癌症是全球疾病和死亡的主要原因之一，儘管目前已有多種治療方式和藥物，臨床上仍面臨許多挑戰；因此研發與目前藥物具不同作用機轉的抗癌新藥實有其必要性，而與多種惡性腫瘤的發生發展具密切關係的致癌性蛋白酪胺酸磷酸酶SHP2即成為我們的目標。在本研究中，我們依序透過小分子資料庫篩選、循理性藥物設計以及核心結構虛擬篩選進行SHP2抑制劑的研發工作，共設計合成嘧啶、吡嗪和咪唑並[1,2-b]噠嗪等三個系列化合物，並探討它們對SHP2的抑制能力。活性評估結果顯示，具2-苯基-咪唑並[1,2-b]噠嗪骨架的化合物38和79有較佳的抑制效果。

Cancer has been a major health burden and is one of the leading causes of death worldwide. Given the growing number of anticancer drugs on the market, there are still clinical challenges that need to be addressed. Therefore, development of novel molecules with new modes of action for cancer treatment is required, and the protein tyrosine phosphatase SHP2, closely related to the occurrence and development of various malignant tumors, is one such promising strategy. In this study, we sequentially performed the discovery of SHP2 inhibitors through the screening of a small compound library, rational drug design, and the virtual screening of core structures. Based on the results obtained, three series of compounds including pyrimidine, pyrazine, and imidazo[1,2-b]pyridazine were designed and synthesized, and their inhibition against SHP2 was evaluated. The results of activity evaluation indicated that compounds 38 and 79, bearing the 2-phenyl-imidazo[1,2-b]pyridazine scaffold, exhibited better inhibitory effects.

摘要 I
Abstract II
謝誌 III
目錄 IV
圖目錄 XVI
表目錄 XIX
流程目錄 XX
縮寫對照表 XXI
第一章、緒論 1
1.1 癌症的威脅與治療困境 1
1.1.1 手術治療(Surgery) 1
1.1.2 化學治療(Chemotherapy) 2
1.1.3 放射治療(Radiotherapy) 2
1.1.4 標靶治療(Targeted Therapy) 3
1.1.5 免疫療法(Immunotherapy) 4
1.2 具Src同源區2結構域的蛋白酪胺酸磷酸酶2 (Src Homology
Region 2 Domain-Containing Phosphatase-2)之生理功能 6
1.2.1 SHP2訊號調控路徑 8
1.2.2 細胞核內的SHP2 11
1.2.3 SHP2的泛素化作用 12
1.3 SHP2的結構及活性調節 12
1.4 SHP2抑制劑的發展 14
第二章、結果與討論 22
2.1 SHP2的抑制活性實驗 22
2.2 嘧啶系列SHP2抑制劑 23
2.2.1 嘧啶-哌啶化合物2的合成 25
2.2.2 嘧啶-三唑化合物3–6的合成 26
2.2.3 嘧啶系列化合物2–6對SHP2的抑制能力 27
2.3 吡嗪系列SHP2抑制劑 29
2.3.1 吡嗪系列化合物27–31的合成 30
2.3.2 吡嗪系列化合物27–31對SHP2的抑制能力 33
2.4 咪唑並[1,2-b]噠嗪系列SHP2抑制劑 34
2.4.1 2-苯基-咪唑並[1,2-b]噠嗪系列化合物的合成 37
2.4.2 2-苯基-咪唑並[1,2-b]噠嗪系列化合物對SHP2的抑制能力 47
2.4.3 2-苯硫基-咪唑並[1,2-b]噠嗪系列化合物的合成 49
2.4.4 2-苯硫基-咪唑並[1,2-b]噠嗪系列化合物對SHP2的抑制能
力 55
2.4.5 2-苯基-咪唑並[1,2-b]噠嗪化合物38的衍生物 56
2.4.6 2-苯基-咪唑並[1,2-b]噠嗪化合物73、75和79-81對SHP2
的抑制能力 57
第三章、總結 59
第四章、實驗部分 61
4.1 一般實驗方法 61
