Synthesis and in vitro biological evaluation of novel quinazoline derivatives

Yaling Zhang Ying Zhang Juan Liu Li Chen Lijun Zhao Baolin Li Wei Wang

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry National

Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China School of Chemistry amp

Chemical Engineering Shaanxi Normal University Xirsquoan 710062 P R China

Corresponding author E-mail addresdes baolinlisnnueducn (Baolin Li) wwlzzsnnueducn (Wei Wang)

Content1 Experiment for chemistry S1

11 General information S1

12 Experimental procedures for synthesis of intimidates and target compounds S1

2 Experiment for Biological evaluationS621 Cell proliferation and growth assays S6

22 In vitro EGFR kinase assay S6

23 Molecular modeling S7

24 Western blotting S7

3 Spectra for compounds S84 References S38

1 Experiment for chemistry

11 General information

Unless otherwise noted reagents and solvents were obtained from commercial suppliers and were used without further purification 1H NMR and 13C NMR spectra were recorded on a 300 400 600 MHz (BrukerAvance III) instrument and chemical shifts were reported in parts per million (ppm d) downfield from tetramethylsilane (TMS) Coupling constants (J) were reported in Hz Spin multiplicities were described as s (singlet) brs (broad singlet) d (double) t (triplet) q (quartet) and m (multiplet) Mass spectra were obtained on a BrukerEspuire 3000plus instrument Infrared Spectroscopy (IR) was measured on Nicolet 170SXFT-IR instrument Melting point (mp) was determined on X-6 micro melting point apparatus and was uncorrected

12 Experimental procedures for synthesis of intermediates and target compounds

121 2-amino-5-iodobenzonitrile (A)

Followed previous procedures 1 a mixture of 2-aminobenzonitrile (002 mol) and ammonium iodide (002 mol) were dissolved in acetic acid (50 mL) and then 30 aqueous hydrogen peroxide solution (013 mol) was slowly added at room temperature and stirred for 12 h After reaction completion the reaction solution was treated with aqueous sodium thiosulfate solution 40 mL (003 mol) and basified to about pH~8 by the addition of 20 sodium hydroxide The reaction mixture was stirred at room temperature for 05 h The desired product which was partially precipitated during this step was isolated by vacuum filtration to afford A as silvery white flake solid (yield 926)

122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)

A mixture of 2-amino-5-iodobenzonitrile (A) (001 mol) toluene (20 mL) and DMFndashDMA (002 mol) were heated up to 35 degC and acetic acid (025 mL) was added 05 h later the resultant mixture was cooled to approximately 25 degC Toluene was completely stripped off The mixture was added to water and basified to about pH~13 by the addition of 20 sodium hydroxide The mixture was extracted with methylene chloride (CH2Cl2 2 times 30 mL) and the combined organic extracts were washed with water (2 times 200 mL) and brine (1 times 200 mL) dried over Mg 2SO4 The organic solvent was evaporated to give B as yellow solid (yield 893)2

123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)

To B (300 mmol) were added acetic acid (30 mL) and R2 substituted aniline (330 mol) The reaction mixture was heated to 125 ndash 130 degC and stirred for 15 min The reaction mixture was then cooled to 25 degC The acetic acid was evaporated The reaction mixture was quenched in ice-water (25 mL) and adjusted pH~9 with ammonia solution The mixture was stirred for 05 h The precipitated product

was filtered and the filter cake was washed with water (3 times 10 mL) to afford crude product The crude

product was chromatographed by silica gel eluting with EtOAcPE (14) to afford residue C1-4 as white

solid (yield 843~925)3

1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)

Yield 925 1H NMR (300 MHz DMSO-d6) δ(ppm) 985 (s 1H) 895 (d J = 20 Hz 1H) 861 (s

1H) 811 (dd J = 120 Hz 1H) 803 (d J = 36 Hz 1H) 775 (dd J = 120 Hz 1H) 775 (dd J = 120 Hz

S1

1H) 756 (d J = 120 Hz1H) 744-751 (m1H) 729-735 (m 3H) 715-722 (m 1H) 526 (s 2H) (Figure

S1)

1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)

Yield 861 1H NMR (300 MHz DMSO-d6) δ(ppm) δ 989 (s 1H) 893 (s 1H) 865 (s 1H) 819

(dd J = 68 24 Hz 1H) 810 (dd J = 87 15 Hz 1H) 789 ndash 776 (m 1H) 756 (d J = 87 Hz 1H) 743

(t J = 91 Hz 1H) (Figure S2) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1561 1550 1545 1502 (d 1JC-F =

2306 Hz) 1413 1362 (d 4JC-F = 29 Hz) 1313 1297 1234 1222 (d 3JC-F = 69 Hz) 1188 (d 2JC-F =

184 Hz) 1167 1164 (d 2JC-F = 217 Hz) 917 (Figure S3)

1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)

Yield 843 1H NMR (300 MHz DMSO-d6) δ(ppm) 990 (s 1H) 900 (s 1H) 868 (s 1H) 812 (dd

J = 88 16 Hz 2H) 796 (d J = 82 Hz 1H) 758 (d J = 87 Hz 1H) 744 (t J = 79 Hz 1H) 727 (d J =

77 Hz 1H) 423 (s 1H) (Figure S4) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1563 1546 1488 1413

1393 1314 1298 1289 1269 1249 1226 1218 1168 917 834 806 (Figure S5)

1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)

Yield 867 1H NMR (300 MHz DMSO-d6) δ(ppm) 988 (s 1H) 901 (s 1H) 862 (s 1H) 811 (d J

= 83 Hz 1H) 782 (d J = 77 Hz 2H) 756 (d J = 83 Hz 1H) 740 (d J = 77 Hz 2H) 641 (d J = 158

Hz 1H) 633 - 615 (m 1H) 186 (d J = 54 Hz 3H) (Figure S6)

124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)

To a 100 mL round bottomed flask residue C1-4 (060 mmol) 5-formyl-2-furanboronic acid (090

mmol) PbC 10 triethylamine (24 mmol) 12-dimethoxyethane (60 mL) methanol (30 mL) were added

The suspension was stirred and heated to 50 degC for 05 h The reaction mixture was filtered with diatomite

and the filter cake was washed with THF (3 times 10 mL) The filtrate combined with washings was evaporated

The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (110) to afford compound

D1-4 as orange solid (yield 572~834)4

1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)

Yield 834 1H NMR (400 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 968 (s 1H) 894 (d J = 16 Hz

1H) 860 (s 1H) 833 ndash 825 (m 1H) 800 (d J = 26 Hz 1H) 785 (d J = 88 Hz 1H) 773 (dd J = 88

31 Hz 2H) 749 (td J = 80 60 Hz 1H) 740 (d J = 38 Hz 1H) 734 (dd J = 119 51 Hz 2H) 729 (d

J = 90 Hz 1H) 723 ndash 716 (m 1H) 527 (s 2H) (Figure S7)

1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)

Yield 652 1H NMR (300 MHz DMSO-d6) δ(ppm) 1011 (s 1H) 965 (s 1H) 887 (s 1H) 860 (s

1H) 818 (dd J = 352 67 Hz 2H) 781 (d J = 86 Hz 2H) 771 (d J = 35 Hz 1H) 744 (t J = 91 Hz

1H) 736 (d J = 35 Hz 1H) (Figure S8)

1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)

Yield 746 1H NMR (300 MHz DMSO-d6) δ(ppm) 1013 (s 1H) 969 (s 1H) 897 (s 1H) 865 (s

1H) 828 (dd J = 88 14 Hz 1H) 805 (s 1H) 793 (d J = 82 Hz 1H) 786 (d J = 88 Hz 1H) 774 (d J

= 37 Hz 1H) 746 (t J = 79 Hz 1H) 741 (d J = 37 Hz 1H) 730 (d J = 76 Hz 1H) 426 (s 1H)

(Figure S9) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1778 1577 1576 1551 1520 1501 1391 1295

S2

1289 1287 1271 1263 1256 1254 1232 1218 1195 1153 1098 834 807 (Figure S10)

1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)

Yield 572 1H NMR (300 MHz DMSO-d6) δ(ppm) 1005 (s 1H) 964 (s 1H) 894 (s 1H) 856 (s

1H) 822 (d J = 86 Hz 1H) 778 (dd J = 137 85 Hz 3H) 770 (d J = 36 Hz 1H) 738 (d J = 86 Hz

3H) 638 (d J = 158 Hz 1H) 631 ndash 610 (m 1H) 183 (d J = 59 Hz 3H) (Figure S11)

125 General method for preparation of 4-arylamino-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)

To a reaction flask were added 2-(methylsulfonyl)ethylamineHCl (075 mmol) methanol (50 mL)

anhydrous sodium sulfate (200 mmol) and triethylamine (05 mL) cooled to 0 degC The mixture was stirred

20 min and adjusts pH~5-6 with formic acid The reactor was added the solution of 4-arylamino-6-(5-

formylfuran-2-yl)quinazoline (D1-4) (050 mmol) resolved in THF (5 mL) and DMF (5 mL) Sodium

cyanoborohydride (200 mmol) was added in two portions over a 20 min period After stirring for 2 h the

precipitated product was filtered and the filtrate was evaporated The crude product was chromatographed by

silica gel eluted with MeOHCHCl3 (115) to afford 1a-1d as pale yellow solid (yield 781~826)5 6

1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)

Yield 820 1H NMR (600 MHz DMSO-d6) δ(ppm) 991 (s 1H) 874 (s 1H) 857 (s 1H) 816 (dd

