CN102216298B - 作为hiv-1逆转录酶抑制剂的咪唑并吡啶和咪唑并嘧啶 - Google Patents
作为hiv-1逆转录酶抑制剂的咪唑并吡啶和咪唑并嘧啶 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/18—Antivirals for RNA viruses for HIV
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明提供了用于治疗已感染HIV的受试者的式A化合物或式B化合物。
Description
技术领域
本发明涉及具有抗HIV-1逆转录酶活性的化合物和组合物。
背景技术
高活性抗逆转录病毒治疗(HAART)是一种用于HIV-AIDS患者的治疗方案,该方案将选自于许多不同类型的抗逆转录病毒药物的混合物结合起来。这些类药物中的一种包括非核苷逆转录酶抑制剂(NNRTI)。这些药物通过抑制HIV-1逆转录酶起作用。这种酶是开发抗-HIV药物的有效靶点。经FDA批准的NNRTI有许多,这些药物之一总体上构成抗HIV-AIDS一线治疗方案的一部分。这种类型的药物具有许多优点。优点之一就是这些药物显示出优异的选择性指数(50%细胞毒性浓度与50%抗病毒有效浓度的比值),所述选择性指数通常约为10,000-100,000。如此高的选择性使得NNRTI类型成为临床上认可的最低毒的抗逆转录病毒剂,并使得这些药物适用于预防母婴传播。选择性高的原因在于以下事实:NNRTI仅识别和结合至HIV-1逆转录酶,而不结合至任何其他的逆转录酶(RT)或DNA聚合酶或RNA聚合酶。这些药物通过结合至亲脂性非底物结合袋(binding pocket)起作用,所述结合袋位于距离底物结合位点约的地方。这种结合引起逆转录酶催化位点内产生构象变化,从而造成催化活性显著降低。逆转录酶(RT)的变构抑制剂拥有极其不同的结构特征,并且已发现多达50种不同结构类型的变构抑制剂具有抗逆转录酶的活性。第一代NNRTI(例如,奈韦拉平和地拉韦啶)对耐药性的发展敏感,因而即使RT的NNRTI结合域上单个氨基酸突变也能赋予高水平的耐药性。因此,对能够抑制尽可能多的不同RT突变体的NNRTI存在需求。
申请人了解要求USSN 60/986,990(于2007年11月9日提交)的优先权、标题为“Non-nucleoside reverse transcriptase inhibitors”的PCT/US2008/082531(于2008年11月5日提交)。该文件中公开的通式结构覆盖了非常大量的化合物。该文件具体公开了约11600种化合物。然而,仅为约30种化合物提供了抑制数据。本申请通式的公开实质上覆盖了较少量的化合物,通过引入但书(provisos)将落入本申请通式结构范围内的PCT/US2008/082531的那些化合物排除在外。
发明内容
根据本发明的第一方面,提供了化合物,所述化合物选自于式A化合物或式B化合物。
其中,对于式A:
R选自烷基、支链烷基、环烷基、芳基、取代芳基、萘基、苄基、金刚烷基和多环烷基;
R1选自烷基、环烷基、取代烷基、支链烷基、苯基、取代苯基、取代苄基、杂芳基、取代杂芳基、氧杂环烷基、二环烷基、呋喃基、取代呋喃基、噻吩基和取代噻吩基、异噁唑基、取代异噁唑基;
R2-R5各自独立地选自H、卤素、氰基、烷氧基、芳氧基、取代芳基、烷基和取代烷基;或R2和R3一起形成碳环;或独立地,R4和R5一起形成碳环,
R6为H、烷基或烷酰基;
但是:
(a)如果R为环己基,并且R2-R6为H,那么R1不是2-溴苯基、3-溴苯基、2-氯苯基、3-氯苯基、2-三氟甲基苯基、2,4-二氯苯基、2,6-二氯苯基、2,6-二氟苯基、4-氟苯基、异丙基、2-呋喃基、2-羟基苯基、4-甲氧基苯基、3,4-二甲氧基苯基或2-氟苯基;
(b)如果R为环戊基,并且R2-R6为H,那么R1不是2-溴苯基、3-溴苯基、2-氯苯基、2,4-二氯苯基、2,6-二氯苯基、2,6-二氟苯基、2,4-二氟苯基、2-三氟甲基苯基或2-氟苯基;
(c)如果R为环己基或环戊基,R3、R4、R5和R6为H,并且R2为甲基,那么R1不是2-氯苯基;
(d)如果R为环己基或环戊基,R2、R4、R5和R6为H,并且R3为甲基,那么R1不是2-氯苯基;
(e)如果R为环己基或环戊基,R2、R3、R5和R6为H,并且R4为甲基,那么R1不是2-氯苯基;
(f)如果R为环己基或环戊基,R2、R3、R4和R6为H,并且R5为甲基、乙基或三氟甲基,那么R1不是2-氯苯基、2-氟苯基、2,6-二氟苯基、2-氟-5-甲基苯基、2-氟-6-甲氧基苯基、2,6-二氟-4-甲氧基苯基、2,4-二氟苯基、2-氯-4-氟苯基、2-氯-4-吡啶基、2-氟-4-吡啶基或2-氯-6-氟苯基;
(g)如果R为环己基,R2、R3和R5为H,并且R4为氟、氯或溴,那么R1不是2-氯苯基;
(h)如果R为环己基,R3和R5为甲基,并且R2、R4和R6为H,那么R1不是2-氯苯基;
并且其中,对于式B:
R为环烷基,并且R1为取代芳基。
R1的烷基和支链烷基可任选地被一个或多个杂原子取代。所述杂原子可为氧、氮或硫。例如,所述烷基可被甲硫基取代。因此,所述取代烷基可为2-甲硫基乙基。所述苯基可任选地被选自如下基团的一个或多个取代基取代:卤素、羟基、烷基、烷氧基、氰基、氨基、取代烷基、卤代或硝基。所述杂芳基可以为O、N或S杂芳基,并且可选自于例如噁唑基、异噁唑基、取代异噁唑基、呋喃基和噻吩基。
所述卤素可选自F、Cl和Br中的一个或多个。
所述环烷基可选自C3-C6环烷基和金刚烷。例如,所述环烷基可为环丙基、环丁基、环戊基、环己基或四氢呋喃基。
所述烷基和支链烷基可选自C2-C12烷基和C2-C12支链烷基。优选的烷基和支链烷基包括2-戊基、1-丁基、2-丙基、2-丁基和1-戊基和1-辛基。
本发明的式A的优选化合物的例子为如下化合物,在所优选的化合物中:
(a)R选自乙基、2-吗啉基乙基(2-morpholinoethyl)、1-丁基、2-戊基、1-戊基、1,1,3,3-四甲基丁基、异丙基、环己基、环丙基、4-(3,4-二氯苯氧基)丁基、1-金刚烷基、4-甲氧基苯基、2-萘基、苄基、4-氯苄基、2-氯-6-甲基苯基、2-氯苯基、3-氯苯基、环戊基;
(b)R1选自乙基、2-(甲硫基)乙基、1-丙基、2-丁基、2-甲基-1-丙基、2,2-二甲基-1-丙基、环丙基、环戊基、环己基、1-戊基、2-戊基、3-戊基、叔丁基、异丙基、异丁基、1-辛基、1-苯基乙基、2-羟基苯基、4-羟基苯基、4-甲氧基苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-硝基苯基、2-氟苯基、4-氟苯基、3-乙氧基-4-羟基-苯基、4-二甲基氨基苯基、3,4-二甲氧基苯基、3,5-二甲氧基-4-羟基苯基、4-苄氧基苯基、2,4-二甲氧基苯基、4-羟基-3-甲氧基-苯基、3-羟基-4-甲氧基-苯基、2,3,6-三氯苯基、2-氟-(3-甲氧基)苯基、3-氯-2-氟-苯基、2-三氟甲基苯基、4-三氟甲基苯基、2,4-二氯苯基、2,4-二氟苯基、2,5-二氯苯基、2,6-二氯苯基、2,6-二氟苯基、4-氯-3-氟-苯基、2-氯-6-氟-5-甲基-苯基、3-(5-甲基)异噁唑基、2-(5-羟基甲基)呋喃基、2-呋喃基、2-(5-氯)呋喃基、2-(5-乙基)噻吩基、2-(3-甲基)噻吩基、2,4,5-三氟苯基、3-(2,5-二甲氧基)四氢呋喃基、4-氰基苯基、3-氰基苯基、二环[3.1.1]庚-2-烯-2-基(norpinenyl);
(c)R2选自H、苄氧基、甲基、氯;
(d)R3选自H、甲基、氯;
(e)R4选自H、氯、氟、甲基、溴、腈、2-甲基苯基、4-甲氧基苯基;
(f)R5选自H、甲基、氯、溴、2-甲基苯基、苯氧基、4-甲氧基苯基、乙氧基、氰基;
(g)R6选自H、乙基、乙酰基;
(h)R4和R5一起形成芳香环;
(i)R2和R3一起形成芳香环。
根据本发明的第二方面,提供了用于治疗已感染HIV的受试者的组合物,所述组合物包含选自于上述式A化合物或式B化合物的化合物。
根据本发明的第三方面,提供了用于治疗已感染HIV的受试者的方法中的物质或组合物,所述物质或组合物包含选自于上述式A化合物或式B化合物的化合物。
根据本发明的第四方面,提供了选自于上述式A化合物或式B化合物的化合物在制造用于治疗已感染HIV的受试者的药物方面的用途。
已发现,本发明的化合物在微摩尔范围具有抗逆转录酶活性。此外,还发现,在全细胞PBMC或MAGI抗-HIV试验(assay)中,这些化合物在μM至nM范围抗HIV有效。
根据本发明的第五方面,提供了治疗已感染HIV的受试者的方法,所述方法包括对需要治疗的受试者给予选自于上述式A化合物或式B化合物的化合物。
