 15 mL) and brine (1 × 15 mL) and dried over Na
2SO
4, and solvents were removed under reduced pressure to give a residue that was used as such for compound 9 or purified by flash chromatography for 45 and 68. The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to afford the titled compounds 45 and 68 as amorphous solids.
General procedure F. General procedure F outlines the synthesis of triazole derivative 46–48 reported in
Scheme 3. A suspension of the alkyne 9 (1.0 equiv.) and the azide derivative d1–d3 (1.5 equiv.) in 5.0 mL of
tert-butanol/water (1:1) was treated with sodium ascorbate (0.5 equiv.) and copper (II) sulfate (0.1 equiv.) and left to stir on. The reaction was quenched with water and extracted with EtOAc (3 × 15 mL); the combined organic layers were dried over Na
2SO
4 and the solvents were evaporated under reduced pressure to obtain a crude that was purified by flash column chromatography. The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to afford the compounds 46–48 as amorphous solids.
General procedure G. General procedure G outlines the metal-free synthesis of cross-coupling products 49–51 reported in
Scheme 4. A solution of aldehyde 1 (1.0 equiv.) and tosylhydrazide (1.0 equiv.) in 5 mL of 1,4-dioxane was heated to 80 °C for 2 h in a sealed tube; then, the mixture was cooled down to rt, and potassium carbonate (1.5 equiv.) and phenyl boronic acid e1–e3 (1.5 equiv.) were added to the mixture and heated to 110 °C until the consumption of the starting materials (UPLC monitoring). The reaction was quenched with water; solvents were removed under reduced pressure to obtain a crude that was purified by flash chromatography. The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to afford products 49–51 as amorphous solids.
General procedure H. General procedure H outlines the synthesis of products 52–53 by nucleophilic fluorination reactions reported in
Scheme 5. A solution of the aldehyde derivative 1 and the alcohol derivative 7 (1.0 equiv.) in 10 mL DCM was treated with DAST (3.5–6.5 equiv.) dropwise at −10 °C and left to warm to rt. The reaction was stirred until the consumption of the starting materials (UPLC monitoring), quenched with a saturated solution of sodium bicarbonate, and extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over Na
2SO
4, and solvents were removed under reduced pressure to obtain a residue that was purified by flash chromatography on silica gel with EtOAc in
n-heptane (10–80%). The combined pure fractions were evaporated under vacuum and subsequently dried under high vacuum for 5 h to afford the title compounds
53 and
52 as amorphous solids, respectively.
Brown Solid, 60% yield. 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.51 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.44–7.35 (m, 2H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.32 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 184.7, 154.3, 144.8, 143.8, 139.1, 130.6, 129.7, 127.9, 124.8, 122.4, 122.3, 119.7, 118.0, 117.7, 64.6, 64.4. UPLC/MS (ESI): m/z = 306.9 [M+H]+.
3-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2) [29].
Yellow solid, 43% yield. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 9.31 (s, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.62–7.53 (m, 2H), 7.53–7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.11 (s, 2H). 13C NMR (101 MHz, DMSO) δ 184.3, 153.2, 149.1, 148.4, 139.0, 136.2, 130.7, 128.6, 126.0, 123.9, 122.9, 120.1, 109.7, 109.3, 102.3. UPLC/MS (ESI): m/z = 293.1 [M+H]+.
Beige Solid, 55% yield, 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 9.30 (s, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.61–7.51 (m, 4H), 7.42 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H); 13C NMR (101 MHz, DMSO) δ 185.7, 153.6, 150.7, 149.5, 139.6, 136.0, 130.6, 128.6, 124.7, 123.0, 122.4, 120.2, 113.0, 112.5, 56.5.
A suspension of compound 1 (2.0 g, 1.0 equiv.) in 20 mL water/pyridine (1:1) mixture was treated with potassium permanganate (1.0 equiv.) portion-wise. The reaction mixture was stirred until the disappearance of the violet color; then, the manganese dioxide precipitate was filtered off and washed with 1M aqueous solution of sodium hydroxide. This was followed by acidification of the solution by 1M aqueous HCl solution to obtain a precipitate that was filtered off, washed with water (3 × 30 mL), and dried under vacuum to afford the titled compound 6.
Beige solid. 77% yield, 1H NMR (400 MHz, DMSO) δ 12.57 (brs, 1H, COOH), 9.03 (s, 1H), 7.96 (d, J = 7.7 Hz, 2H), 7.53 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.40–7.33 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H); 13C NMR (101 MHz, DMSO) δ 164.8, 153.1, 144.8, 143.6, 139.7, 134.6, 130.6, 128.1, 126.1, 123.1, 119.9, 118.9, 117.4, 114.5, 65.2, 65.0. UPLC/MS (ESI): m/z = 323.1 [M+H]+.
Brown solid, 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.3, 2.1 Hz, 1H), 7.29 (m, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.76 (s, 2H), 4.30 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 151.2, 143.9, 143.8, 140.0, 129.6, 127.8, 126.5, 121.2, 120.6, 119.0, 117.6, 116.9, 64.6, 64.5, 56.2. UPLC/MS (ESI): m/z = 309.1 [M+H]+.
Brown solid, 75% yield, 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 5.20 (brs, 1H), 4.53 (s, 2H), 3.81 (s, 3H); 13C NMR (101 MHz, DMSO) δ 159.6, 150.8, 140.5, 130.5, 129.6, 129.5, 127.3, 126.5, 122.0, 118.9, 114.9, 56.1, 55.1.
White solid, 55% yield, 1H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 7.93 (d, J = 7.7 Hz, 2H), 7.60–7.51 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.14–7.09 (m, 3H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.43 (s, 2H), 4.30 (s, 4H), 2.28 (s, 3H); 13C NMR (101 MHz, DMSO) δ 154.4, 146.8, 144.9, 144.5, 139.9, 138.5, 132.7, 130.5, 129.0, 128.0, 126.4, 126.1, 123.0, 119.8, 118.6, 118.4, 108.3, 65.2, 65.0, 51.1, 21.7.
