實施例1
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘甲酸之製備
將N,N-二異丙基乙胺(1.575 ml,8.53 mmol)在20至30℃下添加至DMF (1 mL)中的4-(吲哚啉-5-基)-1-萘甲酸 2,2,2-三氟乙酸乙酸鹽(0.172 g,0.426 mmol)之溶液中。將溴化1-((2,4-二胺基嘧啶-5-基)甲基)吡啶-1-鎓氫溴酸鹽[根據文獻程序製備J. Med. Chem. 2003, 46, 2304-2312](0.155 g,0.426 mmol)在20至30℃下添加至反應混合物中。將所得懸浮液在80至90℃下攪拌2 h。以TLC監控反應進程。將產物以使用移動相ACN-水之製備性HPLC純化以供給成為淺黃色固體的35 mg之4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘甲酸。
1H NMR (DMSO-d
6, 400 MHz) δ:9.00 (d,
J=8.8Hz, 1H), 8.33 (s, 1H), 7.84 (d, J =8.0Hz, 1H), 7.70(d,
J=6.8Hz, 2H), 7.40(d,
J=6.8Hz,2H), 7.24 (d,
J=7.2Hz, 1H), 7.15 (s, 1H), 6.82 (d,
J=8.4Hz, 1H), 6.17 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.01 (s, 2H), 3.23 (t, J =0.4Hz, 2H), 2.96 (t,
J=0.4Hz, 2H);ESI-MS (m/z):412.170(100%) (M+H)
+;UPLC純度:98.28% (2.93 min)。
中間物1之合成:
4-溴-1-萘甲醯氯(中間物4)之製備
將亞硫醯氯(1.454 ml,19.91 mmol)在20至30℃下以攪拌逐滴添加至4-溴-1-萘甲酸(中間物3)(1.000 g,3.98 mmol)中且在20至30℃下持續攪拌3 h。以TLC監控反應進程。在反應完成後,在旋轉蒸發器上於減壓下蒸發揮發物以供給成為棕色油的4-溴-1-萘甲醯氯(中間物4)(1.07 g,3.98 mmol,定量產量),其直接用於下一步驟而無需進一步純化。
4-溴-1-萘甲酸三級丁酯(中間物5)之製備
將三級丁醇鉀(0.891 g,7.94 mmol)在0至10℃下以少部分添加至THF (30 mL)中的4-溴-1-萘甲醯氯(中間物4)(1.070 g,3.97 mmol)之溶液中。將反應混合物在20至30℃下攪拌18 h。以TLC監控反應進程。將反應混合物倒入水(50 mL)中且以EtOAc萃取。將有機層分離,以飽和碳酸氫鈉清洗,隨後以水清洗且經硫酸鈉乾燥。蒸發溶劑以供給成為黃色油的4-溴-1-萘甲酸三級丁酯(0.33 g,1.074 mmol,27.1%之產率)。
1H NMR (DMSO-d
6, 400 MHz) δ:8.71-8.70 (dd,
J=0.4 Hz, 1H), 8.27-8.26 (dd,
J=0.4 Hz, 1H), 8.01(d,
J=8.0 Hz, 1H), 7.91(d,
J=8.0 Hz,1H), 7.78 (t,
J=1.2Hz, 1H), 7.77 (t,
J=1.2 Hz, 1H), 1.63(s, 9H);ESI-MS (m/z):390.17 (M-tBu)。
5-(4-三級丁氧基羰基)萘-1-基)吲哚啉-1-甲酸三級丁酯(中間物7)之製備
將5-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)吲哚啉-1-甲酸三級丁酯[中間物6係遵照
J. Med. Chem. 2012,
55(16), 7193-7207中所述之程序製備](0.371 g,1.074 mmol)在25至30℃下於氮氛圍下添加至DMF(2.4 mL)中的4-溴-1-萘甲酸三級丁酯(中間物5)(0.330 g,1.074 mmol)之溶液中。將三苯基膦(0.085 g,0.322 mmol)、二乙醯氧基鈀(diacetoxy palladium)(0.024 g,0.107 mmol)、乙醇(2.4 mL)及水(1.5 mL)添加至反應混合物中。將反應混合物在20至30℃下於氮氛圍下攪拌18 h。以TLC監控反應進程。將反應混合物倒入水中且以EtOAc萃取。將有機層分離,以飽和碳酸氫鈉清洗,隨後以水清洗且經硫酸鈉乾燥。在旋轉蒸發器上蒸發揮發物以供給成為棕色油的粗製5-(4-(三級丁氧基羰基)萘-1-基)吲哚啉-1-甲酸三級丁酯。將粗製產物以管柱層析術純化以供給成為棕色油的5-(4-(三級丁氧基羰基)萘-1-基)吲哚啉-1-甲酸三級丁酯(中間物7)(0.19 g,0.426 mmol,39.7%之產率)。
1H NMR (DMSO- d
6, 400 MHz) δ:8.74 (d,
J=8.4Hz, 1H), 8.04 (d,
J=7.6Hz, 1H), 7.93-7.87(q,
J=0.4Hz, 1H), 7.67(d,
J=1.2Hz,1H), 7.65(s, 1H), 7.57 (d,
J=7.2Hz, 1H), 7.47 (d,
J=7.2Hz, 1H), 7.39 (d,
J=8.8Hz, 1H), 7.32(s, 1H), 7.26 (d,
J=8.0Hz, 1H), 4.0 (t,
J=0.4Hz, 2H), 3.04 (t,
J=0.4Hz, 2H), 1.68(s, 9H), 1.55(s, 9H);ESI-MS (m/z):390.17 (M-tBu)。
4-(吲哚啉-5-基)-1-萘甲酸-2,2,2-三氟乙酸鹽(中間物1)之製備
將2,2,2-三氟乙酸(2 ml,0.426 mmol)在25至30℃下添加至DCM (2 mL)中的5-(4-(三級丁氧基羰基)萘-1-基)吲哚啉-1-甲酸三級丁酯(中間物7)(0.190 g,0.426 mmol)之溶液中。將反應混合物在20至30℃下於氮氛圍下攪拌18 h。以TLC監控反應進程。將反應混合物在旋轉蒸發器上於減壓下蒸發以供給成為棕色油的4-(吲哚啉-5-基)-1-萘甲酸-2,2,2-三氟乙酸鹽(0.172 g,0.426 mmol,100%之產率),其直接用於下一步驟而無需進一步分析及純化。
下列的實施例係依照實施例1之製備法所述之程序製備。
實施例2
5-((6-苯基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 1H), 7.63 (t,
J=6.0Hz, 2H), 7.44 (d,
J=7.2Hz, 2H), 7.41 (s, 1H), 7.32 (t,
J=1.6Hz, 1H), 7.12 (d,
J=7.6Hz, 1H), 6.91 (t,
J=4.4Hz, 1H), 6.16 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.02 (s, 2H), 3.17 (t,
J=0.4Hz, 2H), 2.87 (t,
J=0.4Hz, 2H)。
實施例3
5-((6-(3-甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 7.13 (t,
J =1.6
Hz, 2H), 6.98 (d,
J =1.2
Hz, 1H), 6.92 (d,
J =1.2
Hz, 2H), 6.16 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.02 (s, 2H), 3.82 (s, 2H, OCH
3), 3.17 (t,
J =0.4
Hz, 2H), 2.87 (t,
J =0.4
Hz, 2H)。
實施例4
1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.66 (s, 1H), 7.60 (d,
J=8.74Hz, 1H), 7.63 (s, 1H), 6.64 (d,
J=8.4Hz, 1H), 6.16 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 3.98 (s, 2H), 3.23 (t,
J=16.0Hz, 2H), 2.87 (t,
J=16.0Hz, 2H)。
實施例5
5-((6-(3-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 2H), 7.68 (d,
J =2.4
Hz, 1H), 7.61 (t,
J =2.8
Hz, 1H), 7.60 (d,
J =1.2Hz, 1H), 7.13 (d,
J =7.6Hz, 1H), 7.05 (d,
J =1.2Hz, 1H), 6.94 (d,
J =1.6Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.04 (s, 2H), 3.17 (t,
J =0.4
Hz, 2H), 2.88 (t,
J =1.6
Hz, 2H)。
實施例6
5-((2,3-二氫-1H-吡咯并[2,3-b]吡啶-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.75 (dd,
J=1.2Hz, 1H), 7.66 (s, 1H), 7.25 (dd,
J=1.6Hz, 1H), 6.43 (t,
J=0.4 Hz, 1H), 6.41 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 4.15 (s, 2H), 3.39 (t,
J=0.4Hz, 2H), 2.91 (t,
J=0.4Hz, 2H)。
實施例7
5-((6-(3-(三氟甲氧基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 2H), 7.68 (d
, J=1.6Hz, 1H), 7.59 (d,
J=6.0Hz, 1H), 7.31 (t,
J=2.4Hz, 1H), 7.14 (d,
J=7.6Hz, 1H), 7.06 (d,
J=1.2Hz, 1H), 6.96, 6.94 (dd,
J=1.6Hz, 1H), 6.15 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.04 (s, 2H), 3.18 (t,
J=2.0Hz, 2H), 2.90(t,
J=0.8Hz, 2H)。
實施例8
5-((6-(2-甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 1H), 7.32 (d,
J =2.0
Hz, 1H), 7.30 (d,
J =0.8
Hz, 1H), 7.28 (d,
J =2.0
Hz, 2H), 7.04 (s, 1H), 7.00 (t,
J =5.2
Hz, 1H), 6.70(s,
J =4.4
Hz, 1H), 6.22 (s, 2H, NH
2), 5.93 (s, 2H, NH
2), 3.95 (s, 2H), 3.76 (s, 3H, OCH
3), 3.21 (t,
J =0.4
Hz, 2H), 2.87 (t,
J =16.0
Hz, 2H)。
實施例9
5-((5-(苯基乙炔基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.83 (s, 1H, HCl), 7.68 (s, 1H), 7.62 (s, 2H, NH
2), 7.67 (s, 1H), 7.48 (d
, J=2.0Hz, 1H), 7.6 (s, 2H, NH
2), 7.38 (d,
J=3.2Hz, 3H), 7.25 (t, J =0.8Hz, 2H), 6.64 (t,
J=3.2Hz, 1H), 4.07 (s, 2H), 3.34 (t,
J=1.6Hz, 2H), 2.68 (t,
J=0.8Hz, 2H)。
實施例10
5-((4,6-二氟吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.64 (s, 1H), 6.45 (d,
J=2.0Hz, 1H), 6.42 (d,
J= 2.0Hz, 1H), 6.17 (s, 2H, NH
2), 5.89 (s, 2H, NH
2), 3.99 (s, 2H), 3.29 (t,
J=16.8Hz, 2H), 2.86 (t,
J=0.4Hz, 2H)。
實施例11
5-((5-(吡啶-4-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.0 (小的HCl駝峰,但未整合), 8.69 (d,
J=6.8Hz, 2H) 8.50(s, 1H), 8.17 (d,
J=6.8Hz, 3H), 7.83 (s, 2H, NH
2), 7.68 (s, 2H, NH
2), 6.79 (d,
J=8.4Hz, 1H), 4.20(s, 2H), 3.51 (t,
J=16.8Hz, 2H), 2.68 (t,
J=0.4Hz, 2H)。
實施例12
5-((5-(3-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.99 (s, 1H, HCl), 8.41 (s, 1H), 7.75 (s, 4H, NH
2), 7.73 (s, 1H), 7.08 (d
, J=1.2Hz, 1H), 7.61 (t,
J=0.4Hz, 1H), 7.44 (d,
J=8.0Hz, 2H), 7.29 (s, 1H), 6.71 (d,
J=8.4Hz, 1H), 4.06 (s, 2H), 3.33 (t,
J=0.4Hz, 2H), 2.99 (t,
J=16.0Hz, 2H)。
實施例13
5-((5-(萘-2-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.99 (s, 1H, HCl), 8.43 (s, 1H), 8.10 (s, 1H), 7.94 (d
, J=8.4Hz, 2H), 7.90 (d,
J= 8.0Hz, 1H), 7.80 (s, 3H, NH
2), 7.79 (d,
J= 2Hz, 2H), 7.76 (s, 1H), 7.53 (t,
J=0.4Hz, 2H), 7.44 (s, 1H, NH
2), 6.77 (d,
J=8.4Hz, 1H), 4.08 (s, 2H), 3.35 (t,
J=16.8Hz, 2H), 3.05 (t,
J=0.4Hz, 2H)。
實施例14
5-((6-氯吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.99 (s, 1H, HCl), 8.39 (s, 1H), 7.71 (s, 4H, NH
2), 7.06 (d,
J=7.6Hz, 1H), 6.72 (s, 1H), 6.64 (d,
J=2Hz, 1H), 4.01 (s, 2H), 3.29 (t,
J=16.8Hz, 2H), 2.90 (t,
J=0.4Hz, 2H)。
實施例15
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-6-基)苯甲酸化合物與乙酸(1:3)
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.89 (d,
J=8.4Hz, 2H), 7.68 (s, 1H), 7.51 (d,
J=8.4Hz, 2H), 7.48 (s, 1H), 7.11 (d,
J=7.6Hz, 1H), 7.28 (s, 1H), 6.93, 6.91 (dd,
J=0.4Hz, 1H), 6.28 (s, 1H, NH
2), 6.17 (s, 1H, NH
2), 5.81 (s, 2H, NH
2), 4.01 (s, 2H), 3.15 (t,
J =0.4Hz, 2H), 2.86 (t,
J=0.4Hz, 2H), 2.06 (d,
J=10.4Hz, 9H,三乙酸鹽)。
實施例16
5-((5-(4-(甲基磺醯基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.90 (d,
J =8.8
Hz, 2H), 7.83 (d,
J =8.8
Hz, 2H), 7.67 (s, 1H), 7.36 (d,
J =8.8
Hz, 2H), 6.79 (d,
J =8.0
Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.02 (s, 2H), 3.37 (s, 3H), 3.26 (t,
J =16.8
Hz, 2H), 2.96 (t,
J =8.0
Hz, 2H)。
實施例17
5-((5-(4-(二乙基胺基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.36 (d,
J=8.8Hz, 2H), 7.28 (s, 1H), 7.23 (d,
J=1.6Hz, 1H), 6.70 (d,
J=5.2Hz, 3H), 6.20 (s, 2H, NH
2), 5.77 (s, 2H, NH
2), 3.95 (s, 2H), 3.35-3.30 (m, 4H), 3.17 (t,
J=0.4Hz, 2H), 2.90(t,
J=3.6Hz, 2H), 1.08 (t,
J=0.4Hz, 6H)。
實施例18
5-((5-(2,4-二氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 2H), 7.65 (d,
J=2.0Hz, 1H), 7.45 (d,
J=2.0Hz, 1H), 7.43 (s, 2H), 7.37 (d,
J=8.4Hz, 1H), 6.73 (s, 2H, NH
2), 6.00 (s, 2H, NH
2), 3.99 (s, 2H), 3.23 (t
, J=0.4Hz, 2H), 2.91 (t,
J=0.4Hz, 2H)。
實施例19
5-((4-(2,4-二氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.71 (d,
J =2.4
Hz, 1H), 7.67 (s, 1H), 7.48 (d,
J =2.0
Hz, 1H), 7.36 (d,
J =8.4
Hz, 1H), 7.11 (s, 1H), 6.74 (d,
J =7.6
Hz, 1H), 6.53 (t,
J =6.0
Hz, 1H), 6.15 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.97 (s, 2H), 3.12 (t,
J =0.4
Hz, 2H), 2.65 (t,
J =0.4
Hz, 2H)。
實施例20
5-((4-(4-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.50 (d,
J=12.4Hz, 4H), 7.14 (t,
J=0.4Hz, 1H), 6.72 (d,
J=8.4Hz, 2H), 6.27 (s, 2H, NH
2), 5.98 (s, 2H, NH
2), 3.96 (s, 2H), 3.13 (t,
J=16.0Hz, 2H), 2.92 (t,
J=16.0Hz,2H)。
實施例21
5-((6-(4-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.66 (d
, J=1.6Hz, 2H), 7.48 (d,
J=2.0Hz, 2H), 7.47 (s, 1H), 7.13 (d,
J=7.2Hz, 1H), 6.99 (d,
J=0.8Hz, 1H), 6.17 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.02 (s, 2H), 3.17 (t,
J=0.4Hz, 2H), 2.87 (t,
J=0.4Hz, 2H)。
實施例22
5-((5-(喹啉-3-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:9.19 (d
, J=2.4Hz, 1H), 8.49 (d,
J=2.0Hz, 1H), 8.00 (t,
J=1.2Hz, 2H), 7.99-7.68 (m, 2H), 7.62-7.57 (m, 3H), 6.84 (d,
J=8.4Hz, 1H), 6.17 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 4.03 (s, 2H), 3.27 (t,
J=0.4Hz, 2H), 2.98 (t
, J=0.4Hz, 2H)。
實施例23
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.96 (d,
J=8.8Hz, 2H), 7.73 (d,
J=8.8Hz, 2H), 7.67 (s, 1H), 7.46 (d,
J=8.0Hz, 2H), 6.78 (d,
J=8.4Hz, 1H), 6.15 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 4.32 (q,
J=21.6Hz, 2H), 4.01 (s, 2H), 3.25 (t,
J=0.4Hz, 2H), 2.95 (t,
J=0.4Hz, 2H), 1.34 (t,
J=14.4Hz, 3H)。
實施例24
5-((5-(4-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.59 (d,
J=2.0Hz, 2H), 7.57 (d,
J=1.6Hz, 2H), 7.56 (s, 1H), 7.49 (d,
J=2.0Hz, 1H), 6.74 (d,
J=8.4Hz, 1H), 6.40 (s, 2H, NH
2), 6.10 (s, 2H, NH
2), 4.13 (s, 2H), 3.23 (t,
J=0.4Hz, 2H), 2.93 (t,
J=0.4Hz, 2H)。
實施例25
5-((5-氟-2-甲基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.63 (s, 1H), 6.91 (t,
J=3.2Hz, 1H), 6.89 (s, 1H), 6.77 (d,
J=1.6Hz, 1H), 6.13 (s, 2H, NH
2), 5.84 (s, 2H, NH
2), 3.91 (s, 1H), 3.89 (s, 1H), 3.60 (d
, J=6.0Hz, 1H), 2.90 (m, 1H), 2.55-2.50 (m, 1H), 1.18 (d,
J=6.0Hz, 3H)。
實施例26
5-((5-(3-氯-4-甲基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.58 (d,
J =1.6
Hz, 1H), 7.45 (d,
J =1.6
Hz, 1H), 7.43 (d,
J =1.6
Hz, 1H), 7.36 (s, 2H), 6.74 (d,
J =8.0
Hz, 1H), 6.14 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.11 (s, 2H), 3.21 (t,
J =0.4
Hz, 2H), 2.92 (t,
J =0.4
Hz, 2H), 2.33 (s, 3H)。
實施例27
5-((4-(3-氯-4-甲基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.46 (s, 1H), 7.41 (d,
J =8.0
Hz, 1H), 7.34 (d,
J =1.6
Hz, 1H), 7.13 (t,
J =0.4
Hz, 1H), 6.72, 6.70 (dd,
J =5.2
Hz, 2H), 6.33 (s, 2H, NH
2), 6.04 (s, 2H, NH
2), 4.11 (s, 2H), 3.14 (t,
J =0.8
Hz, 2H), 2.94 (t,
J =0.4
Hz, 2H), 2.51 (s, 3H)。
實施例28
5-((4-(4-氯-3-甲基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.45 (d,
J =8.4
Hz, 2H), 7.30 (d,
J =2.0
Hz, 1H), 7.13 (t,
J =0.4
Hz, 1H), 6.73-6.69 (q,
J =0.4
Hz, 2H), 6.16 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 3.96 (s, 2H), 3.12 (t,
J =0.4
Hz, 2H), 2.91 (t,
J =0.4
Hz, 2H), 2.38 (s, 3H)。
