8. 9mmol)悬浮于500mL甲醇和150mL乙酸乙酯中，加入10% Pd/C (7g)，室温搅拌过夜。次日，TLC监测原料反应完全，垫硅藻土过滤，固体多次加二氯甲 烷/甲醇=1/1溶液洗涤，滤液合并浓缩至约l〇〇mL，析出固体，过滤得一黄色固体，加少量 的DCM洗涤，得黄色固体ZM-2,6. 5g，收率50% .
[0190] NMR(300MHz,CDC13) 58.24-8.20(m,2H),8.11(d,J = 7. 8Hz, 2H), 7. 98 (s, 1H), 7. 42 (d, J = 7. 8Hz, 2H), 7. 20 - 7. 15 (m, 1H), 4. 65 (s, 2H), 3. 94 (s, 3H), 3. 55-3. 50 (t, 2H), 2. 92 - 2. 97ppm(t, 2H).
[0191] 制备实施例3N-(3,4_二甲氧基苄基）-4-((2-(4-氟-3-(三氟甲基）苯 基）-3-氧_6, 7-二氢-2H-吡唑[4, 3-c]吡啶-5 (3H)-基）甲基）苯甲酰胺
[0192] (1)4-((2-(4-氟-3-(三氟甲基）苯基）-3_ 氧-6,7-二氢-2H-吡唑[4, 3-c]吡 啶-5(3H)_基）甲基）苯甲酸
[0194] 化合物 ZM-2(7. lg, 15. 8mmol)悬浮于 250mL 甲醇中，加入 Li0H(l. 33g, 31. 6mmol) 的水溶液120mL，室温搅拌过夜。次日，溶液澄清，TLC监测原料反应完全，减压除去大部分 的甲醇溶，加 IN HC1溶液调至PH = 1-2之间，析出固体，减压过滤收集固体，固体加水洗涤 3次，真空干燥后得白色固体6. 4g，收率90%.
[0195] (2) N- (3, 4-二甲氧基苄基）-4- ((2- (4-氟-3-(三氟甲基）苯基）-3-氧-6, 7-二 氢-2H-吡唑[4, 3-c]吡啶-5 (3H)-基）甲基）苯甲酰胺
[0196]
[0197] 化合物 433 (6. lg, 14mmol)和 3, 4-二甲氧基节胺（2. 8g, 16. 8mmol)溶解于 200mLDMF，依次加入HOBT(lOOmg)，三乙胺（5ml，35.6mmol)，室温搅拌10分钟后，加入 EDCI (6. 6g，35. 6mmol)，室温搅拌过夜。次日，TLC监测原料反应完全。反应液倒入600mL冰 水中，析出固体，收集固体，固体依次用5%柠檬酸溶液和水洗涤，干燥后得7. 5g。进一步纯 化，固体加二氯甲烷/石油醚=1/5的溶液100mL搅拌30分钟，收集固体，如此重复3次， 得白色固体6. 9g，收率84%，HPLC>99. 74%。
[0198] ZM-1
[0199] NMR (300MHz, CDC13) δ 8. 23 - 8. 21 (m, 2Η), 7. 98 (s, 1Η), 7. 84 (d, J = 8. 1Hz, 2H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 6. 92-6. 83 (m, 3H), 6. 33 (t, 1H), 4. 65 (s, 2H), 4. 60 (d, J = 5. 7Hz, 2H), 3. 88 (s, 6H), 3. 55-3. 50 (t, 2H), 2. 92 - 2. 87ppm(t, 2H)
[0200] 同样的方法，得到化合物：
[0201] ZM-6
[0202] NMR(300MHz, CDC13) δ 8. 26 - 8. 24 (m, 2H), 7. 95 (s, 1H), 7. 54 (d, J = 8. 1Hz, 2H), 7. 33 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 10 (m, 1H), 6. 93-6. 86 (m, 3H), 6. 75 (t, 1H), 4. 68 (s, 2H), 4. 63 (d, J = 5. 7Hz, 2H), 3. 88 (s, 6H), 3. 56-3. 510 (t, 2H), 2. 92 - 2. 87 (t, 2H), 2. 90ppm (s, 3H).