Pale yellow solid, 8% yield. 1H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.86 (d, J = 7.7 Hz, 2H), 7.56–7.46 (m, 2H), 7.36–7.24 (m, 3H), 7.10 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 7.6 Hz, 2H), 6.58 (t, J = 7.6 Hz, 1H), 5.91 (t, J = 4.9 Hz, 1H, NH), 4.26 (s, 4H), 4.18 (d, J = 4.9 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 151.1, 149.6, 144.4, 144.3, 140.4, 130.5, 129.9, 129.8, 127.1, 127.0, 121.4, 119.4, 118.9, 118.2, 117.1, 116.9, 113.3, 65.1, 65.0, 39.1. UPLC/MS (ESI): m/z = 384.3 [M+H]+.
Pale yellow solid 7% yield. 1H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 8.2 Hz, 2H), 7.36–7.24 (m, 3H), 7.01–6.89 (m, 3H), 6.72–6.60 (m, 2H), 5.87 (t, J = 5.0 Hz, 1H, NH), 4.26 (m, 4H), 4.15 (d, J = 5.0 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 155.5 (d, 1JC–F = 230 Hz), 151.1, 146.3 (d, 4JC–F = 2 Hz), 144.3 (d, 3JC–F = 8 Hz), 140.4, 130.5, 129.9, 127.1, 127.0, 121.4, 119.4, 118.9, 118.2, 117.0, 116.2 (d, 2JC–F = 22 Hz), 114.1, 114.1, 65.1, 65.0, 39.7. UPLC/MS (ESI): m/z = 402.3 [M+H]+.
White solid, 35% yield, 1H NMR (400 MHz, DMSO) δ 9.44 (s, 2H, NH2), 8.75 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.61–7.48 (m, 4H), 7.48–7.40 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.30 (s, 4H), 4.26–4.19 (m, 4H); 13C NMR (101 MHz, DMSO) δ 152.0, 144.6, 144.4, 140.2, 132.7, 131.3, 131.2, 130.7, 129.8, 129.5, 127.7, 126.1, 122.1, 119.3, 118.2, 117.7, 112.8, 65.2, 65.0, 50.5, 41.3. UPLC/MS (ESI): m/z = 398.3 [M+H]+.
Pale brown solid, 55% yield. 1H NMR (400 MHz, DMSO) δ 9.70 (s, 2H, NH2), 8.85 (s, 1H), 7.83–7.77 (m, 2H), 7.61 (m, 2H), 7.55 (m, 2H), 7.40–7.33 (m, 1H), 7.26 (t, J = 8.9 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.29 (s, 4H), 4.22 (s, 2H), 4.17 (s, 2H); 13C NMR (101 MHz, DMSO) δ 163.3 (d, 1JC-F = 245 Hz), 151.9, 144.7, 144.4, 140.1, 133.5 (d, 3JC-F = 8 Hz), 131.2, 130.7, 129.0, 127.7, 126.0, 122.1, 119.3, 118.2, 117.6, 116.4 (d, 2JC-F = 21 Hz), 112.8, 65.2, 65.0, 49.8, 41.3. UPLC/MS (ESI): m/z = 416.3 [M+H]+.
White solid, 85% yield. 1H NMR (400 MHz, DMSO) δ 9.33 (s, 2H, NH2), 8.83 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.40–7.29 (m, 3H), 7.29–7.21 (m, 3H), 7.21–7.12 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 4.30 (s, 4H), 4.24 (m, 2H), 3.22 (m, 2H), 2.99 (m, 2H); 13C NMR (101 MHz, DMSO) δ 151.8, 144.7, 144.4, 140.1, 138.0, 131.1, 130.7, 129.6, 129.5, 127.7, 126.1, 122.1, 119.3, 118.3, 117.6, 112.9, 65.2, 65.1, 48.5, 41.9, 32.4. UPLC/MS (ESI): m/z = 412.3 [M+H]+.
Pale yellow solid, 8% yield. 1H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.31 (q, J = 5.0 Hz, 1H, NH), 8.04 (d, J = 2.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.39–7.19 (m, 3H), 7.09 (dd, J = 8.5, 2.7 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.84 (t, J = 4.9 Hz, 1H, NH), 4.28 (m, 6H), 2.76 (d, J = 5.0 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 165.8, 151.1, 147.4, 144.4, 144.3, 140.6, 139.1, 134.6, 130.5, 130.0, 127.1, 126.9, 123.6, 121.4, 119.0, 118.4, 118.2, 118.1, 116.9, 65.1, 65.0, 38.5, 26.7. UPLC/MS (ESI): m/z = 442.3 [M+H]+.
Brown solid, 68% yield. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 2H, NH2), 9.02 (s, 1H), 8.86 (d, J = 5.9 Hz, 2H), 7.99 (d, J = 5.9 Hz, 2H), 7.78 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.24–7.11 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 4.30 (s, 4H), 4.21 (m, 2H), 3.48–3.31 (m, 4H); 13C NMR (101 MHz, DMSO) δ 151.8, 144.7, 144.4, 143.1, 140.1, 131.6, 131.2, 130.7, 128.1, 127.7, 126.1, 122.2, 119.2, 118.3, 117.7, 112.8, 65.1, 65.0, 46.4, 42.0, 32.2. UPLC/MS (ESI): m/z = 413.3 [M+H]+.
White solid, 35% yield. 1H NMR (400 MHz, DMSO) δ 9.80 (brs, 2H, NH2), 9.00 (m, 1H), 8.89 (s, 1H), 8.79 (d, J = 5.6 Hz, 1H), 8.45 (m, 1H), 7.95 (m, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.21–7.12 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 4.30 (s, 4H), 4.22 (m, 2H), 3.37 (m, 2H), 3.28 (m, 2H); 13C NMR (101 MHz, DMSO) δ 151.8, 146.7, 144.7, 144.4, 143.3, 141.4, 140.1, 138.1, 131.2, 130.7, 127.6, 126.1, 122.2, 119.2, 118.3, 117.7, 112.8, 65.1, 65.0, 47.2, 42.0, 29.2. UPLC/MS (ESI): m/z = 413.3 [M+H]+.
