Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

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Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents Jinfeng Wang, Lin Zhang, Xiaoyan Pan, Bingling Dai, Ying Sun, Chuansheng Li, Jie Zhang School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi an, 710061, P.R. China Table of Contents 1. The nomenclature, structure, melting point, HRMS, 1 H-NMR spectra, 13 C-NMR spectra of Title Compounds (CDAU-1~CDAU-11). 2. The nomenclature, structure, melting point, HRMS, 1 H-NMR spectra, 13 C-NMR spectra of Title Compounds (CDAU-12~CDAU-25). Corresponding author. Tel/Fax: +86-29-82655451; E-mail: zhj8623@xjtu.edu.cn (Jie Zhang).

N-(5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecar boxamide(cdau-1) 5.0 441.1514 4.0 3.0 2.0 1.0 212.0801 274.2722 318.2979 373.1248 463.1341 525.2918 569.3042 200 250 300 350 400 450 500 550 m/z

mp:270~272, HRMS m/z calcd for C 23 H 19 F 3 N 4 O 2 ([M+H] + ) 441.1538, found 441.1514. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.7 Hz, 2H), 8.04 (m, J = 8.7, 2.4 Hz, 1H), 7.65 (t, J = 8.3 Hz, 4H), 7.58 (d, J = 8.7 Hz, 2H), 2.03 (t, J = 12.3, 8.6, 4.8 Hz, 1H), 0.92 0.71 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.01, 152.91, 151.41, 145.65, 141.00, 139.51, 135.96, 131.04, 130.98, 130.40, 130.15, 129.84, 127.15, 126.04, 123.34, 122.36, 119.35, 118.58, 114.65, 114.61, 113.69, 14.69, 8.15. N-(5-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarb oxamide(cdau-2) 3.5 475.1113 3.0 2.5 2.0 1.5 1.0 279.0914 301.0727 0.5 212.0795 407.1304 233.0716 323.1499352.1785380.2122 437.1915 472.8293 579.1620 200 250 300 350 400 450 500 550 m/z

mp:273~275, HRMS m/z calcd for C 23 H 18 ClF 3 N 4 O 2 ([M+H] + ) 475.1149, found 475.1113. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 9.10 (s, 1H), 8.95 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.09 8.02 (m, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.60 7.57 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 2.03 (m, J = 12.1, 8.5, 4.7 Hz, 1H), 0.95 0.69 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.01, 152.79, 151.43, 145.64, 139.77, 139.36, 135.95, 132.42, 131.13, 131.02, 127.35, 127.13, 127.04, 124.64, 123.51, 122.82, 121.93, 119.47, 117.28, 117.22, 113.70, 14.70, 8.14.

N-(5-(4-(3-(3,4-bis(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxa mide(cdau-3) 1.50 509.1394 1.25 1.00 0.75 0.50 279.0915 0.25 407.1373 590.3869 233.0668 318.2990 359.2290 437.1941 0 543.8083 200 250 300 350 400 450 500 550 m/z

mp:241~243, HRMS m/z calcd for C 24 H 18 F 6 N 4 O 2 ([M+H] + ) 508.1412, found 509.1394. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.44 (s, 1H), 9.14 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 8.9 Hz, 3H), 8.05 (m, J = 8.7, 2.4 Hz, 1H), 7.67 (t, J = 5.9 Hz, 3H), 7.60 (d, J = 8.7 Hz, 2H), 2.09 1.98 (m, 1H), 0.82 (m, J = 14.6, 6.4 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.01, 152.80, 151.46, 145.65, 142.28, 139.17, 135.95, 131.66, 131.34, 131.01, 130.98, 130.69, 127.84, 127.10, 125.13, 122.42, 119.69, 118.45, 114.77, 114.73, 113.69, 14.68, 8.10. N-(5-(4-(3-(3,4-difluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU -4) 4.0 409.1456 3.0 2.0 1.0 410.1478 212.0803 274.2721 349.1807 441.1525 388.2551 481.2601 525.2864 569.3155 200 250 300 350 400 450 500 550 m/z

mp:280~282, HRMS m/z calcd for C 22 H 18 F 2 N 4 O 2 ([M+H] + ) 409.1476, found 409.1456. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.04 (m, J = 8.7, 2.3 Hz, 1H), 7.72 7.62 (m, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.35 (m, J = 19.6, 9.3 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 2.09 1.98 (m, 1H), 0.82 (m, J = 14.9, 6.4 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.01, 152.85, 151.40, 150.87, 150.74, 148.46, 148.33, 146.21, 146.09, 145.62, 143.83, 143.70, 139.56, 137.31, 137.29, 137.22, 137.20,