本发明的化合物可通过如图示1示出的酸催化的三组分偶联反应很容易地一步制得,在该反应中,在蒙脱土K-10粘土或任何其他合适的酸催化剂的存在下,将2-氨基吡啶或取代2-氨基吡啶(其中,R、R1、R2、R3、R4和R5如前所述)与醛和异腈在常规的加热下、于95-100℃反应5-8小时,或者在微波照射下反应15-30分钟。所述产物通常通过柱色谱法分离。
图示1:咪唑并[1,2-a]吡啶的制备
因此,根据本发明的第六方面,提供了选自于上述式A化合物或式B化合物的化合物的合成方法,所述方法包括使2-氨基嘧啶或2-氨基吡啶或下式表示的取代2-氨基吡啶与式R1CHO的醛和式RNC的异氰化物缩合的步骤,其中,R、R1、R2、R3、R4、R5和R6如上所述。
图示2给出本发明的化合物的例子。
图示2
现在通过参考如下实施例描述本发明。
具体实施方式
所有化合物通过四种方法之一进行制备。
方法1
在蒙脱土K-10粘土(250mg)的存在下,将适量的2-氨基吡啶(1.33mmol)、醛(1.33mmol)和异氰化物(1.36mmol)在二噁烷(2.5ml)中,于95-100℃加热5-8小时。反应后,从粘土滤出液体,并用二噁烷或乙酸乙酯(2×2.5ml)冲洗粘土。真空除去溶剂,并通过柱色谱法(洗脱剂:己烷∶乙酸乙酯)提纯残余物以得到所需的产品。
方法1适用于化合物:1-15、17-31、33-41、43、49-64、67-77、106-110、112-115和117-183。
方法2
相对于方法1,不使用加热,而是使所述反应在室温搅拌48小时。
方法2适用于化合物:45-47。
方法3
相对于方法1,不使用常规加热,而是在密封的压力管中,使反应组分在150W的微波照射下、于100℃反应15-30分钟。
方法3适用于化合物:42、44、48、65、66、78-105、111、116、186-194。在制备嘧啶193的情况下,没有溶剂,使适当的2-氨基嘧啶(1.33mmol)和醛(2.66mmol)在150W的功率下、于150℃微波照射35分钟。然后添加异氰化物(1.60mmol)、二噁烷(1.5ml)和蒙脱土K-10粘土(250mg),并在150W和100℃照射25分钟。反应后,从粘土中滤出液体,并用二噁烷或乙酸乙酯冲洗粘土。
真空除去溶剂,并通过柱色谱法提纯(洗脱剂:乙酸乙酯)残余物以得到所需产品。
方法4:
将通过方法1或方法3制备的咪唑并[1,2-a]吡啶进一步修饰以制备化合物16、32、184和185。制备如下所述。
N-丁基-N-(2-异丙基咪唑并[1,2-a]吡啶-3-基)乙酰胺16
在K2CO3(2eq.,2.16mmol,299mg)的存在下,使N-丁基-2-异丙基咪唑并[1,2-a]吡啶-3-胺5(250mg,1.08mmol)与乙酰氯(2eq.,2.16mmol,154μl)在乙腈(10ml)中、于室温反应。采用TLC监测反应进度。通过柱色谱法(洗脱剂:乙酸乙酯∶己烷)实现产品的提纯。
N-丁基-N-乙基-2-异丙基咪唑并[1,2-a]吡啶-3-胺32
在室温下,使N-丁基-N-(2-异丙基咪唑并[1,2-a]吡啶-3-基)乙酰胺16(287mg,1.05mmol)与LiAlH4(2eq.,2.10mmol,80mg)在THF(10ml)中反应。采用TLC监测反应进度。使用NaOH水溶液来淬灭所述反应。滤出固体,并用乙酸乙酯洗涤所述固体,通过柱色谱法(洗脱剂:乙酸乙酯)提纯得到的产品。
2-(2-氯苯基)-N-环己基-5-苯氧基咪唑并[1,2-a]吡啶-3-胺184
使苯酚(40.43mg,0.687mmol)溶解在DMF(5ml)中,再分批添加金属钠(10.31mg,0.687mmol)。将5-溴-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺42(139.1mg,0.344mmol)添加到上述苯酚钠溶液中,并在90℃加热4小时。用水淬灭所述反应,并萃取到乙酸乙酯中。通过柱色谱法(洗脱剂:乙酸乙酯∶己烷)提纯得到的产品。
2-(2-氯苯基)-N-环己基-5-乙氧基咪唑并[1,2-a]吡啶-3-胺185
将5-溴-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺42(152mg,0.376mmol)添加到乙醇钠中(所述乙醇钠通过将金属钠(17.32mg)添加至无水乙醇(10ml)中原位产生)。将所得到的混合物加热回流8小时。真空除去过量的溶剂,并用水处理所形成的混合物,再萃取到乙酸乙酯中,用硫酸镁干燥,过滤。减压除去过量的溶剂,得到油,将所得到的油通过柱色谱法(洗脱剂:己烷∶乙酸乙酯)提纯。
下面给出化合物1-194的分析数据。
1 MLB133-607A N-环己基-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.05-7.94(m,1H),7.46-7.33(m,1H),7.01(ddd,J=1.3,6.7,9.0,1H),6.69(td,J =1.0,6.7,1H),3.07-2.67(m,2H),2.11-1.82(m,3H),1.82-1.67(m,2H),1.67-1.48(m,1H),1.41-1.10(m,5H),1.05(dt,J=4.1,5.2,2H),1.01-0.85(m,2H).
13C NMR(50MHz,CDCl3)δ141.22,140.49,124.82,122.67,121.94,116.62,110.82,57.24,34.37,25.85,24.94,8.18,7.73.
HRMS(ESI):m/z 256.1810(M+H)+;计算为C16H22N3:256.1814.
2 MLB133-607C N-环己基-2-(2-(甲硫基)乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.10-7.94(m,1H),7.48-7.38(m,1H),7.06(ddd,J=1.3,6.6,9.0,1H),6.72(td,J =1.1,6.8,1H),3.20-2.78(m,6H),2.18-2.00(m,3H),1.76(ddt,J=6.2,10.2,18.4,5H),1.41-1.03(m,5H).
13C NMR(50MHz,CDCl3)δ141.43,137.54,125.25,123.10,122.53,116.90,111.11,57.16,34.43,34.35,27.81,25.79,24.91,15.87.
HRMS(ESI):m/z 290.1684(M+H)+;计算为C16H24N3S:290.1691.
3 MLB133-608A 2-仲丁基-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14-7.93(m,1H),7.48(dt,J=1.3,9.5,1H),7.04(ddd,J=1.2,6.7,8.8,1H),6.71(td,J=1.1,6.9,1H),3.10-2.63(m,2H),2.12-1.48(m,9H),1.48-1.06(m,10H),1.06-0.90(m,2H),0.85(t,J=7.3,3H).
13C NMR(50MHz,CDCl3)δ143.77,141.75,124.39,123.01,122.71,117.13,111.12,57.58,34.55,34.51,33.63,30.16,26.09,25.23,25.15,21.07,12.87.
HRMS(ESI):m/z 272.2127(M+H)+;计算为C17H26N3:272.2127.
4 MLB133-609A N-环己基-2-(5-甲基异噁唑-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(d,J=6.9,1H),7.52(d,J=9.1,1H),7.18-7.05(m,1H),6.78(td,J=0.7,6.8,1H),6.63-6.55(m,1H),4.79-3.86(m,1H),3.17-2.91(m,1H),2.48(s,3H),2.03-1.46(m,5H),1.46-0.91(m,5H).
13C NMR(50MHz,CDCl3)δ168.61,159.55,141.64,129.39,123.54,123.02,117.87,111.94,100.67,56.38,34.07,25.70,25.08,12.21.
HRMS(ESl):m/z297.1701(M+H)+;计算为C17H21N4O:297.1715.
5 MLB133-616C N-丁基-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.92(d,J=6.8,1H),7.56-7.30(m,1H),6.97(ddd,J=0.9,6.7,8.6,1H),6.64(td,J=0.6,6.7,1H),3.24-2.97(m,1H),2.90(t,J=6.8,3H),1.65-1.34(m,4H),1.30(d,J=6.9,6H),0.87(t,J=7.1,3H).