Brown solid, 20% yield. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 2H, NH2), 8.93 (s, 1H), 8.70 (d, J = 7.2 Hz, 1H), 8.23 (t, J = 7.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.22–7.13 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 4.34–4.20 (m, 6H), 3.61–3.34 (m, 4H); 13C NMR (101 MHz, DMSO) δ 154.5, 151.8, 144.7, 144.4, 140.1, 131.2, 130.7, 127.7, 127.3, 126.1, 125.4, 122.2, 119.3, 118.3, 117.6, 112.8, 65.2, 65.1, 45.9, 42.1, 31.2. UPLC/MS (ESI): m/z = 413.3 [M+H]+.
White solid, 26% yield. 1H NMR (400 MHz, DMSO) δ 8.76 (q, J = 4.7 Hz, 1H, NH), 8.59 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 2.6 Hz, 1H), 7.34–7.28 (m, 3H), 7.10 (dd, J = 5.6, 2.6 Hz, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 9.0 Hz, 1H), 6.78 (d, J = 8.9 Hz, 2H), 6.12 (t, J = 4.8 Hz, 1H, NH), 4.28 (s, 4H), 4.22 (d, J = 4.8 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 167.7, 164.8, 153.2, 151.1, 151.1, 147.8, 144.4, 144.3, 144.2, 140.4, 130.5, 129.9, 127.1, 127.0, 122.6, 121.4, 119.2, 118.9, 118.2, 116.9, 114.7, 114.3, 109.3, 65.1, 65.0, 39.5, 26.9. UPLC/MS (ESI): m/z = 534.2 [M+H]+.
Yellow solid, 35% yield. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.26–7.21 (m, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.30 (m, 6H), 3.16 (m, 4H), 1.88 (m, 4H); 13C NMR (101 MHz, DMSO) δ 165.1, 152.1, 144.7, 144.4, 140.1, 131.1, 130.6, 127.6, 126.3, 122.1, 119.3, 118.3, 117.7, 65.2, 65.1, 53.7, 48.6, 23.6. UPLC/MS (ESI): m/z = 362.3 [M+H]+.
Yellow oil, 60% yield. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.47–7.38 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.27 (s, 4H), 3.48 (s, 2H), 2.90–2.37 (m, 8H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.1, 143.6, 143.5, 140.1, 129.4, 128.1, 127.0, 126.1, 121.6, 118.7, 117.5, 117.2, 64.6, 64.4, 55.2, 52.7, 52.4, 46.0. UPLC/MS (ESI): m/z = 391.3 [M+H]+.
(1r,3r)-N-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methyl)adamantan-2-amine hydrochloride (25).
White solid, 13% yield. 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.56–7.46 (m, 3H), 7.40 (dd, J = 8.3, 2.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.27 (s, 4H), 3.68 (m, 2H), 2.77 (m, 1H), 2.12 (m, 2H), 1.87 (m, 2H), 1.84–1.72 (m, 5H), 1.68 (m, 4H), 1.42 (m, 2H). 13C NMR (101 MHz, DMSO) δ 151.1, 144.2, 144.2, 140.5, 130.4, 129.5, 127.4, 126.7, 121.5, 121.3, 118.8, 117.9, 117.3, 65.1, 65.0, 62.7, 38.5, 37.9, 32.4, 31.9, 28.1. UPLC/MS (ESI): m/z = 442.4 [M+H]+.
N-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methyl)-2-(pyrrolidin-1-yl)ethan-1-amine dihydrochloride (26) [
21].
White solid, 21% yield. 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H, NH), 9.79 (s, 2H, NH2), 8.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.19 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 4.30 (m, 6H), 3.76–3.41 (m, 6H), 3.05 (m, 2H), 2.07–1.81 (m, 4H); 13C NMR (101 MHz, DMSO) δ 151.7, 144.7, 144.4, 140.1, 130.8, 127.8, 126.0, 122.1, 119.3, 118.3, 117.6, 112.8, 65.2, 65.1, 54.2, 50.5, 43.4, 42.4, 23.5. UPLC/MS (ESI): m/z = 405.4 [M+H]+.
Orange solid, 28% yield. 1H NMR (400 MHz, DMSO) δ 11.53 (m, 1H, NH), 9.56 (m, 2H, NH), 8.70 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 6.95–6.81 (m, 2H), 6.68 (d, J = 8.2 Hz, 1H), 4.06–3.86 (m, 7H), 3.51–2.63 (m, 13H), 2.20 (t, J = 1.9 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 151.3, 144.4, 144.3, 140.4, 130.5, 130.0, 127.1, 127.0, 121.7, 119.0, 118.1, 117.7, 65.1, 65.0, 56.8, 55.3, 53.2, 46.3, 45.7, 43.6. UPLC/MS (ESI): m/z = 434.4 [M+H]+.
White solid, 40% yield. 1H NMR (400 MHz, DMSO) δ 11.36 (s, 1H, NH), 9.91 (s, 2H, NH2), 8.94 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.22–7.12 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 4.33–4.25 (m, 6H), 3.99 (m, 2H), 3.81 (m, 2H), 3.55 (m, 6H), 3.16 (m, 2H) 13C NMR (101 MHz, DMSO) δ 151.6, 144.7, 144.4, 140.1, 130.8, 130.7, 127.7, 126.0, 122.1, 119.2, 118.3, 117.6, 112.7, 65.1, 65.0, 64.2, 52.9, 52.5, 42.3, 41.4. UPLC/MS (ESI): m/z = 421.3 [M+H]+.
N1-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methyl)-N3,N3-dimethylpropane-1,3-diamine dihydrochloride (29) [
21].
Orange solid, 77% yield. 1H NMR (400 MHz, DMSO) δ 10.47 (brs, 1H, NH), 9.52 (brs, 2H, NH2), 8.93 (s, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.24–7.09 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 4.30 (s, 4H), 4.20 (t, J = 5.6 Hz, 2H), 3.16 (m, 2H), 3.08 (m, 2H), 2.74 (m, 6H), 2.10 (p, J = 7.5 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 151.8, 144.7, 144.4, 140.1, 131.2, 130.7, 127.7, 126.1, 122.2, 119.3, 118.3, 117.7, 112.8, 65.2, 65.1, 54.5, 44.6, 42.9, 41.9, 21.6. UPLC/MS (ESI): m/z = 393.3 [M+H]+.