135.90, 131.06, 130.92, 127.13, 119.28, 117.88, 117.70, 114.88, 114.85, 114.82, 114.79, 113.71, 107.78, 107.57, 14.71, 8.13. N-(5-(4-(3-(3-chloro-4-methylphenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide( CDAU-5) Inten. (x100,000) 2.5 422.1366 2.0 1.5 274.2725 1.0 318.3004 349.1792 393.2104 444.1180 0.5 301.0765 481.2620 242.1526 228.1472 384.3076 453.8219 529.8849 577.4137 200 250 300 350 400 450 500 550 m/z

mp:229~231, HRMS m/z calcd for C 23 H 21 ClN 4 O 2 ([M+2H] + ) 422.1510, found 422.1366. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.96 (s, 2H), 8.91 (s, 1H), 8.85 (s, 1H), 7.71 (m, J = 5.3, 3.3 Hz, 3H), 7.59 (d, J = 8.7 Hz, 2H), 7.22 (m, J = 8.3, 5.1 Hz, 2H), 2.27 (s, 3H), 2.22 2.12 (m, 1H), 0.92 0.76 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.25, 156.75, 155.72, 152.81, 140.30, 139.25, 133.59, 131.63, 128.81, 128.34, 127.71, 127.19, 119.21, 118.67, 117.50, 19.29, 14.80, 8.49. N-(5-(4-(3-(3-chlorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide (CDAU-6) 5.0 408.1186 4.0 3.0 2.0 410.1174 1.0 349.1807 213.0757 274.2723 305.1544 34937 437.2198 261.1296 481.2587 374.1596 525.2840 453.2013 497.2314 569.3132 200 250 300 350 400 450 500 550 m/z

mp:270~272, HRMS m/z calcd for C 22 H 19 ClN 4 O 2 ([M+2H] + ) 408.1197, found 408.1186. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.96 (s, 4H), 7.72 (d, J = 8.2 Hz, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 6.2 Hz, 2H), 7.04 (d, J = 6.0 Hz, 1H), 2.18 (s, 1H), 0.85 (s, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.24, 156.78, 155.74, 152.77, 141.63, 140.18, 133.68, 130.87, 128.33, 127.86, 127.22, 122.04, 119.31, 118.13, 117.21, 14.79, 8.47.

N-(5-(4-(3-(2-fluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide (CDAU-7) 7.5 392.1488 5.0 2.5 213.0755 274.2721 324.1227 414.1288 353.2635 256.2598 381.2958 437.2148 481.2578 550.1064 200 250 300 350 400 450 500 550 m/z

mp:222~224, HRMS m/z calcd for C 22 H 19 FN 4 O 2 ([M+2H] + ) 392.1492, found m/z =392.1148. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.94 (s, 1H), 9.26 (s, 1H), 8.96 (s, 2H), 8.62 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.30 7.22 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 2.16 (s, 1H), 0.90 0.78 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.23, 156.77, 155.74, 153.72, 152.57, 151.32, 140.17, 128.31, 127.94, 127.83, 127.30, 125.02, 124.99, 123.11, 123.03, 121.10, 119.01, 115.56, 115.37, 14.79, 8.48. N-(5-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)cyclopropanecarboxamide (CDAU-8) 7.5 458.1398 5.0 390.1136 2.5 349.1805 437.2325 213.0749 305.1544 481.2568 274.2718 525.2835 302.3029 340.1759 371.2255 415.2466 497.2311 541.2557569.3081 200 250 300 350 400 450 500 550 m/z

mp:236~238, HRMS m/z calcd for C 23 H 19 F 3 N 4 O 3 ([M+2H] + ) 458.1409, found 458.1398. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.96 (s, 3H), 8.93 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.67 7.45 (m, 4H), 7.31 (d, J = 8.6 Hz, 2H), 2.24 2.11 (m, 1H), 0.91 0.77 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.24, 156.76, 155.91, 155.73, 152.87, 143.12, 140.28, 139.37, 128.33, 127.75, 127.22, 126.13, 122.21, 121.93, 119.96, 119.87, 119.39, 119.22, 14.79, 8.47.