J = 87 15 Hz 1H) 804 (d J = 25 Hz 1H) 781 (d J = 87 Hz 1H) 777 (dd J = 90 25 Hz 1H) 748

(dd J = 140 78 Hz 1H) 737 ndash 731 (m 2H) 729 (d J = 90 Hz 1H) 723 ndash 717 (m 1H) 706 (d J =

32 Hz 1H) 651 (d J = 32 Hz 1H) 527 (s 2H) 386 (s 2H) 331 (t J = 67 Hz 2H) 306 (s 3H) 303

(t J = 67 Hz 2H) 193 (s 1H) (Figure S12)

1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1b)

Yield 781 mp 1306-1315 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

857 (s 1H) 815 (d J = 86 Hz 1H) 784 ndash 778 (m 2H) 748 ndash 728 (m 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 385 (s 2H) 323 ndash 213 (m 7H) (Figure S13) HRMS (C22H20ClFN4O3S) mz

[M+H]+ calculated 4751007 found 4750996 (Figure S14)

1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline

(1c)

Yield 797 mp 729-737 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 877 (s 1H)

861 (s 1H) 818 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 87 Hz 1H) 785 ndash 780 (m 1H) 742 (d J =

80 Hz 1H) 726 (d J = 80 Hz 1H) 708 (d J = 31 Hz 1H) 651 (d J = 31 Hz 1H) 422 (s 1H) 385 (s

2H) 305 ndash 297 (m 7H) (Figure S15) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1548 1541 1514

1489 1393 1289 1285 1285 1269 1252 1243 1230 1218 1164 1154 1096 1080 834 806

536 451 420 415 (Figure S16) HRMS (C24H22N4O3S) mz [M+H]+ calculated 4471491 found

4471486 (Figure S17)

1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1d)

Yield 826 mp 2153-2159 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

S3

857 (s 1H) 815 (d J = 86 Hz 1H) 795 ndash 771 (m 3H) 740 (d J = 83 Hz 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 640 (d J = 158 Hz 1H) 634 ndash 614 (m 1H) 385 (s 2H) 331 (t J = 61 Hz

2H) 316 - 293 (m 5H) 185 (d J = 60 Hz 3H) (Figure S18) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1547 1542 1515 1489 1378 1331 1304 1285 1284 1283 1257 1244 1225 1165 1155 1095 1078 536 452 421 415 182 (Figure S19) IR νmax(KBr) cm-1 3970 3030 2904 1637 1599 1572 1516 1416 1288 962 846 785 (Figure S20) HRMS (C25H26N4O3S) mz [M+H]+ calculated 4631804 found 4631789 (Figure S21)

126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-

2d)

Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (10 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL) and then cooled to 0 degC NaBH 4 (10 mmol) was added in four portions over 15 min After 4 h the solvent was removed under reduced pressure and water (10 mL) was added The precipitated product was filtered and the filter cake was washed with water (3 times10 mL) and dried to afford 2a-2d as a yellow solid (yield 903~946)

1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)

Yield 911 mp 2407-2415 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 999 (s 1H) 878 (s 1H) 859 (s 1H) 819 (dd J = 88 12 Hz 1H) 805 (d J = 23 Hz 1H) 783 (d J = 88 Hz 1H) 778 (dd J = 89 23 Hz 1H) 757 ndash 744 (m 1H) 740 ndash 729 (m 3H) 726 ndash 718 (m 1H) 709 (d J = 32 Hz 1H) 655 (d J = 32 Hz 1H) 539 (t J = 45 Hz 1H) 530 (s 2H) 457 (d J = 45 Hz 2H) (Figure S22) 13C NMR (75 MHz DMSO-d6) δ(ppm) 16218 (d 1JC-F = 2437 Hz) 1576 1562 1542 1517 1498 1488 1396 (d 3JC-F = 74 Hz) 1331 1305 (d 3JC-F = 83 Hz) 1286 (d 2JC-F = 211 Hz) 1283 1244 1233 (d 4JC-F = 28 Hz) 1226 1210 1164 1153 1147 (d 2JC-F = 210 Hz) 1142 1141 1139 1096 1078 694 558 (Figure S23) IR νmax(KBr) cm-1 3314 3074 3457 1608 2927 1579 1504 1428 936 791 678 (Figure S24) HRMS (C26H19ClFN3O3) mz [M+H]+ calculated 4761177 found 4761157 (Figure S25)

1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)

Yield 917 mp 2246-2258 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 875 (s 1H) 858 (s 1H) 818 (s 1H) 815 (d J = 13 Hz 1H) 781 (d J = 87 Hz 2H) 754 ndash 730 (m 1H) 707 (d J = 32 Hz 1H) 651 (d J = 32 Hz 1H) 542 (s 1H) 453 (s 2H) (Figure S26) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1562 1551 1540 1519 1502 (d 1JC-F = 2067 Hz) 1363 (d 4JC-F = 27 Hz) 12866 (d 2JC-F = 286 Hz) 1240 12280 (d 3JC-F = 70 Hz) 1189 1187 11650 (d 2JC-F = 201 Hz) 1164 1153 1096 1081 1080 5579 (Figure S27) IR νmax(KBr) cm-1 3441 3296 3123 2923 1617 1581 1501 1446 1008 931 840 784 (Figure S28) HRMS (C19H14ClFN3O2) mz [M+H]+ calculated 3700759 found 3700742 (Figure S29)

1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)

Yield 903 mp 2189-2202 degC 1H NMR (300 MHz DMSO) δ 1006 (s 1H) 883 (s 1H) 866 (s 1H) 823 (dd J = 87 14 Hz 1H) 810 (s 1H) 798 (d J = 80 Hz 1H) 787 (d J = 87 Hz 1H) 754 ndash 742 (m 1H) 731 (d J = 76 Hz 1H) 712 (d J = 32 Hz 1H) 657 (d J = 32 Hz 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 427 (s 1H) (Figure S30) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1562 1541 1541 1516 1489 1394 1289 1288 1284 1269 1253 1230 1218 1165 1155 1096 1080 834 806 558 (Figure S31) IR νmax(KBr) cm-1 3443 320 3085

S4

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

1 Experiment for chemistry

11 General information

Unless otherwise noted reagents and solvents were obtained from commercial suppliers and were used without further purification 1H NMR and 13C NMR spectra were recorded on a 300 400 600 MHz (BrukerAvance III) instrument and chemical shifts were reported in parts per million (ppm d) downfield from tetramethylsilane (TMS) Coupling constants (J) were reported in Hz Spin multiplicities were described as s (singlet) brs (broad singlet) d (double) t (triplet) q (quartet) and m (multiplet) Mass spectra were obtained on a BrukerEspuire 3000plus instrument Infrared Spectroscopy (IR) was measured on Nicolet 170SXFT-IR instrument Melting point (mp) was determined on X-6 micro melting point apparatus and was uncorrected

12 Experimental procedures for synthesis of intermediates and target compounds

121 2-amino-5-iodobenzonitrile (A)

Followed previous procedures 1 a mixture of 2-aminobenzonitrile (002 mol) and ammonium iodide (002 mol) were dissolved in acetic acid (50 mL) and then 30 aqueous hydrogen peroxide solution (013 mol) was slowly added at room temperature and stirred for 12 h After reaction completion the reaction solution was treated with aqueous sodium thiosulfate solution 40 mL (003 mol) and basified to about pH~8 by the addition of 20 sodium hydroxide The reaction mixture was stirred at room temperature for 05 h The desired product which was partially precipitated during this step was isolated by vacuum filtration to afford A as silvery white flake solid (yield 926)

122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)

A mixture of 2-amino-5-iodobenzonitrile (A) (001 mol) toluene (20 mL) and DMFndashDMA (002 mol) were heated up to 35 degC and acetic acid (025 mL) was added 05 h later the resultant mixture was cooled to approximately 25 degC Toluene was completely stripped off The mixture was added to water and basified to about pH~13 by the addition of 20 sodium hydroxide The mixture was extracted with methylene chloride (CH2Cl2 2 times 30 mL) and the combined organic extracts were washed with water (2 times 200 mL) and brine (1 times 200 mL) dried over Mg 2SO4 The organic solvent was evaporated to give B as yellow solid (yield 893)2

123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)

To B (300 mmol) were added acetic acid (30 mL) and R2 substituted aniline (330 mol) The reaction mixture was heated to 125 ndash 130 degC and stirred for 15 min The reaction mixture was then cooled to 25 degC The acetic acid was evaporated The reaction mixture was quenched in ice-water (25 mL) and adjusted pH~9 with ammonia solution The mixture was stirred for 05 h The precipitated product

was filtered and the filter cake was washed with water (3 times 10 mL) to afford crude product The crude

product was chromatographed by silica gel eluting with EtOAcPE (14) to afford residue C1-4 as white

solid (yield 843~925)3

1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)

Yield 925 1H NMR (300 MHz DMSO-d6) δ(ppm) 985 (s 1H) 895 (d J = 20 Hz 1H) 861 (s

1H) 811 (dd J = 120 Hz 1H) 803 (d J = 36 Hz 1H) 775 (dd J = 120 Hz 1H) 775 (dd J = 120 Hz

S1

1H) 756 (d J = 120 Hz1H) 744-751 (m1H) 729-735 (m 3H) 715-722 (m 1H) 526 (s 2H) (Figure

S1)

1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)

Yield 861 1H NMR (300 MHz DMSO-d6) δ(ppm) δ 989 (s 1H) 893 (s 1H) 865 (s 1H) 819

(dd J = 68 24 Hz 1H) 810 (dd J = 87 15 Hz 1H) 789 ndash 776 (m 1H) 756 (d J = 87 Hz 1H) 743