實施例29
2-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-4-基)苯甲酸化合物與乙酸(1:3)
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.65 (s, 2H), 7.23 (s, 1H), 7.03 (s, 1H), 6.90 (t,
J =0.8
Hz, 1H), 6.80 (t,
J =0.8
Hz, 1H), 6.63 (d,
J =7.6
Hz, 1H), 6.50 (d,
J =6.8
Hz, 1H), 6.17 (s, 2H, NH
2), 5.81 (s, 2H, NH
2), 3.93 (s, 2H), 3.04 (t,
J =8.0
Hz, 2H), 2.78 (t,
J =0.4
Hz, 2H), 2.33 (s, 9H,三乙酸鹽)。
實施例30
3-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-4-基)苯甲酸化合物與乙酸(1:3)
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.95 (s, 2H), 7.86 (s, 1H), 7.68 (s, 1H), 7.15 (t,
J =0.8
Hz, 2H), 6.72 (d,
J =7.6
Hz, 2H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.96 (s, 2H), 3.13 (t,
J =0.8
Hz, 2H), 2.92 (t,
J =16.8
Hz, 2H), 2.29 (s, 9H,三乙酸鹽)。
實施例31
5-((5-(4-氯-3-甲基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.53 (s, 1H), 7.39 (d,
J =4.4
Hz, 3H), 7.34 (d,
J =9.2
Hz, 1H), 6.67 (d,
J =8.4
Hz, 1H), 6.16 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 4.01 (s, 2H), 3.29 (t,
J =0.4
Hz, 2H), 2.94 (t,
J =0.4
Hz, 2H), 2.31 (s, 3H)。
實施例32
4-(1-(3-(2,4-二胺基嘧啶-5-基)丙-2-炔-1-基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.84 (d,
J =8.0
Hz, 3H), 7.74 (s, 1H), 7.46 (d,
J =8.0
Hz, 1H), 7.40(s, 1H), 7.36 (d,
J =8.4
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 6.27 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.23 (s, 2H), 3.41 (d,
J =8.4
Hz, 2H), 2.96 (d,
J =8.4
Hz, 2H)。
實施例33
3-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.06 (s, 1H), 7.72 (d,
J =7.2
Hz, 1H), 7.68 (s, 1H), 7.45 (d,
J =7.2
Hz, 1H), 7.36 (s, 1H), 7.32 (d,
J =8.4
Hz, 1H), 7.26 (t,
J =16.8
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 6.14 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.97 (s, 2H), 3.19 (t,
J =0.4
Hz, 2H), 2.93 (t,
J =0.4
Hz, 2H)。
實施例34
5-((5-(3-氯苯基)吲哚啉-1-基)甲基)-6-乙基嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.60 (s, 1H), 7.53 (d,
J =8.0
Hz, 1H), 7.39 (d,
J =8.0
Hz, 2H), 7.38 (s, 1H), 7.28 (d,
J =7.6
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 6.05 (s, 2H, NH
2), 5.78 (s, 2H, NH
2), 4.06 (s, 2H), 3.19 (t,
J =0.4
Hz, 2H), 2.89 (t,
J =16.8
Hz, 2H), 2.51-2.46 (q,
J =6.4
Hz, 2H), 1.10 (t,
J =15.2
Hz, 3H)。
實施例35
5-((5-(4-(3-甲氧基氧呾-3-基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.62 (d,
J =8.4
Hz, 2H), 7.44 (d,
J =8.4
Hz, 2H), 7.40(d,
J =9.6
Hz, 1H), 7.37 (s, 1H), 6.76 (d,
J =8.4
Hz, 1H), 6.14 (s, 2H, NH
2), 5.85 (s, 2H, NH
2), 4.78 (s, 4H), 3.99 (s, 2H), 3.22 (t,
J =0.4
Hz, 2H), 3.04 (s, 3H, OCH
3), 2.94 (t,
J =8.4
Hz, 2H)。
實施例36
2-氯-4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.39 (s, 1H), 7.32 (d,
J =1.6
Hz, 3H), 7.32 (s, 1H), 6.73 (d,
J =8.4
Hz, 1H), 6.13 (s, 2H, NH
2), 5.85 (s, 2H, NH
2), 3.98 (s, 2H), 3.20 (t,
J =0.4
Hz, 2H), 2.92 (t,
J =7.6
Hz, 2H)。
實施例37
1-環丙基-7-(4-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲醯基)哌𠯤-1-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.63 (s, 1H), 7.66 (d,
J =10
Hz, 1H), 7.49 (d,
J =8.0
Hz, 3H), 7.48 (s, 3H), 7.42 (t,
J =0.4
Hz, 2H), 6.76 (d,
J =8.4
Hz, 1H), 6.15 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.00(s, 2H), 3.23 (t,
J =0.4
Hz, 2H), 2.94 (t,
J =0.4
Hz, 2H), 1.30, 1.24 (dd,
J =7.2
Hz, 2H), 1.09, 1.04 (dd,
J =6.0
Hz, 2H)。註:環丙基CH之1H被合併至哌𠯤環質子中)。
實施例38
5-((5-碘吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.63 (s, 1H), 7.30 (d,
J =12.4
Hz, 2H), 6.68 (s, 1H), 6.12 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.01 (s, 2H), 3.15 (t,
J =13.6
Hz, 2H), 2.90 (t,
J =0.8
Hz, 2H)。
實施例39
5-((5-(3-N-
啉基丙氧基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.33 (s, 1H), 7.65 (s, 1H), 6.60 (d,
J =1.2
Hz, 2H), 6.12 (s, 2H, NH
2), 5.85 (s, 2H, NH
2), 3.91 (s, 2H), 3.88 (t,
J =12.8
Hz, 2H), 3.57 (t,
J =0.4
Hz, 4H), 3.03 (t,
J =0.4
Hz, 2H), 2.80 (t,
J =0.4
Hz, 2H), 2.52 (t,
J =3.2
Hz, 6H), 1.85-1.80 (m, 2H)。
實施例40
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-硝基苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (d,
J =1.2
Hz, 1H), 7.66, 7.65 (dd,
J =0.4
Hz, 2H), 7.66 (s, 2H), 7.42 (s, 1H), 7.31 (d,
J =2.0
Hz, 1H), 6.56 (s, 2H, NH
2), 5.79 (s, 2H, NH
2), 3.47 (t,
J =0.4
Hz, 2H), 3.36 (s, 2H), 2.97 (t,
J =16.8
Hz, 2H)。
實施例41
(4-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲醯胺基)丁基)胺甲酸三級丁酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.44 (s, 1H), 7.85 (d,
J =8.8
Hz, 2H), 7.66 (d,
J =4.8
Hz, 2H), 7.60(s, 1H), 7.44 (d,
J =0.8
Hz, 2H), 6.76 (d,
J =8.0
Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.00(s, 2H), 3.22 (t,
J =2.4
Hz, 4H), 3.20 (s, 1H, -NH), 2.94 (t,
J =0.6
Hz, 4H), 1.49 (d,
J =7.6
Hz, 2H), 1.37 (s, 9H)。
實施例42
2-乙醯胺基-5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.04 (s, 1H,
-COOH), 10.99 (s, 1H, HCl), 8.47 (d,
J =8.8
Hz, 1H), 8.42 (s, 1H), 8.11 (d,
J =2.4
Hz, 1H), 7.81 (d,
J =2.4
Hz, 1H), 7.94 (s, 2H, NH
2), 7.43 (s, 2H, NH
2), 7.42 (s, 1H, -NH), 7.35 (d,
J =8.0
Hz, 1H), 6.72 (d,
J =8.0
Hz, 1H), 4.05 (s, 2H), 3.32 (t,
J =16.8
Hz, 2H), 2.99 (t,
J =1.2
Hz, 2H), 2.15 (s, 3H)。
實施例43
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)噻吩-2-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.66 (s, 1H), 7.28 (s, 1H), 7.10 (d,
J =3.6
Hz, 2H), 7.06 (d,
J =3.6
Hz, 1H), 6.68 (d,
J =8.0
Hz, 1H), 6.13 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.96 (s, 2H), 3.19 (t,
J =0.4
Hz, 2H), 2.90 (t,
J =16.8
Hz, 2H)。
實施例44
2-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯基)丁二酸4-乙酯-1-甲酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.51 (d,
J =8.0
Hz, 2H), 7.36 (s, 1H), 7.29 (d,
J =8.4
Hz, 3H), 6.74 (d,
J =8.4
Hz, 1H), 6.14 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 4.06 (t,
J =0.8
Hz, 3H), 3.97 (s, 2H), 3.32 (d,
J =2.4
Hz, 3H), 3.20 (t,
J =0.4
Hz, 2H), 3.06 (d,
J =10.4
Hz, 1H), 2.92 (t,
J =8.0
Hz, 2H), 2.74 (t,
J =4.8
Hz, 1H), 1.16 (t,
J =16.8
Hz, 3H)。
實施例45
2-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯基)-1,1,1,3,3,3-六氟丙-2-醇二甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.47 (s, 8H,額外的質子), 8.47 (s, 1H), 7.68 (d,
J =4.0
Hz, 4H), 7.43 (s, 1H), 7.40(d,
J =8.0
Hz, 1H), 6.76 (d,
J =8.4
Hz, 1H), 6.15 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.99 (s, 2H), 3.23 (t,
J =0.8
Hz, 2H), 2.93 (t,
J =0.8
Hz, 2H)。
實施例46
2-乙醯胺基-4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.73 (s, 1H), 8.15 (s, 1H), 7.95 (d,
J =8.0
Hz, 1H), 7.68 (s, 1H), 7.37 (d,
J =8.4
Hz, 2H), 7.11 (d,
J =8.4
Hz, 1H), 6.78 (s, 4H, NH
2), 4.01 (s, 2H), 3.24 (t,
J =6.0
Hz, 2H), 2.68 (t,
J =0.4
Hz, 2H), 2.04 (s, 3H)。
實施例47
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-羥基苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.14 (s, 1H), 7.67 (d,
J =3.6
Hz, 2H), 7.38 (s, 1H), 7.33 (s, 1H), 6.50 (d,
J =8.8
Hz, 1H), 6.81 (d,
J =8.4
Hz, 1H), 5.77 (s, 4H, NH
2), 4.00 (s, 2H), 3.26 (t,
J =0.4
Hz, 2H), 2.95 (t,
J =8.8
Hz, 2H)。
實施例48
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)菸鹼酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.97 (s, 1H), 8.91 (d,
J =1.6
Hz, 1H), 8.33 (d,
J =2.0
Hz, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 6.79 (d,
J =8.0
Hz, 1H), 6.26 (s, 2H, NH
2), 6.00 (s, 2H, NH
2), 4.02 (s, 2H), 3.24 (t,
J =16.8
Hz, 2H), 2.68 (t,
J =0.4
Hz, 2H)。
實施例49
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-羥基苯甲酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.04 (s, 1H, -HCl), 11.20 (s, 1H, -OH), 8.41 (s, 1H), 7.93 (s, 1H), 7.74 (d,
J =2.4
Hz, 3H), 7.67 (s, 1H), 7.30(d,
J =1.6
Hz, 1H), 7.02 (s, 1H, NH
2), 6.99 (s, 1H, NH
2), 6.72 (s, 1H, NH
2), 6.70(s, 1H, NH
2), 4.12 (s, 2H), 3.30 (t,
J =0.4
Hz, 2H), 2.98 (t,
J =0.4
Hz, 2H)。
實施例50
5-((5-(4-(乙基磺醯基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.16 (s, 1H), 7.85 (d,
J =8.0
Hz, 3H), 7.67 (s, 1H), 7.48 (d,
J =8.4
Hz, 2H), 6.78 (d,
J =8.0
Hz, 1H), 6.31 (s, 2H, NH
2), 6.03 (s, 2H, NH
2), 4.03 (s, 2H), 3.28 (t,
J =8.8
Hz, 4H), 2.96 (t,
J =0.4
Hz, 2H), 1.12 (t,
J =14.4
Hz, 3H)。
實施例51
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)酞酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.73 (s, 1H), 7.71 (d,
J =6.4
Hz, 1H), 7.69 (d,
J =6.0
Hz, 2H), 7.49 (s, 2H), 7.43 (d,
J=8.0
Hz,1H), 7.28 (s, 2H, NH
2), 7.04 (s, 2H, NH
2), 4.06 (s, 2H), 3.00(t,
J =0.4
Hz, 2H), 2.51 (t,
J =0.4
Hz, 2H)。
實施例52
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)呋喃-2-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.66 (s, 1H), 7.39 (d,
J =8.0
Hz, 2H), 6.72 (d,
J =8.0
Hz, 1H), 6.53 (d,
J=8.4
Hz, 1H), 6.52 (s, 1H), 6.13 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.97 (s, 2H), 3.18 (t,
J =0.4
Hz, 2H), 2.68 (t,
J =0.4
Hz, 2H)。
實施例53
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-5-甲基噻吩-2-甲酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.02 (s, 1H, HCl), 8.41 (s, 1H), 7.73 (s, 2H, NH
2), 7.70 (s, 2H, NH
2), 7.60 (s, 1H), 7.19 (s, 1H), 7.12 (d,
J =8.0
Hz, 1H), 6.69 (d,
J =8.4
Hz, 1H), 4.03 (s, 2H), 3.31 (t,
J =0.4
Hz, 2H), 2.97 (t,
J =0.4
Hz, 2H), 2.29 (s, 3H)。
實施例54
2-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯基)乙酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.50 (s, 1H,
-COOH,寬峰), 8.47 (d,
J =9.6
Hz, 2H), 8.15 (s, 2H), 7.51 (d,
J =8.0
Hz, 2H), 7.39 (s, 2H , NH
2), 7.35 (d,
J =8.0
Hz, 1H), 7.28 (s, 2H, NH
2), 6.72 (d,
J =8.0
Hz, 1H), 4.78 (s, 2H, HCl), 4.04 (s, 2H), 3.58 (s, 2H), 3.29 (t,
J =0.4
Hz, 2H), 2.96 (t,
J =0.4
Hz, 2H)。
實施例55
5-((5-(喹啉-8-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.5 (s, 1H, HCl), 9.03 (d,
J =3.6
Hz, 1H), 8.92 (s, 1H), 8.46 (s, 1H), 8.16 (d,
J =7.2
Hz, 1H), 7.84 (s, 4H, NH
2), 7.40 (d,
J =10.4
Hz, 3H), 7.33 (d,
J =1.6
Hz, 1H), 7.31 (d,
J =1.6
Hz, 1H), 6.81 (d,
J =8.4
Hz, 1H), 4.13 (s, 2H), 3.41 (t,
J =0.4
Hz, 2H), 3.03 (t,
J =0.4
Hz, 2H)。
實施例56
5-((5-(8-甲氧基喹啉-5-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.37 (s, 1H, HCl), 9.13 (d,
J =4.8
Hz, 1H), 8.89 (d,
J =7.2
Hz, 1H), 8.45 (s, 1H), 8.00 (s, 1H), 7.72 (d,
J =8.4
Hz, 1H), 7.64 (s, 2H, NH
2), 7.23 (s, 2H, NH
2), 7.17 (d,
J =8.0
Hz, 1H), 7.16 (d,
J =8.0
Hz, 1H), 7.15 (d,
J =1.6
Hz, 1H), 6.82 (d,
J =8.0
Hz, 1H), 4.01 (s, 2H), 3.99 (s, 3H, -OCH
3), 3.24 (t,
J =0.4
Hz, 2H), 2.95 (t,
J =0.8
Hz, 2H)。
實施例57
5-((5-(6,7-二甲氧基-2,3-二氫-1H-茚-4-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.37 (s, 1H, HCl), 8.42 (s, 1H), 7.12 (d,
J =6.4
Hz, 1H), 7.69 (s, 4H, NH
2), 7.38 (s, 1H), 7.25 (s, 1H), 6.67 (d,
J =8.4
Hz, 1H), 4.24 (s, 2H), 3.81 (s, 3H, -OCH
3), 3.80 (s, 3H, -OCH
3), 3.29 (t,
J =16.8
Hz, 2H), 2.96 (t,
J =0.8
Hz, 2H), 2.52-2.50 (m,
4H), 1.97-1.91 (t,
J =14.4
Hz, 2H)。
實施例58
5-((5-(喹啉-5-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.11 (s, 1H, HCl), 9.22 (d,
J =4.4
Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.23 (d,
J =12.8
Hz, 1H), 8.05 (d,
J =7.6
Hz, 1H), 7.75 (d,
J =0.4
Hz, 1H), 7.29 (s, 1H), 7.28 (s, 4H, NH
2), 7.22 (d,
J =1.2
Hz, 1H), 7.20 (d,
J =1.6
Hz, 1H), 6.83 (d,
J =8.0
Hz, 1H), 4.34 (s, 2H), 3.40 (t,
J =0.4
Hz, 2H), 3.04 (t,
J =0.4
Hz, 2H)。
實施例59
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-羥基-2-萘甲酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.30 (s, 1H, -HCl), 11.90 (s, 1H, -OH), 8.44 (s, 1H), 8.39 (d,
J =1.2
Hz, 1H), 8.37 (d,
J =1.2