[0203] ZM-7
[0204] 4 MMR(300MHz，CDC13) δ 8. 14 - 8. 12(m, 1H), 8. (Π-7. 90(m, 4H), 7. 62(s, 1H), 7. 4 2-7. 40 (m，1H)，7. 33-7. 30 (m，1H)，7. 05-7. 02 (m，1H)，6. 75-6. 71 (m，2H)，6. 64-6. 61 (m，1H)， 4. 52 (s, 2H), 4. 44 (d, J = 5. 7Hz, 2H), 3. 73 (s, 3H), 3. 71 (s, 3H), 3. 43-3. 38 (t, 2H), 2. 63 - 2. 58ppm(t, 2H)
[0205] ZM-8
[0206] NMR (300MHz, CDC13) δ 8. 25 - 8. 21 (m, 2H), 7. 92 (s, 1H), 7. 84 (d, J = 8. 1Hz, 2H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 33-7. 30 (m, 5H), 7. 21 - 7. 14 (m, 1H), 6. 62 (t, 1H), 4. 65 (s, 2H), 4. 60 (d, J = 5. 7Hz, 2H), 3. 53-3. 48 (t, 2H), 2. 89 - 2. 84ppm(t, 2H)
[0207] ZM-9
[0208] NMR(300MHz, CDC13) δ 8. 27 - 8. 21 (m, 2H), 7. 92 (s, 1H), 7. 85 (d, J = 8. 1Hz, 2H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 30-7. 28 (m, 1H), 7. 20-7. 15 (t, 1H), 6. 95-6. 87 (m, 3H) ,6. 36 (t, 1H), 4. 65 (s, 2H), 4. 63 (d, J = 5. 7Hz, 2H), 3. 81 (s, 3H), 3. 54-3. 50 (t, 2H), 2. 92 - 2. 87ppm(t, 2H)
[0209] ZM-10
[0210] NMR(300MHz, CDC13) δ 8. 24 - 8. 21 (m, 2H), 7. 95 (s, 1H), 7. 82 (d, J = 8. 1Hz, 2H), 7. 33 (d, J = 8. 1Hz, 2H), 7. 18 - 7. 15 (m, 1H), 6. 13 (s, 1H), 4. 65 (s, 2H), 3. 56-3. 50 (m, 4H), 3. 02 (s, 3H), 2. 92 - 2. 86 (t, 2H), L 27-1. 24ppm (t, 3H)
[0211] ZM-11
[0212] NMR(300MHz, CDC13) δ 8. 22 - 8. 21 (m, 2H), 7. 97 (s, 1H), 7. 83 (d, J = 8. 1Hz, 2H), 7. 34 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 6. 46 (s, 2H), 6. 31 (t, 1H), 4. 64 (s, 2H), 4. 61 (d, J = 5. 7Hz, 2H), 3. 90 (s, 9H), 3. 54-3. 50 (t, 2H), 2. 92 - 2. 86ppm(t, 2H)
[0213] ZM-12
[0214] NMR (300MHz, CDC13) δ 8. 23 - 8. 21 (m, 2H), 7. 92 (s, 1H), 7. 84 (d, J = 8. 1Hz, 2H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 6. 85-6. 78 (m, 3H), 6. 38 (t, 1H), 5. 95 (s, 2H), 4. 65 (s, 2H), 4. 54 (d, J = 5. 7Hz, 2H), 3. 54-3. 50 (t, 2H), 2. 91 - 2. 87ppm(t, 2H)
[0215] ZM-13
[0216] NMR(300MHz, CDC13) δ 8. 24 - 8. 21 (m, 2H), 7. 96 (s, 1H), 7. 83 (d, J = 8. 1Hz, 2H), 7. 37 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 6. 88-6. 83 (m, 3H), 6. 45 (t, 1H), 5. 96 (s, 2H), 4. 62 (s, 2H), 4. 60 (d, J = 5. 7Hz, 2H), 3. 55-3. 50 (t, 2H), 2. 92 - 2. 87ppm(t, 2H)
[0217] ZM-14
[0218] 4 NMR(300MHz, CDC13) δ 8. 23 - 8. 21(m, 2H), 7. 92(s, 1H), 7. 82(d, J = 8. 1Hz, 2H) ,7. 38-7. 36 (m, 5H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 6. 38 (d, 1H), 5. 36-5. 32 (m ,1H), 4. 64 (s, 2H), 3. 53-3. 48 (t, 2H), 2. 90 - 2. 85 (t, 2H), L 52ppm (d, 3H)