(t J = 91 Hz 1H) (Figure S2) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1561 1550 1545 1502 (d 1JC-F =

2306 Hz) 1413 1362 (d 4JC-F = 29 Hz) 1313 1297 1234 1222 (d 3JC-F = 69 Hz) 1188 (d 2JC-F =

184 Hz) 1167 1164 (d 2JC-F = 217 Hz) 917 (Figure S3)

1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)

Yield 843 1H NMR (300 MHz DMSO-d6) δ(ppm) 990 (s 1H) 900 (s 1H) 868 (s 1H) 812 (dd

J = 88 16 Hz 2H) 796 (d J = 82 Hz 1H) 758 (d J = 87 Hz 1H) 744 (t J = 79 Hz 1H) 727 (d J =

77 Hz 1H) 423 (s 1H) (Figure S4) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1563 1546 1488 1413

1393 1314 1298 1289 1269 1249 1226 1218 1168 917 834 806 (Figure S5)

1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)

Yield 867 1H NMR (300 MHz DMSO-d6) δ(ppm) 988 (s 1H) 901 (s 1H) 862 (s 1H) 811 (d J

= 83 Hz 1H) 782 (d J = 77 Hz 2H) 756 (d J = 83 Hz 1H) 740 (d J = 77 Hz 2H) 641 (d J = 158

Hz 1H) 633 - 615 (m 1H) 186 (d J = 54 Hz 3H) (Figure S6)

124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)

To a 100 mL round bottomed flask residue C1-4 (060 mmol) 5-formyl-2-furanboronic acid (090

mmol) PbC 10 triethylamine (24 mmol) 12-dimethoxyethane (60 mL) methanol (30 mL) were added

The suspension was stirred and heated to 50 degC for 05 h The reaction mixture was filtered with diatomite

and the filter cake was washed with THF (3 times 10 mL) The filtrate combined with washings was evaporated

The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (110) to afford compound

D1-4 as orange solid (yield 572~834)4

1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)

Yield 834 1H NMR (400 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 968 (s 1H) 894 (d J = 16 Hz

1H) 860 (s 1H) 833 ndash 825 (m 1H) 800 (d J = 26 Hz 1H) 785 (d J = 88 Hz 1H) 773 (dd J = 88

31 Hz 2H) 749 (td J = 80 60 Hz 1H) 740 (d J = 38 Hz 1H) 734 (dd J = 119 51 Hz 2H) 729 (d

J = 90 Hz 1H) 723 ndash 716 (m 1H) 527 (s 2H) (Figure S7)

1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)

Yield 652 1H NMR (300 MHz DMSO-d6) δ(ppm) 1011 (s 1H) 965 (s 1H) 887 (s 1H) 860 (s

1H) 818 (dd J = 352 67 Hz 2H) 781 (d J = 86 Hz 2H) 771 (d J = 35 Hz 1H) 744 (t J = 91 Hz

1H) 736 (d J = 35 Hz 1H) (Figure S8)

1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)

Yield 746 1H NMR (300 MHz DMSO-d6) δ(ppm) 1013 (s 1H) 969 (s 1H) 897 (s 1H) 865 (s

1H) 828 (dd J = 88 14 Hz 1H) 805 (s 1H) 793 (d J = 82 Hz 1H) 786 (d J = 88 Hz 1H) 774 (d J

= 37 Hz 1H) 746 (t J = 79 Hz 1H) 741 (d J = 37 Hz 1H) 730 (d J = 76 Hz 1H) 426 (s 1H)

(Figure S9) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1778 1577 1576 1551 1520 1501 1391 1295

S2

1289 1287 1271 1263 1256 1254 1232 1218 1195 1153 1098 834 807 (Figure S10)

1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)

Yield 572 1H NMR (300 MHz DMSO-d6) δ(ppm) 1005 (s 1H) 964 (s 1H) 894 (s 1H) 856 (s

1H) 822 (d J = 86 Hz 1H) 778 (dd J = 137 85 Hz 3H) 770 (d J = 36 Hz 1H) 738 (d J = 86 Hz

3H) 638 (d J = 158 Hz 1H) 631 ndash 610 (m 1H) 183 (d J = 59 Hz 3H) (Figure S11)

125 General method for preparation of 4-arylamino-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)

To a reaction flask were added 2-(methylsulfonyl)ethylamineHCl (075 mmol) methanol (50 mL)

anhydrous sodium sulfate (200 mmol) and triethylamine (05 mL) cooled to 0 degC The mixture was stirred

20 min and adjusts pH~5-6 with formic acid The reactor was added the solution of 4-arylamino-6-(5-

formylfuran-2-yl)quinazoline (D1-4) (050 mmol) resolved in THF (5 mL) and DMF (5 mL) Sodium

cyanoborohydride (200 mmol) was added in two portions over a 20 min period After stirring for 2 h the

precipitated product was filtered and the filtrate was evaporated The crude product was chromatographed by

silica gel eluted with MeOHCHCl3 (115) to afford 1a-1d as pale yellow solid (yield 781~826)5 6

1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)

Yield 820 1H NMR (600 MHz DMSO-d6) δ(ppm) 991 (s 1H) 874 (s 1H) 857 (s 1H) 816 (dd

J = 87 15 Hz 1H) 804 (d J = 25 Hz 1H) 781 (d J = 87 Hz 1H) 777 (dd J = 90 25 Hz 1H) 748

(dd J = 140 78 Hz 1H) 737 ndash 731 (m 2H) 729 (d J = 90 Hz 1H) 723 ndash 717 (m 1H) 706 (d J =

32 Hz 1H) 651 (d J = 32 Hz 1H) 527 (s 2H) 386 (s 2H) 331 (t J = 67 Hz 2H) 306 (s 3H) 303

(t J = 67 Hz 2H) 193 (s 1H) (Figure S12)

1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1b)

Yield 781 mp 1306-1315 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

857 (s 1H) 815 (d J = 86 Hz 1H) 784 ndash 778 (m 2H) 748 ndash 728 (m 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 385 (s 2H) 323 ndash 213 (m 7H) (Figure S13) HRMS (C22H20ClFN4O3S) mz

[M+H]+ calculated 4751007 found 4750996 (Figure S14)

1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline

(1c)

Yield 797 mp 729-737 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 877 (s 1H)

861 (s 1H) 818 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 87 Hz 1H) 785 ndash 780 (m 1H) 742 (d J =

80 Hz 1H) 726 (d J = 80 Hz 1H) 708 (d J = 31 Hz 1H) 651 (d J = 31 Hz 1H) 422 (s 1H) 385 (s

2H) 305 ndash 297 (m 7H) (Figure S15) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1548 1541 1514

1489 1393 1289 1285 1285 1269 1252 1243 1230 1218 1164 1154 1096 1080 834 806

536 451 420 415 (Figure S16) HRMS (C24H22N4O3S) mz [M+H]+ calculated 4471491 found

4471486 (Figure S17)

1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1d)

Yield 826 mp 2153-2159 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

S3

857 (s 1H) 815 (d J = 86 Hz 1H) 795 ndash 771 (m 3H) 740 (d J = 83 Hz 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 640 (d J = 158 Hz 1H) 634 ndash 614 (m 1H) 385 (s 2H) 331 (t J = 61 Hz

2H) 316 - 293 (m 5H) 185 (d J = 60 Hz 3H) (Figure S18) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1547 1542 1515 1489 1378 1331 1304 1285 1284 1283 1257 1244 1225 1165 1155 1095 1078 536 452 421 415 182 (Figure S19) IR νmax(KBr) cm-1 3970 3030 2904 1637 1599 1572 1516 1416 1288 962 846 785 (Figure S20) HRMS (C25H26N4O3S) mz [M+H]+ calculated 4631804 found 4631789 (Figure S21)

126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-

2d)

Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (10 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL) and then cooled to 0 degC NaBH 4 (10 mmol) was added in four portions over 15 min After 4 h the solvent was removed under reduced pressure and water (10 mL) was added The precipitated product was filtered and the filter cake was washed with water (3 times10 mL) and dried to afford 2a-2d as a yellow solid (yield 903~946)

1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)

Yield 911 mp 2407-2415 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 999 (s 1H) 878 (s 1H) 859 (s 1H) 819 (dd J = 88 12 Hz 1H) 805 (d J = 23 Hz 1H) 783 (d J = 88 Hz 1H) 778 (dd J = 89 23 Hz 1H) 757 ndash 744 (m 1H) 740 ndash 729 (m 3H) 726 ndash 718 (m 1H) 709 (d J = 32 Hz 1H) 655 (d J = 32 Hz 1H) 539 (t J = 45 Hz 1H) 530 (s 2H) 457 (d J = 45 Hz 2H) (Figure S22) 13C NMR (75 MHz DMSO-d6) δ(ppm) 16218 (d 1JC-F = 2437 Hz) 1576 1562 1542 1517 1498 1488 1396 (d 3JC-F = 74 Hz) 1331 1305 (d 3JC-F = 83 Hz) 1286 (d 2JC-F = 211 Hz) 1283 1244 1233 (d 4JC-F = 28 Hz) 1226 1210 1164 1153 1147 (d 2JC-F = 210 Hz) 1142 1141 1139 1096 1078 694 558 (Figure S23) IR νmax(KBr) cm-1 3314 3074 3457 1608 2927 1579 1504 1428 936 791 678 (Figure S24) HRMS (C26H19ClFN3O3) mz [M+H]+ calculated 4761177 found 4761157 (Figure S25)

1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)