Hz, 1H), 7.85 (d,
J =8.0
Hz, 2H), 7.77 (s, 4H, NH
2), 7.58 (s, 1H), 7.19 (s, 1H), 7.12, 7.10 (dd,
J =1.6
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.26 (s, 2H), 3.35 (t,
J =16.0
Hz, 2H), 3.01 (t,
J =1.2
Hz, 2H)。
實施例60
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2,3,5,6-四甲基苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.71 (s, 1H), 6.76 (d,
J =8.0
Hz, 2H), 6.75 (s, 1H), 6.17 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 3.97 (s, 2H), 3.18 (t,
J =1.2
Hz, 2H), 2.90 (t,
J =16.0
Hz, 2H), 2.14 (s, 6H), 1.91 (s, 6H)。
實施例61
5-((5-(4-氟萘-1-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.93 (s, 1H, HCl), 8.44 (s, 1H), 8.11 (d,
J =7.6
Hz, 1H), 7.92 (d,
J =8.4
Hz, 1H), 7.76 (s, 2H, NH
2), 7.68 (s, 2H, NH
2), 7.40 (d,
J =1.2
Hz, 2H), 7.62 (t,
J =1.2
Hz, 2H), 7.20(s, 1H), 7.14 (t,
J =4.0
Hz, 1H), 6.78 (d,
J =8.0
Hz, 1H), 4.08 (s, 2H), 3.36 (t,
J =0.4
Hz, 2H), 3.02 (t,
J =0.4
Hz, 2H)。
實施例62
5-((5-(二苯并[b,d]呋喃-3-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.20 (s, 1H, HCl), 8.43 (s, 1H), 8.36 (s, 1H), 8.22 (d,
J =7.2
Hz, 1H), 7.75 (d,
J =8.8
Hz, 2H), 7.70 (d,
J =8.0
Hz, 1H), 7.56 (s, 4H, NH
2), 7.55 (d,
J =1.6
Hz, 2H), 7.54 (t,
J =2.8
Hz, 1H), 7.47 (t,
J =1.2
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.08 (s, 2H), 3.34 (t,
J =0.4
Hz, 2H), 3.02 (t,
J =16.0
Hz, 2H)。
實施例63
6-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-萘甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.35 (s, 1H), 8.03 (d,
J =2.8
Hz, 2H), 8.02 (s, 1H), 8.00 (d,
J =1.6
Hz, 1H), 7.92 (d,
J =13.2
Hz, 1H), 7.80 (d,
J=8.8
Hz,1H), 7.69 (s, 1H), 7.55 (s, 1H), 6.80 (d,
J =8.0
Hz, 1H), 6.16 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.00(s, 2H), 3.23 (t,
J =16.0
Hz, 2H), 2.96 (t,
J =0.8
Hz, 2H)。
實施例64
6-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-甲基-1H-苯并[de]異喹啉-1,3(2H)-二酮
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.55 (d,
J =1.2
Hz, 2H), 8.53 (d,
J =1.2
Hz, 1H), 8.51 (d,
J =7.6
Hz, 1H), 7.86 (d,
J=7.2
Hz,2H), 7.84 (s, 1H), 7.29 (s, 1H), 6.88 (d,
J =8.0
Hz, 1H), 6.19 (s, 2H, NH
2), 5.89 (s, 2H, NH
2), 4.07 (s, 2H), 3.44 (t,
J =10.4
Hz, 2H), 3.17 (s, 3H), 2.68 (t,
J =4.0
Hz, 2H)。
實施例65
8-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-甲基-2H-苯并[b][1,4]㗁𠯤-3(4H)-酮三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.09 (s, 1H, HCl), 8.41 (s, 1H), 7.73 (s, 2H, NH
2), 7.67 (s, 1H), 7.65 (s, 2H, NH
2), 7.19 (d,
J =1.6
Hz, 1H), 7.11 (d,
J =0.8
Hz, 2H), 7.02 (t,
J =0.8
Hz, 1H), 6.67 (d,
J =8.4
Hz, 1H), 4.62 (s, 2H), 4.03 (s, 2H), 3.85 (s, 3H), 3.31 (t,
J =5.2
Hz, 2H), 2.96 (t,
J =0.8
Hz, 2H)。
實施例66
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)萘-1-磺酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.92 (d,
J =8.4
Hz, 1H), 8.80 (s, 1H, SO
3H), 7.96 (d,
J =7.6
Hz, 1H), 7.87 (d,
J =8.4
Hz, 1H), 7.44 (s, 1H), 7.51 (t,
J =0.4
Hz, 1H), 7.44 (t,
J =14.4
Hz, 1H), 7.35 (s, 2H, NH
2), 7.33 (d,
J =6.4
Hz, 1H), 7.28 (d,
J =7.6
Hz, 1H), 7.17 (s, 2H, NH
2), 6.95 (s, 1H), 6.79 (d,
J =8.0
Hz, 1H), 4.06 (s, 2H), 3.13 (t,
J =0.4
Hz, 2H), 3.00 (t,
J =0.8
Hz, 2H)。
實施例67
5-((5-(4-氯萘-1-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.20 (s, 1H, HCl), 8.43 (s, 1H), 8.26 (d,
J =8.0
Hz, 1H), 7.96 (d,
J =8.0
Hz, 1H), 7.79 (s, 1H), 7.75 (d,
J =8.0
Hz, 1H), 7.72 (t,
J =0.4
Hz, 1H), 7.70 (s, 4H, NH
2), 7.61 (t,
J =3.2
Hz, 1H), 7.36 (d,
J =7.6
Hz, 1H), 7.15-7.13 (q,
J =3.2
Hz, 1H), 6.79 (d,
J =8.0
Hz, 1H), 4.09 (s, 2H), 3.37 (t,
J =0.4
Hz, 2H), 3.02 (t,
J =16.0
Hz, 2H)。
實施例68
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘甲酸乙酯三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.0 (s, 1H, HCl), 8.84 (d,
J =8.8
Hz, 1H), 8.43 (s, 1H), 8.15 (d,
J =7.6
Hz, 1H), 8.0 (d,
J =8.4
Hz, 1H), 7.76 (s, 2H, NH
2), 7.68 (s, 2H, NH
2), 7.68 (t,
J =3.2
Hz, 1H), 7.66 (d,
J =6.8
Hz, 1H), 7.46 (d,
J =7.6
Hz, 1H), 7.24 (s, 1H), 7.17 (d,
J =8.0
Hz, 1H), 6.80 (d,
J =8.0
Hz, 1H), 4.46-4.41 (q,
J =0.4
Hz, 2H), 4.10 (s, 2H), 3.39 (t,
J =0.4
Hz, 2H), 3.04 (d,
J =8.0
Hz, 2H), 1.40 (t,
J =0.4
Hz, 3H)。
實施例69
N-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)萘-1-基)乙醯胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:9.93 (s, 1H, -NH), 8.11 (d,
J =0.4
Hz, 1H), 7.92 (d,
J =8.0
Hz, 1H), 7.72 (s, 1H), 7.66 (d,
J =0.4
Hz, 1H), 7.50 (t,
J =0.4
Hz, 1H), 7.49 (t,
J =0.4
Hz, 1H), 7.34 (d,
J =7.6
Hz, 1H), 7.17 (s, 1H), 7.13 (d,
J =8.4
Hz, 1H), 6.82 (d,
J =8.0
Hz, 1H), 6.40 (s, 2H, NH
2), 6.00 (s, 2H, NH
2), 4.03 (s, 2H), 3.26 (t,
J =0.4
Hz, 2H), 2.96 (d,
J =8.0
Hz, 2H), 2.33 (s, 3H)。
實施例70
5-((5-甲氧基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.65 (s, 1H), 6.74 (s, 1H), 6.62 (d,
J=2Hz, 2H), 6.12 (s, 2H, NH
2), 5.84 (s, 2H, NH
2), 3.83 (s, 2H), 3.66 (s, 3H), 3.4 (t,
J=0.4Hz, 2H), 2.80(t
, J=0.4Hz, 2H)。
實施例71
5-(吲哚啉-1-基甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 1H), 7.10 (d,
J=6.4Hz 2H), 7.02 (d
, J=7.6Hz, 2H), 7.01-7.03 (m, 2H, NH
2), 6.62-6.69 (m, 2H, NH
2), 3.98 (s, 2H), 2.91 (t,
J=16.0Hz, 2H), 2.91 (t,
J=0.4Hz, 2H)。
實施例72
5-((4,5,6-三甲氧基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.69 (s, 2H, NH
2), 7.53 (s, 2H, NH
2), 6.25 (s, 1H), 3.96 (s, 2H), 3.79 (s, 3H, OCH
3), 3.74 (s, 3H, OCH
3), 3.34 (s, 3H, OCH
3), 3.29-3.16 (m, 2H), 3.14-2.84 (m, 2H)。
實施例73
1-((2,4-二胺基嘧啶-5-基)甲基)-4,5,6-三甲氧基吲哚啉-2,3-二酮
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.89 (s, 1H), 6.63 (s, 1H), 6.30 (s, 2H, NH
2), 5.98 (s, 2H, NH
2), 4.60 (s, 2H), 4.03 (s, 3H, OCH
3), 3.93 (s, 3H, OCH
3), 3.63 (s, 3H, OCH
3)。
實施例74
5-((5-氯吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.64 (s, 1H), 7.07 (s, 1H), 7.06 (d,
J=12.4Hz, 1H), 7.03 (d,
J=6.4Hz, 1H), 6.17 (s, 2H, NH
2), 5.91 (s, 2H, NH
2), 3.92 (s, 2H), 3.16 (t,
J=4.0Hz, 2H), 2.85 (t
, J=0.4Hz, 2H)。
實施例75
5-((5-氟吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.65 (s, 1H), 6.95 (d,
J=2.4Hz, 1H), 6.93-6.80(m, 1H), 6.66-6.63 (m, 1H), 6.13 (s, 2H, NH
2), 5.86 (s, 2H, NH
2), 3.87 (s, 2H), 3.11 (t,
J=0.4Hz, 2H), 2.84 (t ,
J=0.4Hz, 2H)。
實施例76
5-((5-溴吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.64 (s, 1H), 7.19 (s, 1H), 7.18-7.14 (m, 1H), 6.62 (d,
J=8.4Hz, 1H), 6.13 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.91 (s, 2H), 3.16 (t,
J=0.4Hz, 2H), 2.88 (t,
J=2.8Hz, 2H)。
實施例77
2-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1,1,1,3,3, 3-六氟丙-2-醇
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.65 (s, 1H), 7.30(d,
J=9.2Hz, 2H), 6.73 (d,
J=8.4Hz, 1H), 6.14 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.98 (s, 2H), 3.23 (t,
J=0.8Hz, 2H), 2.90(t,
J=0.4Hz, 2H), 1.64 (s, 1H)。
實施例78
5-((7-甲氧基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.5 (s, 1H, NH
2), 7.71 (s, 1H), 7.56 (s, 1H), 7.4 (s, 2H), 6.83-6.74 (m, 1H, 2H, NH
2), 4.20(s, 2H), 3.78 (s, 3H), 3.35 (t,
J=7.6Hz, 2H), 2.94 (t,
J=0.4Hz, 2H)。
實施例79
5-((6-甲氧基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.8 (s, 1H, NH
2), 7.68 (s, 1H), 7.54 (s, 2H, NH
2), 6.96 (d,
J=8.0Hz, 1H), 6.27 (s, 1H, NH
2), 6.22-6.20(q, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 3.25 (t,
J= 28Hz, 2H), 2.92 (t,
J=16Hz, 2H)。
實施例80
5-((5,6-二甲氧基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.66 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 6.14 (s, 2H, NH
2), 5.86(s, 2H, NH
2), 3.87 (s, 2H), 3.72 (s, 3H, OCH
3), 3.65 (s, 3H, OCH
3), 2.89 (t
, J=14.4Hz, 2H), 2.73 (t,
J=2Hz, 2H)。
實施例81
5-((5-(1,1,1,3,3,3-六氟-2-甲氧基丙-2-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.66 (s, 1H), 7.15 (s, 2H), 6.78 (d,
J=8.4Hz, 1H), 6.15 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 4.00(s, 2H), 3.40(s, 3H, OCH
3), 3.27 (t
, J=1Hz, 2H), 2.95 (t,
J=8.4Hz, 2H)。
實施例82
5-((5-苯基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.57 (d,
J=14.4Hz, 2H), 7.56-7.33 (m, 4.0H), 7.26-7.22 (m, 2H), 6.76 (d,
J=8.4Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.98 (s, 2H), 3.20(t,
J=0.4Hz, 2H), 2.92 (t,
J=0.4Hz, 2H)。
實施例83
5-((5-(3-甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.38 (s, 1H), 7.34 (d,
J=6.0Hz, 1H), 7.32 (d
, J=6.0Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 7.07 (d,
J=2Hz, 1H), 6.83 (t,
J= 1.6Hz, 1H), 6.76 (t,
J=9.2Hz, 1H), 6.14 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.98 (s, 2H), 3.80(s, 2H, OCH
3), 3.18 (t
, J=6.4Hz, 2H), 2.94 (t,
J=2Hz, 2H)。
實施例84
5-((5-(2-甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.8 (s, 1H, NH
2), 7.71 (s, 1H), 7.26 (t,
J=1.6Hz, 2H), 7.25 (d,
J=1.6Hz, 1H), 7.22 (d,
J=2Hz, 2H), 7.07 (s, 1H), 7.05 (s, 1H), 6.66 (s, 2H, NH
2), 5.76 (s, 1H, NH
2), 4.01 (s, 2H), 3.74 (s, 2H, OCH
3), 3.29 (t,
J=0.4Hz, 2H), 2.95 (t,
J=1.6Hz, 2H)。
實施例85
5-((5-甲氧基-2-甲基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.50(s, 1H, NH
2), 8.20(s, 1H, NH
2), 7.80(s, 1H), 7.54 (s, 寬峰, 2H, NH
2), 6.76 (s, 1H), 6.55 (d,
J=2.8Hz, 1H), 6.26 (d, J =8.4Hz, 1H), 3.85 (t,
J=2.8Hz, 2H), 3.81 (s, 3H, OCH
3), 3.35 (s, 1H), 3.18-3.10(m, 1H), 2.56-2.50(m, 1H), 1.21 (d,
J=6.0Hz, 3H, CH
3)。
實施例86
5-((5-甲氧基-2-甲基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.45 (s, 1H), 7.39 (d,
J=1.6Hz, 2H), 7.37 (s, 3H), 7.09 (s, 1H), 7.08 (s, 1H), 7.05 (s, 2H, NH
2), 6.80(s, 2H, NH
2), 6.71 (t,
J= 1.2Hz, 1H), 6.45 (d, J =8.0Hz, 1H), 4.61 (t
, J=0.4Hz, 1H), 3.86 (s, 2H), 3.40(9, 1H), 2.88 (s, 1H)。
實施例87
5-((5-(三氟甲氧基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.50(s, 1H, NH
2), 7.68 (s, 1H), 7.49 (s, 2H, NH
2), 7.43 (s, 1H, NH
2), 7.08 (s, 1H), 6.64 (d,
J=8.8 Hz, 2H), 3.99 (s, 2H), 3.30(t
, J=16.8Hz, 2H), 2.94 (t,
J=0.4Hz, 2H);ESI-MS(m/z):326.05 (50%) (M+H)
+;UPLC純度:93.22% (3.11 min)
實施例88
5-((5-(6-甲氧基吡啶-3-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.08 (d,
J=2Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.65 (d,
J=2 Hz, 1H), 7.26 (s, 1H), 7.21 (t,
J=6.0Hz, 1H), 6.73 (d, J =8.4Hz, 1H), 6.17 (s, 2H, NH
2), 5.90(s, 2H, NH
2), 3.98 (s, 2H), 3.86 (s, 3H, OCH
3), 3.20(t,
J =0.4Hz, 2H), 2.90(t,
J=5.6Hz, 2H)。
實施例89
5-((6-氯吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.64 (s, 1H), 7.01 (d,
J=7.6Hz, 1H), 6.72 (s, 1H), 6.60(d,
J=2Hz, 1H), 6.15 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 3.94 (s, 2H), 3.19 (t,
J=8.4Hz, 2H), 2.82 (t
, J=8.4Hz, 2H)。
實施例90
5-((5-甲基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.64 (s, 1H), 6.88 (s, 1H), 6.82 (d,
J=8.0Hz, 1H), 6.58 (d,
J=7.6Hz, 1H), 6.18 (s, 2H, NH
2), 5.91 (s, 2H, NH
2), 3.86 (s, 2H), 2.80(t,
J=16.0Hz, 2H), 2.68 (t
, J=0.4Hz, 2H), 2.18 (s, 3H)。
實施例91
5-((5-(吡啶-4-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.50(d,
J=4.4Hz, 2H) 7.67 (s, 1H), 7.60(d
, J=5.6Hz, 2H) 6.78 (d,
J=9.2Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.03 (s, 2H), 3.25 (t,
J=0.4Hz, 2H), 2.95 (t,
J=1.6Hz, 2H)。
實施例92
5-((5-(苯基乙炔基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.48 (s, 1H), 7.48 (d,
J=2Hz, 2H), 7.47 (d
, J=3.2Hz, 3H), 7.41 (s, 1H), 7.22 (d
, J=1.6Hz, 1H), 6.68 (d,
J=8.4Hz, 1H), 6.15 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.00(s, 2H), 3.29 (t,
J=1.6Hz, 2H), 2.89 (t,
J=0.8Hz, 2H)。
實施例93
5-((5-(3,4,5-三甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.39 (s, 1H), 7.35 (d,
J= 7.4Hz, 1H), 6.79 (s, 2H), 6.73 (d,