[0219] ZM-15
[0220] NMR(300MHz, CDC13) δ 8. 24 - 8. 22 (m, 2H), 7. 92 (s, 1H), 7. 82 (d, J = 8. 1Hz, 2H), 7. 33 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 15 (m, 1H), 6. 16 (t, 1H), 4. 65 (s, 2H), 3. 55-3. 51 (t, 2H), 3. 34-3. 29 (t, 2H), 2. 91 - 2. 87 (t, 2H), 1. 86-1. 58 (m, 5H), 1. 28-1. 21 (m, 4H), 1. 0 6-1. 0. 98ppm(m, 2H)
[0221] ZM-16
[0222] NMR(300MHz, CDC13) δ 8. 26 - 8. 25 (m, 2H), 7. 92 (s, 1H), 7. 83 (d, J = 8. 1Hz, 2H), 7. 45 - 7. 43 (m, 1H), 7. 35 (d, J = 8. 1Hz, 2H), 7. 33-7. 30 (m, 1H), 6. 89-6. 85 (m, 3H ),6. 43 (t, 1H), 4. 63 (s, 2H), 4. 58 (d, J = 5. 7Hz, 2H), 3. 88 (s, 6H), 3. 53-3. 48 (t, 2H), 2. 92 - 2. 87ppm(t, 2H)
[0223] ZM-17
[0224] 4 NMR(300MHz, CDC13) δ 8. 04 - 8. 00 (m, 3H)，7. 81-7. 78 (m, 4H)，7. 28 (d, J = 8. 1H z, 2H), 6. 87-6. 80 (m, 3H), 4. 64 (s, 2H), 4. 51 (t, 1H), 3. 81 (s, 6H), 3. 47-3. 44 (t, 2H), 2. 83 - 2. 78ppm(t, 2H)
[0225] ZM-18
[0226] NMR ( 3 0 0MHz, CDC13) δ 8 . 0 6 ( s , 1 H ) , 7 . 9 1 - 7 . 8 8 ( d , J = 8. 4Hz, 1H), 7. 85-7. 82 (d, J = 8. 1Hz, 2H), 7. 77-7. 74 (d, J = 8. 4Hz, 1H), 7. 42-7. 39 (t, 1H), 7. 28 (d, J = 8. 1Hz, 2H), 6. 89-6. 80 (m, 3H), 6. 30 (t, 1H), 4. 65 (s, 2H), 4. 56 (d, 2H), 3. 85 (s, 6H), 3. 55-3. 50 (t, 2H), 2. 96 - 2. 91ppm(t, 2H)
[0227] ZM-19
[0228] 1 H NMR(300MHz, C D C 1 3 ) δ 8 . 24 - 8. 22 (m, 2H), 7. 95(s, 1H), 7. 81-7. 77 (m, 2H), 7. 38 - 7. 35 (m, 1H), 7. 25- 7.20(m,lH),6.89-6.85 (m,3H),6.43(t,lH),4.63(s,2H),4.58(d,J = 5. 7Hz, 2H), 3. 89 (s, 6H), 3. 59-3. 53 (t, 2H), 2. 93 - 2. 87 (t, 2H), 2. 37ppm(s, 3H)
[0229] ZM-20
[0230] NMR (300MHz, CDC13) δ 8. 24 - 8. 2 1 (m, 2H) , 7. 94 (s, 1H) , 7. 83 (d, J =8. 1Hz, 2H) , 7. 32 (d, J = 8. 1 Hz , 2H) , 7. 2 5 - 7. 2 0 (m, 1H) , 6. 9 1 (d, J = 7. 2Hz, 1H) , 6. 65 (d, J = 11. 1Hz, 1H) , 6. 66 (t, 1H) , 4. 64 (s, 2H) , 4. 6 1 (d, J = 5. 7Hz, 2H), 3. 85 (s, 6H), 3. 54-3. 50 (t, 2H), 2. 90 - 2. 87 (t, 2H)
[0231] ZM-21
[0232] NMR(300MHz, CDC13) δ 8. 23 - 8. 21 (m, 2H), 7. 93 (s, 1H), 7. 81 (d, J = 8. 1Hz, 2H), 7. 36 (d, J = 8. 1Hz, 2H), 7. 21 - 7. 14 (m, 1H), 7. 02-6. 98 (m, 2H), 6. 84 (d, lh), 6. 39 (s, 1H), 4. 64 (s, 2H), 3. 87 (s, 3H), 3. 86 (s, 3H), 3. 53-3. 48 (t, 2H), 2. 90 -