13C NMR(50MHz,CDCl3)δ143.98,141.19,124.52,122.64,122.08,117.08,110.96,48.96,32.90,26.45,22.80,20.22,13.92.
HRMS(ESI):m/z 232.1808(M+H)+;计算为C14H22N3:232.1814.
11 MLB133-616A 2-异丙基-N-戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98(d,J=6.8,1H),7.48(d,J=9.0,1H),7.04(dd,J=6.5,8.5,1H),6.71(t,J=6.9,1H),3.20-3.05(m,2H),2.96(t,J=7.0,2H),1.58(ddd,J=3.7,7.9,14.3,2H),1.42-1.10(m,10H),0.90(t,J=7.0,3H).
13C NMR(50MHz,CDCl3)δ143.89,141.17,124.52,122.69,122.08,117.05,111.0049.25,30.50,29.23,26.44,22.79,22.55,14.02.
HRMS(ESI):m/z 246.1950(M+H)+;计算为C15H24N3:246.1970.
12 MLB133-640A 4-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)-2-乙氧基苯酚
1H NMR(200MHz,CDCl3)δ8.09(d,J=6.9,1H),7.74-7.60(m,1H),7.60-7.37(m,2H),7.20-7.03(m,1H),6.98(d,J=8.2,1H),6.75(t,J=7.1,1H),4.35-4.04(m,3H),3.36-2.68(m,2H),1.95-1.52(m,5H),1.45(t,J=6.9,3H),1.37-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ146.08,145.42,141.38,136.83,126.87,124.06,123.53,122.54,119.92,117.13,114.30,111.34,111.17,64.60,56.83,34.24,25.79,24.85,15.00.
HRMS(ESI):m/z 352.2025(M+H)+;计算为C21H26N3O2:352.2025.
13 MLB133-635C 2-环丙基-5,7-二甲基-N-(萘-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.73(d,J=8.7,2H),7.55(d,J=8.2,1H),7.46-7.07(m,3H),6.94(dd,J=2.3,8.8,1H),6.73(d,J=1.4,1H),6.26(s,1H),5.58(s,1H),2.62(s,3H),2.33(s,3H),1.94(ddd,J=5.1,8.5,13.5,1H),1.16-0.97(m,2H),0.87(ddd,J=3.8,6.3,11.8,2H).
13C NMR(50MHz,CDCl3)δ145.76,145.18,144.78,135.27,134.89,134.43,129.52,128.25,127.63,126.48,126.12,122.70,118.67,116.19,115.53,113.68,107.06,20.93,18.76,7.83,7.54.
HRMS(ESI):m/z 328.1803(M+H)+;计算为C22H22N3:328.1814.
14 MLB 133-627A N-异丙基-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14-8.05(m,1H),7.97(d,J=8.9,2H),7.51(dd,J=0.5,8.9,1H),7.17-7.04(m,1H),6.98(d,J=8.9,2H),6.74(td,J=0.9,6.7,1H),3.84(s,3H),3.40(td,J=7.2,13.1,1H),3.16-2.79(m,1H),1.08(d,J=6.3,6H).
13C NMR(50MHz,CDCl3)δ158.95,141.59,138.21,128.31,127.21,123.61,122.54,117.22,113.95,111.34,55.28,49.12,23.45.
HRMS(ESI):m/z 282.1602(M+H)+;计算为C17H20N3O:282.1606.
15 MLB 133-640C N-环己基-5,7-二甲基-2-丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.05(s,1H),6.20(s,1H),2.83(s,3H),2.61(dd,J=8.7,16.6,4H),2.28(s,3H),1.98-1.50(m,7H),1.16(s,5H),0.98(t,J=7.3,3H).
13C NMR(50MHz,CDCl3)δ143.53,140.95,135.08,133.70,125.46,115.34,113.67,59.57,33.61,29.74,26.01,25.17,22.71,20.77,19.51,14.33.
HRMS(ESI):m/z 286.2284(M+H)+;计算为C18H28N3:286.2283.
16 DG120-034 N-丁基-N-(2-异丙基咪唑并[1,2-a]吡啶-3-基)乙酰胺
1H NMR(200MHz,DMSO-d6)δ8.13(d,J=6.3,1H),7.55(d,J=9.3,1H),7.45-7.19(m,1H),6.96(t,J=6.7,1H),3.73-3.26(m,11H),3.10-2.78(m,1H),2.65-2.42(m,1H),1.73(s,1H),1.63(s,2H),1.54-1.32(m,3H),1.26(t,J=6.7,6H),0.82(t,J=6.9,3H).
13C NMR(50MHz,DMSO-d6)δ175.26,171.14,170.96,146.57,141.97,124.82,122.51,118.46,116.80,112.58,47.01,30.61,29.99,25.61,24.08,22.44,22.01,21.82,21.74,20.74,19.56,13.59.
17 MLB133-628B N,2-双(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,DMSO-d6)δ8.13-7.79(m,3H),7.55(dd,J=8.8,14.7,1H),7.39-7.16(m,1H),7.04-6.83(m,3H),6.76(d,J=8.8,2H),6.45(d,J=8.8,2H),3.77(s,3H),3.64(s,3H).
13C NMR(50MHz,DMSO-d6)δ158.66,152.22,141.40,139.19,139.12,137.35,127.65,126.18,124.64,122.81,116.70,114.97,113.79,113.41,111.83,55.19,55.03.HRMS(ESI):m/z 346.1548(M+H)+;计算为C21H20N3O2:346.1556.
18 MLB133-615B N-苄基-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.99(d,J=6.8,1H),7.52(d,J=8.9,1H),7.35(s,5H),7.19-6.97(m,1H),6.72(t,J=6.7,1H),4.15(d,J=3.7,2H),3.35-3.17(m,1H),3.17-2.94(m,1H),1.33(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ144.54,141.34,139.39,128.60,128.22,127.54,123.84,122.89,122.05,117.14,111.10,53.33,26.49,22.74.
HRMS(ESI):m/z 266.1637(M+H)+;计算为C17H20N3:266.1657.
19 MLB133-607B N-环己基-2-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(d,J=7.3,1H),7.49(d,J=9.0,1H),7.17-6.92(m,1H),6.71(t,J=6.8,1H),3.34-3.03(m,1H),3.02-2.64(m,2H),2.12-1.82(m,8H),1.82-1.44(m,5H),1.44-1.00(m,5H).
13C NMR(50MHz,CDCl3)δ142.71,141.52,124.07,122.63,122.31,116.99,110.83,57.19,37.61,34.33,33.53,26.04,25.88,25.00.
HRMS(ESI):m/z 284.2125(M+H)+;计算为C18H26N3:284.2127.
20 MLB133-615C 2-异丙基-N-(萘-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.93-7.79(m,1H),7.73(d,J=8.7,2H),7.69-7.58(m,1H),7.51(d,J=8.1,1H),7.43-7.12(m,3H),6.95(dd,J=2.4,8.8,1H),6.72(td,J=1.1,6.8,1H),6.66(d,J=2.2,1H),5.73(s,1H),3.37-3.03(m,1H),1.37(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ148.20,143.18,142.59,134.74,129.56,128.42,127.63,126.54,126.07,124.12,122.90,122.44,117.36,116.97,116.27,111.68,106.69,26.79,22.31.
HRMS(ESI):m/z 302.1640(M+H)+;计算为C20H20N3:302.1657.
21 MLB 133-608C N-环己基-2-(2,5-二甲氧基四氢呋喃-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.09-7.90(m,1H),7.53-7.37(m,1H),7.15-6.95(m,1H),6.80-6.64(m,1H),5.40-4.99(m,2H),3.81-3.62(m,1H),3.44(dd,J=4.2,10.4,6H),3.04(dd,J=5.3,10.8,1H),2.85(td,J=5.5,9.5,1H),2.72-2.41(m,1H),2.41-2.19(m,1H),1.99-1.37(m,5H),1.17(dq,J=7.5,13.3,5H).
13C NMR(50MHz,CDCl3)δ147.44,141.52,138.14,137.54,136.67,125.76,123.16,122.83,122.49,122.25,117.18,117.03,116.85,113.69,111.51,111.17,109.68,109.13,105.97,105.38,104.83,104.50,57.13,57.08,56.13,55.74,54.92,42.71,41.75,38.71,36.36,34.34,34.18,34.11,25.73,25.01,24.89,24.85.
HRMS(ESI):m/z 346.2094(M+H)+;计算为C19H28N3O3:346.2131.
22 MLB133-623A N-环己基-6-氟-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.96-7.76(m,1H),7.36(dd,J=5.0,9.7,1H),6.99-6.70(m,1H),3.22-2.93(m,1H),2.77(s,2H),1.92-1.41(m,5H),1.28(d,J=6.9,6H),1.22-0.87(m,5H).
13C NMR(50MHz,CDCl3)δ155.15,150.48,146.47,138.82,138.11,124.36,117.28,117.10,114.49,113.97,109.17,108.35,57.01,34.11,26.20,25.63,24.75,22.61.
HRMS(ESI):m/z 276.1858(M+H)+;计算为C16H23N3F:276.1876.