White solid, Yield 45%. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.66 (s, 1H, NH), 7.48 (t, J = 7.8 Hz, 2H), 7.41–7.27 (m, 6H), 7.21 (dd, J = 8.2, 2.1 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.34 (q, J = 5.3 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 160.7, 150.4, 145.0, 144.3, 139.4, 137.9, 131.6, 129.7, 129.1, 127.5, 125.2, 124.3, 122.7, 119.8, 119.5, 118.8, 118.4, 118.1, 64.7, 64.5. UPLC/MS (ESI): m/z = 398.3 [M+H]+.
Pale yellow solid, 67% yield. 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H, NH), 9.04 (s, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.72 (m, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.45–7.31 (m, 3H), 7.20 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.27 (s, 4H); 13C NMR (101 MHz, DMSO) δ 162.5, 159.1 (d, 1JC-F = 238 Hz), 151.3, 144.7, 143.9 139.9, 136.5 (d, 4JC-F = 2 Hz), 131.4, 130.7, 127.9, 126.3, 122.4 (d, 3JC-F = 8 Hz), 122.1, 119.5, 118.5, 117.79, 117.74, 116.3 (d, 2JC-F 22 = Hz), 65.2, 65.0. UPLC/MS (ESI): m/z = 416.3 [M+H]+.
White solid, 84% yield. 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.72 (t, J = 6.0 Hz, 1H, NH), 7.88 (d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.8 Hz, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.38–7.32 (m, 6H), 7.26 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.27 (s, 4H); 13C NMR (101 MHz, DMSO) δ 163.8, 151.2, 144.6, 143.8, 140.3, 140.0, 130.9, 130.6, 129.2, 128.3, 127.8, 127.7, 126.5, 122.3, 119.5, 118.4, 118.1, 117.5, 65.2, 65.0, 43.3. UPLC/MS (ESI): m/z = 412.3 [M+H]+.
Yellow solid, 65% yield. 1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.73 (t, J = 6.0 Hz, 1H, NH), 7.88 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.4 Hz, 2H), 7.45–7.31 (m, 5H), 7.17 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 4.27 (s, 4H); 13C NMR (101 MHz, DMSO) δ 163.8, 162.1 (d, 1JC-F = 240 Hz), 151.2, 144.6, 143.8, 140.0, 136.6 (d, 4JC-F = 3 Hz), 130.9, 130.6, 130.3 (d, 3JC-F = 8 Hz), 127.8, 126.4, 122.3, 119.5, 118.3, 118.0, 117.5, 115.9 (d, 2JC-F = 21 Hz), 65.2, 65.00, 42.7. UPLC/MS (ESI): m/z = 430.3 [M+H]+.
White solid, 56% yield. 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.29 (t, J = 6.8 Hz, 1H, NH), 7.86 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.33–7.18 (m, 6H), 6.87 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 3.45 (q, J = 6.8 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.7, 151.0, 144.6, 143.8, 140.3, 140.0, 130.7, 130.6, 129.6, 129.3, 127.7, 127.1, 126.4, 122.2, 119.4, 118.6, 117.9, 117.6, 65.2, 65.0, 41.4, 36.1. UPLC/MS (ESI): m/z = 426.3 [M+H]+.
White solid, 55% yield. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.47 (d, J = 6.0 Hz, 2H), 8.30 (t, J = 6.8 Hz, 1H, NH), 7.85 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.42–7.33 (m, 2H), 7.28 (d, J = 6.0 Hz, 2H), 7.25 (dd, J = 8.4, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 3.50 (q, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.8, 151.0, 150.4, 149.3, 144.6, 143.8, 139.9, 130.7, 130.6, 127.8, 126.4, 125.2, 122.2, 119.4, 118.5, 117.9, 117.6, 65.1, 65.0, 40.2, 35.2. UPLC/MS (ESI): m/z = 427.3 [M+H]+.
White solid, 45% yield, 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 4.8, 2.3 Hz, 1H), 8.33 (t, J = 6.7 Hz, 1H, NH), 7.86 (d, J = 7.8 Hz, 2H), 7.69 (dt, J = 7.8, 2.3 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.42–7.29 (m, 3H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.27 (s, 4H), 3.48 (q, J = 6.7 Hz, 2H), 2.84 (t, J = 6.7 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.8, 151.0, 150.8, 148.4, 144.6, 143.8, 139.9, 137.2, 135.8, 130.7, 130.6, 127.8, 126.4, 124.4, 122.2, 119.4, 118.5, 117.9, 117.6, 65.2, 65.0, 41.0, 33.1. UPLC/MS (ESI): m/z = 427.3 [M+H]+.
Pale yellow solid, 56% yield. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.29 (t, J = 6.9 Hz, 1H, NH), 7.86 (d, J = 7.9 Hz, 2H), 7.71 (td, J = 7.6, 1.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 7.41–7.33 (m, 2H), 7.30 (m, 2H), 7.26–7.19 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.27 (s, 4H), 3.58 (q, J = 6.9 Hz, 2H), 2.98 (t, J = 6.9 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.7, 160.0, 151.0, 150.0, 144.6, 143.8, 140.0, 137.4, 130.8, 130.6, 127.7, 126.4, 124.1, 122.5, 122.2, 119.4, 118.6, 117.9, 117.6, 65.2, 65.0, 39.8, 38.2. UPLC/MS (ESI): m/z = 427.3 [M+H]+.