Yield 917 mp 2246-2258 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 875 (s 1H) 858 (s 1H) 818 (s 1H) 815 (d J = 13 Hz 1H) 781 (d J = 87 Hz 2H) 754 ndash 730 (m 1H) 707 (d J = 32 Hz 1H) 651 (d J = 32 Hz 1H) 542 (s 1H) 453 (s 2H) (Figure S26) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1562 1551 1540 1519 1502 (d 1JC-F = 2067 Hz) 1363 (d 4JC-F = 27 Hz) 12866 (d 2JC-F = 286 Hz) 1240 12280 (d 3JC-F = 70 Hz) 1189 1187 11650 (d 2JC-F = 201 Hz) 1164 1153 1096 1081 1080 5579 (Figure S27) IR νmax(KBr) cm-1 3441 3296 3123 2923 1617 1581 1501 1446 1008 931 840 784 (Figure S28) HRMS (C19H14ClFN3O2) mz [M+H]+ calculated 3700759 found 3700742 (Figure S29)

1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)

Yield 903 mp 2189-2202 degC 1H NMR (300 MHz DMSO) δ 1006 (s 1H) 883 (s 1H) 866 (s 1H) 823 (dd J = 87 14 Hz 1H) 810 (s 1H) 798 (d J = 80 Hz 1H) 787 (d J = 87 Hz 1H) 754 ndash 742 (m 1H) 731 (d J = 76 Hz 1H) 712 (d J = 32 Hz 1H) 657 (d J = 32 Hz 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 427 (s 1H) (Figure S30) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1562 1541 1541 1516 1489 1394 1289 1288 1284 1269 1253 1230 1218 1165 1155 1096 1080 834 806 558 (Figure S31) IR νmax(KBr) cm-1 3443 320 3085

S4

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

4000 3500 3000 2500 2000 1500 1000 500 0

20

40

60

80

100Tr

ansm

ittanc

e

Wave numbercm-1

Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

4000 3500 3000 2500 2000 1500 1000 500 0

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110

Tran

smitta

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Wave numbercm-1

Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

4000 3500 3000 2500 2000 1500 1000 500 004

05

06

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08

09

10

Wave numbercm-1

Tran

smitta

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

0

100

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1100lj-h30

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427

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748

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100

6

N

N

NH

O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

4000 3500 3000 2500 2000 1500 1000 500 004

05

06

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10

Wave numbercm-1

Tran

smitta

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

4000 3500 3000 2500 2000 1500 1000 500 0

04

05

06

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09

10Tr

ansm

ittanc

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Wave numbercm-1

Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

4000 3500 3000 2500 2000 1500 1000 500 0

03

04

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07

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09

10

11

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smitta

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Wave number cm-1

Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

4000 3500 3000 2500 2000 1500 1000 500 0

00

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04

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12Tr

ansm

ittanc

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

060

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105Tr

ansm

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

1H) 756 (d J = 120 Hz1H) 744-751 (m1H) 729-735 (m 3H) 715-722 (m 1H) 526 (s 2H) (Figure

S1)

1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)

Yield 861 1H NMR (300 MHz DMSO-d6) δ(ppm) δ 989 (s 1H) 893 (s 1H) 865 (s 1H) 819

(dd J = 68 24 Hz 1H) 810 (dd J = 87 15 Hz 1H) 789 ndash 776 (m 1H) 756 (d J = 87 Hz 1H) 743

(t J = 91 Hz 1H) (Figure S2) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1561 1550 1545 1502 (d 1JC-F =

2306 Hz) 1413 1362 (d 4JC-F = 29 Hz) 1313 1297 1234 1222 (d 3JC-F = 69 Hz) 1188 (d 2JC-F =

184 Hz) 1167 1164 (d 2JC-F = 217 Hz) 917 (Figure S3)

1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)

Yield 843 1H NMR (300 MHz DMSO-d6) δ(ppm) 990 (s 1H) 900 (s 1H) 868 (s 1H) 812 (dd

J = 88 16 Hz 2H) 796 (d J = 82 Hz 1H) 758 (d J = 87 Hz 1H) 744 (t J = 79 Hz 1H) 727 (d J =

77 Hz 1H) 423 (s 1H) (Figure S4) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1563 1546 1488 1413

1393 1314 1298 1289 1269 1249 1226 1218 1168 917 834 806 (Figure S5)

1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)

Yield 867 1H NMR (300 MHz DMSO-d6) δ(ppm) 988 (s 1H) 901 (s 1H) 862 (s 1H) 811 (d J

= 83 Hz 1H) 782 (d J = 77 Hz 2H) 756 (d J = 83 Hz 1H) 740 (d J = 77 Hz 2H) 641 (d J = 158

Hz 1H) 633 - 615 (m 1H) 186 (d J = 54 Hz 3H) (Figure S6)

124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)

To a 100 mL round bottomed flask residue C1-4 (060 mmol) 5-formyl-2-furanboronic acid (090

mmol) PbC 10 triethylamine (24 mmol) 12-dimethoxyethane (60 mL) methanol (30 mL) were added

The suspension was stirred and heated to 50 degC for 05 h The reaction mixture was filtered with diatomite

and the filter cake was washed with THF (3 times 10 mL) The filtrate combined with washings was evaporated

The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (110) to afford compound

D1-4 as orange solid (yield 572~834)4

1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)

Yield 834 1H NMR (400 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 968 (s 1H) 894 (d J = 16 Hz

1H) 860 (s 1H) 833 ndash 825 (m 1H) 800 (d J = 26 Hz 1H) 785 (d J = 88 Hz 1H) 773 (dd J = 88

31 Hz 2H) 749 (td J = 80 60 Hz 1H) 740 (d J = 38 Hz 1H) 734 (dd J = 119 51 Hz 2H) 729 (d

J = 90 Hz 1H) 723 ndash 716 (m 1H) 527 (s 2H) (Figure S7)

1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)

Yield 652 1H NMR (300 MHz DMSO-d6) δ(ppm) 1011 (s 1H) 965 (s 1H) 887 (s 1H) 860 (s

1H) 818 (dd J = 352 67 Hz 2H) 781 (d J = 86 Hz 2H) 771 (d J = 35 Hz 1H) 744 (t J = 91 Hz

1H) 736 (d J = 35 Hz 1H) (Figure S8)

1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)

Yield 746 1H NMR (300 MHz DMSO-d6) δ(ppm) 1013 (s 1H) 969 (s 1H) 897 (s 1H) 865 (s

1H) 828 (dd J = 88 14 Hz 1H) 805 (s 1H) 793 (d J = 82 Hz 1H) 786 (d J = 88 Hz 1H) 774 (d J

= 37 Hz 1H) 746 (t J = 79 Hz 1H) 741 (d J = 37 Hz 1H) 730 (d J = 76 Hz 1H) 426 (s 1H)

(Figure S9) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1778 1577 1576 1551 1520 1501 1391 1295

S2

1289 1287 1271 1263 1256 1254 1232 1218 1195 1153 1098 834 807 (Figure S10)

1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)

Yield 572 1H NMR (300 MHz DMSO-d6) δ(ppm) 1005 (s 1H) 964 (s 1H) 894 (s 1H) 856 (s

1H) 822 (d J = 86 Hz 1H) 778 (dd J = 137 85 Hz 3H) 770 (d J = 36 Hz 1H) 738 (d J = 86 Hz

3H) 638 (d J = 158 Hz 1H) 631 ndash 610 (m 1H) 183 (d J = 59 Hz 3H) (Figure S11)

125 General method for preparation of 4-arylamino-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)

To a reaction flask were added 2-(methylsulfonyl)ethylamineHCl (075 mmol) methanol (50 mL)

anhydrous sodium sulfate (200 mmol) and triethylamine (05 mL) cooled to 0 degC The mixture was stirred

20 min and adjusts pH~5-6 with formic acid The reactor was added the solution of 4-arylamino-6-(5-

formylfuran-2-yl)quinazoline (D1-4) (050 mmol) resolved in THF (5 mL) and DMF (5 mL) Sodium

cyanoborohydride (200 mmol) was added in two portions over a 20 min period After stirring for 2 h the

precipitated product was filtered and the filtrate was evaporated The crude product was chromatographed by

silica gel eluted with MeOHCHCl3 (115) to afford 1a-1d as pale yellow solid (yield 781~826)5 6

1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)

Yield 820 1H NMR (600 MHz DMSO-d6) δ(ppm) 991 (s 1H) 874 (s 1H) 857 (s 1H) 816 (dd

J = 87 15 Hz 1H) 804 (d J = 25 Hz 1H) 781 (d J = 87 Hz 1H) 777 (dd J = 90 25 Hz 1H) 748

(dd J = 140 78 Hz 1H) 737 ndash 731 (m 2H) 729 (d J = 90 Hz 1H) 723 ndash 717 (m 1H) 706 (d J =

32 Hz 1H) 651 (d J = 32 Hz 1H) 527 (s 2H) 386 (s 2H) 331 (t J = 67 Hz 2H) 306 (s 3H) 303

(t J = 67 Hz 2H) 193 (s 1H) (Figure S12)

1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1b)

Yield 781 mp 1306-1315 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

857 (s 1H) 815 (d J = 86 Hz 1H) 784 ndash 778 (m 2H) 748 ndash 728 (m 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 385 (s 2H) 323 ndash 213 (m 7H) (Figure S13) HRMS (C22H20ClFN4O3S) mz

[M+H]+ calculated 4751007 found 4750996 (Figure S14)

1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline

(1c)

Yield 797 mp 729-737 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 877 (s 1H)

861 (s 1H) 818 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 87 Hz 1H) 785 ndash 780 (m 1H) 742 (d J =