23 MLB133-623C N-环己基-2-异丙基-5,7-二甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.11(s,1H),6.20(s,1H),3.08(dt,J=6.9,13.7,1H),2.83(s,3H),2.64(s,1H),2.26(s,3H),1.89-1.51(m,5H),1.32(d,J=6.9,6H),1.26-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ146.49,143.95,135.39,133.92,124.12,115.64,115.61,114.12,114.09,59.82,33.80,26.27,26.19,25.45,22.99,21.03,19.85.
HRMS(ESI):m/z 286.2277(M+H)+;计算为C18H28N3:286.2283.
24MLB133-628C 2-环丙基-N-戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.04-7.91(m,1H),7.48-7.34(m,1H),7.14-6.92(m,1H),6.83-6.60(m,1H),3.03(t,J=7.1,3H),1.99(ddd,J=5.2,8.4,13.5,1H),1.74-1.49(m,2H),1.49-1.17(m,4H),1.15-1.00(m,2H),1.00-0.75(m,5H).
13C NMR(50MHz,CDCl3)δ141.31,139.89,126.43,122.93,121.98,116.99,111.18,49.36,30.81,29.51,22.83,14.30,8.33,7.81.
HRMS(ESI):m/z 244.1819(M+H)+;计算为C15H22N3:244.1814.
25 MLB133-624A 8-(苄氧基)-N-环己基-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.66(dd,J=1.0,6.7,1H),7.62-7.45(m,2H),7.45-7.20(m,3H),6.65-6.44(m,1H),6.44-6.20(m,1H),5.41(s,2H),3.32-3.05(m,1H),3.05-2.58(m,2H),2.03-1.54(m,5H),1.42(d,J=6.9,6H),1.35-1.05(m,5H).
13C NMR(50MHz,CDCl3)δ147.73,144.20,137.20,128.73,127.95,127.19,124.30,116.01,110.72,102.01,70.82,57.54,34.55,26.83,26.13,25.23,23.07.
HRMS(ESI):m/z 364.2351(M+H)+;计算为C23H30N3O:364.2389.
26 MLB133-627C 2-(4-甲氧基苯基)-N-(萘-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98(d,J=8.6,2H),7.87-7.57(m,4H),7.57-7.10(m,4H),6.99(dd,J=2.3,8.7,1H),6.86(d,J=8.6,2H),6.78-6.63(m,2H),5.93(s,1H),3.78(s,3H).
13C NMR(50MHz,CDCl3)δ159.65,143.04,142.80,139.81,138.46,135.12,130.15,128.87,128.59,127.94,126.87,126.47,126.27,125.11,123.31,122.93,117.65,116.66,114.29,112.25,107.30,55.47.
HRMS(ESI):m/z 366.1577(M+H)+;计算为C24H20N3O:366.1606.
27 MLB133-629B N-苄基-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.00-7.85(m,3H),7.60-7.45(m,1H),7.40-7.25(m,5H),7.15-6.95(m,3H),6.75-6.65(m,1H),4.20(d,2H),3.85(s,3H),3.50-3.35(m,1H).
13C NMR(50MHz,CDCl3)δ159.02,156.38,141.43,139.05,129.60,128.58,128.23,128.17,128.09,127.53,123.59,122.14,117.21,114.04,111.37,55.26,52.37.
HRMS(ESI):m/z330.1591(M+H)+;计算为C21H20N3O:330.1606.
28 MLB133-634A N-环己基-2-((1R,5S)-6,6-二甲基二环[3.1.1]庚-2-烯-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.18-7.78(m,1H),7.57-7.26(m,1H),7.10-6.82(m,1H),6.63(td,J=0.9,6.7,1H),6.11(ddd,J=1.3,3.2,4.7,1H),3.06(td,J=1.3,5.8,1H),3.01-2.72(m,2H),2.61-2.30(m,3H),2.25-2.03(m,1H),1.92-1.44(m,5H),1.32(s,3H),1.30-1.01(m,6H),0.90(s,3H).
13C NMR(50MHz,CDCl3)δ141.98,138.46,137.13,123.36,122.70,121.85,117.41,111.35,57.61,44.20,41.16,38.12,34.50,34.39,32.50,32.12,26.63,26.10,25.21,21.54.
HRMS(ESI):m/z 336.2413(M+H)+;计算为C22H30N3:336.2440.
29 MLB133-627B N-丁基-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.06-7.92(m,1H),7.45-7.36(m,1H),7.02(ddd,J=1.3,6.7,9.0,1H),6.70(td,J=1.1,6.8,1H),3.25-2.79(m,3H),1.99(ddd,J=5.1,8.3,10.0,1H),1.73-1.31(m,5H),1.15-0.73(m,6H).
13C NMR(50MHz,CDCl3)δ141.04,139.62,126.15,122.71,121.72,116.72,110.95,48.81,32.95,20.22,13.95,8.05,7.56.
HRMS(ESI):m/z 230.1646(M+H)+;计算为C14H20N3:230.1657.
30 MLB133-615A 2-异丙基-N-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.87-7.75(m,1H),7.64-7.50(m,1H),7.23-7.02(m,1H),6.90-6.61(m,3H),6.56-6.31(m,2H),5.23(s,1H),3.73(s,3H),3.27-3.01(m,1H),1.32(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ153.24,147.91,142.37,139.29,123.85,122.40,117.83,117.46,115.05,114.08,111.51,55.70,26.70,22.33.
HRMS(ESI):m/z 282.1582(M+H)+;计算为C17H20N3O:282.1606.
31 MLB133-640B N-环己基-2-辛基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(d,J=6.8,1H),7.44(d,J=8.4,1H),7.12-6.92(m,1H),6.70(t,J=6.7,1H),2.98-2.77(m,2H),2.77-2.58(m,2H),1.95-1.48(m,7H),1.48-1.00(m,15H),0.98-0.72(m,3H).
13C NMR(50MHz,CDCl3)δ141.35,139.73,124.40,122.69,122.37,116.85,110.89,57.21,34.33,31.91,29.85,29.67,29.50,29.29,27.51,25.86,24.93,22.68,14.09.
HRMS(ESI):m/z 328.2747(M+H)+;计算为C21H34N3:328.2753.
32 DG120-036 N-丁基-N-乙基-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.99(d,J=6.8,1H),7.49(d,J=9.0,1H),7.12-6.98(m,1H),6.72(t,J=6.3,1H),3.16(dt,J=7.0,13.8,1H),2.99(dd,J=6.3,12.5,3H),2.88-2.70(m,1H),1.74-1.40(m,5H),1.38(d,J=6.9,7H),0.95(t,J=7.0,4H).
33 MLB133-608B N-环己基-2-(4-(二甲基氨基)苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14-8.04(m,1H),7.94(d,J=8.7,2H),7.54-7.47(m,1H),7.07(ddd,J=1.3,6.6,8.9,1H),6.81(d,J=8.9,1H),6.73(td,J=0.9,6.9,2H),3.01(s,8H),1.93-1.43(m,5H),1.43-0.93(m,5H).
13C NMR(50MHz,CDCl3)δ149.65,141.40,137.26,131.84,127.83,123.07,122.78,122.41,116.87,112.33,110.95,56.80,40.42,34.15,25.79,24.83.
34 MLB133-629A 2-(4-甲氧基苯基)-N-(2,4,4-三甲基戊-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.21(d,J=6.9,1H),7.79(d,J=8.9,2H),7.51(d,J=9.0,1H),7.10(dd,J=7.2,8.5,1H),6.97(d,J=8.9,2H),6.75(t,J=6.8,1H),3.85(s,3H),3.34-2.95(m,1H),1.60(s,2H),1.04(s,9H),0.96(s,6H).
13C NMR(50MHz,CDCl3)δ159.21,142.18,140.03,129.78,128.35,123.91,123.70,123.01,117.39,113.94,111.32,60.88,57.35,55.53,32.15,32.02,29.26.
HRMS(ESI):m/z 352.2379(M+H)+;计算为C22H30N3O:352.2389.
35 MLB133-634B (5-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)呋喃-2-基)甲醇
1H NMR(400MHz,CDCl3)δ8.07-8.02(m,1H),7.49-7.45(m,1H),7.14-7.08(m,1H),6.80-6.71(m,2H),6.33(d,1H),4.66(s,2H),3.49(br s,1H),2.95-2.90(m,2H),1.87-1.82(m,2H),1.75-1.68(m,2H),1.60-1.55(m,1H),1.35-1.10(m,5H).
13C NMR(101MHz,DMSO-d6)δ154.38,148.63,140.53,127.56,125.49,123.72,123.10,116.47,111.52,108.47,106.98,56.25,55.81,33.54,25.36,24.48.
HRMS(ESI):m/z 312.1679(M+H)+;计算为C18H22N3O2:312.1712.
36 MLB133-636A 6-氯-N-环己基-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.10-7.93(m,1H),7.41-7.27(m,1H),7.08-6.89(m,1H),3.19-2.57(m,2H),2.07-1.84(m,3H),1.84-1.68(m,2H),1.68-1.45(m,1H),1.44-1.11(m,5H),1.11-0.80(m,4H).
