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1 upporting Information Discovery of -[4-(quinolin-4-yloxy)-phenyl]-benzenesulfonamides as novel AXL kinase inhibitors István zabadkai,#, Robert Torka,#, Rita Garamvölgyi,, erenc Baska, Pál Gyulavári ±, ándor Boros, Eszter Illyés, Axel hoidas, Axel Ullrich, László Őrfi *,, Vichem hemie Research Ltd., Budapest, ungary Institute of Physiological hemistry, University alle-wittenberg, alle (aale), Germany Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany Lead Discovery enter Gmb, Dortmund, Germany Department of Pharmaceutical hemistry, emmelweis University, Budapest, ungary ± Department of Medical hemistry, Molecular Biology and Pathobiochemistry, emmelweis University, Budapest, ungary # These authors contributed equally to this work. TET Experimental section, general information tructures, synthesis and analytical characterization of the compound Evaluation and interpretation of the MR spectra of compound 18d Evaluation and interpretation of the MR spectra of compound 19e

2 Evaluation and interpretation of the MR spectra of compound 19h Evaluation and interpretation of the MR spectra of compound 19i Evaluation and interpretation of the MR spectra of compound 20b Evaluation and interpretation of the MR spectra of compound 20g Evaluation and interpretation of the MR spectra of compound 21f Table 1. DiscoveRx Kinomescan Kinase electivity Panel (442 kinases) of 20b and 20g at 5µM concentration 124 Table 2. Kinases which inhibition value are smaller than ten times the percentage control value of AXL of 20b and 20g. (DiscoveRx Kinomescan Kinase electivity Panel) 142 Table 3. omplete lists of all kinases that bound to the KinAffinity matrix and of all identified target kinases. Table 4. Abbreviations and names of kinases in the manuscript EXPERIMETAL ETI General information The commercially available reagents and solvents were used without further purification. The reactions were monitored by TL, with Kieselgel (Merck) plates and visualized by UV light. Analytical details can be found in the upporting information. Analytical PL-M was performed on a Waters PL-M system using reverse phase. Method A: Waters XBridge 18 (5 cm x 4.6 mm, 5 µm), gradient 0-95 % B (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 % B, 6.50 min 5 % B, 7.00 min 5 % B), olvent A: Water/ 0.05%, olvent B: Ac/ 0.05% over 7.00 min, flow = 2.0 ml/min. eparation module was Waters Alliance

3 Method B: Waters X Waters XBridge 18 (5 cm x 4.6 mm, 3.5 µm), gradient 0-95 % B (0.00 min 5 % B, 0.50 min 5 % B, 5.5 min 95 % B, 6.00 min 95 % B, 6.50 min 5 % B, 7.00 min 5 % B), olvent A: 5 mm 43, olvent B: Ac over 7.00 min, flow = 2.0 ml/min. The separation module was Waters Alliance UV spectra were recorded using a Waters 996 DAD UV detector. Mass spectra were obtained using Waters QD M detector (ionization: E + /E -, source block temp: 120, desolvation temp: 350, desolvation gas: 400 L/h, cone gas: 100 L/h, capillary: 3000 V, cone: 25 V, extractor: 3 V, Rf lens: 0.2 V, scan: 120 to 1000 m/z in 1 sec., inter-scan delay: 0.1 s). The MR spectra were recorded on a Bruker Avance 300 spectrometer operating at 7.05 Tesla magnetic field, equipped with a 5 mm dual invese z-grad probehead, in deuterated dimethylsulfoxide (DM-d6) solution, at 30. The instrument was controlled and the data were processed using Toppin 1.3 software package. The chemical structures are confirmed based on their 1 -MR, and if it was necessary clip-y 1,2, relayed clip-y 2,3, zqs-ty 2, zqs-easy-rey 2,4,5, hidrogen-decoupled 13 -MR, multiplicity-edited Q and MB spectra. hemical shifts (δ) are reported in parts per million (ppm) referenced to tetramethylsilane. or the multiplicities the standard abbreviations are used, in addition ovl. means overlapping signals, dm means doublet of multiplets. The overlapping and/or higher order multiplets were simulated by WinDMR MR pectrum alculator 6 program. The multiplicities of the 13 signals caused by fluorine atom and the J(,) coupling constants are given in parentheses in the 13 MR data. The whole MR spectra of some selected final products (18d, 19e, 19h, 19i, 20b, 20g and 21f) are inserted into this document with their detailed interpretation (pages ). 3

4 When the side-chain of the quinoline ring system contains basic amine function group at position 7, the acidic sulfonamide partly protonates this amine, forming zwitterionic structure. In this case, the sulfonamide signal may be extremely broad obscuring in the baseline. This phenomenon is mentioned in the lists of the 1 -MR data. The p dependency of the 1 -MR spectrum is illustrated on the set of spectra of compound 20b. (see page 106) RM was performed on an Agilent 6230 T L/M ystem with Agilent Jet tream source, EI positive mode. Buffer: ammonium-formate in water / acetonitrile. Drying gas: 325. V ap: 3000 V. ragmentor 100 V. Melting points were determined on a Büchi Melting Point B-540 instrument. References for the MR measurements: [1] M. R. M. Koos, G. Kummerlöwe, L. Kaltschnee,. M. Thiele, B. Luy: LIP-Y: A lean In-Phase Experiment for the Rapid Acquisition of Y-type orrelatuions, Angew. hem. Int. Ed., 2016, 55, [2] M. J. Thrippleton, J. Keeler: Elimination of Zero-Quantum Interference in Two- Dimensional MR pectra, Angew. hem. Int. Ed., 2003, 42, [3] T. Gyöngyösi, I. Tímári, J. aller, M. R. M. Koos, B. Luy, K. E. Kövér: Boosting the MR assignment of carbohydrates with clean in-phase correlation experiments, hemplushem., 2018, 83, [4]. M. Thiele, K. Petzold, J. chleucher: EAY REY: Reliable ross-peak Integration in Adiabatic ymmetrized REY, hem. Eur. J., 2009, 15, [5]. Boros, Gy. Batta: ffset-compensated and zero-quantum suppressed REY provides accurate 1 1 distances in small to medium-sized molecules, Magn. Reson. hem., 2016, 54,

5 [6] WIDMR, MR pectrum alculator, version (ep. 27, 2009), Author: ans J. Reich, Department of hemistry, Wisconsin University, Madison, WI, UA 5

6 General procedure A ynthesis of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (10a). + A mixture of 4-chloro-6,7-dimethoxy-quinoline (2.24 g, mmol), 4-nitrophenol (1.53 g mmol),,-diisopropylethylamine (1.42 g mmol) and chlorobenzene (25 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled down, diluted with aqueous sodium hydroxide solution (20 ml, 10 wt %) and stirred for 3 hours. The two layers were separated. The aqueous layer was extracted with chloroform (3 x 30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The pure product solidified under diisopropyl ether to give 2.57 g of the title compound. Yellow solid. Yield: 79%. Melting point: MR (300 Mz, DM-d6): δ 8.61 (d, J = 5.1 z, 1), 8.34 (dm, J = 9.1 z, 2), 7.46 (s, 1), 7.43 (dm, J = 9.1 z, 2), 7.37 (s, 1), 6.87 (d, J = 5.1 z, 1), 3.96 (s, 3), 3.88 (s, 3). LM Anal. calculated for : , found m/z: 327 [M+] +, tr = 2.69 min (method A); peak area 99%. ynthesis of 6,7-dimethoxy-4-(3-methyl-4-nitro-phenoxy)-quinoline (10b). + The title compound 10b (yellow solid, 2.38 g) was prepared following the general procedure A, using 3-methyl-4-nitrophenol (1.68 g mmol) Yield: 70%. Melting point:

7 1 MR (300 Mz, DM-d6): δ 8.58 (d, J = 5.2 z, 1), 8.14 (d, J = 9.1 z, 1), 7.44 (s, 1), 7.40 (s, 1), 7.39 (d, J = 2.6 z, 1), 7.26 (dd, J = 9.1, 2.6 z, 1), 6.80 (d, J = 5.2 z, 1), 3.96 (s, 3), 3.90 (s, 3), 2.56 (s, 3). LM Anal. calculated for : , found m/z: 341 [M+] +, tr = 2.43 and 2.66 min (method A); peak area 97%. ynthesis of 6,7-dimethoxy-4-(2-methyl-4-nitro-phenoxy)-quinoline (10c). + The title compound 10c (yellow solid, 2.06 g) was prepared following the general procedure A, using 2-methyl-4-nitrophenol (1.68 g mmol). Yield: 60%. Melting point: MR (300 Mz, DM-d6): δ 8.54 (d, J = 5.2 z, 1), 8.36 (d, J = 2.3 z, 1), 8.16 (dd, J = 8.9, 2.3 z, 1), 7.46 (s, 1), 7.44 (s, 1), 7.30 (d, J = 8.9 z, 1), 6.61 (d, J = 5.2 z, 1), 3.96 (s, 3), 3.92 (s, 3), 2.35 (s, 3). LM Anal. calculated for : , found m/z: 341 [M+] +, tr = 2.44 and 2.63 min (method A); peak area 99%. ynthesis of 6,7-dimethoxy-4-(3-methoxy-4-nitro-phenoxy)-quinoline (10d). + A mixture of 10f (344 mg, 1.00 mmol), anhydrous dimethylsulfoxide (8 ml) and sodium methylate (270 mg, 5.00 mmol) was stirred at room temperature for 4 days, until the starting material disappeared according to TL (eluent: ethyl acetate). The mixture was poured into 7

8 water. The precipitate was filtered, washed with water then dried on air. Thus the title compound was obtained (302 mg). Yellow solid. Yield 85%. Melting point: MR (300 Mz, DM-d6): δ 8.58 (d, J = 5.2 z, 1), 8.04 (d, J = 8.9 z, 1), 7.44 (s, 1), 7.42 (s, 1), 7.32 (d, J = 2.2 z, 1), 6.88 (dd, J = 8.9, 2.2 z, 1), 6.82 (d, J = 5.2 z, 1), 3.96 (s, 3), 3.94 (s, 3), 3.91 (s, 3). LM Anal. calculated for : , found m/z: 357 [M+] +, tr = 2.73 min (method A); peak area 95%. ynthesis of 6,7-dimethoxy-4-(2-methoxy-4-nitro-phenoxy)-quinoline (10e). + The title compound 10e (yellow solid, 1.85 g) was prepared following the general procedure A, using 2-methoxy-4-nitrophenol (1.86 g mmol). Yield: 52%. 1 MR (300 Mz, DM-d6): δ 8.48 (d, J = 5.2 z, 1), 8.04 (d, J = 2.6 z, 1), 7.97 (dd, J = 8.7, 2.6 z, 1), 7.50 (d, J = 8.7 z, 1), 7.46 (s, 1), 7.42 (s, 1), 6.48 (d, J = 5.2 z, 1), 3.95 (s, 3), 3.92 (s, 3), 3.89 (s, 3). LM Anal. calculated for : , found m/z: 357 [M+] +, tr = 2.37 min (method A); peak area 98%, 8

9 ynthesis of 6,7-dimethoxy-4-(3-fluoro-4-nitro-phenoxy)-quinoline (10f). + The title compound 10f (yellow solid, 1.70 g) was prepared following the general procedure A, using 3-fluoro-4-nitrophenol (1.72 g, mmol). Yield: 49%. Melting point: MR (300 Mz, DM-d6): δ 8.64 (d, J = 5.2 z, 1), 8.27 (dd, J = 9.0, 9.0 z, 1), 7.55 (dd, J = 12.4, 2.4 z, 1), 7.46 (s, 1), 7.33 (s, 1), 7.20 (ddd, J = 9.0, 2.4, 1.0 z, 1), 6.98 (d, J = 5.2 z, 1), 3.96 (s, 3), 3.88 (s, 3). LM Anal. calculated for : , found m/z: 345 [M+] +, tr = 2.78 min (method A); peak area 99%. ynthesis of 6,7-dimethoxy-4-(2-fluoro-4-nitro-phenoxy)-quinoline (10g). + The title compound 10g (yellow solid, 1.62 g) was prepared following the general procedure A, using 2-fluoro-4-nitrophenol (1.72 g, mmol). Yield: 47%. Melting point: MR (300 Mz, DM-d6): δ 8.57 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.6 z, 1), 8.20 (ddd, J = 9.0, 2.6, 1.4 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.46 (ovl. s, 2), 6.78 (d, J = 5.2 z, 1), 3.96 (s, 3), 3.92 (s, 3). LM Anal. calculated for : , found m/z: 345 [M+] +, tr = 2.59 min (method A); peak area 99%. 9

10 General procedure B. ynthesis of 6,7-dimethoxy-4-(4-amino-phenoxy)-quinoline (11a). 2 A mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (10a, 2.28 g, 7.00 mmol), ammonium chloride (2.28 g, mmol), zinc powder (13.68 g, mmol) ethyl alcohol (600 ml) and water (60 ml) was stirred at reflux temperature for 3 hours. The hot reaction mixture was filtered through elite, washed with hot ethyl alcohol then the filtrate was evaporated under reduced pressure. The residue was taken up in the mixture of chloroform (50 ml) and aqueous sodium hydroxide solution (10%, 40 ml) and stirred for 1 hour. The two layers were separated. The aqueous layer was extracted with chloroform (3 x 50 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The crude product was purified by column chromatography (eluent: chloroform-methanol=95:5). The pure product solidified under diisopropyl ether to give 1.48 g of the title compound. Gray solid. Yield: 69%. Melting point: MR (300 Mz, DM-d6): δ 8.42 (d, J = 5.2 z, 1), 7.50 (s, 1), 7.36 (s, 1), 6.92 (dm, J = 8.7 z, 2), 6.67 (dm, J = 8.7 z, 2), 6.37 (d, J = 5.2 z, 1), 5.14 (br. s, 2), 3.93 (ovl. s, 6). LM Anal. calculated for : , found m/z: 297 [M+] +, tr = 1.99 min (method A); peak area 99%. 10