N-(5-(4-(3-(tert-butyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-9) 1.50 1.25 354.1905 1.00 0.75 0.50 376.1726 0.25 213.0758 274.2724 340.2794 437.2068 552.7630 595.3734 242.1482 286.1647 393.2064 481.2614 0 529.8829 566.4325 200 250 300 350 400 450 500 550 m/z

mp:214~216, HRMS m/z calcd for C 20 H 24 N 4 O 2 ([M+H] + ) 354.1899, found 354.1905. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.92 (s, 2H), 8.42 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.04 (s, 1H), 2.17 (s, 1H), 1.31 (s, 9H), 0.83 (d, J = 7.9 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.20, 156.61, 155.53, 154.69, 141.44, 128.50, 127.05, 126.47, 118.28, 49.94, 29.46, 14.76, 8.43. N-(5-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(C DAU-10) O H N O H N N N H N 6.0 369.2000 5.0 4.0 3.0 2.0 1.0 213.0760 324.1424 391.1830 242.1448 274.2728301.1802 340.2797 437.2132 481.2612 525.2883 575.2796 200 250 300 350 400 450 500 550 m/z

mp:214~216, HRMS m/z calcd for C 20 H 25 N 5 O 2 ([M+2H] + ) 369.2008, found 369.2000. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.93 (s, 2H), 8.87 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 6.18 (s, 1H), 3.19 (d, J = 5.6 Hz, 2H), 2.32 (m, J = 11.0, 4.8 Hz, 2H), 2.17 (s, 7H), 0.90 0.76 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.21, 156.61, 155.56, 155.47, 141.43, 128.49, 127.07, 126.57, 118.35, 58.93, 45.51, 37.41, 14.77, 8.45.

N-(4-(6-(cycloropanecarboxamido)pyridin-3-yl)phenyl)-2,2-dimethylhydrazinecarboxamide( CDAU-11) 1.00 348.1409 326.1584 0.75 0.50 413.2645 0.25 213.0755 274.2725 393.2089 437.2094 340.2781 369.2004 481.2595 222.1825 281.1017 306.2690 454.2008 0 20 225.0 25 275.0 30 325.0 35 375.0 40 425.0 45 475.0 m/z

mp:230~232, HRMS m/z calcd for C 18 H 20 N 4 O 2 ([M+2H] + ) 326.1586, found 326.1584. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.94 (s, 2H), 8.45 (s, 1H), 7.64 (q, J = 8.9 Hz, 4H), 2.95 (s, 6H), 2.21 2.11 (m, 1H), 0.89 0.77 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.18, 156.64, 156.02, 155.62, 141.56, 128.46, 127.16, 126.62, 120.35, 36.72, 14.77, 8.45. N-(6-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarb oxamide(cdau-12) 3.5 3.0 475.0081 2.5 2.0 1.5 1.0 396.5914 0.5 278.8712 34291 453.2009 134.0157 211.9055 318.0698 53334 588.4068 701.4900 814.5573 100 200 300 400 500 600 700 800 900 m/z

mp:207~209, HRMS m/z calcd for C 23 H 18 ClF 3 N 4 O 2 ([M+H] + ) 475.1070, found 475.0081. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 9.23 (s, 1H), 9.05 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 3.2 Hz, 2H), 7.61 (d, J = 5.4 Hz, 2H), 7.59 (d, J = 4.1 Hz, 1H), 2.09 (m, J = 7.4, 5.1 Hz, 1H), 0.83 (m, J = 9.0, 3.2 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 176.02, 173.17, 154.82, 152.76, 152.19, 140.69,