13C NMR(50MHz,CDCl3)δ141.94,139.49,125.32,123.91,119.89,119.36,116.94,57.21,34.34,25.79,24.91,8.20,7.93.
HRMS(ESI):m/z 290.1408(M+H)+;计算为C16H21N3Cl:290.1424.
37 MR762-137.4 2-(3,4-二甲氧基苯基)-N-(2-吗啉基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.16(d,J=7,1H),8.10(m,2H),7.60(m,2H),7.14-7.32(m,1H),6.93(br t,1H),4.14(br s,1H),3.98(s,3H),3.92(s,3H),3.76(t,4H),3.07-3.10(m,2H),2.52-2.58(m,2H),2.44(t,4H).
13C NMR(50MHz,CDCl3)δ149.6,148.9,138.7,126.2,126.0,124.1,122.5,119.4,117.3,112.0,111.4,111.3,110.0,67.0,58.7,56.4,56.2,54.0,44.3.
38 MLB133-649A N-环己基-2-(戊-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.93(dt,J=1.0,6.8,1H),7.39(dt,J=0.9,9.0,1H),6.93(ddd,J=1.3,6.7,9.0,1H),6.59(td,J=1.1,6.7,1H),3.05-2.60(m,2H),1.91-1.38(m,6H),1.26(d,J=6.9,3H),1.22-0.93(m,7H),0.80(t,J=7.2,3H).
13C NMR(50MHz,CDCl3)δ143.69,141.28,123.68,122.40,122.21,116.71,110.57,57.10,39.10,34.09,31.11,25.63,24.75,24.68,20.86,13.99.
HRMS(ESI):m/z 286.2251(M+H)+;计算为C18H28N3:286.2283.
39 MLB133-648B N-环己基-2-(2,4-二甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.09(dt,J=1.0,6.7,1H),7.76(d,J=8.5,1H),7.53(d,J=9.0,1H),7.08(ddd,J=1.3,6.7,9.1,1H),6.75(td,J=1.1,6.8,1H),6.67(dd,J=2.4,8.5,1H),6.58(d,J=2.2,1H),3.87(s,6H),3.70(s,3H),2.87-2.40(m,1H),2.01-1.27(m,4H),1.27-0.75(m,4H).
13C NMR(50MHz,CDCl3)δ160.67,156.86,132.32,126.71,123.30,122.56,116.96,111.38,105.81,99.31,67.09,56.42,56.12,55.44,34.15,25.74,24.83.
HRMS(ESI):m/z 352.2012(M+H)+;计算为C21H26N3O2:352.2025.
40 MLB133-653B N-环己基-2-新戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(dt,J=1.0,6.6,1H),7.46(dt,J=1.0,9.3,1H),7.03(ddd,J=1.3,6.6,9.0,1H),6.70(td,J=1.1,6.8,1H),3.11-2.75(m,2H),2.64(s,2H),2.07-1.43(m,5H),1.41-1.07(m,5H),1.00(s,9H).
13C NMR(50MHz,CDCl3)δ140.88,137.31,126.04,122.44,122.39,116.98,110.75,56.84,41.34,34.50,33.12,29.85,25.83,24.96.
HRMS(ESI):m/z 286.2247(M+H)+;计算为C18H28N3:286.2283.
41 MLB133-655A N-环己基-2-戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.06-7.96(m,1H),7.51-7.35(m,1H),7.04(ddd,J=1.3,6.7,9.0,1H),6.71(td,J=1.1,6.8,1H),3.14-2.77(m,2H),2.77-2.50(m,2H),1.98-1.47(m,7H),1.47-1.29(m,4H),1.27-1.05(m,5H),0.90(t,J=6.9,3H).
13C NMR(50MHz,CDCl3)δ141.32,139.65,124.40,122.74,122.36,116.81,110.92,57.20,34.32,32.05,29.35,27.43,25.84,24.92,22.57,14.07.
HRMS(ESI):m/z 286.2270(M+H)+;计算为C18H28N3:286.2283.
42 DG 402-49706 5-溴-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ7.60(d,J=2.9,1H),7.60-7.57(m,1H),7.54(d,J=1.8,1H),7.52(d,J=1.8,1H),7.50-7.48(m,1H),7.47(d,J=2.5,1H),7.37-7.29(m,4H),7.03-6.96(m,3H),6.94(t,J=4.1,1H),3.28(d,J=6.2,2H),2.97-2.62(m,2H),1.66(d,J=12.4,5H),1.59-1.48(m,4H),1.48-1.35(m,2H),1.16-0.97(m,7H),0.97-0.75(m,4H).
13C NMR(101MHz,CDCl3)δ143.74,138.16,133.87,133.32,132.60,129.50,129.21,128.45,126.64,123.78,118.62,117.34,112.21,58.29,32.70,25.73,24.50.
HRMS(ESI):m/z 404.0516(M+H)+;计算为C19H20N3ClBr:404.0529.
43 DG 402-49651 2-(2-溴苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.43-7.97(m,3H),7.64(td,J=1.5,7.7,4H),7.58-7.48(m,2H),7.39(td,J=1.3,7.5,2H),7.31-7.21(m,2H),7.21-7.13(m,2H),7.11(dd,J=1.3,6.7,1H),6.80(td,J=1.1,6.7,2H),3.42-3.09(m,2H),2.82-2.48(m,2H),1.80-1.33(m,12H),1.21-0.81(m,13H).
13C NMR(50MHz,CDCl3)δ141.35,136.12,132.67,132.50,129.26,127.26,125.80,123.51,122.87,122.79,117.53,111.46,56.34,33.80,25.64,24.51.
HRMS(ESI):m/z 370.0892(M+H)+;计算为C19H21N3Br:370.0919.
44 DG 402-49659 2-(2-氯苯基)-N-戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.12(dt,J=1.2,6.9,1H),7.79-7.61(m,1H),7.55(dt,J=1.1,9.1,1H),7.51-7.44(m,1H),7.42-7.28(m,2H),7.14(ddd,J=1.3,6.7,9.1,1H),6.82(td,J=1.1,6.8,1H),3.30(t,J=6.2,1H),2.83(q,J=6.7,2H),1.95-1.64(m,1H),1.42-1.24(m,2H),1.24-1.05(m,3H),0.90-0.60(m,3H).
13C NMR(101MHz,CDCl3)δ141.47,133.93,132.84,132.60,129.48,129.14,126.87,123.57,122.60,117.69,111.62,48.27,30.02,28.93,22.38,13.90.
HRMS(ESI):m/z 314.1414(M+H)+;计算为C18H21N3Cl:314.1424.
45 DG789-110 N-丁基-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.08(dt,J=1.2,6.8,1H),7.97-7.89(m,2H),7.61-7.55(m,1H),7.15(ddd,J=1.3,6.7,9.0,1H),6.99-6.94(m,2H),6.82(td,J=1.1,6.8,1H),3.85(s,4H),3.02(t,J=7.1,2H),1.58(dt,J=6.9,14.4,2H),1.41(dq,J=7.2,14.3,2H),0.92(t,J=7.3,3H).
13C NMR(101MHz,CDCl3)δ159.10,140.57,134.37,128.20,125.71,125.54,124.57,122.43,116.53,114.03,112.06,55.22,47.92,32.78,20.18,13.89.
HRMS(ESI):m/z 296.1735(M+H)+;计算为C18H22N3O:296.1763.
46 DG789-112 2-(4-甲氧基苯基)-N-戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.06(dt,J=1.1,6.8,1H),7.95-7.89(m,2H),7.56(d,J=9.0,1H),7.13(ddd,J=1.3,6.7,9.0,1H),7.01-6.94(m,2H),6.80(td,J=1.1,6.8,1H),3.85(s,4H),3.01(t,J=7.1,2H),1.58(dd,J=7.6,14.8,2H),1.34(ddd,J=5.1,9.9,19.4,4H),0.89(t,J=7.1,3H).
13C NMR(101MHz,CDCl3)δ159.04,140.79,134.74,128.20,126.10,125.52,124.24,122.35,116.72,114.01,111.85,55.22,48.20,30.36,29.17,22.47,13.97.
HRMS(ESI):m/z 310.1906(M+H)+;计算为C19H24N3O:310.1919.
47 DG789-116 N-环丙基-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
48 DG 402-49760 5-氯-2-(2-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ7.63-7.58(m,1H),7.52-7.46(m,2H),7.38-7.30(m,2H),7.04(dd,J=7.2,9.0,1H),6.78(dd,J=1.1,7.2,1H),3.57-3.40(m,1H),3.27(d,J=5.7,1H),1.70-1.46(m,2H),1.46-1.30(m,4H),1.30-1.14(m,2H).
13C NMR(101MHz,CDCl3)δ143.66,137.58,133.63,133.36,132.65,129.50,129.27,126.64,126.37,126.13,123.65,116.80,114.02,61.91,32.48,22.98.
HRMS(ESI):m/z 346.0865(M+H)+;计算为C18H18N3Cl2:346.0878.
49 MLB133-635A N-丁基-6-氯-2-(5-甲基异噁唑-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.08-7.95(m,1H),7.46(d,J=9.6,1H),7.06(dd,J=2.0,9.6,1H),6.56(s,1H),4.54(t,J=6.8,1H),3.07(dd,J=6.9,13.8,2H),2.48(s,3H),1.73-1.50(m,2H),1.50-1.22(m,2H),0.92(t,J=7.2,3H).