4.2 SHP2的抑制活性實驗 63
4.3 化合物之實驗步驟與光譜資料 64
4.3.1 化合物2合成 64
4.3.2 化合物3合成 65
4.3.3 化合物4合成 66
4.3.4 化合物5合成 67
4.3.5 化合物6合成 68
4.3.6 化合物8合成 69
4.3.7 化合物9合成 70
4.3.8 化合物10合成 71
4.3.9 化合物11合成 71
4.3.10 化合物12合成 72
4.3.11 化合物13合成 73
4.3.12 化合物14合成 74
4.3.13 化合物15合成 74
4.3.14 化合物17合成 75
4.3.15 化合物18合成 76
4.3.16 化合物19合成 77
4.3.17 化合物20合成 77
4.3.18 化合物21合成 78
4.3.19 化合物22合成 79
4.3.20 化合物23合成 80
4.3.21 化合物24合成 80
4.3.22 化合物25合成 81
4.3.23 化合物26合成 82
4.3.24 化合物27合成 83
4.3.25 化合物28合成 83
4.3.26 化合物29合成 84
4.3.27 化合物30合成 85
4.3.28 化合物31合成 86
4.3.29 化合物32合成 87
4.3.30 化合物33合成 88
4.3.31 化合物36a合成 89
4.3.32 化合物36b合成 90
4.3.33 化合物36c合成 91
4.3.34 化合物36d合成 91
4.3.35 化合物36e合成 92
4.3.36 化合物36f合成 93
4.3.37 化合物36g合成 94
4.3.38 化合物37a合成 94
4.3.39 化合物37b合成 95
4.3.40 化合物37c合成 96
4.3.41 化合物37d合成 97
4.3.42 化合物37e合成 98
4.3.43 化合物37f合成 98
4.3.44 化合物37g合成 99
4.3.45 化合物37h合成 100
4.3.46 化合物37i合成 101
4.3.47 化合物37j合成 102
4.3.48 化合物37k合成 102
4.3.49 化合物37l合成 103
4.3.50 化合物38合成 104
4.3.51 化合物39合成 105
4.3.52 化合物40合成 106
4.3.53 化合物41合成 107
4.3.54 化合物42合成 108
4.3.55 化合物43合成 109
4.3.56 化合物44合成 110
4.3.57 化合物45合成 111
4.3.58 化合物46合成 112
4.3.59 化合物47合成 113
4.3.60 化合物48合成 114
4.3.61 化合物49合成 115
4.3.62 化合物50合成 116
4.3.63 化合物52合成 117
4.3.64 化合物53合成 117
4.3.65 化合物54合成 118
4.3.66 化合物55合成 119
4.3.67 化合物56合成 120
4.3.68 化合物57合成 121
4.3.69 化合物59合成 122
4.3.70 化合物60合成 122
4.3.71 化合物61a合成 123
4.3.72 化合物61b合成 124
4.3.73 化合物61c合成 125
4.3.74 化合物61d合成 126
4.3.75 化合物62a合成 126
4.3.76 化合物62b合成 127
4.3.77 化合物62c合成 128
4.3.78 化合物63a合成 129
4.3.79 化合物63b合成 129
4.3.80 化合物63c合成 130
4.3.81 化合物64合成 131
4.3.82 化合物65合成 132
4.3.83 化合物66合成 133
4.3.84 化合物67合成 134
4.3.85 化合物68合成 134
4.3.86 化合物69合成 135
4.3.87 化合物70合成 135
4.3.88 化合物71合成 136
4.3.89 化合物72合成 137
4.3.90 化合物73合成 139
4.3.91 化合物74合成 140
4.3.92 化合物75合成 141
4.3.93 化合物76合成 142
4.3.94 化合物77合成 143
4.3.95 化合物78合成 143
4.3.96 化合物79合成 144
4.3.97 化合物80合成 146
4.3.98 化合物81合成 147
4.3.99 化合物82合成 148
第五章、參考資料 149
附錄一、核磁共振光譜資料 160
1H NMR Spectrum of 2 162
1H NMR Spectrum of 3 168
1H NMR Spectrum of 4 173
1H NMR Spectrum of 5 175
1H NMR Spectrum of 6 177
1H NMR Spectrum of 8 179
1H NMR Spectrum of 9 180
1H NMR Spectrum of 10 181
1H NMR Spectrum of 13 182
1H NMR Spectrum of 14 183
1H NMR Spectrum of 15 184
1H NMR Spectrum of 18 185