J=8.4Hz, 1H), 6.21 (s, 2H, NH
2), 5.92 (s, 2H, NH
2), 3.98 (s, 2H), 3.84 (s, 6.0H, -OCH
3), 3.66 (s, 3H, OCH
3), 3.20(t,
J= 0.4Hz, 2H), 2.92 (t,
J= 0.4Hz, 2H)。
實施例94
5-((5-(3-(三氟甲氧基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.63 (s, 1H), 7.61 (d,
J=1.6Hz, 2H), 7.53 (s, 2H), 7.39 (t,
J=4.8Hz, 1H), 6.76 (d,
J=8.4Hz, 1H), 6.24 (s, 2H, NH
2), 5.96 (s, 2H, NH
2), 4.00(s, 2H), 3.24 (t,
J=16.8Hz, 2H), 2.92 (t,
J=16.8Hz, 2H)。
實施例95
5-((5-(4-(三氟甲氧基)苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.67 (d,
J= 2.8Hz, 2H), 7.39-7.35 (q,
J=7.2Hz, 4.0H), 6.76 (d,
J=8.4Hz, 1H), 6.14 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.99 (s, 2H), 3.22 (t,
J=0.4Hz, 2H), 2.94 (t,
J=8.0Hz, 2H)。
實施例96
5-((5-(2,4-二甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.68 (s, 1H), 7.12 (d,
J=4.0Hz, 2H), 7.11 (s, 1H), 6.70(s, 1H), 6.69 (s, 1H), 6.61 (d,
J=2.4Hz, 1H), 6.14 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 3.94 (s, 2H), 3.78 (s, 3H, OCH
3), 3.74 (s, 3H, OCH
3), 3.17 (t,
J=0.4Hz, 2H), 2.68 (t,
J= 8.0Hz, 2H)。
實施例97
5-((5-(3-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.67 (s, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.53 (t
, J=2Hz, 1H), 7.42 (d,
J=2Hz, 2H), 7.28 (d,
J=0.8Hz, 1H), 7.28 (d,
J=0.8Hz, 1H), 6.13 (s, 2H, NH
2), 5.76 (s, 2H, NH
2), 4.0 (s, 2H), 3.25 (t,
J=0.4Hz, 2H), 2.94 (t,
J=0.4Hz, 2H)。
實施例98
5-((2,3,3-三甲基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.80 (s, 2H, NH
2), 7.59 (s, 1H), 7.10 (d,
J=7.5Hz, 1H), 6.90 (t,
J=7.5Hz, 1H), 6.66 (t,
J=7.5Hz, 1H), 6.40 (d,
J=7.2Hz, 1H), 6.10 (s, 2H, NH
2), 4.05 (s, 2H), 3.18 (m, 1H), 2.10 (s, 3H), 1.8 (s, 3H), 1.2 (s, 3H),註:發現額外的質子,因為異構物的可能性。
實施例99
5-((5-(萘-2-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.08 (s, 1H), 7.93 (d,
J=8.8Hz, 2H), 7.89 (d,
J =8.0Hz, 1H), 7.80 (d,
J= 2Hz, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.52 (d,
J=1.2Hz, 1H), 6.81 (d,
J=8.0Hz, 1H), 6.16 (s, 2H, NH
2), 5.87 (s, 2H, NH
2), 4.01 (s, 2H), 3.24 (t,
J=0.4Hz, 2H), 2.97 (t,
J=0.4Hz, 2H)。
實施例100
5-((6-氟吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:7.65 (s, 1H), 6.99 (d,
J=0.4Hz, 1H), 6.55 (s, 1H), 6.52 (d,
J= 6.8Hz, 1H), 6.14 (s, 2H, NH
2), 5.88 (s, 2H, NH
2), 3.94 (s, 2H), 3.19 (t, J =0.4Hz, 2H), 2.81 (t,
J=0.4Hz, 2H)。
實施例101
5-((5-(間甲苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ7.67(m,
J = 2.0Hz,1H), 7.37-7.26(m, 5H), 7.10(m, 1H), 6.76-6.74(m, 1H), 6.18-6.15(m, 2H), 5.86-5.85(m, 2H), 3.97(s, 2H), 3.19(m, 2H), 2.91(m, 2H), 2.32(s, 3H)。
實施例102
5-((4-(3-甲氧基苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ 7.67(s, 1H), 7.36-7.32(m, 1H), 7.14-7.10(m, 1H), 7.02-7.0(m, 1H), 6.97-6.96(m, 1H), 6.92-6.90(m, 1H), 6.72-6.70(m, 2H), 6.23(s, 2H), 5.95(s, 2H), 3.95(s, 2H), 3.79(s, 3H), 3.11(t,
J=8.0Hz, 2H), 2.95-2.91(t,
J=8.2Hz, 2H)。
實施例103
5-((4-苯基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) δ 7.67(s, 1H), 7.46-7.41(m, 4H), 7.36-7.32(m, 1H), 7.15-7.11(m, 1H), 6.71(d,
J=8.0Hz, 2H), 6.22(s, 2H), 5.94(s, 2H), 3.95(s, 2H), 3.14-3.10(m, 2H), 2.95-2.90(m, 2H)。
實施例104
5-((5-(吡啶-3-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ 12.01(bs, 1H), 9.11(s, 1H), 8.71-8.68(m, 2H), 8.43(s, 1H), 7.98-7.95(m, 1H), 7.70-7.59(m, 5H), 6.79(d,
J=8.4Hz, 1H), 4.11(s, 2H), 3.54-3.43(m, 2H), 3.17-3.06(m, 2H)。
實施例105
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ 7.82(d, J=8.4Hz, 2H), 7.67(s, 1H), 7.43-7.33(m, 4H), 6.75(d, J=8.0Hz, 1H), 6.13(s, 2H), 5.86(s, 2H), 3.97(s, 2H), 3.20-3.16(m, 2H), 2.93-2.91(m, 2H)。
實施例106
5-((4-(3-氯苯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) 7.67(s, 1H), 7.48-7.40 (m, 4H), 7.16-7.12(m, 1H), 6.75-6.71(m, 2H), 6.23(s, 2H), 5.94(s, 2H), 3.96(s, 2H), 3.15-3.11(m, 2H), 2.95-2.93(m, 2H)。
實施例107
5-((5-(乙基磺醯基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) 7.63(s, 1H), 7.48-7.46 (m, 1H), 7.40(s, 1H), 6.74(d, J=8.4Hz, 1H), 6.17(s, 2H), 5.88(s, 2H), 4.09(s, 2H), 3.41-3.36(m, 2H), 3.13-3.08(m, 2H), 2.99-2.94(m, 2H), 1.07(t, J=7.40, 3H)。
實施例108
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-4-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) 7.93-7.91(m, 2H), 7.67 (s, 1H), 7.46-7.44(m, 2H), 7.16-7.12(m, 1H), 6.74-6.71(m, 2H), 6.14(s, 2H), 5.87(s, 2H), 3.95(s, 2H), 3.14-3.10(m, 2H), 2.96-2.92(m, 2H)。
實施例109
4-(1-((2,4-二胺基-6-乙基嘧啶-5-基)甲基)吲哚啉-5-基)苯甲酸
1H NMR (DMSO-
d
6 , 400 MHz) 7.83-7.81(m, 2H), 7.43-7.34(m, 4H), 6.78-6.76(m, 1H), 6.04(s, 2H), 5.78(s, 2H), 4.04(s, 2H), 3.3-3.28(m, 2H), 3.16-3.14(m, 2H), 2.88(m, 2H), 1.10(t,
J=7.6Hz, 3H)。
實施例110
5-((4-(3-氯苯基)吲哚啉-1-基)甲基)-6-乙基嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) 7.48-7.41(m, 4H), 7.16-7.14(m, 1H), 6.77-6.71(m, 1H), 6.03(s, 2H), 5.76(s, 2H), 3.18-3.09(m, 4H), 2.91-2.87(m, 2H), 1.11(t,
J=7.6Hz, 3H)。
實施例111
5-((5-硝基吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1H NMR (DMSO-
d
6 , 400 MHz) 8.0-7.95(m, 1H), 7.83(m, 1H), 7.63(s, 1H), 6.68(d,
J=8.8Hz, 1H), 6.25(s, 2H), 5.94(s, 2H), 4.20(s, 2H), 3.55-3.51(m, 2H), 3.04-2.99(m,
2H)。
實施例112
1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-甲腈
1H NMR (DMSO-
d
6 , 400 MHz) 7.95(s, 1H), 7.49-7.47 (m, 1H), 7.40(d,
J=1.2Hz, 1H), 6.73(d,
J=8.4Hz, 1H), 4.20(s, 2H), 3.45-3.41(m, 2H), 3.07-3.03(m,
2H)。
實施例113
N-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)異丁醯胺
1HNMR (DMSO-
d 6):9.49 (s, 1H), 7.64 (s, 1H), 7.18 (dd,
J 1= 2 Hz,
J
2 = 8.4Hz, 2H), 6.61 (d,
J= 8.4 Hz, 2H), 6.11 (s, 2H), 5.84 (s, 2H), 3.86 (s, 2H), 3.08 (t,
J= 8.4 Hz, ,2H), 2. (t,
J= 8 Hz, 2H), 1.24 (t,
J= 6.8 Hz, 6H)。
實施例114
N-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)異丁醯胺鹽酸鹽
1HNMR (DMSO-
d 6):9.58 (s, 1H), 8.38 (s, 1H), 7.72-7.66 (m, 3H), 7.39 (m, 1H), 7.24-7.22 (dd,
J 1= 2 Hz,
J
2 = 8.4Hz, 1H), 6.6 (d,
J= 8.8 Hz, 1H), 3.2 (t,
J= 8 Hz, 2H), 2.88 (t,
J= 7.6 Hz, 2H), 1.07 (t,
J= 6.8 Hz, 6H)。
實施例115
1-((2,4-二胺基嘧啶-5-基)甲基)-N,N-二甲基吲哚啉-5-甲醯胺
1HNMR (DMSO-
d 6):7.65 (s, 1H), 7.12 (t,
J= 1.6 Hz, 2H), 6.65 (d,
J= 8.84 Hz, 1H), 6.13 (bs, 2H), 5.68 (bs, 2H), 3.98 (s, 2H), 3.22 (t,
J= 8.4 Hz, 2H), 2.95 (s, 6H), 2.88 (t,
J= 7.6 Hz, 2H)。
實施例116
N-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)乙醯胺
1HNMR (DMSO-
d 6):9.61 (s, 1H), 7.65 (s, 1H), 7.34 (d,
J= 2 Hz, 2H), 7.15 (dd,
J
1 = 8.84,
J 2= 8.4 Hz, 1H), 6.61 (bs, 2H), 5.68 (d,
J= 8.4 Hz, 2H), 6.10 (s, 1H), 5.84 (s, 1H), 3.86 (s, 2H), 2.80 (t,
J= 8 Hz, 2H), 2.67 (t,
J= 1.6 Hz, 2H), 1.97 (s,3H)。
實施例117
1-((2,4-二胺基嘧啶-5-基)甲基)-N-甲基吲哚啉-5-甲醯胺
1HNMR (DMSO-
d 6):8.04-8.03 (m, 1H), 7.64 (s, 1H), 7.57-7.53 (m, 2H), 6.65 (d,
J= 8.4 Hz, 1H), 6.2-6.19 (m, 2H), 5.86 (s, 2H), 4.01 (s, 2H), 2.73-2.68 (m, 2H), 2.55 (s, 3H), 2.34-2.33 (m,2H)。
實施例118
(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)(N-
啉基)甲酮
1HNMR (DMSO-
d 6):7.65 (s, 1H), 7.12 (d,
J= 4.8 Hz, 2H), 6.65 (d,
J= 4.8 Hz, 1H), 6.13 (m, 2H), 5.86 (s, 2H), 3.99 (s, 2H), 3.58 (m, 4H), 3.49 (m, 4H), 3.24 (d,
J= 8.4 Hz, 2H), 2.89 (d,
J= 8.4 Hz, 2H)。
實施例119
1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-甲醯胺
1HNMR (DMSO-
d 6):7.80 (dd,
J
1 = 2 Hz,
J
2 = 8.4 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 6.73 (d,
J= 8.8 Hz, 2H), 4.28(s, 2H), 3.63 (t,
J= 8.8 Hz, 2H), 3.14 (t,
J= 3.2 Hz, 2H)。
實施例120
(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)胺甲酸乙酯
1HNMR (DMSO-
d 6):9.1 (bs, 1H), 7.64 (s, 1H), 7.17 (m, 2H), 6.61 (d,
J= 8.8 Hz, 1H), 6.10 (m, 2H), 5.85 (s, 2H), 4.06 (t,
J= 7.2 Hz, 2H), 3.85(s, 2H), 3.05 (t,
J= 8.8 Hz, 2H), 2.8 (t,
J= 8.0 Hz, 2H)。
實施例121
2-氯-N-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-硝基苯甲醯胺
1HNMR (DMSO-
d 6):10.41 (s, 1H), 8.41 (s, 1H), 8.29 (dd,
J
1 = 2 Hz,
J
2 = 8.4 Hz, 1H), 7.85 (d,
J= 8.4 Hz, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 6.68 (d,
J= 8 Hz, 1H), 6.13 (s, 2H), 5.86 (s, 2H), 3.91 (s, 2H), 3.12 (t,
J= 8.0 Hz, 2H), 2.87 (t,
J= 7.6 Hz, 2H)。
實施例122
2-氯-N-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-3,4-二甲氧基苯甲醯胺
1HNMR (DMSO-
d 6):7.97 (s, 1H), 7.94 (s, 1H), 7.72 (d,
J= 8.4 Hz, 1H), 7.47 (d,
J= 8.8 Hz, 1H), 7.34 (d,
J= 8.8 Hz, 1H), 7.13 (d,
J= 8.8 Hz, 1H), 4.6 (s, 2H), 4.03 (d,
J= 7.6 Hz, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 3.41 (t,
J= 7.6 Hz, 2H)。
實施例123
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)咪唑并[1,2-a]吡啶-2-甲酸
1HNMR (CD
3OD + DCl):8.50 (s, 1H), 8.12 (m, 1H), 7.87 (d,
J= 8.8 Hz, 1H), 7.475 (s, 1H), 7.54 (m, 2H), 7.46 (d,
J= 8.8 Hz, 1H), 6.90 (d,
J= 8.8 Hz, 1H), 5.22 (s, 2H), 3.59-3.50 (m, 2H), 2.11-1.95 (s, 2H)。
實施例124
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2,3-二氫苯并[b][1,4]二奧辛-5-甲酸
1HNMR (CD
3OD):7.73 (s, 1H), 7.32 (s, 1H), 7.30 (m, 1H), 7.24 (d,
J= 2.4 Hz, 1H), 6.97 (d,
J= 2 Hz, 1H), 6.73 (d,
J= 8.4 Hz, 1H), 4.28 (s, 2H), 3.59-3.50 (m, 4H), 4.02 (s, 2H), 3.36-3.35 (m, 1H), 3.18 (t,
J= 8.4 Hz, 1H), 2.97 (t,
J= 8.4 Hz, 2H)。
實施例125
環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (CD
3OD + HCl):9.17 (s, 1H), 8.61-8.56 (m, 2H), 8.13 (d,
J= 7.2 Hz, 1H), 7.84-7.78 (m, 3H), 4.37 (s, 2H), 4.14-4.13 (m, 1H), 3.66 (t,
J= 8.0 Hz, 1H), 3.29 (t,
J= 8.0 Hz, 1H), 1.56 (m, 2H), 1.37 (t,
J= 7.2 Hz, 2H)。
實施例126
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-2-萘甲酸
1H NMR (DMSO-d
6, 400 MHz) δ:8.55 (s, 1H), 8.06 (d, J =8.0Hz, 2H), 7.99 (d, J =8.8Hz, 2H), 7.96(s, 1H), 7.93 (d, J =1.6Hz, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.14 (d, J=8.0Hz, 1H), 6.83 (d, J =8.0Hz, 1H), 6.20 (s, 2H, NH
2), 5.92 (s, 2H, NH
2), 4.03 (s, 2H), 3.25 (t, J =0.4Hz, 2H), 2.96 (t, J =16.0Hz, 2H)。
實施例127
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-4-基)-1-萘甲酸
1H NMR (DMSO-d6, 400 MHz) δ:8.95 (d, J =7.2Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.66 (d, J =7.2Hz, 1H), 7.51 (d, J =8.0Hz, 1H), 7.40 (d, J=1.6Hz, 2H), 7.38 (d, J=1.6Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 6.77 (d, J =7.6Hz, 1H), 6.14 (s, 2H, NH
2), 5.85 (s, 2H, NH
2), 4.00 (s, 2H), 3.09 (t, J =2.4Hz, 2H), 2.68 (t, J =0.4Hz, 2H)。
實施例128
4-(1-((2,4-二胺基嘧啶-5-基)甲基)-6-甲氧基吲哚啉-5-基)-1-萘甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.90 (d,
J =10.0
Hz, 1H), 8.11 (d,
J =7.2
Hz, 1H), 8.74 (s, 1H), 7.63 (d,
J =8.8
Hz, 1H), 7.59 (t,
J=1.2
Hz, 2H), 7.47 (t,
J=0.4
Hz, 1H), 7.36 (d,
J=7.6
Hz, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 6.23 (s, 2H, NH
2), 5.94 (s, 2H, NH
2), 4.09 (s, 2H), 3.54 (s, 3H, -OCH
3), 3.23 (t,
J =2.4
Hz, 2H), 2.85 (t,
J =16.0
Hz, 2H)。
實施例129
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-6-基)-1-萘甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.95 (d,
J =8.8
Hz, 1H), 8.18 (t,
J =0.4
Hz, 1H), 7.95 (d,
J =8.0
Hz, 1H), 7.72 (s, 1H), 7.68 (t,
J=0.4
Hz, 1H), 7.63 (d,
J =1.2
Hz, 1H), 7.47 (d,
J =7.2
Hz, 1H), 7.24 (s, 2H, NH
2), 7.17 (s, 2H, NH
2), 6.83 (s, 1H), 6.73 (d,
J =7.6
Hz, 1H), 6.56 (s, 1H), 4.02 (s, 2H), 3.29 (t,
J =0.4
Hz, 2H), 2.98 (t,
J =0.4
Hz, 2H)。
實施例130
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)萘-2-醇
1H NMR (DMSO-
d
6 , 400 MHz) δ:9.76 (s, 1H, -OH), 8.14 (s, 2H, NH
2), 7.73 (t,
J =2.8
Hz, 2H), 7.38 (s, 1H), 7.21 (s, 1H), 8.14 (s, 2H, NH
2), 7.16 (s, 1H), 7.10 (s, 1H), 7.09 (d,
J =2.0
Hz, 2H), 6.91 (d,
J =2.4
Hz, 1H), 6.75 (d,
J =8.0
Hz, 1H), 4.04 (s, 2H), 3.60 (t,
J =0.4