139.73, 139.49, 132.62, 132.49, 132.00, 129.17, 127.63, 123.63, 118.81, 117.27, 115.19, 112.04, 25.42, 14.68, 8.10. N-(6-(4-(3-(4-chloro-3-methylphenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide( CDAU-13) 2.5 2.0 420.9485 1.5 1.0 422.9488 0.5 274.0538 34295 701.4914 134.0160 211.9048 509.8283 588.4085 814.5759 100 200 300 400 500 600 700 800 900 m/z

mp:272~274, HRMS m/z calcd for C 23 H 21 ClN 4 O 2 ([M+H] + ) 420.9353, found 420.9485. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 1.2 Hz, 2H), 7.58 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.21 (m, J = 8.3, 2.0 Hz, 1H), 2.27 (s, 3H), 2.15 2.04 (m, 1H), 0.83 (m, J = 14.6, 6.4 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.87, 152.78, 152.18, 141.01, 139.46, 139.23, 133.61, 132.30, 131.65, 128.85, 127.62, 118.68, 118.53, 117.51, 115.12, 111.96, 19.29, 14.68, 8.10. N-(6-(4-(3-(4-fluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-14) 3.0 2.5 390.9435 2.0 1.5 1.0 34298 453.1999 0.5 274.0534 509.8288 588.4079 701.4903 134.0164 211.9057 814.5691 100 200 300 400 500 600 700 800 900 m/z

mp:278~280, HRMS m/z calcd for C 22 H 19 FN 4 O 2 ([M] + ) 390.1492, found 390.9435. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.87 (s, 1H), 8.77 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.59 (d, J = 2.7 Hz, 2H), 7.57 (d, J = 1.5 Hz, 1H), 7.52 7.47 (m, 2H), 7.18 7.11 (m, 2H), 2.10 (m, J = 7.5, 5.0 Hz, 1H), 0.87 0.80 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.15, 159.09, 156.71, 154.91, 152.97, 152.17, 141.18, 139.45, 136.38, 132.17, 127.62, 120.59, 120.51, 118.44, 115.88, 115.66, 115.10, 111.94, 14.69, 8.10.

N-(6-(4-(3-(4-(tert-butyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDA U-15) 4.0 429.0407 3.0 2.0 1.0 396.5917 34293 274.0537 134.0157 211.9065 509.8288 588.4078 701.4920 814.5709 100 200 300 400 500 600 700 800 900 m/z

mp:209~211, HRMS m/z calcd for C 26 H 28 N 4 O 2 ([M] + ) 428.2212, found 429.0407. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.59 (d, J = 7.0 Hz, 2H), 7.57 (d, J = 5.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 2.19 2.04 (m, 1H), 1.27 (s, 9H), 0.90 0.77 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.95, 152.91, 152.18, 144.76, 141.31, 139.44, 137.39, 132.04, 127.63, 125.87, 118.61, 118.31, 115.09, 111.91, 34.36, 31.72, 14.69, 8.10. N-(6-(4-(3-(2-chlorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-16 ) 3.0 2.5 406.9230 2.0 1.5 1.0 0.5 34296 453.2000 321.9252 134.0159 211.9078 472.2066 528.8224 588.4066 701.4921 837.2314 100 200 300 400 500 600 700 800 900 m/z

mp:276~278, HRMS m/z calcd for C 22 H 19 ClN 4 O 2 ([M] + ) 406.8700, found 406.9230. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 9.61 (s, 1H), 8.38 (s, 1H), 8.19 (m, J = 8.3, 1.4 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.59 (d, J = 5.0 Hz, 1H), 7.48 (m, J = 8.0, 1.4 Hz, 1H), 7.35 7.29 (m, 1H), 7.05 (td, J = 7.9, 1.5 Hz, 1H), 2.10 (dq, J = 7.6, 5.0 Hz, 1H), 0.87 0.81 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ

173.16, 154.84, 152.50, 152.19, 140.91, 139.49, 136.32, 132.46, 129.71, 128.07, 127.73, 123.92, 122.52, 121.87, 118.43, 115.14, 112.00, 14.69, 8.10. N-(6-(4-(3-(3-isopropylphenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU- 17) 7.0 6.0 415.0137 5.0 4.0 3.0 2.0 1.0 34290 453.1986 134.0177 211.9062 279.8839 509.8286 588.4079 701.4910 814.5842 100 200 300 400 500 600 700 800 900 m/z

mp:207~209, HRMS m/z calcd for C 25 H 26 N 4 O 2 ([M+H] + ) 415.2056, found 415.0137. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 6.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 2.93 2.78 (m, 1H), 2.15 2.04 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H), 0.84 (m, J = 8.5, 6.5 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.93, 152.88, 152.19, 149.54, 141.25, 140, 139.44, 132.11, 129.17, 127.63, 120.53, 118.37, 116.71, 116.37, 115.09, 111.93, 33.98, 24.34, 14.69, 8.10. N-(6-(4-(3-(3-chlorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-18 ) 5.0 406.9224 4.0 3.0 2.0 1.0 34290 134.0161 211.9060 274.0538 453.1996 525.2480 588.4063 701.4918 100 200 300 400 500 600 700 800 900 m/z

mp:216~218, HRMS m/z calcd for C 22 H 19 ClN 4 O 2 ([M] + ) 406.8700, found 406.9224. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.96 (s, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 5.0 Hz, 2H), 7.58 (d, J = 3.5 Hz, 1H), 7.35 7.30 (m, 1H), 7.30 7.27 (m, 1H), 7.04 (m, J = 7.3, 1.8 Hz, 1H), 2.15 2.06 (m, 1H), 0.88 0.80 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.85, 152.73, 152.19, 141.62,

140.90, 139.47, 133.70, 132.42, 130.88, 127.64, 122.05, 118.60, 118.12, 117.19, 115.14, 111.99, 14.69, 8.10. N-(6-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamid e(cdau-19) 6.0 5.0 457.0111 4.0 3.0 2.0 1.0 396.5911 34289 134.0165 211.9060 274.0534 479.0296 588.4067 701.4913 100 200 300 400 500 600 700 800 900 m/z

mp:276~278, HRMS m/z calcd for C 23 H 19 F 3 N 4 O 3 ([M] + ) 456.1409, found 457.0111. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.96 (s, 1H), 8.93 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 1.8 Hz, 2H), 7.59 (d, J = 4.7 Hz, 2H), 7.58 (d, J = 3.9 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 2.14 2.05 (m, 1H), 0.89 0.78 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.88, 152.83, 152.19, 143.16, 141.00, 139.45, 139.36, 132.34, 127.64, 122.20, 119.96, 118.54, 115.13, 111.97, 14.68, 8.09. N-(6-(4-(3-(2,4-dichlorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU -20) 2.5 440.9221 2.0 1.5 1.0 396.5912 0.5 34291 274.0538 701.4910 134.0153 211.9050 475.2216 588.4077 814.5691 100 200 300 400 500 600 700 800 900 m/z

mp:222~224, HRMS m/z calcd for C 22 H 18 Cl 2 N 4 O 2 ([M] + ) 44807, found 440.9221. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 9.64 (s, 1H), 8.46 (s, 1H), 8.23 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.61 (s, 2H), 7.59 (s, 1H), 7.47 7.37 (m, 1H), 2.09 (s, 1H), 0.83 (d, J = 7.7 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.80, 152.36, 152.19, 140.71, 139.50, 135.58, 132.61, 129.06, 128.13, 127.74, 126.72, 123.20, 122.66, 118.50, 115.15, 112.02, 14.69, 8.10.

N-(6-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide( CDAU-21) 4.0 440.9862 3.0 2.0 1.0 396.5913 34290 274.0534 134.0158 211.9055 472.2046525.2531 588.4066 701.4884 898.1825 100 200 300 400 500 600 700 800 900 m/z

mp:275~277, HRMS m/z calcd for C 23 H 19 F 3 N 4 O 2 ([M] + ) 440.1460, found 440.9862. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 9.12 (s, 1H), 9.00 (s, 1H), 8.07 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 2.15 2.06 (m, 1H), 0.83 (m, J = 16.0, 4.7 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.17, 154.85, 152.86, 152.20, 140.95, 140.84, 139.46, 132.49, 130.39, 129.88, 127.63, 126.04, 123.33, 122.38, 118.69, 115.15, 114.65, 112.01, 14.68, 8.09. N-(6-(4-(3-(2,4-difluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU -22) 3.0 408.9433 2.5 2.0 1.5 1.0 0.5 34285 453.1996 274.0528 134.0152 211.9048 509.8285 588.4085 701.4918 814.5842 100 200 300 400 500 600 700 800 900 m/z