80 Hz 1H) 726 (d J = 80 Hz 1H) 708 (d J = 31 Hz 1H) 651 (d J = 31 Hz 1H) 422 (s 1H) 385 (s

2H) 305 ndash 297 (m 7H) (Figure S15) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1548 1541 1514

1489 1393 1289 1285 1285 1269 1252 1243 1230 1218 1164 1154 1096 1080 834 806

536 451 420 415 (Figure S16) HRMS (C24H22N4O3S) mz [M+H]+ calculated 4471491 found

4471486 (Figure S17)

1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1d)

Yield 826 mp 2153-2159 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

S3

857 (s 1H) 815 (d J = 86 Hz 1H) 795 ndash 771 (m 3H) 740 (d J = 83 Hz 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 640 (d J = 158 Hz 1H) 634 ndash 614 (m 1H) 385 (s 2H) 331 (t J = 61 Hz

2H) 316 - 293 (m 5H) 185 (d J = 60 Hz 3H) (Figure S18) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1547 1542 1515 1489 1378 1331 1304 1285 1284 1283 1257 1244 1225 1165 1155 1095 1078 536 452 421 415 182 (Figure S19) IR νmax(KBr) cm-1 3970 3030 2904 1637 1599 1572 1516 1416 1288 962 846 785 (Figure S20) HRMS (C25H26N4O3S) mz [M+H]+ calculated 4631804 found 4631789 (Figure S21)

126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-

2d)

Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (10 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL) and then cooled to 0 degC NaBH 4 (10 mmol) was added in four portions over 15 min After 4 h the solvent was removed under reduced pressure and water (10 mL) was added The precipitated product was filtered and the filter cake was washed with water (3 times10 mL) and dried to afford 2a-2d as a yellow solid (yield 903~946)

1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)

Yield 911 mp 2407-2415 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 999 (s 1H) 878 (s 1H) 859 (s 1H) 819 (dd J = 88 12 Hz 1H) 805 (d J = 23 Hz 1H) 783 (d J = 88 Hz 1H) 778 (dd J = 89 23 Hz 1H) 757 ndash 744 (m 1H) 740 ndash 729 (m 3H) 726 ndash 718 (m 1H) 709 (d J = 32 Hz 1H) 655 (d J = 32 Hz 1H) 539 (t J = 45 Hz 1H) 530 (s 2H) 457 (d J = 45 Hz 2H) (Figure S22) 13C NMR (75 MHz DMSO-d6) δ(ppm) 16218 (d 1JC-F = 2437 Hz) 1576 1562 1542 1517 1498 1488 1396 (d 3JC-F = 74 Hz) 1331 1305 (d 3JC-F = 83 Hz) 1286 (d 2JC-F = 211 Hz) 1283 1244 1233 (d 4JC-F = 28 Hz) 1226 1210 1164 1153 1147 (d 2JC-F = 210 Hz) 1142 1141 1139 1096 1078 694 558 (Figure S23) IR νmax(KBr) cm-1 3314 3074 3457 1608 2927 1579 1504 1428 936 791 678 (Figure S24) HRMS (C26H19ClFN3O3) mz [M+H]+ calculated 4761177 found 4761157 (Figure S25)

1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)

Yield 917 mp 2246-2258 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 875 (s 1H) 858 (s 1H) 818 (s 1H) 815 (d J = 13 Hz 1H) 781 (d J = 87 Hz 2H) 754 ndash 730 (m 1H) 707 (d J = 32 Hz 1H) 651 (d J = 32 Hz 1H) 542 (s 1H) 453 (s 2H) (Figure S26) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1562 1551 1540 1519 1502 (d 1JC-F = 2067 Hz) 1363 (d 4JC-F = 27 Hz) 12866 (d 2JC-F = 286 Hz) 1240 12280 (d 3JC-F = 70 Hz) 1189 1187 11650 (d 2JC-F = 201 Hz) 1164 1153 1096 1081 1080 5579 (Figure S27) IR νmax(KBr) cm-1 3441 3296 3123 2923 1617 1581 1501 1446 1008 931 840 784 (Figure S28) HRMS (C19H14ClFN3O2) mz [M+H]+ calculated 3700759 found 3700742 (Figure S29)

1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)

Yield 903 mp 2189-2202 degC 1H NMR (300 MHz DMSO) δ 1006 (s 1H) 883 (s 1H) 866 (s 1H) 823 (dd J = 87 14 Hz 1H) 810 (s 1H) 798 (d J = 80 Hz 1H) 787 (d J = 87 Hz 1H) 754 ndash 742 (m 1H) 731 (d J = 76 Hz 1H) 712 (d J = 32 Hz 1H) 657 (d J = 32 Hz 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 427 (s 1H) (Figure S30) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1562 1541 1541 1516 1489 1394 1289 1288 1284 1269 1253 1230 1218 1165 1155 1096 1080 834 806 558 (Figure S31) IR νmax(KBr) cm-1 3443 320 3085

S4

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

4000 3500 3000 2500 2000 1500 1000 500 0

20

40

60

80

100Tr

ansm

ittanc

e

Wave numbercm-1

Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

4000 3500 3000 2500 2000 1500 1000 500 0

20

30

40

50

60

70

80

90

100

110

Tran

smitta

nce

Wave numbercm-1

Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

4000 3500 3000 2500 2000 1500 1000 500 004

05

06

07

08

09

10

Wave numbercm-1

Tran

smitta

nce

Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

1100lj-h30

101

209

101

102

103

107

112

106

107

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105

100

427

458

459

540

656

657

712

713

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732

748

786

789

810

821

822

824

866

883

100

6

N

N

NH

O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

4000 3500 3000 2500 2000 1500 1000 500 004

05

06

07

08

09

10

Wave numbercm-1

Tran

smitta

nce

Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

4000 3500 3000 2500 2000 1500 1000 500 0

04

05

06

07

08

09

10Tr

ansm

ittanc

e

Wave numbercm-1

Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

4000 3500 3000 2500 2000 1500 1000 500 0

03

04

05

06

07

08

09

10

11

Tran

smitta

nce

Wave number cm-1

Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

4000 3500 3000 2500 2000 1500 1000 500 0

00

02

04

06

08

10

12Tr

ansm

ittanc

e

Wave number cm-1

Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

060

065

070

075

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085

090

095

100

105Tr

ansm

ittanc

e

Wave number cm-1

Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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05

06

07

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11

Tran

smitta

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Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

1289 1287 1271 1263 1256 1254 1232 1218 1195 1153 1098 834 807 (Figure S10)

1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)

Yield 572 1H NMR (300 MHz DMSO-d6) δ(ppm) 1005 (s 1H) 964 (s 1H) 894 (s 1H) 856 (s

1H) 822 (d J = 86 Hz 1H) 778 (dd J = 137 85 Hz 3H) 770 (d J = 36 Hz 1H) 738 (d J = 86 Hz

3H) 638 (d J = 158 Hz 1H) 631 ndash 610 (m 1H) 183 (d J = 59 Hz 3H) (Figure S11)

125 General method for preparation of 4-arylamino-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)

To a reaction flask were added 2-(methylsulfonyl)ethylamineHCl (075 mmol) methanol (50 mL)

anhydrous sodium sulfate (200 mmol) and triethylamine (05 mL) cooled to 0 degC The mixture was stirred

20 min and adjusts pH~5-6 with formic acid The reactor was added the solution of 4-arylamino-6-(5-

formylfuran-2-yl)quinazoline (D1-4) (050 mmol) resolved in THF (5 mL) and DMF (5 mL) Sodium

cyanoborohydride (200 mmol) was added in two portions over a 20 min period After stirring for 2 h the

precipitated product was filtered and the filtrate was evaporated The crude product was chromatographed by

silica gel eluted with MeOHCHCl3 (115) to afford 1a-1d as pale yellow solid (yield 781~826)5 6

1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-

(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)

Yield 820 1H NMR (600 MHz DMSO-d6) δ(ppm) 991 (s 1H) 874 (s 1H) 857 (s 1H) 816 (dd

J = 87 15 Hz 1H) 804 (d J = 25 Hz 1H) 781 (d J = 87 Hz 1H) 777 (dd J = 90 25 Hz 1H) 748

(dd J = 140 78 Hz 1H) 737 ndash 731 (m 2H) 729 (d J = 90 Hz 1H) 723 ndash 717 (m 1H) 706 (d J =

32 Hz 1H) 651 (d J = 32 Hz 1H) 527 (s 2H) 386 (s 2H) 331 (t J = 67 Hz 2H) 306 (s 3H) 303

(t J = 67 Hz 2H) 193 (s 1H) (Figure S12)

1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1b)

Yield 781 mp 1306-1315 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

857 (s 1H) 815 (d J = 86 Hz 1H) 784 ndash 778 (m 2H) 748 ndash 728 (m 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 385 (s 2H) 323 ndash 213 (m 7H) (Figure S13) HRMS (C22H20ClFN4O3S) mz

[M+H]+ calculated 4751007 found 4750996 (Figure S14)

1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline

(1c)

Yield 797 mp 729-737 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 877 (s 1H)

861 (s 1H) 818 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 87 Hz 1H) 785 ndash 780 (m 1H) 742 (d J =

80 Hz 1H) 726 (d J = 80 Hz 1H) 708 (d J = 31 Hz 1H) 651 (d J = 31 Hz 1H) 422 (s 1H) 385 (s

2H) 305 ndash 297 (m 7H) (Figure S15) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1548 1541 1514

1489 1393 1289 1285 1285 1269 1252 1243 1230 1218 1164 1154 1096 1080 834 806

536 451 420 415 (Figure S16) HRMS (C24H22N4O3S) mz [M+H]+ calculated 4471491 found