Hz, 2H), 3.10 (t,
J =0.4
Hz, 2H)。
實施例131
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)萘-1-醇
1H NMR (DMSO-
d
6 , 400 MHz) δ:10.12 (s, 1H, -OH), 8.20 (d,
J =2.8
Hz, 1H), 7.83 (d,
J =1.6
Hz, 1H), 7.82 (d,
J =3.6
Hz, 1H), 7.28 (s, 1H), 7.43 (t,
J =0.8
Hz, 2H), 7.16 (d,
J =7.6
Hz, 1H), 7.12 (s, 1H), 7.06 (d,
J =8.0
Hz, 1H), 6.90 (d,
J =7.6
Hz, 1H), 6.77 (s, 2H, NH
2), 6.44 (s, 2H, NH
2), 4.02 (s, 2H), 3.25 (t,
J =0.4
Hz, 2H), 2.95 (t,
J =0.4
Hz, 2H)。
實施例132
1-氯-6-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)萘-2-醇
1H NMR (DMSO-
d
6 , 400 MHz) δ:10.20 (s, 1H, -OH), 8.50 (s, 2H, NH
2), 8.04 (s, 1H), 8.03 (d,
J =1.6
Hz, 2H), 7.86 (d,
J =2.0
Hz, 1H), 7.82 (d,
J =7.2
Hz, 1H), 7.68 (s, 1H), 7.26 (d,
J =9.2
Hz, 1H), 6.75 (d,
J =8.0
Hz, 1H), 6.44 (s, 2H, NH
2), 4.00 (s, 2H), 3.24 (t,
J =16.8
Hz, 2H), 2.96 (t,
J =0.4
Hz, 2H)。
實施例133
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-乙基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.48 (s, 1H,
-COOH), 9.07 (d,
J =13.2
Hz, 1H), 8.37 (d,
J =8.8
Hz, 1H), 8.01 (s, 1H), 7.91 (d,
J =8.0
Hz, 1H), 7.69 (s, 2H), 7.64 (d,
J=8.4
Hz,1H), 7.11 (s, 2H, NH
2), 6.80 (d,
J =8.0
Hz, 1H), 6.75 (s, 2H, NH
2), 4.12 (s, 2H), 3.05 (t,
J =0.4
Hz, 2H), 2.66 (t,
J =1.6
Hz, 2H), 1.46 (t,
J =14.4
Hz, 3H)。
實施例134
5-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:9.45 (s, 1H), 8.84 (d,
J =8.8
Hz, 1H), 8.10 (d,
J =8.8
Hz, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.64 (d,
J =6.0
Hz, 1H), 7.54 (t,
J=1.2
Hz, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.62 (s, 2H, NH
2), 6.29 (s, 2H, NH
2), 4.05 (s, 2H), 3.92 (t,
J =4.8
Hz, 2H), 3.59 (t,
J =0.4
Hz, 2H)。
實施例135
1-(4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)苯氧基)-3-(吡咯啶-1-基)丙-2-醇三甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.33 (s
(br), 3H,
-COOH), 7.66 (s, 1H), 7.46 (d, H = 8.4 Hz, 2H), 7.31-7.25 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.23 (s
(br), 2H), 5.99 (s
(br), 2H), 3.99-3.87 (m, 7H), 3.19-3.15 (m, 2H), 2.92-2.89 (m, 2H), 2.80-2.50 (m, 4H), 1.74-1.72 (m, 4H)。
實施例136
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-異丙基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.43 (s, 1H,
-COOH), 8.87 (s, 1H), 8.40 (d,
J =8.8
Hz, 1H), 8.17 (s, 1H), 7.93 (d,
J =8.4
Hz, 1H), 7.70 (s, 2H), 7.65 (d,
J=8.0
Hz,1H), 7.10(s, 2H, NH
2), 6.80 (d,
J =8.0
Hz, 1H), 6.62 (s, 2H, NH
2), 5.51 (t,
J =12.8
Hz, 1H), 4.09 (s, 2H), 3.02 (t,
J =0.4
Hz, 2H), 2.68 (t,
J =3.2
Hz, 2H), 1.60 (d,
J =6.4
Hz, 6H)。
實施例137
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-甲基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.43 (s, 1H,
-COOH), 9.05 (s, 1H), 8.36 (d,
J =8.4
Hz, 1H), 7.96 (d,
J =8.0
Hz, 1H), 7.93 (s, 1H), 7.70 (d,
J =8.8
Hz, 1H), 7.65(s, 1H), 7.64 (s, 1H), 7.11 (s, 2H, NH
2), 6.97 (s, 2H, NH
2), 6.80 (d,
J =8.4
Hz, 1H), 4.19 (s, 2H), 4.10 (s, 2H), 3.36 (t,
J =0.4
Hz, 2H), 2.68 (t,
J =0.4
Hz, 2H)。
實施例138
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-(2-(二甲基胺基)乙基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (CD
3COOD, 400 MHz) δ:9.21 (s, 1H), 8.54 (d,
J =8.4
Hz, 1H), 7.98 (s, 2H), 7.88 (d,
J =8.4
Hz, 1H), 7.64 (d,
J =8.0
Hz, 2H), 6.86 (d,
J =7.6
Hz, 1H), 6.16 (s, 2H,
-NH
2), 5.88m (S, 2H, NH
2), 5.16 (s, 2H), 4.21 (s, 2H), 3.84 (s, 2H), 3.41 (t,
J =16.0
Hz, 2H), 3.14 (d,
J =7.2
Hz, 2H), 3.09 (s, 6H)。
實施例139
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘醯胺
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.45 (s, 1H), 8.04 (s, 1H), 7.99 (d,
J =2.0
Hz, 2H), 7.98 (s, 1H), 7.82 (d,
J =2.0
Hz, 1H), 7.80 (d,
J =1.6
Hz, 1H), 7.44-7.42 (d,
J =2.4
Hz, 1H), 7.47 (t,
J =7.2
Hz, 1H), 7.42 (t,
J =4.0
Hz, 1H), 6.81 (d,
J =8.4
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.88m (S, 2H, NH
2), 4.02 (s, 2H), 3.26 (t,
J =0.4
Hz, 2H), 2.99 (t,
J =0.8
Hz, 2H)。
實施例140
4-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-萘甲腈
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.19-8.17 (dd,
J =0.4
Hz, 2H), 8.14 (d,
J =2.4
Hz, 1H), 7.84 (t,
J =4.8
Hz, 1H), 7.82 (s, 2H), 7.80 (d,
J =1.2
Hz, 1H), 7.69 (t,
J =1.6
Hz, 1H), 7.53 (d,
J =7.6
Hz, 1H), 6.85 (d,
J =8.0
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.88 (S, 2H, NH
2), 4.06 (s, 2H), 3.30 (t,
J =2.0
Hz, 2H), 2.99 (t,
J =0.4
Hz, 2H)。
實施例141
7-(3-(2-乙醯胺基乙基)-1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-環丙基-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯雙(2,2,2-三氟乙酸鹽)
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.20 (s, 1H, -NH), 8.52 (s, 2H), 8.22 (d,
J =8.4
Hz, 2H), 8.15 (d,
J =1.2
Hz, 1H), 7.68 (s, 2H), 7.59 (s, 1H), 6.75 (d,
J =8.0
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.88 (S, 2H, NH
2), 4.23 (s, 2H), 4.22 (m, 1H), 4.20 (q, 2H), 3.30 (t,
J =0.8
Hz, 2H), 3.17 (t,
J =0.4
Hz, 2H), 3.06 (m, 1H), 2.53 (s, 3H), 2.51-2.449 (q, 2H), 1.69 (s, 3H), 1.31-1.13 (q, 4H)。
實施例142
7-(3-(2-乙醯胺基乙基)-1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-環丙基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.78 (s, 1H), 8.34 (s, 1H), 8.22 (d,
J =7.6
Hz, 1H), 8.15 (d,
J =11.6
Hz, 2H), 7.93 (s, 1H, -NH), 7.76 (s, 1H), 7.69 (d,
J =13.2
Hz, 2H), 6.83 (s, 1H), ), 6.16 (s, 2H, -NH
2), 5.88 (S, 2H, NH
2), 4.13 (m, 1H), 4.09 (s, 2H), 3.99 (d,
J =8.8
Hz, 2H), 3.96-3.64 (m, 4H), 3.45 (t,
J =0.8
Hz, 2H), 1.79 (s, 3H) 1.63-1.05 (m, 2H)。
實施例143
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-乙基-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.13 (s, 1H,
-COOH), 9.08 (d,
J =10.0
Hz, 1H), 8.10(s, 1H), 7.98 (s, 1H), 7.69(s, 3H), 7.48 (s, 2H, -NH
2), 6.82 (d,
J =8.0
Hz, 1H), 6.74 (S, 2H, NH
2), 4.72,4.68 (dd,
J =14.4
Hz, 2H), 4.09 (s, 2H), 3.37 (t,
J =2.0
Hz, 2H), 3.02 (t,
J =0.4
Hz, 2H), 1.44 (t,
J =14.4
Hz, 3H)。
實施例144
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-乙基-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.95 (s, 1H,
-COOH), 8.91 (s, 1H), 7.94 (d,
J =9.2
Hz, 1H), 7.72 (s, 1H), 7.25 (s, 2H, -NH
2), 7.22 (s, 1H), 6.85 (S, 2H, NH
2), 6.82 (s, 1H), 6.81 (d,
J =8.0
Hz, 1H), 4.76,4.71 (q,
J =13.6
Hz, 2H), 4.08 (s, 2H), 3.38 (s, 3H, OCH
3), 3.32 (t,
J =0.4
Hz, 2H), 2.68 (t,
J =0.4
Hz, 2H), 1.40 (t,
J =0.4
Hz, 3H)。
實施例145
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)-6-氟吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.90 (s, 1H,
-COOH), 8.80 (s, 1H), 8.78 (s, 1H), 8.25 (d,
J =6.0
Hz, 1H), 8.16 (s, 2H, -NH
2), 8.10 (d,
J =9.6
Hz, 1H), 7.60 (s, 2H,
-NH
2), 7.28 (d,
J =7.6
Hz, 1H), 6.73 (d,
J =10.2
Hz, 1H), 4.13 (s, 2H), 3.94-3.89 (m, 1H), 3.45 (t,
J =16.8
Hz, 2H), 3.01 (t,
J =0.4
Hz, 2H), 1.3-1.2 (d,
J =3.2
Hz, 4H)。
實施例146
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-乙基-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.49 (s, 1H,
-COOH), 8.99 (s, 1H), 8.41 (s, 1H), 7.96 (d,
J =9.6
Hz, 1H), 7.61 (s, 2H, -NH
2), 7.35 (S, 2H, NH
2), 7.26 (s, 1H), 7.22 (s, 1H), 6.80 (d,
J =8.4
Hz, 1H), 4.71,4.66 (q,
J =0.4
Hz, 2H), 4.08 (s, 2H), 3.66 (s, 3H, OCH
3), 3.36 (t,
J =16.0
Hz, 2H), 3.01 (t,
J =0.4
Hz, 2H), 1.39 (t,
J =0.4
Hz, 3H)。
實施例147
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-1-異丙基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.12 (s, 1H,
-COOH), 8.89 (s, 1H), 8.18 (s, 2H), 8.14 (d,
J =8.0
Hz, 1H), 7.98 (s, 2H, -NH
2), 7.70 (s, 2H), 7.17 (S, 2H, NH
2), 6.79 (d,
J =8.4
Hz, 1H), 5.48-5.42 (m, 1H), 4.11 (s, 2H), 3.40 (t,
J =16.8
Hz, 2H), 3.04 (t,
J =16.8
Hz, 2H), 1.58 (d,
J =6.4
Hz, 6H)。
實施例148
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)-6-甲氧基吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.31 (s, 1H,
-COOH), 8.76 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.85 (d,
J =6.4
Hz, 1H), 7.98 (s, 2H, -NH
2), 7.78 (S, 2H, NH
2), 7.26 (s, 2H), 6.60 (s, 1H), 4.16 (s, 2H), 3.90-3.86 (m, 1H), 3.83 (s, 3H, -OCH3), 3.36 (t,
J =2.8
Hz, 2H), 2.95 (t,
J =0.4
Hz, 2H), 1.34 (d,
J =7.6
Hz, 2H), 1.30 (d,
J =7.6
Hz, 2H)。
實施例149
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)-6-氟吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.20 (s, 1H,
-COOH), 8.90 (s, 1H), 8.78 (d,
J =11.6
Hz, 1H), 8.42 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.73 (s, 2H, -NH
2), 7.70 (s, 1H), 7.48 (S, 2H, NH
2), 6.73 (d,
J =13.2
Hz, 1H), 4.12 (s, 2H), 3.93-3.88 (m, 1H), 3.42 (t,
J =0.4
Hz, 2H), 3.00 (t,
J =16.8
Hz, 2H), 1.31 (d,
J =6.0
Hz, 2H), 1.28 (d,
J =6.0
Hz, 2H)。
實施例150
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-(4-氟苯甲基)-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.04 (s, 1H,
-COOH), 9.21 (s, 1H), 8.35 (d,
J =8.4
Hz, 2H), 7.88 (d,
J =1.6
Hz, 2H), 7.86 (s, 2H), 7.75 (s, 2H, -NH
2), 7.65 (s, 1H), 7.55 (d,
J =8.0
Hz, 1H), 7.50 (S, 2H, NH
2), 7.20 (d,
J =8.8
Hz, 2H), 6.70 (d,
J =8.4
Hz, 1H), 5.91 (s, 2H), 4.06 (s, 2H), 3.36 (t,
J =16.8
Hz, 2H), 3.00 (t,
J =0.8
Hz, 2H)。
實施例151
1-環丙基-7-(1-((2,4-二胺基-6-乙基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.78 (s, 1H, NH
2), 12.26 (S, 1H,-COOH), 8.79 (s, 1H), 7.86 (d,
J =9.2
Hz, 1H), 7.66 (s, 2H, -NH
2), 7.63 (S, 1H, NH
2), 7.24 (s, 2H), 6.90 (d,
J =8.8
Hz, 1H), 4.26 (s, 2H), 4.24-4.18 (m, 1H), 3.42 (s, 3H, OCH
3), 3.27 (t,
J =0.4
Hz, 2H), 2.95 (t,
J =0.4
Hz, 2H), 2.33 (q,
J =0.4
Hz, 2H), 1.88 (t,
J =15.2
Hz, 3H), 1.03-0.89 (d,
J =2.0
Hz, 4H)。
實施例152
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲基-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.20 (s, 1H,
-COOH), 8.91 (s, 1H), 8.43 (s, 1H), 7.96 (d,
J =7.2
Hz, 1H), 7.92 (s, 2H, NH
2), 7.78 (s, 2H, -NH
2), 7.37 (s, 1H), 7.13 (s, 1H), 6.79 (d,
J =8.4
Hz, 1H), 4.36-4.34 (m, 1H), 4.07 (s, 2H), 3.71 (s, 3H,-CH
3), 3.35 (t,
J =0.4
Hz, 2H), 3.00 (t,
J =0.8
Hz, 2H), 1.24 (d,
J =6.4
Hz, 2H), 1.03 (d,
J =8.4
Hz, 2H)。
實施例153
(S)-10-(1-((2,4-二胺基-6-乙基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.01 (s, 1H,
-COOH), 9.06 (s, 1H), 7.70 (d,
J =9.6
Hz, 1H), 7.21 (s, 1H), 7.18 (s, 2H, NH
2), 7.17 (s, 1H), 7.10 (s, 2H, -NH
2), 6.84 (d,
J =8.8
Hz, 1H), 4.97 (d,
J =6.4
Hz, 1H), 4.52 (d,
J =10.4
Hz, 2H), 4.30 (d,
J =6.4
Hz, 2H), 4.11 (s, 2H), 3.23 (t,
J =0.4
Hz, 2H), 2.91 (t,
J =16.0
Hz, 2H), 1.46 (d,
J =6.8
Hz, 3H), 1.26 (t,
J =0.4
Hz, 3H)。
實施例154
8-氯-1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.98 (s, 1H,
-COOH), 8.92 (s, 1H), 8.08 (d,
J =8.4
Hz, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 7.30 (s, 2H, NH
2), 7.16 (s, 2H, -NH
2), 7.04 (s, 1H), 6.78 (d,
J =8.0
Hz, 1H), 4.40-4.20 (m, 1H), 4.09 (s, 2H), 3.38 (t,
J =0.4
Hz, 2H), 3.02 (t,
J =1.2
Hz, 2H), 1.24 (d,
J =4.0
Hz, 2H), 1.16 (d,
J =14.4
Hz, 2H)。
實施例155
5-乙醯胺基-1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸三鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.20 (s, 1H,
-COOH), 10.09 (s, 1H, -NH), 8.78 (d, J =7.6Hz, 1H), 8.42 (s, 1H), 7.78 (s, 2H), 7.39 (s, 2H, -NH
2), 7.13 (S, 2H, NH
2), 6.80 (d, J =8.0Hz, 1H), 4.22 (s, 3H, -OCH
3), 4.02 (s, 2H), 3.51-3.38 (m, 1H), 3.03 (t, J =0.4Hz, 2H), 2.67 (t, J =0.4Hz, 2H), 2.11 (s, 3H), 1.04, 1.01 (q, J =4.4Hz, 4H)。
實施例156
5-胺基-1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.68 (s, 1H,
-COOH), 8.64 (s, 1H), 7.73 (s, 1H), 7.6 (s
(br), 2H, -NH
2), 7.29-7.19 (m, 5H), 6.78 (d, J =8.4Hz, 1H), 4.12-4.09 (m, 1H), 4.07 (s, 2H), 3.38-3.33 (m, 5H), 3.00 (t, 2H, J = 8 Hz), 1.04, 1.01 (m,4H)。