Pale yellow solid, 69% yield. 1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H, NH), 9.07 (s, 1H), 8.79 (q, J = 5.0 Hz, 1H, NH), 8.52 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.47–7.33 (m, 4H), 7.24 (d, J = 9.0 Hz, 2H), 7.17 (dd, J = 5.6, 2.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 2.79 (d, J = 5.0 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 166.8, 164.7, 162.6, 153.4, 151.4, 151.3, 149.6, 144.7, 143.9, 139.9, 137.9, 131.5, 130.7, 127.9, 126.2, 122.4, 122.3, 122.1, 119.5, 118.5, 117.8, 117.8, 115.0, 109.7, 65.2, 65.0, 27.4. UPLC/MS (ESI): m/z = 548.2 [M+H]+.
White solid, 65% yield. 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 8.1 Hz, 2H), 7.35 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 3.47 (t, J = 6.8 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.81 (m, 4H); 13C NMR (101 MHz, DMSO) δ 163.9, 149. 5, 144.6, 144.2, 140.1, 130.5, 129.3, 127.5, 126.5, 120.9, 119.4, 118.7, 118.1, 116.4, 65.1, 65.0, 49.0, 46.5, 26.4, 25.0. UPLC/MS (ESI): m/z = 376.3 [M+H]+.
White solid, 18% yield. 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.28–7.16 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 4.33 (s, 4H), 3.65 (m, 4H), 3.31 (m, 4H); 13C NMR (101 MHz, DMSO) δ 164.5, 149.6, 144.8, 144.3, 140.0, 130.5, 129.7, 127.6, 126.1, 121.0, 119.4, 118.3, 116.7, 116.5, 66.8, 65.2, 65.1. UPLC/MS (ESI): m/z = 392.3 [M+H]+.
N-((1r,3r,5r,7r)-adamantan-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazole-4-carboxamide (41).
White solid, 21% yield. 1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H, NH), 7.53 (t, J = 8.1 Hz, 2H), 7.40–7.28 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H), 4.27 (s, 4H), 4.01 (d, J = 7.2 Hz, 1H), 2.00–1.87 (m, 4H), 1.87–1.73 (m, 6H), 1.70 (m, 2H), 1.49 (d, J = 12.5 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.3, 150.8, 144.6, 143.9, 140.1, 131.1, 130.5, 127.6, 126.5, 122.2, 119.5, 119.0, 117.9, 117.8, 65.2, 65.0, 54.5, 38.1, 37.8, 32.3, 27.7. UPLC/MS (ESI): m/z = 456.4 [M+H]+.
Brown solid, 33% yield. 1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.53 (t, J = 7.9 Hz, 2H), 7.49–7.20 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 3.72 (m, 4H), 3.41 (m, 2H), 3.14 (m, 2H), 2.05 (m, 4H); 13C NMR (101 MHz, MeOD) δ 166.8, 164.5, 153.1, 145.8, 144.7, 140.7, 131.5, 130.7, 128.5, 126.7, 123.1, 120.4, 118.9, 118.0, 117.6, 65.8, 65.65, 55.8, 55.6, 37.2, 24.0. UPLC/MS (ESI): m/z = 419.4 [M+H]+.
White solid, 33% yield. 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.97 (t, J = 5.7 Hz, 1H, NH), 7.88 (t, J = 8.1 Hz, 2H), 7.54 (t, J = 8.1 Hz, 2H), 7.42–7.30 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 4.28 (s, 4H), 3.32 (m, 2H), 2.47–2.14 (m, 13H); 13C NMR (101 MHz, DMSO) δ 163.6, 150.9, 144.6, 143.8, 140.0, 130.9, 130.6, 127.7, 126.4, 122.2, 119.4, 118.7, 117.9, 117.6, 65.1, 65.0, 57.8, 55.6, 53.6, 46.7, 37.4. UPLC/MS (ESI): m/z = 448.3 [M+H]+.
Yellow solid, 26% yield. 1H NMR (400 MHz, DMSO) δ 10.89 (brs, 1H, NH), 9.20 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H, NH), 7.87 (d, J = 7.9 Hz, 2H), 7.71–7.19 (m, 5H), 6.89 (d, J = 8.5 Hz, 1H), 4.27 (s, 4H), 4.00–3.79 (m, 4H), 3.65 (m, 2H), 3.53 (m, 2H), 3.28 (m, 2H), 3.13 (m, 2H); 13C NMR (101 MHz, DMSO) δ 164.0, 151.6, 144.6, 143.7, 139.9, 131.7, 130.7, 127.9, 126.4, 122.6, 119.4, 118.4, 117.7, 117.5, 65.2, 65.0, 64.1, 56.4, 52.1, 42.4, 34.3. UPLC/MS (ESI) m/z = 435.3 [M+H]+.
Pale yellow solid, 15% yield. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.60–7.53 (m, 2H), 7.34–7.24 (m, 3H), 7.24–7.15 (m, 3H), 7.11 (t, J = 7.3 Hz, 1H), 6.88 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 4.42 (s, 2H), 4.40 (s, 2H), 4.13 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 162.5 (d, 1JC-F 250 Hz), 151.8, 143.8, 143.6, 140.0, 133.8 (d, 4JC-F 3 Hz), 129.9 (d, 3JC-F 8 Hz), 129.5, 128.4, 126.6, 126.4, 121.3, 118.9, 117.4, 117.0, 115.4 (d, 2JC-F 21 Hz), 71.5, 64.6, 64.4, 63.0. UPLC/MS (ESI) m/z = 417.3 [M+H]+.
4-(((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methoxy)methyl)-1-phenyl-1H-1,2,3-triazole (46).
Pale yellow solid, 65% yield. 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.64 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.9 Hz, 2H), 7.55–7.46 (m, 3H), 7.36–7.25 (m, 3H), 6.90 (d, J = 9.0 Hz, 1H), 4.73 (s, 2H), 4.58 (s, 2H), 4.34–4.08 (m, 4H); 13C NMR (101 MHz, DMSO) δ 151.7, 145.8, 144.4, 144.3, 140.3, 137.6, 131.0, 130.9, 130.5, 129.6, 127.2, 126.7, 123.4, 121.4, 121.0, 119.1, 118.1, 117.9, 116.9, 65.1, 65.0, 63.2, 63.0. UPLC/MS (ESI) m/z = 466.3 [M+H]+.
4-(((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methoxy)methyl)-1-(4-fluorophenyl)-1H-1,2,3-triazole (47).