1H NMR Spectrum of 20 186
1H NMR Spectrum of 22 187
1H NMR Spectrum of 23 188
1H NMR Spectrum of 24 189
1H NMR Spectrum of 25 190
1H NMR Spectrum of 26 191
1H NMR Spectrum of 27 193
1H NMR Spectrum of 28 198
1H NMR Spectrum of 29 200
1H NMR Spectrum of 30 202
1H NMR Spectrum of 31 204
1H NMR Spectrum of 32 206
1H NMR Spectrum of 33 208
1H NMR Spectrum of 36a 210
1H NMR Spectrum of 36b 211
1H NMR Spectrum of 36c 212
1H NMR Spectrum of 36d 213
1H NMR Spectrum of 36e 214
1H NMR Spectrum of 36f 215
1H NMR Spectrum of 36g 216
1H NMR Spectrum of 37a 217
1H NMR Spectrum of 37b 218
1H NMR Spectrum of 37c 219
1H NMR Spectrum of 37d 220
1H NMR Spectrum of 37e 221
1H NMR Spectrum of 37f 222
1H NMR Spectrum of 37g 223
1H NMR Spectrum of 37h 223
1H NMR Spectrum of 37i 224
1H NMR Spectrum of 37j 225
1H NMR Spectrum of 37k 226
1H NMR Spectrum of 37l 227
1H NMR Spectrum of 38 230
1H NMR Spectrum of 39 235
1H NMR Spectrum of 40 237
1H NMR Spectrum of 41 239
1H NMR Spectrum of 42 241
1H NMR Spectrum of 43 244
1H NMR Spectrum of 44 246
1H NMR Spectrum of 45 248
1H NMR Spectrum of 46 250
1H NMR Spectrum of 47 252
1H NMR Spectrum of 48 254
1H NMR Spectrum of 49 256
1H NMR Spectrum of 50 258
1H NMR Spectrum of 54 259
1H NMR Spectrum of 55 260
1H NMR Spectrum of 56 261
1H NMR Spectrum of 57 262
1H NMR Spectrum of 59 263
1H NMR Spectrum of 60 264
1H NMR Spectrum of 61a 265
1H NMR Spectrum of 61b 266
1H NMR Spectrum of 61c 267
1H NMR Spectrum of 61d 268
1H NMR Spectrum of 62a 269
1H NMR Spectrum of 62b 270
1H NMR Spectrum of 62c 271
1H NMR Spectrum of 63a 272
1H NMR Spectrum of 63b 273
1H NMR Spectrum of 63c 274
1H NMR Spectrum of 64 275
1H NMR Spectrum of 65 277
1H NMR Spectrum of 66 279
1H NMR Spectrum of 67 281
1H NMR Spectrum of 70 282
1H NMR Spectrum of 71 283
1H NMR Spectrum of 72 284
1H NMR Spectrum of 73 286
1H NMR Spectrum of 74 288
1H NMR Spectrum of 75 289
1H NMR Spectrum of 76 291
1H NMR Spectrum of 77 292
1H NMR Spectrum of 78 293
1H NMR Spectrum of 79 294
1H NMR Spectrum of 80 296
1H NMR Spectrum of 81 298
1H NMR Spectrum of 82 300
1H NMR Spectrum of a1 301
1H NMR Spectrum of a2 303
1H NMR Spectrum of a3 304
1H NMR Spectrum of a4 306

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