實施例157
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.36 (s
(br), 1H,
-COOH), 8.82 (s, 1H), 8.42 (s, 1H), 7.72-7.71 (m, 1H), 7.65-7.21 (m, 6H), 6.79 (d, J = 8.0 Hz, 1H), 4.28-4.23 (m, 1H), 4.10 (s, 2H), 3.40-3.35 (m, 5H), 3.05-3.01 (t, 2H, J = 3.2 Hz), 1.23-1.18 (m, 4H)。
實施例158
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.83 (s, 1H), 7.80 (d, J =9.6Hz, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.19 (s, 4H, -NH
2), 6.79 (d, J =8.0Hz, 2H), 4.25-4.20 (q, J = 0.4Hz, 2H), 4.22-4.04 (m, 1H), 4.04 (s, 2H), 3.31 (t, J = 0.4Hz, 2H), 2.97 (t, J = 0.4Hz, 2H), 1.27 (t, J = 0.4Hz, 3H), 1.16 (s, 2H), 1.18 (d, J =6.0 Hz, 2H)。
實施例159
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.21 (s, 2H, HCl), 8.71 (s, 1H), 8.53 (d, J =8.8Hz, 1H), 7.82 (s, 2H), 7.56 (s, 4H, -NH
2), 7.19 (s, 2H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.21 (q, J =7.2 Hz, 2H), 4.01 (s, 2H), 3.77-3.72 (m, 1H), 3.46-3.37 (m, 2H), 3.06-2.99 (m, 2H), 1.29 (t, J =7.2 Hz, 3H), 1.16-1.12 (m, 2H), 1.10-1.08 (m, 2H)。
實施例160
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.23 (s
(br), 1H,
-COOH), 8.77 (s, 1H), 8.42 (s, 1H), 7.98-7.96 (m, 1H), 7.77-7.70 (m, 4H), 7.27-7.22 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.18-4.16 (m, 1H), 4.11 (s, 2H), 3.42 (t, J = 8 Hz, 2H), 3.03 (t, 2H, J = 8 Hz), 1.26-1.15 (m,4H)。
實施例161
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-3-乙基-9-氟-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.15 (s
(br), 1H,
-COOH), 9.04 (s, 1H), 8.42 (s, 1H), 7.75-7.67 (m, 5H), 7.21-7.16 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.80-4.76 (m, 1H), 4.67 (d, J = 10 Hz, 1H), 4.40 (d, J = 10 Hz, 1H), 4.06 (s, 2H), 3.35 (t, 2H, J = 8 Hz), 2.98 (t, 2H, J = 8 Hz), 1.88-1.72 (m,2H), 0.93 (t, J = 8 Hz, 3H)。
實施例162
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-1-(4-氟苯基)-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸二鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.15 (s
(br), 1H,
-COOH), 8.48 (s, 1H), 8.38 (s, 1H), 7.97 (d, J = 9 Hz, 1H), 7.77-7.58 (m, 6H), 7.41-7.37(m, 2H), 7.13-7.09 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 3.36-3.31 (m, 2H), 2.97 (t, 2H, J = 8 Hz), 2.69 (s, 3H)。
實施例163
(R)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.59 (s
(br), 1H,
-COOH), 9.08(s, 1H), 7.99 (s, 1H), 7.88-7.85 (m, 1H), 7.34-7.32 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.84-4.81(m, 1H), 4.53-4.50 (m, 2H), 4.20-4.18 (m, 2H), 3.36-3.34 (m, 2H), 3.09-3.03 (m, 2H), 1.66 (d, J = 6 Hz, 3H)。
實施例164
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.08 (s
(br), 1H,
-COOH), 9.05(s, 1H), 7.70-7.67 (m, 2H), 7.20-7.16 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.15 (s
(br), 2H), 5.87 (s
(br), 2H), 4.98-4.95 (m, 1H), 4.53-4.50 (m, 1H), 4.40-4.37 (m, 1H), 4.02 (s, 2H), 3.28-3.24 (m, 2H), 2.95-2.89 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H)。
實施例165
8-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.31 (s
(br), 1H,
-COOH), 12.07 (s
(br), 2H), 8.31-8.28 (m, 1H), 8.10-7.61 (m, 5H), 7.26-7.19 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.42-3.38 (m, 2H), 3.06-3.02 (m, 2H)。
實施例166
6-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-乙基-4-側氧基-1,4-二氫喹啉-3-甲酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:15.36 (s
(br), 1H,
-COOH), 12.07 (s
(br), 2H), 9.09 (s, 1H), 8.49 (s, 1H), 8.42-8.40 (m, 1H), 8.23-8.22 (m, 1H), 8.08-7.31 (m, 5H), 6.79 (d, J = 8 Hz, 1H), 4.64 (q, J = 6.8 Hz, 2H), 4.07 (s, 2H), 3.36-3.32 (m, 2H), 3.04-2.99 (m, 2H), 1.45 (t, J = 6.8 Hz, 3H)。
實施例167
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6): 14.98 (s, 1H), 8.75 (s, 1H), 8.26 (d,
J= 6.8 Hz, 1H), 8.05 (d,
J= 10.8 Hz, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 6.83 (d,
J= 8.4 Hz, 2H), 6.19 (s, 2H), 5.89 (s, 2H), 4.06 (s, 2H), 3.96 (m, 1H), 2.98 (m, 2H), 1.32 (m, 2H), 1.25 (m, 2H)。
實施例168
1-(環丙基甲基)-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (CD
3OD + HCl) : 9.42 (s, 1H), 8.63 (d,
J= 8.05 Hz, 1H), 8.37 (s, 1H), 8.17 (d,
J= 9.2 Hz, 1H), 7.87-7.8 (m, 3H), 7.08 (d,
J= 8.4 Hz, 1H), 4.74 (d,
J= 7.2 Hz, 2H), 4.37 (s, 2H), 3.66 (m, 2H), 3.29 (m, 2H), 1.57 (m, 1H), 0.85-0.8(m, 2H), 0.69-0.60(m, 2H)。
實施例169
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫-1,8-㖠啶-3-甲酸雙2,2,2-三氟乙酸
1HNMR (DMSO-
d 6):14.7 (s, 1H), 12.35 (s, 1H), 8.8 (s, 1H), 8.57 (d,
J= 3.5 Hz,1H), 8.2-8.0 (m, 2H), 7.9-7.7 (m, 3H), 6.78 (d,
J= 2.8 Hz, 1H), 4.1 (s, 2H), 3.96 (m, 1H), 3.54-3.49 (m, 2H), 3.1-3.0 (m, 2H), 1.24-1.1 (m,
4H)。
實施例170
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸雙2,2,2-三氟乙酸
1HNMR (DMSO-
d 6):14.8 (s, 1H), 11.95 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 7.92 (d,
J= 9.6 Hz, 1H), 7.73-7.22 (m, 4H), 6.8 (d,
J= 8.0 Hz, 1H), 4.28 (s, 2H), 4.16 (s, 2H), 3.4 (s, 3H), 3.04-3.0 (m, 2H), 1.26- 1.11 (m, 4H)。
實施例171
7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-1-(2,4-二氟苯基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):14.6 (s, 1H), 8.96 (s, 1H), 8.16 (d,
J= 10.4 Hz, 1H), 8.0-7.96 (m, 1H), 7.76-7.71 (m, 1H), 7.64 (s, 1H), 7.46-7.04 (m, 3H), 6.97-6.7(m, 3H), 4.04 (s, 2H), 2.95 (t,
J= 8 Hz, 2H)。
實施例172
10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸雙2,2,2-三氟乙酸
1HNMR (DMSO-
d 6):15.11 (s, 1H), 11.86 (s, 1H), 8.97 (s, 1H), 8.4 (s, 1H), 7.72-7.52 (m, 5H), 7.2-7.12 (m, 2H), 6.73 (d,
J= 8.0 Hz, 1H), 4.58-4.55 (m, 4H), 4.07 (s, 2H), 3.01-.2.94 (m, 2H)。
實施例173
1-環丙基-7-(1-((2,4-二胺基-6-乙基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):14.99 (s, 1H), 8.76 (s, 1H), 8.26 (d,
J= 6.8 Hz, 1H), 8.07 (d,
J= 10.8 Hz, 1H), 7.47-7.45 (m, 2H), 6.88 (d,
J= 8.0 Hz, 1H), 4.13 (s, 2H), 3.96(m, 1H), 3.29-3.25 (m, 2H), 2.97-2.93 (m, 2H), 1.33-1.24(m, 4H), 1.12(t,
J= 7.2 Hz, 3H)。
實施例174
1-(6-胺基-3,5-二氟吡啶-2-基)-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):14.94 (s, 1H), 9.04 (s, 1H), 8.4 (d,
J= 8 Hz,1H), 8.07 (t,
J= 9.2 Hz,1H), 7.92 (d,
J= 9.6 Hz, 1H), 7.80 (s,1H), 7.71-7.38 (m, 2H), 7.28-7.05 (m, 1H), 6.98-6.68 (m, 5H), 4.03(s,2H), 2.97 (t,
J= 8.2 Hz,1H)。
實施例175
1-(6-胺基-3,5-二氟吡啶-2-基)-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):14.58 (s, 1H), 9.03 (s, 1H), 8.14-8.03 (m, 2H), 7.66 (s, 1H), 7.36-7.24 (m, 3H), 6.87(s, 2H), 6.72 (d,
J= 8.4 Hz, 1H), 4.05 (s, 2H), 2.97 (t,
J= 7.6 Hz, 2H)。
實施例176
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-5,6,8-三氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):14.69 (s, 1H), 8.73 (s, 1H), 7.72-7.64 (m, 1H), 7.26-7.2 (m, 2H), 6.83-6.36 (m, 5H), 4.15-4.06 (m, 1H), 4.0 (s, 2H), 3.07-2.97(m, 2H), 1.28-1.08(m, 4H)。
實施例177
5-((5-(6,7-二氟-2-甲基喹啉-8-基)吲哚啉-1-基)甲基)嘧啶-2,4-二胺
1HNMR (DMSO-
d 6):8.43 (d,
J= 8.4 Hz, 1H), 7.75-7.7 (m, 2H), 7.58 (d,
J= 8.4 Hz, 1H), 7.43 (m,2H), 6.78 (d,
J= 8.4 Hz, 1H), 6.15 (m,2H), 5.86 (s,2H), 4.02(s,2H), 3.24 (t,
J= 8.4 Hz, 1H), 2.94 (d,
J= 8.0Hz, 1H), 2.67 (s, 3H)。
實施例178
1-環丙基-7-((1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)胺基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸
1HNMR (DMSO-
d 6):15.56 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 7.87 (d,
J= 11.6 Hz, 1H), 7.68 (s, 1H), 7.57 (d,
J= 8.0 Hz, 1H), 7.16 (s, 1H), 7.08 (d,
J= 8.4 Hz, 1H), 6.77(d,
J= 8.4 Hz, 1H), 6.15 (s, 2H), 5.85(m, 2H), 3.95(s, 2H), 3.6(m, 1H), 2.91 (t,
J= 8.Hz, 1H), 1.15-1.07 (m,4H)。
實施例179
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸化合物與硫酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.67 (s, 1H,
-COOH), 8.77 (s, 1H), 7.98 (d,
J =8.0
Hz, 1H), 7.70 (s, 2H), 7.55 (s, 2H, NH
2), 7.27 (s, 1H), 7.25 (s, 2H, -NH
2), 6.78 (d,
J =8.4
Hz, 1H), 4.16 (m, 1H), 4.10 (s, 2H), 3.40 (t,
J =8.0
Hz, 2H), 3.03 (t,
J =8.0
Hz, 2H), 1.25 (d,
J =12.0
Hz, 2H), 1.18 (t,
J =12.0
Hz, 2H)。
實施例180
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸化合物與2,3-二羥基丁二酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.62 (s, 1H,
-COOH), 8.77 (s, 1H), 7.98 (d,
J =9.2
Hz, 1H), 7.70 (s, 1H), 7.18 (s, 2H, NH
2), 7.14 (s, 2H, -NH
2), 6.87 (s, 2H), 6.80 (d,
J =8.0
Hz, 1H), 4.24 (s, 2H), 4.16 (m, 1H), 4.08 (s, 2H), 3.35 (t,
J =8.0
Hz, 2H), 3.20 (s, 2H, -OH), 3.00 (t,
J =8.8
Hz, 2H), 1.24 (d,
J =9.2
Hz, 2H), 1.17 (d,
J =6.4
Hz, 2H)。
實施例181
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸化合物與乙酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.60 (s, 1H,
-COOH), 11.86 (s, 1H, -COOH), 8.77 (s, 1H), 7.97 (d,
J =8.0
Hz, 1H), 7.96 (s, 1H), 7.70 (s, 2H, NH
2), 7.35 (s, 2H), 7.25 (s, 2H, -NH
2), 6.80 (d,
J =7.2
Hz, 1H), 4.17-4.16 (m, 1H), 4.08 (s, 2H), 3.38 (t,
J =8.4
Hz, 2H), 3.00 (t,
J =8.0
Hz, 2H), 2.32 (s, 1H), 1.91 (s, 2H), 1.19 (d,
J =6.8
Hz, 2H ), 1.15 (d,
J =7.6
Hz, 2H)。
實施例182
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸化合物與2-羥基丙烷-1,2,3-三羧酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.60 (s, 1H,
-COOH), 8.77 (s, 1H), 7.98 (d,
J =8.0
Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.36 (s, 1H), 7.26 (s, 2H, NH
2), 7.22 (s, 2H, NH
2), 6.80 (d,
J =8.4
Hz, 1H), 4.17-4.16 (m, 1H), 4.08 (s, 2H), 3.64 (s, 4H), 3.09 (t,
J =7.2
Hz, 2H), 3.02 (s, 1H, -OH), 3.00 (t,
J =8.0
Hz, 2H), 1.23 (s, 2H), 1.18 (d,
J =5.2
Hz, 2H)。
實施例183
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸化合物與丁二酸
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.61 (s, 1H,
-COOH), 8.77 (s, 1H), 7.98 (d,
J =8.0
Hz, 1H), 7.70 (s, 1H), 7.22 (s, 2H), 7.09 (s, 2H, NH
2), 6.81 (d,
J =8.0
Hz, 1H), 6.62 (s, 2H, -NH
2), 4.18-4.16 (m, 1H), 4.07 (s, 2H), 3.32 (t,
J =8.0
Hz, 2H), 2.98 (t,
J =8.0
Hz, 2H), 2.67 (t,
J =2.0
Hz, 4H), 1.39 (d,
J =5.6
Hz, 2H ), 1.37 (s, 2H)。
實施例184
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸2,2’,2”-氮基三(乙-1-醇)
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.60 (s, 1H,
-COOH), 8.77 (s, 1H), 7.97 (d,
J =9.6
Hz, 1H), 7.76 (s, 1H), 7.22 (s, 2H), 6.83 (d,
J =8.8
Hz, 1H), 6.29 (s, 2H, -NH
2), 5.17 (s, 2H, -NH
2), 4.61 (s, 3H, -OH), 4.17-4.19 (m ,1H), 4.05 (s, 2H), 3.55 (d,
J =5.6
Hz, 6H), 3.28 (t,
J =8.4
Hz, 2H), 2.98 (t,
J =8.4
Hz, 2H), 2.52 (d,
J =5.2
Hz, 6H), 1.21 (d,
J =7.6
Hz, 2H), 1.18 (d,
J =6.8
Hz, 2H)。
實施例185
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸鈉
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.59 (s, 1H), 7.69 (s, 2H), 7.96 (s, 1H), 7.17 (d,
J =7.2
Hz, 1H), 6.81 (d,
J =8.8
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.88 (s, 2H, NH
2), 4.03 (s, 2H), 3.99-3.95 (m, 1H), 3.27 (t,
J =8.0
Hz, 2H), 2.93 (t,
J =8.0
Hz, 2H), 1.11 (d,
J =5.2
Hz, 2H), 1.05 (s, 2H)。
實施例186
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸鉀
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.78 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.18 (d,
J =10.4
Hz, 1H), 6.81 (d,
J =8.4
Hz, 1H), 6.15 (s, 2H, -NH
2), 5.86 (s, 2H, NH
2), 4.02 (s, 2H), 3.99 (m, 1H), 3.25 (d,
J =8.0
Hz, 2H), 3.11 (d,
J =9.2
Hz, 2H), 1.06 (d,
J =7.6
Hz, 2H), 1.03 (s, 2H)。
實施例187
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸鈣
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.81 (s, 1H), 7.93 (d,
J =4.8
Hz, 1H), 7.90 (s, 1H), 7.21 (s, 2H), 6.82 (d,
J =8.8
Hz, 1H), 6.17 (s, 2H, -NH
2), 5.88 (s, 2H, NH