Pale pink solid. 21% yield. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.99 (s, 1H), 7.80–7.68 (m, 4H), 7.51–7.42 (m, 3H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.35–7.17 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 4.87 (s, 2H), 4.67 (s, 2H), 4.31–4.17 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 162.6 (d, 1JC-F = 248 Hz), 152.0, 146.2, 143.9, 143.6, 140.0, 133.5, 129.6, 128.9, 126.6, 126.5, 122.7 (d, 3JC-F = 9 Hz), 121.4, 121.3, 119.1, 117.6, 117.1, 117.1, 116.8 (d, 2JC-F = 23 Hz), 64.6, 64.5, 63.3, 63.2. UPLC/MS (ESI) m/z = 484.3 [M+H]+.
1-benzyl-4-(((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)methoxy)methyl)-1H-1,2,3-triazole (48).
White solid, 56% yield. 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 8.0 Hz, 2H), 7.26–7.40 (m, 8H), 6.90 (d, J = 8.3 Hz, 1H), 5.61 (s, 2H), 4.63 (s, 2H), 4.51 (s, 2H), 4.27 (s, 4H); 13C NMR (101 MHz, DMSO) δ 151.7, 145.0, 144.5, 144.3, 140.3, 137.0, 130.9, 130.5, 129.7, 129.1, 128.8, 127.1, 126.8, 125.2, 121.4, 119.1, 118.2, 117.9, 116.9, 65.1, 65.1, 63.3, 63.0, 53.7. UPLC/MS (ESI) m/z = 480.3 [M+H]+.
Pale yellow solid, 5% yield. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.41 (t, J 8.0 Hz, 2H), 7.36–7.29 (m, 2H), 7.29–7.19 (m, 6H), 6.91 (d, J = 8.4 Hz, 1H), 4.29 (s, 4H), 4.03 (s, 2H);13C NMR (101 MHz, CDCl3) δ 151.2, 143.6, 140.6, 140.2, 129.4, 128.8, 128.7, 127.4, 127.1, 126.4, 126.1, 121.3, 120.4, 118.7, 117.4, 117.0, 64.6, 64.5, 31.2. UPLC/MS (ESI) m/z = 369.3 [M+H]+.
White solid, 18% yield. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.32–7.22 (m, 4H), 7.22–7.13 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H), 4.29 (s, 4H), 4.00 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 151.1, 143.7, 143.7, 140.1, 139.1, 132.2, 130.1, 129.5, 128.9, 127.4, 126.9, 126.3, 121.3, 119.9, 118.8, 117.5, 117.0, 64.6, 64.5, 30.6. UPLC/MS (ESI) m/z = 403.3 [M+H]+.
White solid, 50% yield. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.33–7.20 (m, 3H), 7.20–7.06 (m, 4H), 6.89 (d, J = 8.3 Hz, 1H), 4.25 (s, 4H), 4.01 (s, 2H); 13C NMR (101 MHz, DMSO) δ 161.6 (d, 1JC-F = 240 Hz), 150.9, 144.2, 140.4, 137.4 (d, 4JC-F = 3 Hz), 130.9 (d, 3JC-F = 8 Hz), 130.4, 129.5, 127.2, 126.9, 121.3, 120.1, 118.9, 118.1, 116.8, 116.1 (d, 2JC-F = 22 Hz), 65.1, 65.0, 30.0. UPLC/MS (ESI) m/z = 387.3 [M+H]+.
White solid, 50% yield, 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 3.2 Hz, 1H), 7.72 (d, J = 7.4 Hz, 2H), 7.49–7.39 (m, 2H), 7.34 (d, J = 2.1 Hz, 1H), 7.32–7.25 (m, 2H), 6.94 (d, J = 8.3 Hz, 1H), 5.40 (d, JCH2-F = 49.5 Hz, 2H), 4.28 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 152.6 (d, 3J = 2.1 Hz), 144.2, 143.8, 139.9, 129.6, 129.4, 126.9, 126.0, 121.4 (d, 3JC-F = 2.2 Hz), 119.3, 117.7, 117.1 (d, 4JC-F = 2.2 Hz), 116.0 (d, 2JC-F = 21.1 Hz), 75.49 (d, 1JC-F = 161.9 Hz), 64.67, 64.51. UPLC/MS (ESI) m/z = 311.1 [M+H]+.
Pale yellow solid, 76% yield. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 55.4 Hz, 1H), 4.31 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 150.8 (t, 3JC-F = 5.2 Hz), 144.4, 143.9, 139.6, 129.7, 127.4 (t, 3JC-F = 4.8 Hz), 127.3, 125.4, 121.4, 119.5, 117.8, 117.1, 116.1 (t, 2JC-F = 25.4 Hz), 111.3 (t, 1JC-F = 233.6 Hz), 64.6, 64.5. UPLC/MS (ESI) m/z = 329.1 [M+H]+.
A solution of 12 (0.1 g, 1.0 equiv.) was treated with 4-fluorophenyl isocyanate (1.1 equiv.) in acetonitrile (10 mL) and the reaction was continued until the consumption of the starting materials (UPLC monitoring). The reaction was quenched with water, extracted with EtOAc (3 × 15 mL), the combined organic layers were dried over Na2SO4 and the solvents were evaporated under reduced pressure to obtain a crude that was purified by flash column chromatography to afford the compound 54.
White solid, 23% yield. 1H NMR (400 MHz, DMSO) δ 8.48 (m 2H), 7.86 (d, J = 7.9 Hz, 2H), 7.50 (t, J = 7.9Hz, 2H), 7.45–7.34 (m, 2H), 7.31 (m, 1H), 7.24 (d, J = 6.4 Hz, 2H), 7.06 (m 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.48 (brs, 1H, NH), 4.40–4.21 (m, 6H). 13C NMR (101 MHz, DMSO) δ 157.9 (d, 1JC-F = 235 Hz), 156.0, 150.5, 144.4 (d, 4JC-F = 3 Hz), 140.4, 137.7, 130.5, 129.6, 127.1, 127.0, 121.4, 120.2 (d, 3JC-F = 8 Hz), 119.8, 119.0, 118.2, 116.8, 116.1 (d, 2JC-F = 22 Hz), 65.1, 65.0, 35.2. UPLC/MS (ESI) m/z = 445.3 [M+H]+.
