1 (d, J = 13. 6Hz, 1H), 7. 47 (dd, J = 18. 0, 7. 6Hz, 3H), 7. 25 (m, 1H), 4. 97 (m, 1H), 4. 37 (s, 2H), 4. 19 (t, J = 9. 2Hz, 1H), 3. 77 (t, J = 6. 0Hz, 1H), 2. 43 (s, 3H). 13C-NMR (DMS〇-d6): δ 154. 50, 153. 54, 152. 05, 150. 76, 149. 45, 145. 28, 139. 25, 138. 33, 136. 96, 131. 89, 130 .20, 129. 51, 127. 63, 125. 17, 124. 71, 123. 06, 121. 71, 119. 91, 114. 09, 106. 31, 106. 06, 9 9.49,70. 10, 45. 82, 21.07. MS m/z :509. 1 (M+). HR-MS m/z :509. 1303 (M+), 531. 1108(M+Na) (calcd for C25H21FN405S: 508. 1217).
[0078]實施例4.⑶-N- {[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-4-乙基哌嗪（14)
[0079]
[0080] 量取0· 075mLl-乙基哌嗪溶于lOmL乙腈中，室溫攪拌下加入57. 19mg DIPEA，然后 升溫至70°C，穩(wěn)定后加入150mgl0,繼續(xù)升溫至80°C攪拌反應6小時，停止反應。反應液加 水，反應液加水，飽和NaHC03調pH至中性，DCM萃取，萃取液Na2S04干燥，并減壓蒸餾，最后 80/1的DCM/甲醇柱層析得到淡黃色固體70. 39mg。
[0081]熔點：159. 9-161. 9°C ·
[0082] 4匪R(400MHz，DMS0) δ 8. 73(s，1H)，8. 57(d，J = 4· 0Hz，1H)，8. 36(s，1H)， 7. 83(m, 4H), 7. 31 (d, J = 9. 2Hz, 1H), 7. 25 (d, J = 4Hz, 1H), 4. 88 (m, 1H), 4. 20 (t, J = 9. 2Hz, 1H), 3. 77 (t, J = 6. 0Hz, 1H), 2. 68 (m, 2H), 2. 41 (m, 8H), 0. 99 (t, J = 6. 8Hz, 3H). 1 3C-匪R(DMS0-d6) : δ 159. 36, 156. 03, 154. 60, 150. 92, 144. 70, 142. 88, 142. 18, 133. 27, 1 30. 74, 130. 35, 129. 95, 126. 94, 125. 14, 119. 36, 111. 40, 76. 53, 65. 59, 58. 27, 57. 40, 56. 73, 53. 50, 34. 21, 25. 99, 16. 92. MS m/z : 451. 2 (M+). HR-MS m/z: 451. 2254 (M+) (calcd for C24H27FN602:450. 2180).
[0083]實施例5.⑶-N- {[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-4-甲基哌嗪（13)
[0084]
[0085]目標化合物13的合成操作步驟與4的操作步驟相同，得到白色固體，收率為54%。
[0086]熔點：158. 2-162. (TC ·
[0087] NMR (400MHz, CDC13) 58.61(d,J = 4. 4Hz, 1H) , 8. 5 1 (d, J = 2. 0Hz, 1H), 8. 22 (s, 1H), 7. 93 (t, J = 8. 8Hz, 1H), 7. 79 (dd, J = 14. 0, 2. 0Hz, 1H), 7. 70 (t, J =7. 6Hz, 1H), 7. 55 (d, J = 8. 0Hz, 1H), 7. 30 (d, J = 8. 8Hz, 1H), 7. 15 (dd, J = 6. 4, 5. 2Hz, 1H ),4. 80 (m, 1H), 4. 10 (t, J = 8. 8Hz, 1H), 3. 92 (t, J = 8. 0Hz, 1H), 2. 88 (m, 2H), 2. 64 (m, 4H), 1 .80 (m, 4H), L 60 (s, 3H). 13C-NMR (DMS〇-d6) : δ 159. 35, 156. 02, 154. 69, 150. 82, 144. 45, 14 2. 92, 142. 21, 133. 28, 130. 74, 130. 39, 129. 87, 126. 96, 125. 16, 119. 37, 111. 53, 76. 52, 65. 35, 59. 42, 57. 66, 53. 45, 50. 10, 34. 21, 25. 99. MS m/z: 437. 2 (M+). HR-MS m/z: 437. 2097 (M+) (calcd for C23H25FN602:436. 2023).