13C NMR(50MHz,CDCl3)δ168.93,159.22,139.76,131.08,124.93,124.54,120.57,120.51,118.33,100.50,47.42,32.64,20.13,13.85,12.21.
HRMS(ESI):m/z 305.1180(M+H)+;计算为C15H18N4ClO:305.1169.
50 MLB 133-634C N-苄基-6-氯-2-(5-甲基异噁唑-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98(dd,J=0.9,1.9,1H),7.48(dd,J=0.8,9.6,1H),7.44-7.22(m,5H),7.08(dd,J=2.0,9.6,1H),6.61-6.54(m,1H),4.80(t,J=6.4,1H),4.25(d,J=6.5,2H),2.49(d,J=11.7,3H).
13C NMR(50MHz,CDCl3)δ169.36,159.09,140.09,138.64,130.45,128.80,128.50,127.88,125.78,121.07,120.93,118.35,100.84,52.22,12.49.
HRMS(ESI):m/z 339.0979(M+H)+;计算为C18H16N4OCl:339.1013.
51 MLB133-635B N-丁基-5,7-二甲基-2-(5-甲基异噁唑-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.09(s,1H),6.56(d,J=0.6,1H),6.25(s,1H),3.98(t,J=7.2,1H),3.09-2.73(m,5H),2.45(s,3H),2.26(s,3H),1.76-1.50(m,2H),1.38(dq,J=7.1,13.8,2H),0.90(t,J=7.2,3H).
13C NMR(50MHz,CDCl3)δ168.42,159.50,143.95,135.77,134.93,132.46,126.01,116.10,114.03,100.75,52.08,31.99,20.86,20.19,18.57,13.93,12.10.
HRMS(ESI):m/z 299.1869(M+H)+;计算为C17H23N4O:299.1872.
52 MLB133-636B N-苄基-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.96(d,J=6.8,1H),7.55-7.18(m,6H),7.12-6.97(m,1H),6.77-6.54(m,1H),4.21(s,2H),3.52-2.83(m,1H),1.85(ddd,J=5.1,8.3,9.9,1H),1.11-0.97(m,2H),0.91(dtd,J=2.1,4.9,7.3,2H).
13C NMR(50MHz,CDCl3)δ139.53,128.72,128.55,128.28,127.88,127.46,122.92,121.68,116.70,111.00,107.42,53.26,8.00,7.57.
HRMS(ESI):m/z 264.1477(M+H)+;计算为C17H18N3:264.1501.
53 MR762-137.15 N-环己基-2-(呋喃-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.07(dd,J=6.7,1.2,1H),7.53(d,J=9.0,1H),7.51(d,J=1.6,1H),7.15(ddd,J=9.0,6.7,1.2,1H),6.91(d,J=3.3,1H),6.79(td,J=6.7,1.0,1H),6.55(dd,J=3.3,1.6,1H),3.62(br s,1H)2.85-3.10(m,1H),1.50-2.00,1.05-1.45(m,9H).
13C NMR(50MHz,CDCl3)δ149.72,141.56,141.37,127.40,125.45,124.45,122.81,116.90,111.91,111.52,106.98,57.12,34.13,25.76,25.01.
54 10061 N-环己基-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.11(d,J=6.8,2H),8.02(d,J=8.6,2H),7.16-7.08(m,1H),7.02-6.98(d,J=8.6,2H),6.80-6.73(m,1H),3.87(s,3H),1.80-1.59(br m,10H).
13C NMR(50MHz,CDCl3)δ158.3,141.6,138.3,137.1,128.6,127.3,124.3,123.9,118.5,117.3,116.2,57.1,55.5,34.4,26.0,25.1.
55 MR762-137.8 2-(呋喃-2-基)-N-(2-吗啉基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.07(dd,J=6.4,1.2,1H),7.51(d,J=8.0,1H),7.45(d,J=0.8,1H),7.11(ddd,J=8.0,6.4,1.2,1H),6.89(d,J=3.2,1H),6.78(td,J=6.4,0.8,1H),6.53(dd,J=3.2,1.2,1H),4.34(br s,1H),3.76(m 4H),3.13(t,J=6.0,2H),2.61(t,J=6.4,2H),2.50(br s,4H).
13C NMR(50MHz,CDCl3)δ150.3,141.7,141.3,126.9,126.7,123.9,122.4,117.3,111.6,111.5,106.3,67.0,58.2,53.5,44.3.
56 MR762-137.11 N-环己基-2-(3,4-二甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(d,J=6.8,1H),7.71(d,J=1.8,1H),7.60-7.48(m,2H),7.12-6.94(m,1H),6.90,(d,J=8.4,1H),3.97(s,3H),3.91(s,3H),3.20-2.81(m,2H),1.83-1.21(br m,10H).
13C NMR(50MHz,CDCl3)149.3,148.7,141.6,136.7,127.6,124.4,123.9,122.8,119.7,117.3,111.7,111.4,110.9,67.3,57.0,56.2,56.1,34.5,26.0,25.1.
57 MLB133-639A 4-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)-2,6-二甲氧基苯酚
1H NMR(200MHz,DMSO-d6)δ8.49-8.22(m,2H),7.45(d,J =8.8,1H),7.21-7.06(m,1H),6.86(t,J=6.7,1H),4.87-4.59(m,1H),3.85(s,6H),3.07-2.81(m,1H),1.86-1.43(m,5H),1.43-0.92(m,5H).
13C NMR(50MHz,DMSO-d6)δ147.76,140.11,135.09,134.79,124.95,124.41,123.44,123.03,116.24,110.93,104.05,56.18,55.86,33.58,25.44,24.40.
HRMS(ESI):m/z 368.1946(M+H)+;计算为C21H26N3O3:368.1974.
58 MLB133-639C 2-(4-(苄氧基)苄基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.10(d,J=6.8,1H),8.01(d,J=8.8,2H),7.59-7.27(m,7H),7.13-7.00(m,2H),6.76(t,J=6.8,1H),5.13(s,2H),2.98(m,1H),1.75(m,5H),1.47-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ158.10,141.42,136.97,136.56,129.52,128.45,128.28,127.83,127.43,124.05,123.51,122.52,117.07,114.82,111.27,69.99,56.77,34.13,25.73,24.79.
HRMS(ESI):m/z 412.2364(M+H)+:计算为C27H30N3O:4122389.
59 MLB133-639B 2-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)苯酚
1H NMR(200MHz,DMSO-d6+CD3OD)δ8.36(d,J=6.8,1H),8.17(dd,J=1.7,8.1,1H),7.54(d,1H),7.40-7.15(m,2H),7.10-6.85(m,3H),3.05-2.81(m,1H),1.99-1.44(m,5H),1.44-1.01(m,5H).
13C NMR(50MHz,DMSO-d6+CD3OD)δ158.77,141.58,135.94,129.75,129.14,125.78,125.08,123.89,119.89,117.86,116.87,113.01,57.65,34.24,26.43,25.54.
HRMS(ESI):m/z 308.1767(M+H)+;计算为C19H22N3O:308.1763.
60 MLB 133-649C N-环己基-2-(戊-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.05(dt,J=1.0,6.8,1H),7.58-7.38(m,1H),7.03(ddd,J=1.3,6.6,9.0,1H),6.70(td,J=1.1,6.7,1H),3.20-2.72(m,1H),2.72-2.42(m,1H),1.99-1.44(m,9H),1.41-1.01(m,6H),0.80(t,J=7.4,6H).
13C NMR(50MHz,CDCl3)δ142.04,141.60,125.60,122.61,122.45,116.96,110.69,57.56,40.98,34.25,28.31,25.86,24.92,12.62.
HRMS(ESI):m/z 286.2281(M+H)+;计算为C18H28N3:286.2283.
61 MLB 133-648A N-环己基-2-(4-硝基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.49-8.21(m,4H),8.07(dt,J=1.0,6.9,1H),7.55(d,J=8.3,1H),7.18(ddd,J=1.3,6.7,9.1,1H),6.83(td,J=1.0,6.8,1H),3.28-2.79(m,2H),2.04-1.47(m,5H),1.47-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ146.55,142.06,141.13,134.43,127.26,126.47,124.83,123.80,122.65,117.89,112.23,57.12,34.36,25.66,24.87.
HRMS(ESI):m/z 337.1670(M+H)+;计算为C19H21N4O2:337.1665.
62 MLB133-648C N-环己基-2-异丁基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.08-7.95(m,1H),7.50-7.36(m,1H),7.03(ddd,J=1.2,6.7,9.0,1H),6.70(td,J=0.9,6.7,1H),3.00-2.69(m,2H),2.58(d,J=7.1,2H),2.20(dt,J=6.8,13.4,1H),2.04-1.49(m,5H),1.38-1.07(m,5H),0.95(d,J=6.6,6H).
13C NMR(50MHz,CDCl3)δ141.29,138.72,125.17,122.65,122.38,116.83,110.81,57.21,36.67,34.34,28.88,25.83,24.92,22.74.