White solid, 36% yield. 1H NMR (400 MHz, DMSO) δ 9.65 (brs, 2H, NH2), 8.84 (s, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.61 (m, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.27 (m, 2H), 7.19 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 7.9, 1.7 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.09 (s, 2H), 4.23 (t, J = 5.2 Hz, 2H), 4.18 (t, J = 5.2 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 163.3 (d, 1JC-F = 243 Hz), 152.2, 148.5, 148.4, 140.1, 133.6 (d, 3JC-F = 8 Hz), 131.4, 130.7, 129.0 (d, 4JC-F = 3 Hz), 127.7, 126.7, 123.0, 119.3, 116.3 (d, 2JC-F = 21 Hz), 112.8, 109.4, 102.2, 49.7, 41.2. UPLC/MS (ESI) m/z = 402.3 [M+H]+.
White solid, 60% yield. 1H NMR (400 MHz, DMSO) δ 9.47 (brs, 2H, NH2), 8.89 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.34–7.23 (m, 3H), 7.23–7.10 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 6.10 (s, 2H), 4.22 (m, 2H), 3.26–3.15 (m, 2H), 3.11–2.93 (m, 2H); 13C NMR (101 MHz, DMSO) δ 162.1 (d, 1JC-F = 241 Hz), 152.0, 148.6, 148.4, 140.1, 134.4 (d, 4JC-F = 3 Hz), 131.4 (d, 3JC-F = 8 Hz), 131.3, 130.7, 127.7, 126.8, 123.1, 119.3, 116.3 (d, 2JC-F = 21 Hz), 113.1, 109.5, 109.4, 102.2, 48.5, 41.8, 31.5. UPLC/MS (ESI) m/z = 416.3 [M+H]+.
Pale yellow solid, 60% yield. 1H NMR (400 MHz, DMSO) δ 9.88 (s, 2H, NH2), 9.00 (s, 1H), 8.92–8.79 (m, 2H), 7.95 (d, J = 4.0 Hz, 2H), 7.86–7.74 (m, 2H), 7.61–7.51 (m, 2H), 7.42–7.33 (m, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.17 (dd, J = 8.0, 1.7 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.10 (s, 2H), 4.23 (m, 2H), 3.37 (m, 4H); 13C NMR (101 MHz, DMSO) δ 158.3, 152.0, 148.5, 148.4, 142.5, 140.1, 131.4, 130.7, 128.3, 127.7, 126.8, 123.1, 119.2, 112.9, 109.5, 109.5, 102.2, 46.4, 42.0, 32.2. UPLC/MS (ESI) m/z = 399.3 [M+H]+.
White solid, 59% yield. 1H NMR (400 MHz, DMSO) δ 9.90 (brs, 2H, NH2), 9.03 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.81 (dd, J = 5.6, 1.7 Hz, 1H), 8.49 (dt, J = 8.0, 1.7 Hz, 1H), 7.98 (dd, J = 8.0, 5.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.17 (dd, J = 8.1, 1.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.10 (s, 2H), 4.21 (t, J = 5.5 Hz, 2H), 3.37 (m, 2H), 3.30 (m, 2H). 13C NMR (101 MHz, DMSO) δ 152.0, 148.5, 148.4, 146.5, 143.6, 141.6, 140.1, 137.9, 131.3, 130.7, 127.7, 127.5, 126.8, 123.1, 119.3, 112.9, 109.5, 109.4, 102.2, 47.2, 42.0, 29.2. UPLC/MS (ESI) m/z = 399.3 [M+H]+.
White solid, 48% yield. 1H NMR (400 MHz, DMSO) δ 9.82 (brs, 2H, NH2), 8.96 (s, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8.42–8.14 (m, 1H), 7.81 (m, 3H), 7.77–7.67 (m, 1H), 7.56 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.10 (s, 2H), 4.27 (t, J = 5.7 Hz, 2H), 3.47 (m, 4H); 13C NMR (101 MHz, DMSO) δ 154.8, 152.4, 148.9, 148.8, 145.5, 144.4, 140.3, 131.5, 131.1, 128.2, 127.3, 126.9, 125.6, 123.3, 119.7, 112.7, 109.9, 109.6, 102.6, 46.1, 42.2, 31.6. UPLC/MS (ESI) m/z = 399.3 [M+H]+.
Brown solid, 9% yield. 1H NMR (400 MHz, DMSO) δ 8.77 (q, J = 5.1 Hz, 1H, NH), 8.50 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.50 (t, J = 8.1 Hz, 2H), 7.37–7.24 (m, 4H), 7.08 (dd, J = 5.6, 2.6 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.03 (m, 3H, 1H NH), 4.21 (m, 2H), 2.77 (d, J = 5.1 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 167.7, 164.8, 153.2, 151.3, 151.1, 148.5, 148.1, 147.8, 144.2, 140.4, 130.5, 130.0, 127.8, 127.0, 122.6, 122.2, 119.3, 119.0, 114.7, 114.4, 109.5, 109.3, 108.6, 102.1, 39.5, 26.9. UPLC/MS (ESI) m/z = 520.3 [M+H]+.
White solid, 45% yield. 1H NMR (400 MHz, DMSO) δ 11.31 (brs, 1H, NH), 9.87 (brs, 2H, NH2), 8.93 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.10 (s, 2H), 4.28 (m, 2H), 3.99 (m, 2H), 3.81 (m, 2H), 3.55 (m, 6H), 3.16 (m, 2H); 13C NMR (101 MHz, DMSO) δ 151.8, 148.6, 148.5, 140.1, 131.0, 130.8, 127.8, 126.7, 123.1, 119.3, 112.8, 109.5, 109.4, 102.3, 64.2, 52.9, 52.5, 42.3, 41.4. UPLC/MS (ESI) m/z = 407.3 [M+H]+.