[0088]實施例6.⑶-N- {[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-2-羥乙基甲胺（11)
[0089]
[0090]目標化合物11的合成操作步驟與4的操作步驟相同，得到白色固體，收率為56%。
[0091]熔點：mpl22. 9-125. 3°C ·
[0092] NMR (400MHz, CDC13) 58.61(d,J = 4. 8Hz, 1H) , 8. 5 1 (d, J = 2. 0Hz, 1H), 8. 22 (s, 1H), 7. 94 (t, J = 8. 8Hz, 1H), 7. 78 (dd, J = 14. 0, 2. 0Hz, 1H), 7. 70 (t, J =8. 0Hz, 1H), 7. 54 (d, J = 8. 0Hz, 1H), 7. 29 (s, 1H), 7. 15 (dd, J = 7. 2, 5. 6Hz ,1H), 4. 82 (m, 1H), 4. 13 (t, J = 8. 8Hz, 1H), 3. 82 (t, J = 8. 0Hz, 1H), 3. 66 (t, J =5. 2Hz, 2H) , 2. 8 7 (m, 3H) , 2. 70 (m, 2H) , 2. 44 (s, 3H) . 13C-NMR (DMS〇-d6): δ 154. 14, 152. 08, 150. 78, 149. 45, 139. 20, 138. 76, 136. 93, 129. 52, 129. 45, 125. 10 ,124. 69, 121. 69, 119, 89, 114. 07, 106, 13, 71. 61, 60. 00, 58. 89, 48. 16, 43. 28. MS m/ z:412. l(M+),434. 1 (M+Na). HR-MS m/z:412. 1785 (M+) (calcd for C24H27FN602:450. 2180).
[0093] 實施例7.⑶-N- {[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 燒-5-基]甲基-2-丙氰基甲胺（12)
[0094]
[0095]目標化合物12的合成操作步驟與4的操作步驟相同，得到淡黃色固體，收率為51%。
[0096]熔點：mpl28. 3-132. (TC ·
[0097] NMR(400MHz, CDC13) δ 8. 61 (d, J = 4. 0Hz, 1H), 8. 51(s,lH),8.22(s,lH),7.94(t,J = 8. 8Hz, 1H) , 7. 79 (dd, J = 13. 6, 0. 4Hz, 1H), 7. 70 (t, J = 8. 0Hz, 1H) , 7. 55 (d, J = 8. 0Hz, 1H), 7. 3 1 (d, J =9. 6Hz, 1H), 7. 15 (m, 1H), 4. 79 (m, 1H), 4. 14 (t, J = 8. 8Hz, 1H), 3. 96 (t, J = 7. 2Hz, 1H), 2. 88 (m, 4H), 2. 52 (t, J = 6. 4Hz, 2H), 2. 45 (s, 3H). 13C-NMR (DMS〇-d6) :δ 154. 09, 152. 08, 150. 78, 149. 46, 139. 21, 138. 76, 136. 93, 129. 50, 125. 13, 124. 70 ,122. 85, 121. 69, 119. 93, 114. 10, 106. 29, 106. 03, 71. 47, 58. 85, 52. 84, 48. 07, 42. 10 ,15. 34. MS m/z : 443. 1 (M+Na). HR-MS m/z : 420. 1785 (M+), 443. 1607 (M+Na) (calcd for C22H21FN602:420. 1710).
[0098] 實施例8.⑶-N- {[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-4-羥乙基哌嗪（15)
[0099]
[0100]目標化合物15的合成操作步驟與4的操作步驟相同，得到淡黃色固體，收率為 59%〇
[0101]熔點：mpl68. 1-169. 9°C ·
[0102] NMR(400MHz, DMS0) δ 8. 73(s, 1H), 8. 57(d, J = 4. 4Hz, 1H) , 8. 36(s,1H) , 7. 86(t,J= 8. 8Hz, 1H) , 7. 80 (m, 3H) , 7. 53 (d,J=9. 2Hz, 1H) , 7. 25 (dd,J= 8. 0, 4. 0 Hz , 1H) , 4. 8 8 (m, 1H) , 4. 3 9 (t,J= 4. 4Hz, 1H) , 4. 20(t,J= 8. 8Hz, 1H) , 3. 8 2 (t,J= 7. 6Hz , 1H) , 3. 49 (dd,J =11. 2, 5. 6Hz, 2H), 2. 68(m, 2H), 2. 42(m, 10H). 13C-NMR(DMS〇-d6): δ 154. 12, 152. 08, 150. 77, 149, 45, 139. 20, 136. 95, 129. 49, 125. 11, 124. 69, 121. 70, 11 9. 90, 114. 12, 106. 28, 106. 02, 71. 27, 60. 42, 60. 09, 58. 28, 53. 25, 53. 06, 48. 27. MS m/ z: 467. 2 (M+), 489. 2 (M+Na). HR-MS m/z :467. 2203 (M+) (calcd for C24H27FN603:466. 2127).