HRMS(ESI):m/z 272.2105(M+H)+;计算为C17H26N3:272.2127.
63 MLB133-649B 4-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)苯酚
1H NMR(200MHz,DMSO-d6)δ9.41(s,1H),8.26(d,J=6.9,1H),8.03(d,J=8.6,2H),7.41(d,J=8.9,1H),7.28-7.01(m,1H),6.83(t,J=7.3,3H),4.60(d,J=5.5,1H),3.45-3.38(m,1H),3.00-2.65(m,1H),2.01-1.40(m,5H),1.40-0.85(m,5H).
13C NMR(50MHz,DMSO-d6)δ154.73,138.53,133.82,126.11,123.79,122.44,121.29,121.20,114.42,113.20,109.01,54.45,31.83,23.77,22.78.
HRMS(ESI):m/z 308.1754(M+H)+;计算为C19H22N3O:308.1763.
64 MLB133-650A 2-叔丁基-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.08(dt,J=1.0,6.9,1H),7.47(d,J=9.0,1H),7.04(ddd,J=1.3,6.6,8.9,1H),6.69(td,J=0.9,6.7,1H),3.17-2.71(m,2H),2.06-1.51(m,6H),1.47(s,9H),1.40-1.02(m,5H).
13C NMR(50MHz,CDCl3)δ140.10,138.20,123.62,122.89,116.56,111.17,109.72,58.68,34.13,33.19,30.66,25.82,25.05.
HRMS(ESI):m/z 272.2102(M+H)+;计算为C17H26N3:272.2127.
65 MLB133-650B N-(4-(3,4-二氯苯氧基)丁基)-2-(呋喃-2-基)咪唑并[1,2-a]吡啶-3-胺
1H MMR(200MHz,CDCl3)δ7.88(d,J=6.9,1H),7.50-7.25(m,2H),7.15(d,J=8.9,1H),6.98(ddd,J=1.0,6.7,8.2,1H),6.83(d,J=2.9,1H),6.79-6.72(m,1H),6.70-6.50(m,2H),6.47-6.24(m,1H),3.79(dd,J =7.6,13.5,2H),3.59(d,J=6.1,1H),2.98(dd,J=6.4,12.9,2H),1.88-1.31(m,4H).
13C NMR(50MHz,CDCl3)δ157.76,150.15,141.52,141.32,132.52,130.38,129.19,127.45,126.16,123.57,122.13,117.09,116.14,115.54,114.26,111.51,106.26,68.07,48.10,26.99,26.46.
HRMS(ESI):m/z 416.0902(M+H)+;计算为C21H20N3O2Cl2:416.0933.
66 MLB133-650C N-(4-(3,4-二氯苯氧基)丁基)-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.88(dt,J=1.0,6.8,1H),7.37(br dt,J=9.0,1H),7.16(d,J=8.9,1H),6.95(dd,J=1.2,6.7,1H),6.90(dd,J=1.3,6.8,1H),6.85(d,J=2.9,1H),6.71-6.49(m,1H),3.82(t,J=6.0,2H),3.20-2.99(m,1H),2.92(d,J=6.1,3H),1.89-1.44(m,4H),1.27(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ157.76,144.16,141.06,132.51,129.16,128.99,123.96,122.57,121.87,120.40,116.86,115.52,114.26,110.86,68.08,48.68,27.25,26.51,26.25,22.64.
HRMS(ESI):m/z 392.1259(M+H)+;计算为C20H24N3OCl2:392.1296.
67 MLB133-650D N-(4-氯苄基)-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.96(d,J=6.8,2H),7.52(d,J=9.0,2H),7.18-6.99(m,2H),6.73(t,J=6.7,2H),4.03(s,2H),3.39-3.07(m,1H),3.07-2.81(m,1H),1.23(d,J=6.9,6H).
13C NMR(101MHz,CDCl3)δ144.68,141.38,137.86,133.42,129.58,128.75,123.52,123.24,122.00,117.17,111.34,52.60,26.43,22.69.
HRMS(ESI):m/z 300.1241(M+H)+;计算为C17H19N3Cl:300.1268.
68 MLB133-653A 2-(5-氯呋喃-2-基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98(dt,J=1.1,6.8,1H),7.47-7.34(m,1H),7.04(ddd,J=1.3,6.7,9.1,1H),6.76(d,J=3.4,1H),6.69(td,J=1.0,6.8,1H),6.21(d,J=3.4,1H),3.42(d,J=6.6,1H),3.07-2.73(m,1H),2.01-1.41(m,5H),1.41-0.99(m,5H).
13C NMR(50MHz,CDCl3)δ149.97,141.83,135.16,127.34,125.70,124.15,122.79,117.22,111.66,108.25,108.04,57.38,34.18,25.76,24.95.
HRMS(ESI):m/z 316.1195(M+H)+;计算为C17H19N3OCl:316.1217.
69 MLB133-653C N-环己基-2-(5-乙基噻吩-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.07(dt,J=1.1,6.9,1H),7.50(d,J=9.0,1H),7.41(d,J=3.6,1H),7.10(ddd,J=1.3,6.6,9.0,1H),6.92-6.79(m,1H),6.79-6.66(m,1H),3.27-2.97(m,2H),2.90(dd,J=7.6,15.1,2H),2.09-1.51(m,5H),1.36(t,J=7.5,4H),1.30-1.00(m,4H).
13C NMR(50MHz,CDCl3)δ147.81,140.51,125.43,125.06,124.05,123.45,122.97,116.09,112.42,57.03,34.26,25.74,24.92,23.51,15.86.
HRMS(ESI):m/z 326.1695(M+H)+;计算为C19H24N3S:326.1691.
70 MLB133-654C 4-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)-2-甲氧基苯酚
1H NMR(200MHz,DMSO-d6)δ8.98(s,1H),8.30(d,1H),7.80(s,1H),7.65(d,1H),7.45(d,1H),7.15(t,1H),6.95-6.75(m,2H),4.70(d,1H),3.85(s,3H),3.00-2.80(m,1H),1.85-0.95(m,10H).
13C NMR(50MHz,DMSO-d6)δ147.31,145.71,140.23,135.31,126.14,124.33,123.28,123.08,119.41,116.30,115.33,110.96,110.62,56.21,55.49,33.55,25.44,24.43.
HRMS(ESI):m/z 338.1872(M+H)+;计算为C20H24N3O2:338.1869.
71 MLB133-654A 5-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)-2-甲氧基苯酚
1H NMR(200MHz,CDCl3-CD3OD)δ8.04(d,1H),7.50-7.25(m,3H),7.15-7.00(m,1H),6.85(d,1H),6.75-6.65(m,1H),3.83(s,3H),3.75-3.45(m,1H),2.95-2.75(m,1H),1.85-0.90(m,10H).
13C NMR(50MHz,CDCl3-DMSO-d6)δ147.18,145.94,140.35,134.58,125.63,125.20,124.38,122.77,118.47,115.46,113.79,112.21,111.22,56.50,55.59,33.78,25.46,24.61.
HRMS(ESI):m/z 338.1873(M+H)+;计算为C20H24N3O2:338.1869.
72 MLB133-654B N-环己基-2-(3-甲基噻吩-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.12(d,J=6.9,1H),7.56(d,J=8.9,1H),7.28(d,J=4.3,1H),7.20-7.06(m,1H),6.96(d,J=5.1,1H),6.80(td,J=0.7,6.8,1H),3.46-3.04(m,1H),3.04-2.76(m,1H),2.47(s,3H),2.02-1.43(m,5H),1.36-0.94(m,5H).
13C NMR(50MHz,CDCl3)δ141.26,135.92,131.79,130.54,129.38,125.91,124.12,123.58,122.66,117.33,111.51,56.75,33.92,25.73,24.74,15.24.
HRMS(ESI):m/z 312.1534(M+H)+;计算为C18H22N3S:312.1534.
73 DG 402-49647 N-环己基-2-(4-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.22(d,J=8.2,2H),8.08(dt,J=1.0,6.0,1H),7.68(d,J=8.3,2H),7.60-7.45(m,1H),7.15(ddd,J=1.2,6.7,9.0,1H),6.80(td,J=1.0,6.7,1H),3.29-2.67(m,2H),1.96-1.42(m,5H),1.42-0.91(m,5H).
13C NMR(50MHz,CDCl3)δ141.75,138.01,135.14,128.46,126.91,125.59,125.31(dd,J=3.8,7.6),124.45,124.34,122.64,117.57,111.84,56.94,34.22,25.65,24.81.HRMS(ESI):m/z 360.1683(M+H)+;计算为C20H21N3F3:360.1688.
74 DG 402-496482-(6-氯-2-氟-3-甲基苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.14(d,J=6.9,1H),7.57(d,J=9.1,1H),7.26-7.05(m,3H),6.82(dd,J=3.8,9.7,1H),3.02(s,1H),2.82-2.60(m,1H),2.31(d,J=2.1,3H),1.75(d,J=11.7,2H),1.65-1.54(m,2H),1.54-1.40(m,1H),1.22-0.87(m,5H).