11 ynthesis of 6,7-dimethoxy-4-(3-methyl-4-amino-phenoxy)-quinoline (11b). 2 The title compound 11b (gray solid, 700 mg) was prepared following the general procedure B, using 10b (1000 mg, 2.93 mmol). Yield: 77%. Melting point: MR (300 Mz, DM-d6): δ 8.41 (d, J = 5.2 z, 1), 7.50 (s, 1), 7.36 (s, 1), 6.85 (d, J = 2.2 z, 1), 6.81 (dd, J = 8.4, 2.2 z, 1), 6.70 (d, J = 8.4 z, 1), 6.37 (d, J = 5.2 z, 1), 4.88 (br. s, 2), 3.93 (ovl. s, 6), 2.09 (s, 3). LM Anal. calculated for : , found m/z: 311 [M+] +, tr = 2.08 min (method A); peak area 100%. ynthesis of 6,7-dimethoxy-4-(2-methyl-4-amino-phenoxy)-quinoline (11c). 2 The title compound 11c (gray solid, 880 mg) was prepared following the general procedure B, using 10c (1310 mg, 3.85 mmol). Yield: 73%. Melting point: MR (300 Mz, DM-d6): δ 8.40 (d, J = 5.2 z, 1), 7.54 (s, 1), 7.37 (s, 1), 6.84 (d, J = 7.4 z, 1), 6.55 (d, J = 2.3 z, 1), 6.50 (dd, J = 7.4, 2.3 z, 1), 6.25 (d, J = 5.2 z, 1), 5.04 (br. s, 2), 3.94 (ovl. s, 6), 1.95 (s, 3). LM Anal. calculated for : , found m/z: 311 [M+] +, tr = 1.97 min (method A); peak area 100%. 11

12 ynthesis of 6,7-dimethoxy-4-(3-methoxy-4-amino-phenoxy)-quinoline (11d). 2 The title compound 11d (gray solid, 207 mg) was prepared following the general procedure B, using 10d (290 mg, 0.81 mmol). Yield: 78%. Melting point: MR (300 Mz, DM-d6): δ 8.43 (d, J = 5.2 z, 1), 7.51 (s, 1), 7.37 (s, 1), 6.76 (d, J = 2.3 z, 1), 6.72 (d, J = 8.2 z, 1), 6.60 (dd, J = 8.2, 2.3 z, 1), 6.41 (d, J = 5.2 z, 1), 4.75 (br. s, 2), 3.94 (ovl. s, 6), 3.76 (s, 3). LM Anal. calculated for : , found m/z: 327 [M+] +, tr = 2.13 min (method A); peak area 94%. ynthesis of 6,7-dimethoxy-4-(2-methoxy-4-amino-phenoxy)-quinoline (11e). 2 The title compound 11e (gray solid, 897 mg) was prepared following the general procedure B, using 10e (1380 mg, 3.87 mmol). Yield: 71%. Melting point: MR (300 Mz, DM-d6): δ 8.39 (d, J = 5.2 z, 1), 7.49 (s, 1), 7.35 (s, 1), 6.87 (d, J = 8.4 z, 1), 6.43 (d, J = 2.1 z, 1), 6.27 (d, J = 5.2 z, 1), 6.21 (dd, J = 8.4, 2.1 z, 1), 5.17 (br. s, 2), 3.93 (ovl. s, 6), 3.62 (s, 3). LM Anal. calculated for : , found m/z: 327 [M+] +, tr = 2.05 min (method A); peak area 100%. 12

13 ynthesis of 6,7-dimethoxy-4-(3-fluoro-4-amino-phenoxy)-quinoline (11f). 2 The title compound 11f (gray solid, 4.90 g) was prepared following the general procedure B, using 10f (7.30 g, mmol). Yield: 73%. Melting point: MR (300 Mz, DM-d6): δ 8.45 (d, J = 5.2 z, 1), 7.49 (s, 1), 7.37 (s, 1), 7.05 (dd, J = 12.5, 2.5 z, 1), 6.86 (dd, J = 8.7, 8.4 z, 1), 6.83 (dd, J = 8.7, 2.5 z, 1), 6.43 (d, J = 5.2 z, 1), 5.18 (br. s, 2), 3.94 (s, 3), 3.93 (s, 3). LM Anal. calculated for : , found m/z: 315 [M+] +, tr = 2.38 min (method A); peak area 98%. ynthesis of 6,7-dimethoxy-4-(2-fluoro-4-amino-phenoxy)-quinoline (11g). 2 The title compound 11g (gray solid, 1.41 g) was prepared following the general procedure B, using 10g (1.80 g, 5.22 mmol). Yield: 86%. Melting point: MR (300 Mz, DM-d6): δ 8.45 (d, J = 5.2 z, 1), 7.51 (s, 1), 7.38 (s, 1), 7.07 (dd, J = 9.1, 8.9 z, 1), 6.55 (dd, J = 13.1, 2.4 z, 1), 6.47 (dd, J = 8.9, 2.4 z, 1), 6.39 (d, J = 5.2 z, 1), 5.47 (br. s, 2), 3.94 (ovl. s, 6). LM Anal. calculated for : , found m/z: 315 [M+] +, tr = 2.40 min (method A); peak area 100%. 13

14 General procedure. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]-benzenesulfonamide (12a). The mixture of benzenesulfonyl chloride (60 mg, 0.34 mmol), pyridine (3 ml) and 11f (94 mg 0.30 mmol) was stirred at room temperature for 2 days. The mixture was poured into 1 hydrochloric acid solution then the precipitate was collected, washed with water, dissolved in the mixture of ethyl acetate and saturated sodium acetate solution and stirred for 2 hours. The two layers were separated then the organic layer was evaporated. The residue was purified on preparative TL plate (eluents: chloroform-methanol=9:1, the chamber was saturated with ammonia). The pure product solidified under diisopropyl ether to give 80 mg of the title compound. White solid. Yield: 59%. Melting point: MR (300 Mz, DMd6): δ (br. s, 1), 8.50 (d, J = 5.2 z, 1), 7.74 (dm, J = 7.8 z, 2), 7.65 (ttm, J = 7.2, 1.8 z, 1), 7.58 (ddm, J = 7.8, 7.2 z, 2), 7.41 (s, 1), 7.40 (s, 1), 7.32 (dd, J = 9.0, 8.8 z, 1), 7.20 (dd, J = 11.0, 2.6 z, 1), 7.03 (dd, J = 9.0, 2.6, 1.0 z, 1), 6.53 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.90 (s, 3). LM Anal. calculated for : , found m/z: 453 [M-] -, 455 [M+] +, tr = 2.54 and 2.70 min (method A); peak area 98%. 14

15 ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2-methylbenzenesulfonamide (12b). The title compound 12b (white solid, 87 mg) was prepared following the general procedure, using 2-methyl-benzenesulfonyl chloride (61 mg, 0.31 mmol). Yield: 62%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.50 (d, J = 5.2 z, 1), 7.92 (dm, J ~ 7.5 z, 1), 7.53 (dd, J = 7.5, 7.5 z, 1), 7.43 (dm, J ~ 7.5 z, 1), 7.40 (s, 1), 7.39 (s, 1), 7.33 (ddm, J ~ z, 1), 7.32 (dd, J = 9.0, 8.8 z, 1), 7.20 (dd, J = 11.0, 2.6 z, 1), 7.03 (dd, J = 9.0, 2.6, 1.0 z, 1), 6.50 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3), 2.63 (s, 3). LM Anal. calculated for : , found m/z: 467 [M-] -, 469 [M+] +, tr = 2.82 min (method A); peak area 94%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2-trifluoromethylbenzenesulfonamide (12c). The title compound 12c (white solid, 113 mg) was prepared following the general procedure, using 2-trifluoromethylbenzenesulfonyl chloride (76 mg, 0.31 mmol). Yield: 72%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 8.02 (ovl. m, 2), 7.87 (ovl. m, 2), (s, 1), (s, 1), 7.34 (dd, J = 9.0,