4471486 (Figure S17)

1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-

yl)quinazoline (1d)

Yield 826 mp 2153-2159 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 992 (s 1H) 878 (s 1H)

S3

857 (s 1H) 815 (d J = 86 Hz 1H) 795 ndash 771 (m 3H) 740 (d J = 83 Hz 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 640 (d J = 158 Hz 1H) 634 ndash 614 (m 1H) 385 (s 2H) 331 (t J = 61 Hz

2H) 316 - 293 (m 5H) 185 (d J = 60 Hz 3H) (Figure S18) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1547 1542 1515 1489 1378 1331 1304 1285 1284 1283 1257 1244 1225 1165 1155 1095 1078 536 452 421 415 182 (Figure S19) IR νmax(KBr) cm-1 3970 3030 2904 1637 1599 1572 1516 1416 1288 962 846 785 (Figure S20) HRMS (C25H26N4O3S) mz [M+H]+ calculated 4631804 found 4631789 (Figure S21)

126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-

2d)

Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (10 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL) and then cooled to 0 degC NaBH 4 (10 mmol) was added in four portions over 15 min After 4 h the solvent was removed under reduced pressure and water (10 mL) was added The precipitated product was filtered and the filter cake was washed with water (3 times10 mL) and dried to afford 2a-2d as a yellow solid (yield 903~946)

1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)

Yield 911 mp 2407-2415 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 999 (s 1H) 878 (s 1H) 859 (s 1H) 819 (dd J = 88 12 Hz 1H) 805 (d J = 23 Hz 1H) 783 (d J = 88 Hz 1H) 778 (dd J = 89 23 Hz 1H) 757 ndash 744 (m 1H) 740 ndash 729 (m 3H) 726 ndash 718 (m 1H) 709 (d J = 32 Hz 1H) 655 (d J = 32 Hz 1H) 539 (t J = 45 Hz 1H) 530 (s 2H) 457 (d J = 45 Hz 2H) (Figure S22) 13C NMR (75 MHz DMSO-d6) δ(ppm) 16218 (d 1JC-F = 2437 Hz) 1576 1562 1542 1517 1498 1488 1396 (d 3JC-F = 74 Hz) 1331 1305 (d 3JC-F = 83 Hz) 1286 (d 2JC-F = 211 Hz) 1283 1244 1233 (d 4JC-F = 28 Hz) 1226 1210 1164 1153 1147 (d 2JC-F = 210 Hz) 1142 1141 1139 1096 1078 694 558 (Figure S23) IR νmax(KBr) cm-1 3314 3074 3457 1608 2927 1579 1504 1428 936 791 678 (Figure S24) HRMS (C26H19ClFN3O3) mz [M+H]+ calculated 4761177 found 4761157 (Figure S25)

1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)

Yield 917 mp 2246-2258 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 875 (s 1H) 858 (s 1H) 818 (s 1H) 815 (d J = 13 Hz 1H) 781 (d J = 87 Hz 2H) 754 ndash 730 (m 1H) 707 (d J = 32 Hz 1H) 651 (d J = 32 Hz 1H) 542 (s 1H) 453 (s 2H) (Figure S26) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1562 1551 1540 1519 1502 (d 1JC-F = 2067 Hz) 1363 (d 4JC-F = 27 Hz) 12866 (d 2JC-F = 286 Hz) 1240 12280 (d 3JC-F = 70 Hz) 1189 1187 11650 (d 2JC-F = 201 Hz) 1164 1153 1096 1081 1080 5579 (Figure S27) IR νmax(KBr) cm-1 3441 3296 3123 2923 1617 1581 1501 1446 1008 931 840 784 (Figure S28) HRMS (C19H14ClFN3O2) mz [M+H]+ calculated 3700759 found 3700742 (Figure S29)

1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)

Yield 903 mp 2189-2202 degC 1H NMR (300 MHz DMSO) δ 1006 (s 1H) 883 (s 1H) 866 (s 1H) 823 (dd J = 87 14 Hz 1H) 810 (s 1H) 798 (d J = 80 Hz 1H) 787 (d J = 87 Hz 1H) 754 ndash 742 (m 1H) 731 (d J = 76 Hz 1H) 712 (d J = 32 Hz 1H) 657 (d J = 32 Hz 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 427 (s 1H) (Figure S30) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1562 1541 1541 1516 1489 1394 1289 1288 1284 1269 1253 1230 1218 1165 1155 1096 1080 834 806 558 (Figure S31) IR νmax(KBr) cm-1 3443 320 3085

S4

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

4000 3500 3000 2500 2000 1500 1000 500 0

20

40

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80

100Tr

ansm

ittanc

e

Wave numbercm-1

Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

4000 3500 3000 2500 2000 1500 1000 500 0

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100

110

Tran

smitta

nce

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

4000 3500 3000 2500 2000 1500 1000 500 004

05

06

07

08

09

10

Wave numbercm-1

Tran

smitta

nce

Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

0

100

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700

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1100lj-h30

101

209

101

102

103

107

112

106

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101

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100

427

458

459

540

656

657

712

713

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732

748

786

789

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100

6

N

N

NH

O

OHCH

2c

Figure S30 1H NMR of 2c

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S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

857 (s 1H) 815 (d J = 86 Hz 1H) 795 ndash 771 (m 3H) 740 (d J = 83 Hz 2H) 706 (d J = 27 Hz 1H)

650 (d J = 27 Hz 1H) 640 (d J = 158 Hz 1H) 634 ndash 614 (m 1H) 385 (s 2H) 331 (t J = 61 Hz

2H) 316 - 293 (m 5H) 185 (d J = 60 Hz 3H) (Figure S18) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1547 1542 1515 1489 1378 1331 1304 1285 1284 1283 1257 1244 1225 1165 1155 1095 1078 536 452 421 415 182 (Figure S19) IR νmax(KBr) cm-1 3970 3030 2904 1637 1599 1572 1516 1416 1288 962 846 785 (Figure S20) HRMS (C25H26N4O3S) mz [M+H]+ calculated 4631804 found 4631789 (Figure S21)

126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-

2d)

Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (10 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL) and then cooled to 0 degC NaBH 4 (10 mmol) was added in four portions over 15 min After 4 h the solvent was removed under reduced pressure and water (10 mL) was added The precipitated product was filtered and the filter cake was washed with water (3 times10 mL) and dried to afford 2a-2d as a yellow solid (yield 903~946)

1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)

Yield 911 mp 2407-2415 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 999 (s 1H) 878 (s 1H) 859 (s 1H) 819 (dd J = 88 12 Hz 1H) 805 (d J = 23 Hz 1H) 783 (d J = 88 Hz 1H) 778 (dd J = 89 23 Hz 1H) 757 ndash 744 (m 1H) 740 ndash 729 (m 3H) 726 ndash 718 (m 1H) 709 (d J = 32 Hz 1H) 655 (d J = 32 Hz 1H) 539 (t J = 45 Hz 1H) 530 (s 2H) 457 (d J = 45 Hz 2H) (Figure S22) 13C NMR (75 MHz DMSO-d6) δ(ppm) 16218 (d 1JC-F = 2437 Hz) 1576 1562 1542 1517 1498 1488 1396 (d 3JC-F = 74 Hz) 1331 1305 (d 3JC-F = 83 Hz) 1286 (d 2JC-F = 211 Hz) 1283 1244 1233 (d 4JC-F = 28 Hz) 1226 1210 1164 1153 1147 (d 2JC-F = 210 Hz) 1142 1141 1139 1096 1078 694 558 (Figure S23) IR νmax(KBr) cm-1 3314 3074 3457 1608 2927 1579 1504 1428 936 791 678 (Figure S24) HRMS (C26H19ClFN3O3) mz [M+H]+ calculated 4761177 found 4761157 (Figure S25)

1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)

Yield 917 mp 2246-2258 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1008 (s 1H) 875 (s 1H) 858 (s 1H) 818 (s 1H) 815 (d J = 13 Hz 1H) 781 (d J = 87 Hz 2H) 754 ndash 730 (m 1H) 707 (d J = 32 Hz 1H) 651 (d J = 32 Hz 1H) 542 (s 1H) 453 (s 2H) (Figure S26) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1575 1562 1551 1540 1519 1502 (d 1JC-F = 2067 Hz) 1363 (d 4JC-F = 27 Hz) 12866 (d 2JC-F = 286 Hz) 1240 12280 (d 3JC-F = 70 Hz) 1189 1187 11650 (d 2JC-F = 201 Hz) 1164 1153 1096 1081 1080 5579 (Figure S27) IR νmax(KBr) cm-1 3441 3296 3123 2923 1617 1581 1501 1446 1008 931 840 784 (Figure S28) HRMS (C19H14ClFN3O2) mz [M+H]+ calculated 3700759 found 3700742 (Figure S29)

1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)

Yield 903 mp 2189-2202 degC 1H NMR (300 MHz DMSO) δ 1006 (s 1H) 883 (s 1H) 866 (s 1H) 823 (dd J = 87 14 Hz 1H) 810 (s 1H) 798 (d J = 80 Hz 1H) 787 (d J = 87 Hz 1H) 754 ndash 742 (m 1H) 731 (d J = 76 Hz 1H) 712 (d J = 32 Hz 1H) 657 (d J = 32 Hz 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 427 (s 1H) (Figure S30) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1576 1562 1541 1541 1516 1489 1394 1289 1288 1284 1269 1253 1230 1218 1165 1155 1096 1080 834 806 558 (Figure S31) IR νmax(KBr) cm-1 3443 320 3085

S4

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

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Figure S17 HRMS of 1c

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Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

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Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

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Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

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Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Wave number cm-1

Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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Tran

smitta

nce

Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

2108 2949 1607 1575 1497 1485 1007 945 887 842 (Figure S32) HRMS (C21H15N3O2) mz [M+H]+ calculated 3421243 found 3421230 (Figure S33)

1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)

Yield 946 mp 2359-2363 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1H NMR (300 MHz DMSO) δ 1004 (s 1H) 884 (s 1H) 861 (s 1H) 822 (d J = 85 Hz 1H) 786 (d J = 83 Hz 3H) 747 (d J = 82 Hz 2H) 712 (d J = 26 Hz 1H) 657 (d J = 24 Hz 1H) 648 (d J = 157 Hz 1H) 641 ndash 627 (m 1H) 540 (s 1H) 459 (d J = 36 Hz 2H) 192 (d J = 59 Hz 3H) (Figure S34) 13C NMR (75 MHz DMSO-d6) δ(ppm) 1777 1761 1577 1552 1520 1502 1375 1332 1304 1293 1287 1262 1257 1244 1227 1196 1154 1096 486 182 (Figure S35) IR νmax(KBr) cm-

1 3442 3261 3023 2964 1602 1572 1519 1492 1387 1007 842 794 (Figure S36) HRMS (C22H19N3O2) mz [M+H]+ calculated 3581556 found 3851542 (Figure S37)

127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-

3d)

A mixture of 2a-2d (05 mmol) acetic oxide (055 mmol) and sodium acetate trihydrate (005 mmol) with less DMF were stirred at RT for 05 h The product was adjusted pH~7 with 5 NaOH the precipitated product was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate filtered and concentrated The crude product was chromatographed by silica gel eluted with EtOAcCHCl3 (15) to afford residue 3a-3d as pale yellow solid (yield 847~896)

1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)

Yield 896 mp 1777-1787 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 996 (s 1H) 879 (s 1H) 857 (s 1H) 818 (d J = 87 Hz 1H) 802 (d J = 19 Hz 1H) 782 (d J = 87 Hz 1H) 775 (dd J = 88 19 Hz 1H) 748 (dd J = 141 78 Hz 1H) 738 ndash 725 (m 3H) 724 ndash 715 (m 1H) 712 (d J = 31 Hz 1H) 675 (d J = 31 Hz 1H) 527 (s 2H) 516 (s 2H) 210 (s 3H) (Figure S38) 13C NMR (101 MHz DMSO-d6) δ(ppm) 1705 1627 (d 1JC-F = 2436 Hz) 1581 1550 1535 1503 1503 1496 1401 (d 3JC-F = 75 Hz) 1335 1310 (d 3JC-F = 83 Hz) 1292 (d 2JC-F = 243 Hz) 1283 1249 1238 (d 4JC-F = 27 Hz) 1231 1215 1175 1158 1153 1151 1148 1145 (d 2JC-F = 219 Hz) 1140 1085 699 582 211 (Figure S39) IR νmax(KBr) cm-1 3447 3059 1738 1616 1572 1499 1455 1241 1026 847 784 (Figure S40) HRMS (C28H21ClFN3O4) mz [M+H]+ calculated 5181283 found 5181291 (Figure S41)

1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)

Yield 893 mp 1654-1666 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1007 (s 1H) 879 (s 1H) 862 (s 1H) 820 (d J = 76 Hz 2H) 784 (d J = 84 Hz 2H) 754 ndash 739 (m 1H) 713 (d J = 29 Hz 1H) 676 (d J = 29 Hz 1H) 516 (s 2H) 210 (s 3H) (Figure S42) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1753 1628 1589 (d 1JC-F = 2048 Hz) 1579 1552 1544 1416 1343 1342 1339 1332 1293 (d 2JC-F = 225 Hz) 1281 1241 (d 2JC-F = 184 Hz) 1222 (d 3JC-F = 93 Hz) 1218 1205 1188 1134 (d 3JC-F = 127 Hz) 630 259 (Figure S43) IR νmax(KBr) cm-1 3470 3096 1732 1612 1576 1497 1424 1245 836 786 (Figure S44) HRMS (C21H15ClFN3O3) mz [M+H]+ calculated 4120864 found 4120870 (Figure S45)

1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)

Yield 861 mp 1597-1608 degC 1H NMR (300 MHz DMSO-d6) δ(ppm) 1002 (s 1H) 883

S5

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

4000 3500 3000 2500 2000 1500 1000 500 0

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40

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80

100Tr

ansm

ittanc

e

Wave numbercm-1

Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

4000 3500 3000 2500 2000 1500 1000 500 004

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

0

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1100lj-h30

101

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427

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748

786

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821

822

824

866

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100

6

N

N

NH

O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

4000 3500 3000 2500 2000 1500 1000 500 004

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

4000 3500 3000 2500 2000 1500 1000 500 0

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ansm

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

4000 3500 3000 2500 2000 1500 1000 500 0

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12Tr

ansm

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Wave number cm-1

Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

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ansm

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

(s 1H) 863 (s 1H) 820 (d J = 87 Hz 1H) 806 (s 1H) 794 (d J = 81 Hz 1H) 784 (d J = 87 Hz 1H) 750 ndash 739 (m 1H) 727 (d J = 73 Hz 1H) 714 (d J = 28 Hz 1H) 676 (d J = 28 Hz 1H) 517 (s 2H) 423 (s 1H) 210 (s 3H) (Figure S46) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1543 1530 1499 1492 1393 1289 1289 1286 1279 1269 1253 1231 1218 1171 1154 1135 1081 834 806 577 206 (Figure S47) IR νmax(KBr) cm-1 3421 3040 2987 2075 1717 1616 1583 1505 1456 1437 1173 787 627 (Figure S48) HRMS (C23H17N3O3) mz [M+H]+ calculated 3841348 found 3841359 (Figure S49)

1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)

Yield 847 mp 1687-1699 degC 1H NMR (600 MHz DMSO-d6) δ(ppm) 997 (s 1H) 883 (s 1H) 857 (s 1H) 818 (dd J = 87 12 Hz 1H) 789 ndash 777 (m 3H) 747 ndash 736 (m 2H) 713 (d J = 33 Hz 1H) 675 (d J = 33 Hz 1H) 642 (d J = 156 Hz 1H) 632 ndash 623 (m 1H) 515 (s 2H) 209 (s 3H) 187 (d J = 64 Hz 3H) (Figure S50) 13C NMR (151 MHz DMSO-d6) δ(ppm) 1700 1576 1545 1530 1498 1492 1377 1332 1304 1287 1285 1277 1257 1244 1227 1172 1155 1135 1080 577 206 182 (Figure S51) IR νmax(KBr) cm-1 3415 3012 2989 2065 1719 1616 1543 1502 1024 833 791 (Figure S52) HRMS (C24H21N3O3) mz [M+H]+ calculated 4001661 found 4001668 (Figure S53)

2 Experiment for Biological evaluation

21 Cell proliferation and growth assays

According to the reference described7-10 SW480 A431 A549 and NCI-H1975 cells were seeded in 96-well plates in regular Dulbeccorsquos modified Eaglersquos medium (DMEM) supplemented with 10 (vv) fetal bovine serum (FBS) 100 unitsmL of penicillin 100 microgmL of streptomycin 2 mM L-glutamine and were maintained at 37thinspdegC in a humidified incubator containing 5 CO2 The following day 3-fold serial dilutions of compounds or 05 DMSO were added to each well Cells were then incubated for further 72 h Then cell viability was determined by MTT assay The plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 570 nm and 630 nm was reference wavelength The IG50 values were calculated from the inhibition curves by normalized nonlinear regression analysis using GraphPad Prism5 (GraphPadSoftware Inc)

The inhibition rate () was calculated using the following equation Inhibition Rate () = [1 - (OD570 - OD630) (OD570control - OD630control)] times 100 (1)

22 In vitro EGFR kinase assay

The effects of compounds on the activity of EGFR kinase were determined using enzyme-linked immunosorbent assays (ELISAs)11 with purified recombinant proteins (Sino Biological Inc) Briefly 50 microgmL poly (GluTyr) 41 (Sigma) was pre-coated in 96-well plates at 37 degC as a substrate The enzyme reaction was carried in kinase reaction buffer (50 mmolL HEPES (pH 74) 001 BRIJ-35 10 mmolL MgCl2 4 mmolL MnCl2 01 mmolL EGTA and 2 mmolL DTT) 10 microL of various concentrations of indicated compounds and 20 microL of purified tyrosine kinase proteins were added to each reaction well DMSO (05 vv) was used as the negative control The kinase reaction was initiated by addition of a 50 microL of 5micromolL ATP solution which diluted in kinase reaction buffer After incubation for 60 min at 37 thinspdegC the plates was washed 6 times with phosphate-buffered saline (PBS) containing 01 Tween 20 (PBST) Anti-phosphotyrosine mouse mAb (PTM Bio) antibody was then added After a 60min incubation at 37 degC the plate was washed 3 times with PBST and horseradish

S6

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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748

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821

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824

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6

N

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O

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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11

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

4000 3500 3000 2500 2000 1500 1000 500 0

00

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

peroxidase-conjugated goat anti-mouse IgG was added The plate was then incubated at 37 thinspdegC for 40 min and washed 5 times with PBST A 100 microL aliquot of a solution containing 003 H2O2 and 2 mgml TMB in 01 molL citrate buffer (pH 55) was added The reaction was terminated by addition of 100 microL of 2 M H2SO4 as the color changed and the plate was analyzed using a multi-well spectrophotometer (PE Enspire) at 450 nm The IC50 values were calculated from the inhibition curves using GraphPad Prism5 (GraphPad Software Inc) in at least three separate experiments