Pale brown solid, 55% yield. 1H NMR (400 MHz, DMSO) δ 9.88 (brs, 2H, NH2), 9.00 (s, 1H), 8.84 (d, J = 5.9 Hz, 2H), 7.94 (d, J = 5.9 Hz, 2H), 7.80 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.24 (m, 2H), 3.82 (s, 3H), 3.37 (m, 4H); 13C NMR (101 MHz, DMSO) δ 160.4, 158.4, 152.1, 142.5, 140.2, 131.3, 130.8, 130.5, 128.3, 127.6, 125.3, 119.3, 115.2, 112.8, 56.2, 46.4, 42.1, 32.2. UPLC/MS (ESI) m/z = 385.3 [M+H]+.
Pale brown solid, 43% yield. 1H NMR (400 MHz, DMSO) δ 9.95 (brs, 2H, NH2), 9.05 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.81 (dd, J = 5.6, 2.0 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 8.2, 5.6 Hz, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.22 (m, 2H), 3.82 (s, 3H), 3.45–3.26 (m, 4H); 13C NMR (101 MHz, DMSO) δ 160.4, 152.1, 146.8, 143.3, 141.3, 140.2, 138.1, 131.3, 130.7, 130.4, 127.6, 127.6, 125.3, 119.2, 115.1, 112.8, 56.2, 47.2, 42.1, 29.2. UPLC/MS (ESI) m/z = 385.3 [M+H]+.
Pale brown solid, 10% yield. 1H NMR (400 MHz, DMSO) δ 9.92 (brs, 2H, NH2), 8.99 (s, 1H), 8.75 (d, J = 7.9 Hz, 1H), 8.34 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.80 (m, 3H), 7.66 (d, J = 8.3 Hz, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 4.25 (t, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.50 (m, 4H); 13C NMR (101 MHz, DMSO) δ 152.7, 152.4, 144.5, 141.2, 132.7, 130.1, 122.0, 121.8, 121.0, 119.0, 118.2, 116.5, 114.5, 111.6, 111.5, 106.5, 47.2, 41.2, 35.7, 29.7. UPLC/MS (ESI) m/z = 385.3 [M+H]+.
White solid, 64% yield. 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 4.34 (s, 2H), 3.82 (s, 3H), 3.16 (m, 4H), 1.87 (m, 4H); 13C NMR (101 MHz, DMSO) δ 165.4, 160.3, 152.4, 140.1, 131.1, 130.6, 130.4, 127.5, 125.5, 119.3, 115.1, 112.9, 56.1, 53.6, 48.6, 23.6. UPLC/MS (ESI) m/z = 334.2 [M+H]+.
Yellow solid, 62% yield. 1H NMR (400 MHz, DMSO) δ 11.11 (brs, 1H, NH), 8.93 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.56 (t, J = 7.9 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 4.53–4.29 (m, 2H), 4.01–3.69 (m, 7H), 3.34 (m, 2H), 3.11–2.91 (m, 2H); 13C NMR (101 MHz, DMSO) δ 160.4, 153.1, 140.1, 132.5, 130.7, 127.8, 125.2, 119.4, 115.1, 109.9, 64.0, 56.1, 61.4, 50.8. UPLC/MS (ESI) m/z = 350.3 [M+H]+.
White solid, 70% yield. 1H NMR (400 MHz, DMSO) δ 9.55 (brs, 2H, NH2), 8.89 (s, 1H), 7.83 (m, 2H), 7.61–7.51 (m, 2H), 7.41–7.34 (m, 1H), 7.32–7.26 (m, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 7.17–7.13 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 4.24 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.20 (s, 2H), 3.07–2.93 (m, 2H); 13C NMR (101 MHz, DMSO) δ 162.1 (d, 1JC-F = 241 Hz), 152.4, 150.1, 149.8, 140.2, 134.3 (d, 4JC-F = 3 Hz), 131.5 (d, 3JC-F = 8 Hz), 131.2, 130.7, 127.7, 125.5, 121.6, 119.3, 116.3 (d, 2JC-F = 21 Hz), 113.0, 112.8, 112.7, 56.6, 56.5, 48.4, 41.9, 31.5. UPLC/MS (ESI) m/z = 432.3 [M+H]+.
Pale yellow, 47% yield. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.43 (m, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.20 (m, 2H), 7.02 (d, J = 8.3 Hz, 2H), 4.57 (s, 2H), 4.52 (s, 2H), 3.80 (s, 3H); 13C NMR (101 MHz, DMSO) δ 162.6 (d, 1JC-F = 242 Hz), 160.1, 151.9, 140.4, 135.3 (d, 4JC-F = 3 Hz), 130.9 (d, 3JC-F = 8 Hz), 130.7, 130.5, 129.6, 127.1, 126.1, 119.1, 118.0, 116.0 (d, 2JC-F = 21 Hz), 115.0, 71.3, 63.1, 56.1. UPLC/MS (ESI) m/z = 389.2 [M+H]+.
Brown solid, 10% yield. 1H NMR (400 MHz, DMSO+D2O) δ 8.97 (s, 1H), 8.49 (d, J = 6.1 Hz, 1H), 8.06–7.92 (m, 2H), 7.39 (t, J = 6.1 Hz, 1H), 7.24–7.11 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 4.40–4.18 (m, 6H), 3.62 (m, 2H), 3.55–3.37 (m, 4H), 3.03 (m, 2H), 2.10–1.77 (m, 4H). 13C NMR (101 MHz, DMSO+D2O) δ 152.9, 151.5, 149.8, 145.4, 144.9, 141.3, 130.3, 126.1, 124.0, 122.7, 118.9, 118.0, 113.5, 113.3, 65.6, 65.5, 55.0, 50.8, 43.9, 43.0, 23.9. UPLC/MS (ESI) m/z = 406.4 [M+H]+.
The
1H and
13C NMR spectra of compounds
13–
69; UPLC chromatograms and HRMS spectra of
13,
14,
17,
22,
26,
29,
33,
35,
38,
41,
44,
48,
49,
54,
68 and
69 are available in
Supplementary Materials.