16 z, 1), 7.23 (dd, J = 11.0, 2.5 z, 1), 7.06 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.53 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for : , found m/z: 521 [M-] -, 523 [M+] +, tr = 2.80 and 2.95 min (method A); peak area 96%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-trifluoromethylbenzenesulfonamide (12d). The title compound 12d (white solid, 83 mg) was prepared following the general procedure, using 3-trifluoromethylbenzenesulfonyl chloride (80 mg 0.31 mmol). Yield: 53%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.50 (d, J = 5.2 z, 1), 8.08 (dm, J ~ 7.5 z, 1), 8.02 (d, J ~ 8.0 z, 1), 8.05 (dd, J ~ 1.5, 1.5 z, 1), 7.85 (dd, J ~ 8.0, 7.5 z, 1), (s, 1), (s, 1), 7.33 (dd, J = 9.0, 8.8 z, 1), 7.25 (dd, J = 11.0, 2.5 z, 1), 7.08 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.53 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for , Mw=522.48, found m/z: 521 [M-] -, 523 [M+] +, tr = 2.88 and 3.03 min (method A); peak area 95%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2-methoxybenzenesulfonamide (12e). 16

17 The title compound 12e (white solid, 79 mg) was prepared following the general procedure, using 2-methoxybenzenesulfonyl chloride (66 mg 0.31mmol). Yield: 55%. Melting point: MR (300 Mz, DM-d6): δ 9.79 (br. s, 1), 8.50 (d, J = 5.2 z, 1), 7.66 (dd, J = 7.8, 1.6 z, 1), 7.61 (ddd, J = 8.5, 7.6, 1.6 z, 1), 7.39 (s, 1), 7.39 (s, 1), 7.33 (dd, J = 9.0, 8.8 z, 1), 7.23 (dd, J = 8.5, 0.8 z, 1), 7.19 (dd, J = 11.0, 2.7 z, 1), 7.03 (ddd, J = 7.8, 7.6, 0.8 z, 1), 7.00 (ddd, J = 8.8, 2.7, 1.3 z, 1), 6.50 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3), 3.88 (s, 3). LM Anal. calculated for : , found m/z: 483 [M-] -, 485 [M+] +, tr = 2.54 and 2.71 min (method A); peak area 98%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2-trifluoromethoxy-benzenesulfonamide (12f). The title compound 12f (white solid, 112 mg) was prepared following the general procedure, using 2-trifluoromethoxybenzenesulfonyl chloride (83 mg, 0.31 mmol). Yield: 69%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 7.90 (dd, J = 7.8, 1.7 z, 1), 7.80 (ddd, J = 8.5, 7.6, 1.7 z, 1), 7.59 (ddm, J = 8.5, 1.0 z, 1), 7.55 (ddd, J = 7.8, 7.6, 1.0 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.36 (dd, J = 9.0, 8.8 z, 1), 7.24 (dd, J = 11.0, 2.6 z, 1), 7.06 (ddd, J = 8.8, 2.6, 1.2 z, 1), 6.52 (d, J = 5,2 z, 1), 3.94 (s, 3), 3.90 (s, 3). LM Anal. calculated for : , found m/z: 537 [M-] -, 539 [M+] +, tr = 2.87 and 3.00 min (method A); peak area 96%. 17

18 ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2-fluorobenzenesulfonamide (12g). The title compound 12g (white solid, 72 mg) was prepared following the general procedure, using 2-fluorobenzenesulfonyl chloride (62 mg, 0.31 mmol). Yield: 51%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 7.73 (ddd, J = 7.6, 6.6, 2.0 z, 1), 7.71 (dddd, J = 8.3, 7.6, 4.6, 2.0 z, 1), 7.45 (ddd, J = 10.6, 8.3, 1.0 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.35 (ddd, J = 7.6, 7.6, 1.0 z, 1), 7.34 (dd, J = 9.0, 8.8 z, 1), 7.21 (dd, J = 11.0, 2.5 z, 1), 7.03 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.53 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for : , found m/z: 471 [M-] -, 473 [M+] +, tr = 2.53 and 2.72 min (method A); peak area 98%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2,4-difluorobenzenesulfonamide (12h). The title compound 12h (white solid, 76 mg) was prepared following the general procedure, using 2,4-difluorobenzenesulfonyl chloride (68 mg, 0.31 mmol). Yield: 52%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 18

19 7.78 (ddd, J = 8.5, 8.5, 6.5 z, 1), 7.59 (ddd, J = 10.7, 9.4, 2.5 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.35 (dd, J = 9.0, 8.8 z, 1), 7.26 (dd, J = 11.0, 2.5 z, 1), 7.25 (dddd, J = 11.0, 8.5, 2.5, 1.0 z, 1), 7.06 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.55 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for : , found m/z: 489 [M-] -, 491 [M+] +, tr = 2.61 and 2.81 min (method A); peak area 95%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2,5-difluorobenzenesulfonamide (12i). The title compound 12i (white solid, 66 mg) was prepared following the general procedure, using 2,5-difluorobenzenesulfonyl chloride (68 mg, 0.31 mmol). Yield: 45%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), (ovl. m, 3), 7.41 (s, 1), 7.40 (s, 1), 7.36 (dd, J = 9.0, 8.8 z, 1), 7.26 (dd, J = 11.0, 2.5 z, 1), 7.05 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.55 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for : 490.4, m/z: 489 [M-] -, 491 [M+] +, tr = 2.64 and 2.82 min (method A); peak area 99%. 19

20 ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-2,6-difluorobenzenesulfonamide (12j). The title compound 12j (white solid, 66 mg) was prepared following the general procedure, using 2,6-difluorobenzenesulfonyl chloride (68 mg, 0.31 mmol). Yield: 45%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.52 (d, J = 5.2 z, 1), 7.74 (tt, J = 8.8, 6.3 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.39 (dd, J = 9.0, 8.8 z, 1), 7.30 (ddm, J = 9.0, 8.8 z, 2), 7.28 (dd, J = 11.0, 2.5 z, 1), 7.08 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.55 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.90 (s, 3). LM Anal. calculated for : , found m/z: 489 [M-] -, 491 [M+] +, tr = 2.51 and 2.73 min (method A); peak area 96%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-fluorobenzenesulfonamide (12k). The title compound 12k (white solid, 69 mg) was prepared following the general procedure, using 3-fluorobenzenesulfonyl chloride (62 mg, 0.31 mmol). Yield: 49%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 7.66 (ddd, 7.9, 7.9, 5.3, 1), (ovl. m, 3), 7.41 (s, 1), 7.40 (s, 1), 7.32 (dd, J = 9.00, 20

21 8.8 z, 1), 7.25 (dd, J = 11.0, 2.6 z, 1), 7.07 (ddd, J = 8.8, 2.6, 1.2 z, 1), 6.56 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.90 (s, 3). LM Anal. calculated for : , found m/z: 471 [M-] -, 473 [M+] +, tr = 2.61 and 2.80 min (method A); peak area 97%. ynthesis of 2-chloro--[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]- benzenesulfonamide (12l). l The title compound 12l (white solid, 111 mg) was prepared following the general procedure, using 2-chlorobenzenesulfonyl chloride (68 mg, 0.31 mmol). Yield: 76%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.50 (d, J = 5.2 z, 1), 7.91 (dd, J = 7.8, 1.5 z, 1), 7.67 (dd, J = 8.0, 1.6 z, 1), 7.63 (ddd, J = 8.0, 7.0, 1.5 z, 1), 7.49 (ddd, J = 7.8, 7.0, 1.6 z, 1), 7.40 (s, 1), 7.39 (s, 1), 7.31 (dd, J = 9.0, 8.8 z, 1), 7.20 (dd, J = 11.0, 2.6 z, 1), 6.99 (ddd, J = 8.8, 2.6, 1.2 z, 1), 6.52 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for 2318l25: , found m/z: 487 [M-] -, 489 [M+] +, tr = 2.65 and 2.81 min (method A); peak area 98%. ynthesis of 2,5-dichloro--[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]- benzenesulfonamide (12m). l l 21