2), 4.15-4.10 (m, 1H), 4.04 (s, 2H), 3.05 (d,
J =6.0
Hz, 2H), 2.95 (d,
J =5.2
Hz, 2H), 1.18 (s, 4H)。
實施例188
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.83 (s, 1H), 7.80 (d,
J =9.6
Hz, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.19 (s, 4H, -NH
2), 6.79 (d,
J =8.0
Hz, 2H), 4.25-4.20 (q,
J =7.2
Hz, 2H), 4.22-4.04 (m, 1H), 4.04 (s, 2H), 3.31 (t,
J =8.0
Hz, 2H), 2.97 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.18 (d,
J =6.0
Hz, 2H)。
實施例189
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸甲酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.78 (d,
J =8.8
Hz, 1H), 7.69 (s, 1H), 7.19 (s, 2H), 6.81 (d,
J =8.4
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.93 (s, 2H, -NH
2), 4.03 (s, 2H), 4.00-3.86 (m, 1H), 3.76 (s, 3H), 3.28 (t,
J =8.4
Hz, 2H), 2.96 (t,
J =8.0
Hz, 2H), 1.17 (s, 2H), 1.10 (d,
J =6.8
Hz, 2H)。
實施例190
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸異丁酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.70 (s, 1H), 7.20 (s, 2H), 6.81 (d,
J =8.4
Hz, 1H), 6.62 (s, 2H, -NH
2), 6.30 (s, 2H, -NH
2), 4.14 (s, 2H), 4.05 (s, 1H), 3.99 (d,
J =6.4
Hz, 2H), 3.32 (t,
J =8.0
Hz, 2H), 2.98 (t,
J =8.0
Hz, 2H), 2.02-1.94 (m, 1H), 1.12 (d,
J =6.8
Hz, 4H), 0.98 (d,
J =6.8
Hz, 6H)。
實施例191
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯丁二酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.80 (d,
J =9.2
Hz, 1H), 7.79 (s, 1H), 7.25 (s, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.53 (s, 2H, -NH
2), 6.24 (s, 2H, -NH
2), 4.28-4.23 (q,
J =7.6
Hz, 2H), 4.05 (s, 2H), 4.01-3.91 (m, 1H), 3.30 (t,
J =8.0
Hz, 2H), 3.19 (t,
J =8.0
Hz, 2H), 2.33 (s, 4H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.11 (d,
J =6.4
Hz, 2H)。
實施例192
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2-羥基丙烷-1,2,3-三甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.44-11.19 (s, 2H,
-COOH, 寬峰), 8.52 (s, 1H), 7.81 (d,
J =9.2
Hz, 1H), 7.70 (s, 1H), 7.66 (s, 2H), 7.19 (s, 2H, -NH
2), 7.04 (s, 2H, -NH
2), 6.78 (d,
J =8.0
Hz, 1H), 4.28-4.23 (q,
J =7.2
Hz, 2H), 4.07 (s, 2H), 4.00 (m, 1H), 3.35 (t,
J =8.0
Hz, 2H), 3.12 (s, 1H, -OH), 3.00 (t,
J =8.0
Hz, 2H), 2.33 (s, 4H), 1.29 (t,
J =7.2
Hz, 3H), 1.24 (s, 4H)。
實施例193
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯硫酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.66 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d,
J =9.6
Hz, 1H), 7.75 (s, 2H,
-NH
2), 7.71 (s, 2H, -NH
2), 7.25 (s, 1H), 7.19 (s, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.22 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 3.99 (s, 1H), 3.39 (t,
J =8.0
Hz, 2H), 3.02 (t,
J =8.8
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (d,
J =5.6
Hz, 2H)。
實施例194
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯乙磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.80 (s, 1H, -SO
3H), 8.52 (s, 1H), 8.42 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.75 (s, 2H, -NH
2), 7.65 (s, 2H, -NH
2), 7.24 (s, 1H), 7.19 (s, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.24-4.20 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.39 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.4
Hz, 2H), 2.42-2.37 (q,
J =7.2
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.24 (t,
J =2.0
Hz, 2H), 1.22 (s, 2H), 1.17 (s, 3H)。
實施例195
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯甲磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.69 (s, 1H, -SO
3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d,
J =9.6
Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H, -NH
2), 7.63 (s, 2H, -NH
2), 7.24 (s, 1H,
-NH
2), 7.21 (d,
J =8.4
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.22 (q,
J =6.8
Hz, 2H), 4.09 (s, 2H), 4.00-4.00 (m, 1H), 3.37 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.0
Hz, 2H), 2.31 (s, 3H), 1.29 (t,
J =7.2
Hz, 3H), 1.12 (d,
J =5.6
Hz, 2H), 1.09 (d,
J =6.8
Hz, 2H)。
實施例196
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯苯磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.69 (s, 1H, -SO
3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d,
J =8.8
Hz, 1H), 7.75 (s, 1H), 7.70 (s, 1H), 7.40 (s, 4H, -NH
2), 7.30 (t,
J =2.4
Hz, 3H), 7.24 (s, 1H), 7.20 (d,
J =7.2
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.21 (q,
J =6.8
Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.45 (t,
J =7.2
Hz, 2H), 3.02 (t,
J =8.4
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.12 (d,
J =5.2
Hz, 2H), 1.07 (d,
J =7.2
Hz, 2H)。
實施例197
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯4-甲基苯磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.67 (s, 1H, -SO
3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d,
J =8.4
Hz, 1H), 7.75 (s, 2H, -NH
2), 7.71 (s, 1H), 7.60 (s, 2H, -NH
2), 7.47 (t,
J =8.4
Hz, 2H), 7.24 (s, 1H), 7.20 (d,
J =8.0
Hz, 1H), 7.11 (d,
J =8.0
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.21 (q,
J =6.8
Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.39 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.4
Hz, 2H), 2.29 (s, 3H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (d,
J =5.6
Hz, 2H)。
實施例198
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯萘-1,5-二磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.67 (s, 1H, -SO
3H), 8.86 (d,
J =8.4
Hz, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 7.93 (d,
J =0.8
Hz, 2H), 7.92 (s, 1H), 7.81 (d,
J =8.4
Hz, 1H), 7.75 (s, 2H, -NH
2), 7.71 (s, 2H, -NH
2), 7.40 (t,
J =7.2
Hz, 2H), 7.21 (s, 1H), 7.18 (d,
J =8.0
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.08 (s, 2H), 4.01-3.99 (m, 1H), 3.38 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.4
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (t,
J =5.2
Hz, 2H)。
實施例199
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:14.60 (s
(br), 1H), 12.03 (s
(br), 1H, -COOH), 8.77 (s, 1H), 8.42 (s, 1H), 7.98-7.96 (m, 1H), 7.77-7.70 (m, 4H), 7.27-7.22 (m, 2H), 6.79 (d,
J= 8.0 Hz, 1H), 4.18-4.16 (m, 1H), 4.11 (s, 2H), 3.42 (t,
J= 8 Hz, 2H), 3.03 (t, 2H,
J= 8 Hz), 1.26-1.15 (m, 4H)。
實施例200
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2-羥基乙烷-1-磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.68 (s, 1H, -SO
3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.83, 7.80 (dd,
J =1.2
Hz, 1H), 7.71 (s, 2H, -NH
2), 7.25 (s, 2H, -NH
2), 7.21 (s, 1H), 7.19 (s, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.08 (s, 2H), 4.01-3.99 (m, 1H), 3.62 (t,
J =6.8
Hz, 2H), 3.39 (t,
J =8.0
Hz, 2H), 3.02 (t,
J =8.0
Hz, 2H), 2.61 (t,
J =6.8
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (t,
J =5.2
Hz, 2H)。
實施例201
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯((1S,4R)-7,7-二甲基-2-側氧基雙環[2.2.1]庚-1-基)甲烷磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.76 (s, 1H, -SO
3H), 8.52 (s, 1H), 8.41 (s, 1H), 7.81 (d,
J =8.8
Hz, 1H), 7.75 (s, 2H, -NH
2), 7.71 (s, 2H, -NH
2), 7.24 (s, 1H), 7.19 (s, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.23 (q,
J =6.8
Hz, 2H), 4.09 (s, 2H), 4.09-3.99 (m, 1H), 3.39 (t,
J =8.0
Hz, 2H), 3.02 (t,
J =8.0
Hz, 2H), 2.89 (s, 1H), 2.40 (s, 1H), 2.33 (s, 1H), 2.26 (t,
J =3.6
Hz, 1H), 2.21 (t,
J =3.6
Hz, 1H), 1.93 (t,
J =4.8
Hz, 1H), 1.92 (s, 1H), 1.88 (s, 1H), 1.31 (s, 4H), 1.11 (s, 2H), 1.04 (d,
J =6.8
Hz, 2H), 0.99 (s, 3H), 0.75 (s, 3H)。
實施例202
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯(S)-2-羥基-2-苯基乙酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.81 (d,
J =8.8
Hz, 1H), 7.69 (s, 1H), 7.40 (d,
J =7.2
Hz, 2H), 7.31 (d,
J =7.2
Hz, 2H), 7.26 (t,
J =7.2
Hz, 1H), 7.21 (s, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.41 (s, 2H, -NH
2), 6.23 (s, 2H, -NH
2), 4.93 (s, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.04-4.00 (m, 1H), 3.70 (s, 1H, -OH), 3.29 (t,
J =8.0
Hz, 2H), 3.05 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.12 (t,
J =6.4
Hz, 2H), 1.08 (d,
J =6.0
Hz, 2H)。
實施例203
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯丙二酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.70 (s, 1H), 7.35 (s, 2H, -NH
2), 7.19 (s, 2H), 6.98 (s, 2H, -NH
2), 6.79 (d,
J =8.4
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.07 (s, 2H), 4.07-3.99 (m, 1H), 3.34 (t,
J =8.0
Hz, 2H), 2.99 (t,
J =8.0
Hz, 2H), 2.91 (s, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (d,
J =4.8
Hz, 2H)。
實施例204
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2-羥基丁二酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.70 (s, 1H), 7.18 (s, 2H, -NH
2), 7.08 (s, 2H, -NH
2), 6.84 (s, 1H), 6.80 (d,
J =8.4
Hz, 2H), 4.37 (s, 1H, 寬峰), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.11 (d,
J =6.4
Hz, 1H), 4.08 (s, 2H), 4.05-4.00 (m, 1H), 3.31 (t,
J =8.4
Hz, 2H), 2.98 (t,
J =8.0
Hz, 2H), 2.36 (d,
J =5.6
Hz, 2H), 1.29 (t,
J =6.8
Hz, 3H), 1.24 (s, 2H), 1.12(d,
J =6.0
Hz, 2H)。
實施例205
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯乙烷-1,2-二磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.74 (s, 1H, -SO
3H), 8.52 (s, 1H), 8.43 (s, 1H), 7.81 (d,
J =8.4
Hz, 1H), 7.72 (s, 2H, -NH
2), 7.64 (s, 2H, -NH
2), 7.24 (s, 1H), 7.20 (d,
J =7.6
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.45 (t,
J =7.2
Hz, 4H), 3.02 (t,
J =8.0
Hz, 2H), 2.66 (d,
J =7.2
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.25 (s, 2H), 1.12 (d,
J =5.6
Hz, 2H)。
實施例206
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯萘-2-磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.80 (s, 1H, -SO
3H), 8.52 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.97 (t,
J =3.6
Hz, 1H), 7.90 (t,
J =3.2
Hz, 1H), 7.86 (d,
J =8.4
Hz, 2H), 7.81 (d,
J =9.2
Hz, 1H), 7.76 (s, 1H), 7.72 (s, 2H, -NH
2), 7.70 (s, 1H), 7.61 (s, 2H, -NH
2), 7.52-7.50 (q,
J =2.8
Hz, 1H), 7.24 (s, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.38 (t,
J =8.4
Hz, 2H), 3.01 (t,
J =8.4
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.24 (s, 2H), 1.12 (d,
J =5.6
Hz, 2H)。
實施例207
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2-羥基苯甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:13.50 (s, 1H,
-COOH), 8.52 (s, 1H), 7.81 (d,
J =9.2
Hz, 3H), 7.76 (s, 2H, -NH
2), 7.71 (s, 2H, -NH
2), 7.21 (t,
J =8.0
Hz, 3H), 6.79 (d,
J =8.4
Hz, 1H), 6.68 (d,
J =7.2
Hz, 2H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.36 (t,
J =8.4
Hz, 2H), 3.00 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 2H), 1.24 (s, 2H), 1.16 (s, 2H)。
實施例208
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2,5-二羥基苯甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:13.23 (s, 1H,
-COOH), 8.69 (s, 1H), 8.52 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.74 (s, 1H), 7.52 (s, 2H, -NH
2), 7.38 (s, 2H, -NH
2), 7.22 (t,
J =6.8
Hz, 2H), 7.13 (s, 1H), 6.80 (d,
J =8.0
Hz, 1H), 6.74, 6.72 (dd,
J =3.2
Hz, 1H), 6.58 (d,
J =8.4
Hz, 1H), 4.36 (s, 1H, -OH), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.07 (s, 2H), 4.01-4.00 (m, 1H), 3.45 (t,
J =7.2
Hz, 2H), 3.35 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 2H), 1.27 (s, 2H), 1.16 (s, 2H)。
實施例209
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2-羥基-5-磺苯甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.66 (s, 1H, -OH), 11.35 (s, 1H, -COOH), 8.53 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H, -SO