The emission ration was calculated using the following equation Emission Ration = OD450OD450control (2)

23 Molecular modeling

All the calculations reported were carried out on a Lenovo PC with Windows 81 system using the TriposSybyl-X 21 (TriposInc St Louis MO USA) molecular modeling package The parameters involved in the study were set to default values except those specifically mentioned

Surflex-Dock docks ligands automatically into a receptors ligand-binding site using a protomol-based method and an empirically derived scoring function Protomol is a computational representation of the intended binding site to which putative ligands are aligned There are three kinds of modes to generate protomol automatic ligand and residues mode12

The crystal structure of EGFR kinase domain (PDB code 1xkk) complexed with a quinazoline inhibitor- GW572016 (lapatinib)13 was obtained from RCSB Protein Data Bank Prior to docking the ligand was extracted from protein structure and was regarded as the reference structure for the calculation of root mean squaredeviation (RMSD) values The ligands and water molecules were removed and the polar hydrogen atoms were added The other parameters were set to default values

24 Western blotting

Followed the reference methods7 11 cells were seeded in 6-well plates the cultured cells were serum-starved for 24 h when confluence was reached 90 then treated with indicated concentrations of compounds in 2 ml total medium for 2 h At desired time point cells were harvested using RIPA lysis buffer Briefly the culture medium was removed and the cells were washed 3 times with cold PBS and then lysed by 100 microl ice-cold RIPA lysis buffer together with protease and phosphatase inhibitor tablet Cells were scraped off the tissue culture dish and lysed on ice for 30 min with occasional agitation The supernatant was collected by centrifugation (12000 timesg 20 min 4 degC) The protein concentration in the supernatant was determined by using a BCA protein assay kit

After BCA analysis to quantify proteins samples were prepared in SDS-PAGE loading buffer then boiled for 10 min at 95 degC Western blot analyses were conducted after separation by SDS-PAGE electrophoresis and transfer to polyvinylidenedifluoride (PVDF) membranes (millipore) Immunoblotting was performed according to the antibody manufacturersrsquo recommendations The primary antibody-bound membranes were washed for 5 min times 5 times with a washing buffer (TBS solution containing 01 Tween-20) before incubation with corresponding secondary antibodies conjugated with horseradish peroxidase After a 30 min washing immune reactive signals were visualized by enhanced chemiluminescence using ImageLabeTM software (BioRAD) Anti-phosphotyrosine mouse mAb was purchased from PTM Bio and other antibodies were all obtained from Cell Signaling Technology

S7

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

3 Spectra for compounds

Figure S1 1H NMR of C1

S8

C1

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S2 1H NMR of C2

Figure S3 13C NMR of C2

S9

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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N

N

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O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S4 1H NMR of C3

Figure S5 13C NMR of C3

S10

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

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Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S6 1H NMR of C4

S11

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S7 1H NMR of D1

S12

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S8 1H NMR of D2

S13

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S9 1H NMR of D3

Figure S10 13C NMR of D3

S14

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S11 1H NMR of D4

S15

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S12 1H NMR of lapatinib (1a)

S16

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

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883

100

6

N

N

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O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S13 1H NMR of 1b

Figure S14 HRMS of 1b

S17

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S15 1H NMR of 1c

Figure S16 13C NMR of 1c

S18

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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O

OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S17 HRMS of 1c

S19

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S18 1H NMR of 1d

Figure S19 13C NMR of 1d

S20

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

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Figure S20 IR of 1d

Figure S21 HRMS of 1d

S21

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S22 1H NMR of 2a

Figure S23 13C NMR of 2a

S22

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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N

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

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Figure S24 IR of 2a

Figure S25 HRMS of 2a

S23

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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824

866

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6

N

N

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OHCH

2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S26 1H NMR of 2b

Figure S27 13C NMR of 2b

S24

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

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Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

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Figure S28 IR of 2b

Figure S29 HRMS of 2b

S25

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

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Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

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Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

-050005101520253035404550556065707580859095100105110115f1 (ppm)

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2c

Figure S30 1H NMR of 2c

Figure S31 13C NMR of 2c

S26

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

4000 3500 3000 2500 2000 1500 1000 500 0

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

4000 3500 3000 2500 2000 1500 1000 500 0

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

4000 3500 3000 2500 2000 1500 1000 500 004

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Figure S32 IR of 2c

Figure S33 HRMS of 2c

S27

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S34 1H NMR of 2d

Figure S35 13C NMR of 2d

S28

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

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Figure S36 IR of 2d

Figure S37 HRMS of 2d

S29

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S38 1H NMR of 3a

Figure S39 13C NMR of 3a

S30

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

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Figure S40 IR of 3a

Figure S41 HRMS of 3a

S31

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S42 1H NMR of 3b

Figure S43 13C NMR of 3b

S32

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

4000 3500 3000 2500 2000 1500 1000 500 0

00

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Figure S44 IR of 3b

Figure S45 HRMS of 3b

S33

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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11

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Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S46 1H NMR of 3c

Figure S47 13C NMR of 3c

S34

4000 3500 3000 2500 2000 1500 1000 500 0

060

065

070

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080

085

090

095

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ansm

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Wave number cm-1

Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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08

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10

11

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Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

4000 3500 3000 2500 2000 1500 1000 500 0

060

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Figure S48 IR of 3c

Figure S49 HRMS of 3c

S35

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

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11

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Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

Figure S50 1H NMR of 3d

Figure S51 13C NMR of 3d

S36

4000 3500 3000 2500 2000 1500 1000 500 003

04

05

06

07

08

09

10

11

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nce

Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

4000 3500 3000 2500 2000 1500 1000 500 003

04

05

06

07

08

09

10

11

Tran

smitta

nce

Wave number cm-1

Figure S52 IR of 3d

Figure S53 HRMS of 3d

S37

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References

4 References

1 Narender N Reddy K S K Mohan K V V K Kulkarni S J Tetrahedron Letters 2007 48 6124

2 Chana S WO2008056149A1 2008 22pp

3 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2011039759A1 2011 32pp

4 Metsger L Yurkovski S Gorohovsky-Rosenberg S Kipnis N Lavy D WO2010017387A2 2010 41pp

5 Lackey K E Spector N Wood E R III Xia W WO2002056912A2 2002 57 pp

6 Jyothi Prasad R Adibhatla Kali Satya B R Venkaiah Chowdary N WO2010061400A1 2010 34pp

7 Wong R Turlova E Feng Z P Rutka J T Sun H S Oncotarget 2017

8 Liu H-W Yu X-Z Padula D Pescitelli G Lin Z-W Wang F Ding K Lei M Gao J-M European journal of

medicinal chemistry 2013 59 265

9 Qiu H Yang B Pei Z C Zhang Z Ding K The Journal of biological chemistry 2010 285 32638

10 Chen W L Turlova E Sun C L Kim J S Huang S Zhong X Guan Y Y Wang G L Rutka J T Feng Z P

Sun H S Marine drugs 2015 13 2505

11 Yan W Wang X Dai Y Zhao B Yang X Fan J Gao Y Meng F Wang Y Luo C Ai J Geng M Duan W J

Med Chem 2016 59 6690

12 Zhang J Shan Y Pan X Wang C Xu W He L Chem Biol Drug Des 2011 78 709

13 Wood E R Truesdale A T McDonald O B Yuan D Hassell A Dickerson S H Ellis B Pennisi C Horne E

Lackey K Alligood K J Rusnak D W Gilmer T M Shewchuk L Cancer Res 2004 64 6652

S38

• 1 Experiment for chemistry
• • 11 General information
  • 12 Experimental procedures for synthesis of intermediates and target compounds
  • • 121 2-amino-5-iodobenzonitrile (A)
    • 122 N-(2-cyano-4-iodophenyl)-NN-dimethyl formamidine (B)
    • 123 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4)
    • • 1231 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1)
      • 1232 4-(3-chloro-4-fluorophenylamino)-6-iodoquinazoline (C2)
      • 1233 4-(3-ethynylphenylamino)-6-iodoquinazoline (C3)
      • 1234 4-(4-(E)-(propen-1-yl)phenylamino)-6-iodoquinazoline (C4)
      • • 124 General method for preparation of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4)
        • • 1241 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1)
          • 1242 4-(3-chloro-4-fluorophenylamino)-6-(5-formylfuran-2-yl)quinazoline (D2)
          • 1243 4-(3-ethynylphenylamino)-6-(5-formylfuran-2-yl)quinazoline (D3)
          • 1244 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D4)
          • • 125 General method for preparation of 4-arylamino-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1a-1d)
            • • 1251 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib 1a)
              • 1252 4-(3-chloro-4-fluorophenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1b)
              • 1253 4-(3-ethynylphenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1c)
              • 1254 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (1d)
              • • 126 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d)
                • • 1261 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a)
                  • 1262 4-(3-chloro-4-fluorophenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2b)
                  • 1263 4-(3-ethynylphenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2c)
                  • 1264 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2d)
                  • • 127 General method for preparation of 4-arylamino-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a-3d)
                    • • 1271 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3a)
                      • 1272 4-(3-chloro-4-fluorophenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3b)
                      • 1273 4-(3-ethynylphenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3c)
                      • 1274 4-(4-(E)-(propen-1-yl)phenylamino)-6-(5-acetoxymethylfuran-2-yl)quinazoline (3d)
                      • • 2 Experiment for Biological evaluation
                        • • 21 Cell proliferation and growth assays
                          • 22 In vitro EGFR kinase assay
                          • 23 Molecular modeling
                          • 24 Western blotting
                          • • 3 Spectra for compounds
                            • 4 References