22 The title compound 12m (white solid, 98 mg) was prepared following the general procedure, using 2,5-dichlorobenzenesulfonyl chloride (76 mg, 0.31 mmol). Yield: 63%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.52 (d, J = 5.2 z, 1), 7.85 (m, 1), (ovl. m, 2), (s, 1), 7.40, (s, 1), 7.35 (dd, J = 9.0, 8.8 z, 1), 7.26 (dd, J = 11.0, 2.5 z, 1), 7.06 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.56 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for 2317l225: , found m/z: 521 [M-] -, 523 [M+] +, tr = 2.90 and 3.05 min (method A); peak area 95%. ynthesis of 2,6-dichloro--[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]- benzenesulfonamide (12n). l l The title compound 12n (white solid, 91 mg) was prepared following the general procedure, using 2,6-dichlorobenzenesulfonyl chloride (76 mg, 0.31 mmol). Yield: 58%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 7.65 (dm, J = 8.0 z, 2), 7.57 (tm, J = 8.0 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.34 (dd, J = 9.0, 8.8 z, 1), 7.25 (dd, J = 11.0, 2.5 z, 1), 7.06 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.53 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.89 (s, 3). LM Anal. calculated for 2317l225: , found m/z: 521 [M-] -, 523 [M+] +, tr = 2.77 and 2.92 min (method A); peak area 96%. 22

23 ynthesis of 3-chloro--[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-4-fluorobenzenesulfonamide (12o). l The title compound 12o (white solid, 98 mg) was prepared following the general procedure, using 3-chloro-4-fluorobenzenesulfonyl chloride (76 mg, 0.31 mmol). Yield: 65%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.51 (d, J = 5.2 z, 1), 7.90 (dd, J = 6.8, 2.2 z, 1), 7.74 (ddd, 8.8, 4.7, 2.2 z, 1), 7.66 (dd, J = 8.8, 8.8 z, 1), 7.41 (s, 1), 7.40 (s, 1), 7.32 (dd, J = 9.0, 8.8 z, 1), 7.28 (dd, J = 11.0, 2.5 z, 1), 7.07 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.56 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.90 (s, 3). LM Anal. calculated for 2317l225: , found m/z: 505 [M-] -, 507 [M+] +, tr = 2.84 and 3.00 min (method A); peak area 95%. General procedure D. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-2- trifluoromethyl-benzenesulfonamide (12p). The mixture of 2-trifluoromethylbenzenesulfonyl chloride (78 mg, 0.34 mmol), pyridine (3 ml) and 11a (89 mg 0.30 mmol) was stirred at room temperature for 2 days. The mixture was poured into 1 hydrochloric acid solution then the precipitate was collected, washed with water, dissolved in the mixture of ethyl acetate and saturated sodium hydrogencarbonate 23

24 solution and stirred for 2 hours. The two layers were separated then the organic layer was evaporated. The residue was purified on preparative TL plate (eluents: chloroformmethanol=9:1, the chamber was saturated with ammonia). The pure product solidified under diisopropyl ether to give 89 mg of the title compound. White solid. Yield: 59%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.45 (d, J = 5.2 z, 1), 8.11 (dm, J = 6.9 z, 1), 8.02 (dm, J = 7.2 z, 1), (ovl. m, 2), 7.44 (s, 1), 7.38 (s, 1), 7.21 (dm, J = 9.0 z, 2), 7.18 (dm, J = 9.0 z, 2), 6.37 (d, J = 5.2 z, 1), 3.93 (s, 3), 3.89 (s, 3). LM Anal. calculated for : , found m/z: 503 [M-] -, 505 [M+] +, tr = 2.77 and 2.88 min (method A); peak area 99%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methyl-phenyl]-2-trifluoromethylbenzenesulfonamide (12q). The title compound 12p (white solid, 50 mg) was prepared following the general procedure D, using 11b (93 mg, 0.30 mmol). Yield: 32%. Melting point: MR (300 Mz, DM-d6): δ 9.88 (br. s, 1), 8.48 (d, J = 5.2 z, 1), 8.01 (m, 1), 7.95 (m, 1), (ovl. m, 2), 7.44 (s, 1), 7.39 (s, 1), 7.09 (d, J = 2.5 z, 1), 7.07 (d, J = 8.7 z, 1), 7.02 (dd, J = 8.7, 2.5 z, 1), 6.43 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.91 (s, 3), 2.01 (s, 3). LM Anal. calculated for : , found m/z: 517 [M-] -, 519 [M+] +, tr = 2.81 and 2.96 min (method A); peak area 96%. 24

25 ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-2-trifluoromethylbenzenesulfonamide (12r). The title compound 12r (white solid, 91 mg) was prepared following the general procedure D, using 11c (93 mg, 0.30 mmol). Yield: 59%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.42 (d, J = 5.2 z, 1), 8.12 (dm, J = 7.3 z, 1), 8.01 (dm, J = 7.6 z, 1), (ovl. m, 2), 7.50 (s, 1), 7.38 (s, 1), 7.13 (d, J = 2.5 z, 1), 7.09 (d, J = 8.7 z, 1), 7.03 (dd, J = 8.7, 2.5 z, 1), 6.18 (d, J = 5.2 z, 1), 3.93 (s, 3), 3.91 (s, 3), 2.03 (s, 3). LM Anal. calculated for : , found m/z: 517 [M-] -, 519 [M+] +, tr = 2.85 and 2.98 min (method A); peak area 100%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-2-trifluoromethyl-benzenesulfonamide (12s). The title compound 12s (white solid, 85 mg) was prepared following the general procedure D, using 11d (98 mg, 0.30 mmol). Yield: 53%. Melting point: MR (300 Mz, DM-d6): δ 9.63 (br. s, 1), 8.49 (d, J = 5.2 z, 1), (ovl. m, 2), (ovl. m, 2), 7.45 (s, 1), 7.39 (s, 1), 7.30 (d J = 8.5 z, 1), 6.88 (d, J = 2.5 z, 1), 6.78 (dd, J = 8.5, 2.5 z, 1), 6.44 (d, J = 5.2 z, 1), 3.94 (s, 3), 3.91 (s, 3), 3.40 (s, 3). LM 25