mp:273~275, HRMS m/z calcd for C 22 H 18 F 2 N 4 O 2 ([M] + ) 408.1398, found 408.9433. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.96 (s, 1H), 8.94 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.70 (md, J = 13.4, 7.4, 2.6 Hz, 1H), 7.60 (d, J = 2.1 Hz, 2H), 7.58 (s, 1H), 7.36 (m, J = 19.7, 9.2 Hz, 1H), 7.18 7.12 (m, 1H), 2.10 (m, J = 7.5, 5.0 Hz, 1H), 0.89 0.76 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.86, 152.81, 152.18,

140.89, 139.47, 132.41, 132.00, 127.63, 118.62, 117.96, 117.77, 115.14, 114.95, 111.99, 107.85, 107.63, 14.68, 8.09. N-(6-(4-(3-(2-fluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-23) 2.5 390.9432 2.0 1.5 1.0 0.5 34285 453.1994 274.0526 134.0144 211.9048 509.8291 588.4085 701.4905 814.5810 100 200 300 400 500 600 700 800 900 m/z

mp:239~241, HRMS m/z calcd for C 22 H 19 FN 4 O 2 ([M+H] + ) 390.1492, found 390.9432. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 9.27 (s, 1H), 8.63 (s, 1H), 8.18 (t, J = 7.9 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 3.8 Hz, 2H), 7.59 (s, 1H), 7.31 7.21 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 5.5 Hz, 1H), 2.10 (s, 1H), 0.83 (d, J = 8.0 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.16, 154.86, 153.73, 152.54, 152.19, 140.90, 139.48, 132.41, 127.72, 125.03, 123.11, 121.09, 118.35, 115.56, 115.37, 115.14, 111.99, 14.69, 8.10. N-(6-(4-(3-(3-fluorophenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDAU-24) 7.0 6.0 390.9424 5.0 4.0 3.0 2.0 1.0 34282 453.1987 134.0153 211.9057 279.8847 525.2501 588.4085 701.4906 100 200 300 400 500 600 700 800 900 m/z

mp:275~277, HRMS m/z calcd for C 22 H 19 FN 4 O 2 ([M+H] + ) 390.1492, found 390.9424. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.99 (s, 1H), 8.95 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.54 (m, J = 8.0, 6.0 Hz, 1H), 7.32 (m, J = 15.2, 8.1 Hz, 1H), 7.18 7.13 (m, 1H), 6.80 (t, J = 8.4, 2.2 Hz, 1H), 2.18 2.05 (m, 1H), 0.90 0.78 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.17,

164.10, 161.70, 154.88, 152.74, 152.20, 142.00, 141.89, 140.92, 139.44, 132.42, 130.83, 130.74, 127.65, 118.59, 115.13, 114.48, 112.00, 108.84, 108.62, 105.56, 105.30, 14.70, 8.10. N-(6-(4-(3-(2,6-dimethylphenyl)ureido)phenyl)pyridin-2-yl)cyclopropanecarboxamide(CDA U-25) 1.75 1.50 400.9888 1.25 1.00 0.75 0.50 34288 453.1989 0.25 472.2056 274.0526 588.4086 701.4914 999.5688 211.9047 525.2490 0 613.3367 792.5848 100 200 300 400 500 600 700 800 900 m/z

mp:202~204, HRMS m/z calcd for C 24 H 24 N 4 O 2 ([M] + ) 400.1899, found 400.9888. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 8.96 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 6.3 Hz, 1H), 7.12 7.06 (m,2h), 2.23 (s,6h), 2.14 2.05 (m, 1H), 0.83 (m, J = 14.8, 6.2 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 173.14, 154.98, 153.47, 152.15, 141.83, 139.42, 136.03, 135.67, 131.70, 129.28, 128.20, 127.56, 126.50, 118.75, 118.12, 115.02, 111.84, 18.74, 14.68, 8.09.

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