[0103] 實施例9.⑶-N-{[3- (3-氟-4- (4- (2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基哌啶（16)
[0104]
[0105]目標化合物16的合成操作步驟與4的操作步驟相同，得到淡黃色固體，收率為 81%〇
[0106]熔點：mpl53. 8-157. 5°C·
[0107] NMR (400MHz, CDC13) 58.61(d,J = 4. 4Hz, 1H) , 8. 5 1 (d, J = 1. 2Hz, 1H), 8. 22 (s, 1H), 7. 94 (t, J = 8. 8Hz, 1H), 7. 78 (dd, J = 13. 6, 1. 2Hz, 1H), 7. 70 (t, J =7. 6Hz, 1H), 7. 55 (d, J = 8. 0Hz, 1H), 7. 29 (d, J = 9. 6Hz, 1H), 7. 15 (dd, J = 6. 0, 5. 2Hz ,1H), 4. 92(m, 1H), 4. 14(t, J = 8. 4Hz, 1H), 3. 84 (t, J = 11. 6Hz, 1H), 2. 79 (m, 2H), 2. 62 ( m, 4H)，1. 65 (m, 4H)，1. 48 (m, 2H) · 13C-NMR (DMS0-d6) : δ 154. 52, 152. 06, 150. 79, 149. 45， 139. 19, 138. 75, 136. 91, 129. 46, 125. 06, 124. 70, 121. 68, 119. 88, 114. 04, 106. 24, 105. 9 8, 71. 33, 61. 24, 54. 63, 48. 34, 28. 99, 25. 58, 23. 73, 13. 89. MS m/z : 422. 2 (M+). HR-MS m/ z :422. 1912 (M+) (calcd for C23H24FN502:421. 1914).
[0108] 實施例10.⑶-N-{[3-(3-氟-4-(4-(2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-4-乙酰甲酯基哌啶（17)
[0109]
[0110] 目標化合物17的合成操作步驟與4的操作步驟相同，得到淡黃色固體，收率為 72%。
[0111]熔點：mpl36. 9-138. 3°C.
[0112] NMR (400MHz, CDC13) 58.61(d,J = 4. 0Hz, 1H) , 8. 5 1 (d, J = 2. 0Hz, 1H), 8. 22(s, 1H), 7. 94(t, J = 8. 8Hz, 1H), 7. 77 (dd, J = 13. 6, 2. 0Hz, 1H), 7. 7 0(m, 1H), 7. 55(d, J = 8. 0Hz, 1H), 7. 29 (dd, J = 8. 8, 1. 2Hz, 1H), 7. 15 (dd, J = 7.2,5 .6Hz, 1H), 4. 86 (m, 1H), 4. 12 (t, J = 6. 0Hz, 1H), 3. 83 (t, J = 8. 4Hz, 1H), 3. 68 (s, 3H )，2. 95 (m, 3H)，2. 79 (m, 2H)，2. 26 (d, J = 6. 8Hz, 4H)，1. 77 (m, 4H) · 13C-匪R(DMS0-d6): δ 172. 36, 154. 14, 150. 78, 149. 46, 139. 20, 138. 70, 136. 93, 129. 45, 125. 10, 124. 70, 122 .91, 121. 69, 119. 89, 114. 10, 106. 27, 106. 01, 71. 34, 60. 72, 53. 78, 53. 55, 51. 12, 48. 34, 32. 27, 31. 46. MS m/z: 494. 2 (M+), 516. 2 (M+Na). HR-MS m/z :494. 2206 (M+), 516. 2028 (M+Na) (calcd for C26H28FN504:493. 2125).
[0113] 實施例11.⑶-N-{[3_(3-氟-4-(4-(2-吡啶基）吡唑基）苯基）-2-氧代噁唑 烷-5-基]甲基-4-羥基哌啶（18)
[0114]
[0115]目標化合物18的合成操作步驟與4的操作步驟相同，得到白色固體，收率為65%。
[0116]熔點：mp 196. 7-199. 1°C .
[0117] NMR(400MHz,CDCl3)58.61(d,J = 4.4Hz,lH),8.51(s,lH ),8. 22 (s, 1H) , 7. 94 (q, J = 8. 4Hz , 1H) , 7. 78 (dd, J = 1 4. 4, 1. 2Hz , 1H) ,7. 70 (m, 1H) , 7. 53 (d, J = 8 . 0 Hz , 1 H) , 7 . 3 0 (d, J = 5 . 2Hz , 1 H) , 7. 1 6 ( m, 1H) , 4. 82 (m, 1H) , 4. 12 (t, J = 8 . 0Hz , 1 H) , 3. 8 6 (t, J = 7.6Hz,lH), 3. 74 (s, 1H) , 2. 8 5 (m, 5H) , 2. 3 7 (m, 3H) , 1. 91 (m, 3H) . 13C-NMR (DMS〇-d6): δ 154. 14, 152. 08, 150. 79, 149. 45, 139. 20, 138. 75, 136. 93, 129. 49, 125. 10, 124. 69, 121. 6 9, 119. 89, 114. 06, 106. 25, 106. 00, 71. 45, 65. 97, 60. 43, 51. 74, 51. 55, 48. 33, 34