26 Anal. calculated for : , found m/z: 533 [M-] -, 535 [M+] +, tr = 3.11 and 3.21 min (method A); peak area 95%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-2-trifluoromethyl-benzenesulfonamide (12t). The title compound 12t (white solid, 78 mg) was prepared following the general procedure D, using 11e (98 mg, 0.30 mmol). Yield: 49%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.39 (d, J = 5.2 z, 1), 8.16 (dm, J = 7.8 z, 1), 8.02 (dm, J = 7.2 z, 1), (ovl. m, 2), 7.45 (s, 1), 7.36 (s, 1), 7.15 (d, J = 8.6 z, 1), 6.98 (d, J = 2.5 z, 1), 6.73 (dd, J = 8.6, 2.5 z, 1), 6.16 (d, J = 5.2 z, 1), 3.93 (s, 3), 3.90 (s, 3), 3.62 (s, 3). LM Anal. calculated for : , found m/z: 533 [M-] -, 535 [M+] +, tr = 2.76 and 2.91 min (method A); peak area 99%. ynthesis of -[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-2-trifluoromethylbenzenesulfonamide (12u). The title compound 12u (white solid, 80 mg) was prepared following the general procedure D, using 11g (94 mg, 0.30 mmol). Yield: 51%. Melting point: MR (300 Mz, 26

27 DM-d6): δ (br. s, 1), 8.45 (d, J = 5.2 z, 1), 8.16 (dm, J = 7.7 z, 1), 8.03 (dm, J = 7.3 z, 1), (ovl. m, 2), 7.47 (s, 1), 7.39 (s, 1), 7.38 (dd, J = 9.0, 8.8 z, 1), 7.16 (dd, J = 12.3, 2.5 z, 1), 7.02 (ddd, J = 9.0, 2.5, 1.0 z, 1), 6.37(dd, J = 5.2, 1.0 z, 1), 3.94 (s, 3), 3.91 (s, 3). LM Anal. calculated for : , found m/z: 523 [M+] +, tr = 2.86 and 2.99 min (method A); peak area 99%. General procedure E. ynthesis of 6-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-quinoline (14a). + A mixture of 6-benzyloxy-4-chloro-quinoline (13a) (2.09 g, 7.74 mmol), 2-fluoro-4- nitrophenol (1.34 g, 8.52 mmol),,-diisopropylethylamine (1.16 g 9.00 mmol) and chlorobenzene (16 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled down, diluted with aqueous sodium hydroxide solution (10 wt%, 30 ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3 x 30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue solidified under diisopropyl ether to give g of the title compound. Yellow solid. Yield: 66%. Melting point: MR (300 Mz, DM-d6): δ 8.65 (d, J = 5.1 z, 1), 8.46 (dd, J = 10.5, 2.6 z, 1), 8.18 (ddd, J = 9.0, 2.6, 1.4 z, 1), 8.03 (d, J = 9.0 z, 1), (ovl. m, 2), 7.57 (dd, J = 9.0, 8.2 z, 1), 7.50 (dm, J = 7.1 z, 2), 7.39 (tm, J = 7.0 z, 2), 7.32 (m, 1), 6.95 (d, J = 5.1 z, 1), 5.28 (s, 2). 27

28 LM Anal. calculated for : , found m/z: 391 [M+] +, tr = 4.05 min (method A); peak area 99%. ynthesis of 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-quinoline (14b). + The title compound 14b (yellow solid, 1.60 g) was prepared following the general procedure E, using 7-benzyloxy-4-chloro-quinoline (13b, 2.09 g, 7.74 mmol). Yield: 53%. 1 MR (300 Mz, DM-d6): δ 8.71 (d, J = 5.1 z, 1), 8.46 (dd, J = 10.4, 2.6 z, 1), 8.19 (ddd, J = 9.0, 2.6, 1.4 z, 1), 8.17 (d, J = 9.0 z, 1), 7.63 (dd, J = 9.0, 8.2 z, 1), 7.56 (d, J = 2.3 z, 1), 7.53 (dm, J = 7.3 z, 2), 7.43 (m, 2), 7.41 (dd, J = 9.0, 2.3 z, 1), 7.36 (m, 1), 6.80 (d, J = 5.1 z, 1), 5.33 (s, 2). LM Anal. calculated for : , found m/z: 391 [M+] +, tr = 3.88 min (method A); peak area 97%. ynthesis of 6-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-7-methoxy-quinoline (14c). + The title compound 14c (yellow solid, 2.12 g) was prepared following the general procedure E, using 6-benzyloxy-4-chloro-7-methoxy-quinoline 13c (2.32 g, 7.74 mmol). Yield: 65%. Melting point: MR (300 Mz, DM-d6): δ 8.59 (d, J = 5.2 z, 1), 8.46 (dd, J = 10.5, 2.7 z, 1), 8.16 (ddd, J = 9.1, 2.7, 1.4 z, 1), 7.56 (s, 1), 7.52 (dd, J = 9.1, 28

29 8.2 z, 1), 7.49 (s, 1), 7.48 (m, 2), (m, 3), 6.82 (d, J = 5.2 z, 1), 5.26 (s, 2), 3.97 (s, 3). LM Anal. calculated for : , found, m/z: 421 [M+] +, tr = 3.53 min (method A); peak area 95%. ynthesis of 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (14d). + A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (13d) (23.98 g, 80 mmol), 2-fluoro- 4-nitrophenol (13.98 g 89 mmol),,-diisopropylethylamine (13.22 g 102 mmol) and chlorobenzene (120 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled down, diluted with aqueous sodium hydroxide solution (10 wt%, 80 ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3 x 60 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue solidified under diisopropyl ether to give g of the title compound. Yellow solid. Yield: 82%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.1 z, 1), 8.45 (dd, J = 10.5, 2.5 z, 1), 8.20 (ddd, J = 8.8, 2.5, 1.5 z, 1), 7.61 (dd, J = 8.8, 8.8 z, 1), 7.56 (s, 1), 7.53 (m, 2), 7.48 (s, 1), (m, 3), 6.78 (d, J = 5.1 z, 1), 5.33 (s, 2), 3.93 (s, 3). LM Anal. calculated for : , m/z: 421 [M+] +, tr = 3.42 min (method A); peak area 98%. 29

30 General procedure. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-quinolin-6-ol (15a). + 6-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-quinoline (14a) (1170 mg, 3.00 mmol) was added slowly in portions into hydrobromic acid solution (33 % in acetic acid, 30 ml). The mixture was stirred at room temperature for 2 hours then poured into diethyl ether (130 ml). The precipitate was filtered and washed with diethyl ether. The solid hydrobromide salt was stirred in the mixture of sodium acetate aqueous solution (10 %, 85 ml) and ethyl acetate (15 ml) for 1 day. The precipitate was filtered, washed with water and dried to give 488 mg of the title compound. Yellow solid. Yield: 54%. Melting point: MR (300 Mz, DM-d6): δ 10.9 (br. s, 1), 8.56 (d, J = 5.0 z, 1), 8.45 (dd, J = 10.5, 2.6 z, 1), 8.16 (ddd, J = 8.9, 2.6, 1.5 z, 1), 7.93 (d, J = 9.1 z, 1), 7.61 (dd, J = 8.9, 8.3 z, 1), 7.4, (dd, J = 9.1, 2.5 z, 1), 7.32 (d, J = 2.5 z, 1), 6.90 (d, J = 5.0 z, 1). LM Anal. calculated for 15924: , found m/z: 299 [M-] -, 301 [M+] +, tr = 2.48 min (method A), peak area; 98 %. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-quinolin-7-ol (15b). + The title compound 15b (yellow solid, 641 mg) was prepared following the general procedure, using 14b (1170 mg, 3.00 mmol). Yield: 71%. Melting point: MR (300 30