3H), 8.03 (t,
J =4.4
Hz, 2H), 7.80 (s, 1H), 7.75 (s, 2H, -NH
2), 7.71 (s, 2H, -NH
2), 7.20 (d,
J =8.0
Hz, 2H), 6.89 (d,
J =8.4
Hz, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.27-4.22 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.39 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.17 (s, 2H), 1.12 (d,
J =4.8
Hz, 2H)。
實施例210
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯2,3-二羥基丁二酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.81 (t,
J =9.2
Hz, 1H), 7.69 (s, 1H), 7.21 (s, 2H), 6.80 (d,
J =8.0
Hz, 1H), 6.61 (s, 2H, -NH
2), 6.32 (s, 2H, -NH
2), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.13 (s, 2H), 4.05 (s, 2H), 4.01-4.00 (m, 1H), 3.30 (t,
J =8.4
Hz, 2H), 2.97 (t,
J =8.4
Hz, 2H), 2.50 (d,
J =1.6
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.11 (d,
J =6.8
Hz, 2H)。
實施例211
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯1-羥基-2-萘甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 8.21 (t,
J =8.4
Hz, 1H), 7.81 (d,
J =10.0
Hz, 2H), 7.75 (s, 2H, -NH
2), 7.73 (s, 2H), 7.52 (s, 2H, -NH
2), 7.49 (d,
J =6.8
Hz, 1H), 7.21 (s, 1H), 7.20 (d,
J =8.0
Hz, 2H), 7.08 (d,
J =8.0
Hz, 1H), 6.79 (d,
J =8.0
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.38 (t,
J =8.4
Hz, 2H), 3.01 (t,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.12 (t,
J =6.8
Hz, 2H)。
實施例212
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯菸鹼酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:9.06 (d,
J =1.6
Hz, 1H), 8.75, 8.74 (dd,
J =1.6
Hz, 1H), 8.52 (s, 1H), 8.26 (t,
J =2.0
Hz, 1H), 7.81 (d,
J =8.4
Hz, 1H), 7.71 (s, 1H), 7.51 (t,
J =4.8
Hz, 1H), 7.19 (t,
J =9.6
Hz, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.51 (s, 2H, -NH
2), 6.40 (s, 2H, -NH
2), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.05 (s, 2H), 4.01-3.99 (m, 1H), 3.30 (t,
J =8.4
Hz, 2H), 2.97 (t,
J =8.4
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.11 (t,
J =6.8
Hz, 2H)。
實施例213
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯戊烷-1-磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.82 (s, 1H, -SO
3H), 8.52 (s, 1H), 8.41 (s, 1H), 7.81 (d,
J =9.6
Hz, 1H), 7.72 (s, 2H, -NH
2), 7.63 (s, 2H, -NH
2), 7.24 (s, 1H), 7.20 (d,
J =7.2
Hz, 1H), 6.77 (d,
J =8.0
Hz, 1H), 4.27-4.21 (q,
J =7.2
Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 2H), 3.39 (t,
J =8.4
Hz, 2H), 3.02 (t,
J =8.4
Hz, 2H), 2.50 (t,
J =2.0
Hz, 2H), 1.57-1.53 (m, 1H), 1.31-1.27 (m, 7H), 1.25 (t,
J =3.6
Hz, 3H), 1.17 (s, 2H), 1.12 (t,
J =5.2
Hz, 2H)。
實施例214
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯(R)-5-側氧基吡咯啶-2-甲酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.52 (s, 1H), 7.89 (s, 1H), 7.81 (t,
J =9.6
Hz, 1H), 7.69 (s, 1H), 7.21 (s, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.23 (s, 2H, -NH
2), 5.96 (s, 2H, -NH
2), 4.24 (d,
J =6.8
Hz, 2H), 4.05 (s, 3H), 3.27 (d,
J =8.0
Hz, 2H), 2.97 (d,
J =8.0
Hz, 2H), 2.15 (s, 2H), 2.12 (t,
J =6.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.16 (s, 2H), 1.11 (d,
J =6.0
Hz, 2H)。
實施例215
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.49 (s, 1H), 8.06 (d,
J =6.8
Hz, 1H), 7.87 (d,
J =10.4
Hz, 1H), 7.69 (s, 1H), 7.38 (d,
J =9.6
Hz, 2H), 6.81 (d,
J =8.0
Hz, 1H), 6.45 (s, 2H,
-NH
2), 6.14 (s, 2H, -NH
2), 4.26-4.20 (q,
J =7.2
Hz, 2H), 4.05 (s, 2H), 3.72 (s, 1H), 3.30 (t,
J =8.4
Hz, 2H), 2.99 (t,
J =8.0
Hz, 2H), 1.30 (t,
J =7.2
Hz, 3H), 1.25 (s, 2H), 1.13 (s, 2H)。
實施例216
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.99 (s, 1H, -HCl), 8.51 (s, 1H), 8.42 (s, 1H), 8.06 (d,
J =6.8
Hz, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.76 (s, 2H, -NH
2), 7.72 (s, 2H, -NH
2), 7.44 (s, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.26-4.21 (q,
J =6.8
Hz, 2H), 4.10 (s, 2H), 3.78-3.76 (m, 1H), 3.04 (t,
J =8.0
Hz, 2H), 2.53 (t,
J =7.2
Hz, 2H), 1.29 (t,
J =6.8
Hz, 3H), 1.26 (t,
J =6.4
Hz, 2H), 1.14 (t,
J =2.4
Hz, 2H)。
實施例217
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯乙磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.79 (s, 1H, -SO
3H), 8.51 (s, 1H), 8.42 (s, 1H), 8.06 (d,
J =6.4
Hz, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.71 (s, 2H, -NH
2), 7.71 (s, 2H, -NH
2), 7.44 (s, 1H), 6.77 (d,
J =8.4
Hz, 1H), 4.26-4.21 (q,
J =6.8
Hz, 2H), 4.10 (s, 2H), 3.79-3.74 (m, 1H), 3.41 (t,
J =7.6
Hz, 2H), 3.04 (t,
J =8.0
Hz, 2H), 2.42-2.38 (q,
J =7.2
Hz, 2H), 1.27 (t,
J =7.2
Hz, 3H), 1.21 (t,
J =8.0
Hz, 3H), 1.14 (t,
J =2.4
Hz, 2H), 1.08 (s, 2H)。
實施例218
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.67 (s, 1H), 7.69 (s, 1H), 7.52 (d,
J =10.0
Hz, 1H), 7.16 (s, 2H), 6.77 (d,
J =8.4
Hz, 1H), 6.15 (s, 2H, -NH
2), 5.87 (s, 2H, -NH
2), 4.76 (d,
J =6.8
Hz, 1H), 4.45 (d,
J =1.2
Hz, 1H), 4.35-4.25 (m, 1H), 4.22 (d,
J =4.4
Hz, 2H), 4.01 (s, 2H), 3.24 (t,
J =8.4
Hz, 2H), 2.92 (t,
J =8.4
Hz, 2H), 1.42 (d,
J =6.8
Hz, 3H), 1.29 (t,
J =7.2
Hz, 3H)。
實施例219
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸乙酯鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:12.10 (s, 1H, -HCl), 8.68 (s, 1H), 8.41 (s, 1H), 7.75 (s, 2H, -NH
2), 7.68 (s, 2H,
-NH
2), 7.51 (s, 1H), 7.41 (s, 1H), 7.15 (d,
J =8.4
Hz, 1H), 6.72 (d,
J =8.4
Hz, 1H), 4.76 (d,
J =6.8
Hz, 1H), 4.43 (d,
J =10.0
Hz, 1H), 4.33-4.25 (m, 1H), 4.23 (d,
J =4.0
Hz, 2H), 4.07 (s, 2H), 3.45 (t,
J =7.2
Hz, 2H), 3.35 (t,
J =7.2
Hz, 2H), 1.42 (d,
J =6.8
Hz, 3H), 1.30 (t,
J =7.2
Hz, 3H)。
實施例220
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸乙酯乙磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.76 (s, 1H, -SO
3H), 8.68 (s, 1H), 8.41 (s, 1H), 7.72 (s, 2H, -NH
2), 7.62 (s, 2H,
-NH
2), 7.52 (d,
J =10.0
Hz, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.72 (d,
J =8.0
Hz, 1H), 4.76 (d,
J =6.8
Hz, 1H), 4.43 (d,
J =10.0
Hz, 1H), 4.43 (q,
J =4.0
Hz, 2H), 4.27-4.21 (m, 1H), 4.06 (s, 2H), 3.44 (d,
J =6.8
Hz, 2H), 2.99 (t,
J =8.4
Hz, 2H), 2.42-2.36 (q,
J =7.2
Hz, 2H), 1.42 (d,
J =6.8
Hz, 3H), 1.30 (t,
J =7.2
Hz, 3H), 1.29 (t,
J =7.2
Hz, 3H)。
實施例221
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸乙酯2-羥基乙烷-1-磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.69 (s, 1H, -SO
3H), 8.68 (s, 1H), 8.41 (s, 1H, -NH
2), 7.72 (d,
J =6.4
Hz, 2H), 7.61 (s, 2H, -NH
2), 7.51 (s, 1H, -NH
2), 7.20 (s, 1H), 7.16 (d,
J =8.0
Hz, 1H), 6.72 (d,
J =8.4
Hz, 1H), 4.77 (d,
J =6.8
Hz, 1H), 4.28 (d,
J =3.6
Hz, 1H), 4.27-4.25 (m, 1H), 4.23 (t,
J =3.2
Hz, 2H), 4.06 (s, 2H), 3.68 (t,
J =6.8
Hz, 2H), 3.36 (t,
J =8.4
Hz, 2H), 2.99 (t,
J =8.4
Hz, 2H), 2.62 (t,
J =6.8
Hz, 2H), 1.42 (d,
J =6.8
Hz, 3H), 1.30 (t,
J =7.2
Hz, 3H)。
實施例222
(S)-10-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-9-氟-3-甲基-7-側氧基-2,3-二氫-7H-[1,4]㗁𠯤并[2,3,4-ij]喹啉-6-甲酸乙酯甲磺酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.75 (s, 1H, -SO
3H), 8.68 (s, 1H), 8.41 (s, 1H, -NH
2), 7.72 (s, 2H), 7.62 (s, 2H,
-NH
2), 7.51 (s, 1H), 7.20 (s, 1H, -NH
2), 7.15 (d,
J =8.0
Hz, 1H), 6.72 (d,
J =8.4
Hz, 1H), 4.77 (d,
J =6.8
Hz, 1H), 4.43 (d,
J =10.0
Hz, 1H), 4.42-4.31 (m, 1H), 4.22 (t,
J =3.2
Hz, 2H), 4.06 (s, 2H), 3.35 (t,
J =8.4
Hz, 2H), 2.99 (t,
J =8.4
Hz, 2H), 2.32 (s, 3H), 1.42 (d,
J =6.8
Hz, 3H), 1.30 (t,
J =7.2
Hz, 3H)。
實施例223
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯
1H NMR (DMSO-
d
6 , 400 MHz) δ:8.55 (s, 1H), 7.72 (t,
J =10.0
Hz, 2H), 7.18 (d,
J =9.2
Hz, 2H), 6.82 (d,
J =8.0
Hz, 1H), 6.16 (s, 2H, -NH
2), 5.87 (s, 2H, -NH
2), 4.26-4.12 (q,
J =6.8
Hz, 2H), 4.05 (m, 1H), 4.03 (s, 2H), 3.33 (s, 3H,
-OCH
3), 3.27 (d,
J =8.4
Hz, 2H), 2.95 (d,
J =8.4
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.11 (t,
J =7.2
Hz, 2H), 1.07 (s, 2H)。
實施例224
1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6-氟-8-甲氧基-4-側氧基-1,4-二氫喹啉-3-甲酸乙酯鹽酸鹽
1H NMR (DMSO-
d
6 , 400 MHz) δ:11.97 (s, 1H, -HCl), 8.56 (s, 1H), 8.42 (s, 1H), 7.75 (s, 1H, -NH
2), 7.73 (d,
J =9.6
Hz, 2H), 7.65 (s, 2H, -NH
2), 7.23 (s, 1H, -NH
2), 7.20 (d,
J =8.0
Hz, 1H), 6.78 (d,
J =8.0
Hz, 1H), 4.26-4.21 (q,
J =6.8
Hz, 2H), 4.08 (m, 1H), 4.06 (s, 2H), 3.68 (s, 3H,
-OCH
3), 3.47 (d,
J =7.2
Hz, 2H), 3.01 (d,
J =8.0
Hz, 2H), 1.29 (t,
J =7.2
Hz, 3H), 1.11 (d,
J =7.6
Hz, 2H), 1.09 (d,
J =5.2
Hz, 2H)。
在一實施態樣中,本發明提供醫藥組成物,其包含治療有效量的式(I)化合物及視需要的一或多種醫藥上可接受的賦形劑。本發明之新穎化合物可藉由如熟知的技術和方法及濃度與適合的賦形劑組合而調配成適合的醫藥上可接受的組成物。
式(I)化合物係藉由經口、i.v、局部或非經腸投予而有用於治療哺乳動物的微生物感染。
在一些實施態樣中,本發明包括用於治療細胞增生性疾病、自體免疫疾病、發炎性疾病、或細菌、真菌或寄生蟲感染中至少一者之方法,其包含對有其需要的個體投予治療有效量的新穎式(I)化合物之化合物或鹽。
用於治療上述疾病中任一者之式(I)化合物可以含有慣例的醫藥上可接受的無毒性載劑、佐劑及媒劑之單位劑量調配物例如經口、局部、非經腸投予。
醫藥組成物係藉由使用慣例的技術而提供。組成物較佳地呈單位劑型,其含有有效量的活性組分,亦即根據本發明之式(I)化合物。
活性組分,亦即根據本發明之式(I)化合物在醫藥組成物及其單位劑型中的量可取決於特定的應用方法、特定的化合物效力及所欲濃度而廣泛地改變或調整。活性組分的量通常係在介於組成物重量的0.5%至90%之間的範圍內。
在一實施態樣中,式(I)化合物可單獨或與一或多種治療劑之任何組合使用,諸如氟喹啉酮(Fluoroquinolone)、㗁唑啶酮、胺基糖苷、b-內醯胺抗生素和b-內醯胺酶(Lactamase)抑制劑、混成抗生素(Hybrid antibiotic)、維生素或其醫藥上可接受的鹽。
DHFR檢定方案
DHFR抑制檢定係藉由監測NADPH氧化速率來執行。檢定係在含有20 mM Tris HCl、200 mM NaCl及0.1 mM EDTA,pH 7.2之緩衝液中進行。將DHFR (0.8 mg/mL)與NADPH (0.02 mM)及試驗化合物在25℃下預培育10 min,然後藉由添加DHF (0.02 mM)開始反應。螢光強度係使用Tecan M1000 pro在340 nm之激發波長及440 nm之發射波長下以動力學模式測量。酵素抑制作用係自反應中消耗的NADPH量來計算。IC
50值係使用Graph pad prism來計算。
測定試管內MIC
MIC係使用如Clinical and Laboratory Standards
Institute (CLSI)所述之參考培養液微量稀釋法測定。簡言之,將細菌細胞(金黃色葡萄球菌ATCC 29213(革蘭+ve)、大腸桿菌ATCC 25922(革蘭-ve))在Mueller Hinton瓊脂平皿上培養。NCE及陽性對照物的儲備溶液係根據其溶解度在DMSO或水中製備。更多的NCE稀釋液係在經陽離子調整之Mueller Hinton培養液(CAMHB)中製備。將NCE在96孔平皿中連續兩倍稀釋。接種物密度維持在每孔5×10
4個細胞。將平皿在37℃下培育20至24 h。所有的QC結果係在CLSI文件M100-S25中公布的指定範圍內。
表2:新穎DHFR抑制劑 1-環丙基-7-(1-((2,4-二胺基嘧啶-5-基)甲基)吲哚啉-5-基)-6,8-二氟-4-側氧基-1,4-二氫喹啉-3-甲酸鹽酸鹽[實施例199]對抗各種革蘭氏陽性菌之試管內MIC值(µg/mL)
細菌菌株
| MIC
90(µg/mL)
|
二甲苯青黴素抗性金黃色葡萄球菌(ATCC 29213)
| ≤ 0.125
|
萬古黴素(Vancomycin)抗性糞腸球菌(ATCC 29212)
| ≤ 0.125
|
肺炎鏈球菌(ATCC 49619)
| ≤ 0.125
|
空腸曲桿菌(ATCC 33560)
| 0.12
|
流感嗜血桿菌(ATCC 49766)
| ≤ 0.03
|
藥物動力學:試驗化合物1及曲美普林之藥物動力學係經由在7至12週齡的BALB/c小鼠中經口及靜脈內速注途徑投予來研究(表3)。將動物禁食12小時且在投予試驗化合物4.0 h後供給食物。在整個研究中自由獲取水。試驗物質的均勻懸浮液係在純化水中的1%之Tween 80、0.5% w/v之CMC中製備且投予3 mg/kg之經口劑量。在投予試驗化合物後,以不同的時間間隔通過眶後血管叢抽取血液樣品且收集至肝素化微量離心管中。血漿係在周圍溫度下以4000 rpm離心15分鐘而分離且立即分析。將剩餘樣品儲存在-70℃下直到分析。
樣品係以蛋白質沉澱法製備:30 µL等分血漿樣品內摻入6 µL內標準(阿普唑侖(Alprazolam))且在2 mL微量離心管中以添加0.5 mL乙腈萃取。將樣品劇烈震盪混合(vortex
-mixed)1分鐘且在10000 rpm下離心5分鐘。將上清液轉移至HPLC小瓶中用於分析。將經萃取之樣品在由Shimadzu LC-20-AD所組成之LC-MS/MS系統、配備有二元泵、真空脫氣機和自動取樣器之Prominence系統(日本京都市Shimadzu Corporation)及API 5500®質譜儀(加拿大多倫多Applied Biosystems Sciex)上分析。以Analyst 1.6.1軟體用於數據擷取及分析(加拿大多倫多Applied Biosystems Sciex)。層析分離係使用移動相(A)5 mM甲酸銨+在水中的0.1%之甲酸及(B)甲醇:乙腈(20:80% v/v);在1.0 mL/min之流速下(50%分流至廢液)流過ACE C18 50*4.6mm,5µ而達成。量化係以試驗化合物添加至無藥物的小鼠血漿中而製備的一系列1至5000 ng/mL之校準物範圍為基礎。同步分析質量控制樣品以驗證系統於控制中執行。藥物動力學參數,亦即最大血漿濃度(C
max)、最大血漿濃度的時間點(t
max)、在自0 h至無限之血漿濃度對時間曲線下的面積AUC
0- ∝)及在終止期期間的藥物消除半生期(t
1/2)係以標準的非隔室方法使用Phoenix 64(Certara)軟體自血漿濃度對時間之數據計算。
活體內實驗:使用6至8週齡的雄性ICR小鼠。容許動物隨意獲取飼料及水。在開始實驗感染前,小鼠係在第-4天(150 mg/kg)及第-1天(100 mg/kg)經腹膜內注入環磷醯胺而成為嗜中性白血球低下。在第0天,所有嗜中性白血球低下的小鼠係以大腿組織的肌肉內途徑而受到每0.05毫升 50萬個MRSA(ATCC 33591)的感染。在感染2小時後,將動物每6小時以媒劑及實施例編號200之化合物(6.25、12.5、25、50、100 mg/kg,經口)處理。在處理後24小時後,將小鼠經人道犧牲,將大腿組織經無菌收集至含有5 ml無菌PBS的管中且勻漿化。自PBS中的組織勻漿製備10倍連續稀釋系列且將每一稀釋液以兩個20 µl等分試樣接種至Mueller Hinton瓊脂平皿上。將平皿在35±2℃下培育約16 至18小時且計算CFU的數量。計算每一大腿組織的CFU計數。在以大腿感染的此功效模式中發現經口服(po)及每日4次(qid)的實施例200之化合物的ED
50為33 mg/kg。
CYP抑制及hERG抑制:本發明化合物不具有CYP及hERG傾向且為安全的。