31 Mz, DM-d6): δ (br. s, 1), 8.64 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.8 z, 1), 8.19 (ddd, J = 9.0, 2.8, 1.5 z, 1), 8.09 (d, J = 9.1 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.31 (d, J = 2.5 z, 1), 7.24 (dd, J = 9.1, 2.5 z, 1), 6.70 (d, J = 5.2 z, 1). LM Anal. calculated for 15924: , found m/z: 299 [M-] -, 301 [M+] +, tr = 2.63 min (method A); peak area 99%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-7-methoxy-quinolin-6-ol (15c). + The title compound 15c (yellow solid, 425 mg) was prepared following the general procedure, using 14c (1260 mg, 3.00 mmol). Yield: 43%. Melting point: MR (300 Mz, DM-d6): δ 8.48 (d, J = 5.0 z, 1), 8.40 (dd, J = 10.4, 2.3 z, 1), 8.12 (dm, J = 9.4 z, 1), 7.41 (dd, J = 8.7, 8.5 z, 1), 7.38 (s, 1), 7.26 (s, 1), 6.78 (d, J = 5.0 z, 1), 3.94 (s, 3). LM Anal. calculated for : , found m/z: 329 [M-] -, 331 [M+] +, tr = 2.52 min (method A); peak area 95%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (15d). + 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (14d) (4.20 g, mmol) was added slowly in portions into hydrobromic acid solution (33 % in acetic acid, 100 ml). 31

32 The mixture was stirred at room temperature for 2 hours then poured into diethyl ether (600 ml). The precipitate was filtered and washed with diethyl ether. The solid hydrobromide salt was stirred in the mixture of sodium acetate aqueous solution (10 %, 120 ml) and ethyl acetate (30 ml) for 1 day. The precipitate was filtered, washed with water and dried to give 2.80 g of the title compound. Yellow solid. Yield: 85%. Melting point: MR (300 Mz, DM-d6): δ (br. s, 1), 8.86 (d, J = 6.6 z, 1), 8.56 (dd, J = 10.2, 2.5 z, 1), 8.32 (ddd, J = 9.1, 2.5, 1.4 z, 1), 7.90 (dd, J = 9.1, 7.8 z, 1), 7.75 (s, 1), 7.55 (s, 1), 7.13 (d, J = 6.6 z, 1), 4.04 (s, 3). LM Anal. calculated for : , found m/z: 329 [M-] -, 331 [M+] +, tr = 2.57 min (method A); peak area 98%. General procedure G. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-[3-(4-methylpiperazin-1-yl)-propoxy]-quinoline (16a). + The mixture of 15a (300 mg, 1.00 mmol), cesium carbonate (977 mg, 3.00 mmol), potassium iodide (50 mg, 0.30 mmol) and acetonitrile (30 ml) was stirred at room temperature for 30 minutes. Then 1-(3-chloro-propyl)-4-methyl-piperazine dihydrochloride (275 mg 1.10 mmol) was added to the reaction mixture. It was stirred at room temperature for 45 minutes, and then refluxed for 3 hours. The hot mixture was filtered, the filtrate was evaporated. The residue was taken up in the mixture of chloroform (50 ml) and water (50 ml). The two phases were separated then the aqueous layer was extracted with chloroform (2 x 20 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue solidified under diisopropyl 32

33 ether to give 431 mg crude product. It was purified by column chromatography (eluent: chloroform methanol = 9:1). The pure product solidified under diisopropyl ether. Thus 175 mg of the title compound was obtained. Yellow solid. Yield: 40%. 1 MR (300 Mz, DM-d6): δ 8.63 (d, J = 5.1 z, 1), 8.46 (dd, J = 10.5, 2.6 z, 1), 8.21 (ddd, J = 9.0, 2.6, 1.4 z, 1), 8.00 (dm, J = 10.0 z, 1), 7.64 (dd, J = 9.0, 8.0 z, 1), (ovl. m, 2), 6.92 (d, J = 5.1 z, 1), 4.16 (t, J = 6.3 z, 2), 2.46 (t, J = 7.1 z, 2), 2.37 (m, 4), 2.28 (m, 4), 2.11 (s, 3), 1.92 (quint, J ~ 6.7 z, 2). LM Anal. calculated for : , found m/z: 441 [M+] +, tr = 1.80 and 1.96 min (method A); peak area 99%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinoline (16b). + The title compound 16b (yellow solid, 315 mg) was prepared following the general procedure G, using 15b (330 mg, 1.00 mmol). Yield: 83%. Melting point: MR (300 Mz, DM-d6): δ 8.71 (d, J = 5.1 z, 1), 8.45 (dd, J = 10.5, 2.6 z, 1), 8.19 (ddd, J = 8.8, 2.6, 1.2 z, 1), 8.14 (d, J = 9.1 z, 1), 7.63 (dd, J = 8.8, 8.3 z, 1), 7.45 (d, J = 2.4 z, 1), 7.32 (dd, J = 9.1, 2.4 z, 1), 6.79 (d, J = 5.1 z, 1), 4.20 (t, J = 6.4 z, 2), 2.46 (t, J = 7.3 z, 2), 2.39 (m, 4), 2.33 (m, 4), 2.15 (s, 3), 1.95 (quint, J ~ 6.8 z, 2). LM Anal. calculated for , Mw=440.48, found m/z: 441 [M+] +, tr = 3.65 min (method B); peak area 95%. 33

34 ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-7-methoxy-6-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinoline (16c). + The title compound 16c (yellow solid, 255 mg) was prepared following the general procedure G, using 15c (330 mg, 1.00 mmol). Yield: 54%. Melting point: MR (300 Mz, DM-d6): δ 8.57 (d, J = 5.2 z, 1), 8.46 (dd, J = 10.4, 2.5 z, 1), 8.19 (ddd, J = 9.0, 2.5, 1.2 z, 1), 7.60 (dd, J = 9.0, 8.1 z, 1), 7.45 (s, 1), 7.43 (s, 1), 6.78 (d, J = 5.1 z, 1), 4.15 (t, J = 6.5 z, 2), 3.96 (s, 3), 2.42 (t, J = 6.9 z, 2), 2.36 (m, 4), 2.29 (m, 4), 2.11 (s, 3), 1.92 (quint, J ~ 6.7 z, 2). LM Anal. calculated for : , found m/z: 469 [M-] -, 471 [M+] +, tr = 3.35 min (method B); peak area 96%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinoline (16d). + The mixture of 15d (5.81 g, 17.6 mmol), cesium carbonate (17.6 g, mmol), potassium iodide (0.30 g, 1.80 mmol) and acetonitrile (520 ml) was stirred at room temperature for 30 minutes. Then 1-(3-chloro-propyl)-4-methyl-piperazine dihydrochloride (4.79 g mmol) was added to the reaction mixture. It was stirred at room temperature for 45 minutes, and then refluxed for 3 hours. The hot mixture was filtered, the filtrate was evaporated. The residue 34

35 was taken up in the mixture of chloroform (150 ml) and water (150 ml). The two phases were separated then the aqueous layer was extracted with chloroform (2 x 60 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue solidified under diisopropyl ether to give 6.56 g of crude product. It was recrystallized from acetonitrile (60 ml), thus 5.23 g of the title compound was obtained. Yellow solid. Yield: 61%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.4, 2.6 z, 1), 8.19 (ddd, J = 9.1, 2.6, 1.3 z, 1), 7.61 (dd, J = 9.1, 8.0 z, 1), 7.45 (s, 1), 7.43 (s, 1), 6.77 (d, J = 5.2 z, 1), 4.20 (t, J = 6.4 z, 2), 3.92 (s, 3), 2.46 (t, J = 7.2 z, 2), 2.40 (m, 4), 2.33 (m, 4), 2.15 (s, 3), 1.96 (quint, J ~ 6.8 z, 2). LM Anal. calculated for : , found m/z: 471 [M+] +, tr = 3.40 min (method B); peak area 98%. General procedure. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2- morpholin-4-yl-ethoxy)-quinoline (16e). + The mixture of 15d (330 mg, 1.00 mmol), cesium carbonate (977 mg, 2.99 mmol), potassium iodide (50 mg, 0.30 mmol) and acetonitrile (30 ml) was stirred at room temperature for 30 minutes. Then 4-(2-chloroethyl)morpholine hydrochloride (204 mg, 1.10 mmol) was added to the reaction mixture. It was stirred at room temperature for 45 minutes, and then refluxed for 3 hours. The hot mixture was filtered, the filtrate was evaporated. The residue was taken up in the mixture of chloroform (50 ml) and water (50 ml). The two phases were separated then the aqueous layer was extracted with chloroform (2 x 20 ml). The organic layers were 35

36 combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue solidified under diisopropyl ether to give 431 mg crude product. It was purified by column chromatography (eluent: chloroform methanol = 9:1). The pure product solidified under diisopropyl ether. Thus 314 mg of the title compound was obtained. Yellow solid. Yield: 71%. 1 MR (300 Mz, DM-d6): δ 8.57 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.5 z, 1), 8.20 (ddd, J = 9.0, 2.5, 1.4 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.49 (s, 1), 7.45 (s, 1), 6.78 (d, J = 5.2 z, 1), 4.29 (t, J = 5.7 z, 2), 3.92 (s, 3), 3.60 (m, 4), 2.80 (t, J = 5.7 z, 2), 2.55 (m, 4). LM Anal. calculated for : , found m/z: 444 [M+] +, tr = 3.50 min (method B); peak area 97%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinoline (16f). + The title compound 16f (yellow solid, 381 mg) was prepared following the general procedure, using 4-(3-chloropropyl)morpholine hydrochloride (220 mg, 1.10 mmol). Yield: 83%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.5 z, 1), 8.20 (dm, J = 8.8 z, 1), 7.61 (dd, J = 8.8, 8.4 z, 1), 7.45 (ovl. s, 2), 6.77 (d, J = 5.2 z, 1), 4.22 (t, J = 6.5 z, 2), 3.92 (s, 3), 3.59 (m, 4), 2.47 (t, J = 7.3 z, 2), 2.39 (m, 4), 1.98 (quint, J ~ 7.0 z, 2). LM Anal. calculated for : , found m/z: 458 [M+] +, tr = 3.75 min (method B); peak area 98%. 36

37 ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(4-morpholin-4-yl-butoxy)- quinoline (16g). + This compound was prepared in two steps: 1/. The mixture of 15d (660 mg, 2.00 mmol), cesium carbonate (1954 mg, 6.00 mmol), potassium iodide (100 mg, 0.60 mmol) and acetonitrile (60 ml) was stirred at room temperature for 30 minutes. Then 1-bromo-4-chlorobutane (376 mg, 2.20 mmol) was added to the reaction mixture. It was stirred at room temperature for 45 minutes, and then refluxed for 3 hours. The hot mixture was filtered, the filtrate was evaporated. The residue was taken up in the mixture of chloroform (50 ml) and water (50 ml). The two phases were separated then the aqueous layer was extracted with chloroform (2 x 20 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was recrystallized from 4 ml ethyl alcohol. Thus 372 mg 7-(4-chloro-butoxy)-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline was obtained. Yellow solid. Yield: 44%. Melting point: MR (300 Mz, DMd6): δ 8.56 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.6 z, 1), 8.19 (ddd, J = 9.0, 2.5, 1.4 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.46 (s, 1), 7.45 (s, 1), 6.78 (d, J = 5.2 z, 1), 4.22 (m, 2), 3.93 (s, 3), 3.76 (m, 2), 1.95 (ovl. m, 4). LM Anal. calculated for 2018l25: , found m/z: 421 [M+] +, tr = 3.40 min (method A); peak area 100%. 2/. A solution of 252 mg (0.60 mmol) 7-(4-chloro-butoxy)-4-(2-fluoro-4-nitro-phenoxy)-6- methoxy-quinoline in 5 ml morpholine was stirred at 80 for 5 hours. The excess of the reagent was evaporated in vacuum, and the residue was taken up in the mixture of chloroform 37

38 (30 ml) and water (30 ml). The two phases were separated then the aqueous layer was extracted with chloroform (2 x 20 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified on preparative TL plate (eluent: chloroform methanol = 9:1). The pure product solidified under diisopropyl ether. Thus 121 mg of the title compound (16g) was obtained. Yellow solid. Yield: 43%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.1 z, 1), 8.45 (dd, J = 10.5, 2.5 z, 1), 8.20 (dm, J = 8.8 z, 1), 7.61 (dd, J = 8.8, 8.4 z, 1), 7.45 (ovl. s, 2), 6.77 (d, J = 5.1 z, 1), 4.20 (t, J = 6.0 z, 2), 3.92 (s, 3), 3.57 (m, 4), 2.36 (ovl. m, 6), 1.84 (m, 2), 1.62 (m, 2). LM Anal. calculated for : , found m/z: 472 [M+] +, tr = 3.71 min (method B); peak area 99%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-piperidin-1-yl-propoxy)- quinoline (16h). + The title compound 16h (yellow solid, 377 mg) was prepared following the general procedure, using 1-(3-chloro-propyl)-piperidine hydrochloride (218 mg, 1.10 mmol). Yield: 83%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.5 z, 1), 8.19 (ddd, J = 9.0, 2.5, 1.4 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.45 (s, 1), 7.44 (s, 1), 6.77 (d, J = 5.2 z, 1), 4.20 (t, J = 6.4 z, 2), 3.92 (s, 3), 2.43 (t, J = 7.0 z, 2), 2.35 (m, 4), 1.96 (quint, J ~ 6.7 z, 2), 1.51 (m, 4), 1.39 (m, 2). 38

39 LM Anal. calculated for ,: , found m/z: 456 [M+] +, tr = 3.71 min (method B); peak area 98%. ynthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-[3-(2-methyl-piperidin-1-yl)- propoxy]-quinoline (16i). + The title compound 16i (yellow solid, 377 mg) was prepared following the general procedure, using 1-(3-chloro-propyl)-2-methyl-piperidine hydrochloride (233 mg, 1.10 mmol). Yield: 83%. Melting point: MR (300 Mz, DM-d6): δ 8.56 (d, J = 5.2 z, 1), 8.45 (dd, J = 10.5, 2.7 z, 1), 8.20 (ddd, J = 9.0, 2.7, 1.2 z, 1), 7.61 (dd, J = 9.0, 8.1 z, 1), 7.45 (s, 1), 7.44 (s, 1), 6.77 (d, J = 5.2 z, 1), 4.20 (t, J = 6.4 z, 2), 3.92 (s, 3), (ovl. m, 2), 2.40 (m, 1), 2.30 (m, 1), 2.13 (m, 1), 1.92 (quint, J ~ 6.8 z, 2), (ovl. m, 5), (ovl. m, 1), 1.00 (d, J = 6.2 z, 3). LM Anal. calculated for : , found m/z: 470 [M+] +, tr = 3.83 min (method B); peak area 98%. 39