13C NMR(101MHz,CDCl3)δ160.71,158.24,141.67,132.21,131.55,131.49,127.21,124.60,124.56,123.95,123.77,123.62,122.76,117.77,111.56,56.31,33.76,25.60,24.61,14.54.
HRMS(ESI):m/z 358.1481(M+H)+;计算为C20H22N3ClF:358.1486.
75 DG 402-496492-(4-氯-3-氟苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.06(d,J=6.8,1H),7.97(dd,J=1.9,10.9,1H),7.91-7.77(m,1H),7.52(d,J=9.3,1H),7.44(t,J=8.1,1H),7.23-7.08(m,1H),6.81(td,J=0.8,6.8,1H),3.16-2.79(m,2H),1.99-1.42(m,6H),1.42-0.90(m,7H).
13C NMR(50MHz,CDCl3)δ160.56,155.65,141.62,130.43,125.07,124.50,123.14,123.07,122.58,117.46,115.11,114.66,111.96,56.91,34.24,25.65,24.83.
HRMS(ESI):m/z 344.1323(M+H)+;计算为C19H20N3FCl:344.1330.
76 DG 402-496502-(3-溴苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.35-8.21(m,1H),8.15-8.04(m,1H),8.04-7.90(m,1H),7.61-7.47(m,1H),7.43(ddd,J=1.1,1.9,7.9,1H),7.29(dd,J=5.4,10.3,1H),7.13(ddd,J=1.3,6.7,9.0,1H),6.79(td,J=1.1,6.8,1H),3.29-2.66(m,2H),1.69(M,6H),1.41-0.74(m,7H).
13C NMR(50MHz,CDCl3)δ141.62,136.60,131.01,130.03,129.98,129.89,125.34,124.13,122.69,122.63,117.46,111.72,56.97,34.25,25.70,24.82.
HRMS(ESI):m/z 370.0911(M+H)+;计算为C19H21N3Br:370.0919.
77 DG 402-49653 2-(4-溴苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.09-8.00(m,1H),7.94(d,J=8.6,2H),7.58-7.43(m,3H),7.10(ddd,J=1.3,6.7,9.0,1H),6.75(td,J=1.1,6.8,1H),3.01(s,2H),1.93-1.39(m,5H),1.16(s,5H).
13C NMR(50MHz,CDCl3)δ141.57,135.62,133.46,131.43,128.49,124.83,123.98,122.55,121.09,117.33,111.58,56.77,34.32,25.66,24.76.
HRMS(ESI):m/z 370.0926(M+H)+;计算为C19H21N3Br:370.0919.
78 DG 402-49655 2-(2-氯苯基)-N-(戊-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.26-8.03(m,1H),7.77-7.61(m,1H),7.61-7.50(m,1H),7.50-7.41(m,1H),7.41-7.21(m,2H),7.12(ddd,J=1.1,6.7,8.9,1H),6.78(td,J=0.7,6.7,1H),3.33-3.03(m,1H),3.03-2.74(m,1H),1.44-0.99(m,4H),0.84(d,J=6.3,3H),0.75(dd,J=6.2,7.4,3H).
13C NMR(50MHz,CDCl3)δ141.51,134.02,132.58,132.41,129.29,129.23,128.97,126.73,123.51,123.37,122.63,117.43,111.41,53.14,39.54,20.79,18.85,13.93.
HRMS(ESI):m/z 314.1402(M+H)+;计算为C18H21N3Cl:314.1424.
79 DG 402-49657 2-异丙基-N-(戊-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.12-7.92(m,1H),7.59-7.40(m,1H),7.05(ddd,J=1.2,6.7,8.9,1H),6.71(dd,J=0.8,13.6,1H),3.25-2.98(m,2H),2.95-2.56(m,1H),1.63-1.40(m,3H),1.37(dd,J=2.9,6.9,6H),1.06(d,J=6.3,2H),0.93(dd,J=5.5,8.4,3H).
13C NMR(50MHz,CDCl3)δ144.92,141.51,123.23,122.69,122.36,117.07,110.92,53.66,40.03,26.24,22.73,21.01,19.45,14.24.
HRMS(ESI):m/z 246.1967(M+H)+;计算为C15H24N3:246.1970.
80 DG 402-49667 6,8-二氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.13(d,J=1.8,1H),7.75-7.64(m,1H),7.52-7.42(m,2H),7.42-7.29(m,4H),7.24(d,J=1.8,1H),3.29(s,1H),2.66(dd,J=7.7,11.3,1H),2.01-0.74(m,29H).
13C NMR(101 MHz,CDCl3)δ137.08,133.13,132.79,132.67,129.64,129.60,129.40,128.19,127.05,123.79,123.63,119.68,119.25,67.07,56.46,33.79,25.53,24.49.
HRMS(ESI):m/z 394.0643(M+H)+;计算为C19H19N3Cl3:394.0645.
81 DG 402-49663 2-(2-氯苯基)-N-环己基-6-氟咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.13(d,J=1.8,1H),7.71-7.67(m,1H),7.48-7.44(m,1H),7.38-7.33(m,2H),7.24(d,J=1.8,1H),3.33(d,J=29.8,1H),2.66(s,1H),1.77-1.60(m,3H),1.51(dd,J=14.4,43.3,2H),1.12-0.97(m,5H).
13C NMR(101 MHz, CDCl3)δ154.41,152.06,139.17,136.70,133.59,132.41,129.50,129.33,127.59,127.57,127.01,118.12,118.03,115.96,115.70,109.51,109.10,56.28,33.81,25.55,24.55.
HRMS(ESI):m/z 344.1299(M+H)+;计算为C19H20N3ClF:344.1330.
82 DG 402-49665 6-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.25-8.11(m,1H),7.75-7.56(m,1H),7.55-7.39(m,2H),7.39-7.25(m,2H),7.10(ddd,J=1.2,1.9,9.5,1H),3.27(d,J=6.8,1H),2.80-2.46(m,1H),1.82-1.34(m,5H),1.23-0.76(m,5H).
13C NMR(50MHz,CDCl3)δ139.84,136.39,133.58,132.56,132.38,129.44,129.27,126.88,126.72,124.94,120.67,120.08,117.96,56.36,33.79,25.58,24.52.
HRMS(ESI):m/z 360.1019(M+H)+;计算为C19H20N3Cl2:360.1034.
83 DG 402-49672 N-环戊基-2-(2,4-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.16(dt,J=1.2,7.3,1H),7.63(d,J=8.3,1H),7.58-7.41(m,2H),7.42-7.30(m,1H),7.15(ddd,J=1.3,6.7,9.1,1H),6.82(t,J=6.8,1H),3.33(dt,J=5.7,11.0,1H),3.14(d,J=6.2,1H),1.75-1.37(m,6H),1.37-1.04(m,2H).
13C NMR(50MHz,CDCl3)δ141.65,134.28,134.07,133.27,133.21,132.75,129.24,127.27,127.06,123.97,122.72,117.53,111.72,59.36,33.27,23.29.
HRMS(ESI):m/z 346.0889(M+H)+;计算为C18H18N3Cl2:346.0878.
84 DG 402-49673 2-(4-溴苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.05(dt,J=1.1,6.9,1H),8.00-7.89(m,2H),7.61-7.44(m,3H),7.12(ddd,J=1.3,6.7,9.0,1H),6.76(td,J=1.1,6.8,1H),3.72-3.47(m,1H),2.99(d,J=3.9,1H),1.83-1.60(m,4H),1.60-1.49(m,2H),1.49-1.35(m,2H).
13C NMR(101MHz,CDCl3)δ141.63,135.83,133.49,131.45,128.62,125.49,124.10,122.47,121.18,117.44,111.67,59.06.33.46,23.57.
HRMS(ESI):m/z 356.0727(M+H)+;计算为C18H19N3Br:356.0762.
85 DG 402-49678 2-(3-溴苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.31-8.28(m,1H),8.09(d,J=6.8,1H),8.04-7.97(m,1H),7.52(dt,J=3.5,7.8,1H),7.43(ddd,J=0.9,1.9,7.9,1H),7.32-7.24(m,1H),7.17-7.11(m,1H),6.79(td,J=0.8,6.8,1H),3.66(t,J=10.3,1H),3.01(s,1H),1.88-1.65(m,4H),1.65-1.53(m,2H),1.53-1.39(m,2H).
13C NMR(101MHz,CDCl3)δ141.71,136.63,135.41,130.13,130.10,130.06,129.94,125.80,125.52,124.26,122.70,122.55,117.61,111.82,59.24,33.56,23.61.
HRMS(ESI):m/z 356.0774(M+H)+;计算为C18H19N3Br:356.0762.
86 DG 402-49679 2-(4-氯-3-氟苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.05(d,J=6.7,1H),7.96(d,J=10.9,1H),7.85(d,J=8.4,1H),7.51(d,J=9.0,1H),7.42(t,J=8.0,1H),7.20-7.07(m,1H),6.79(t,J=6.7,1H),3.88-3.40(m,1H),2.97(d,J=3.8,1H),1.87-1.62(m,4H),1.62-1.52(m,2H),1.52-1.35(m,2H).
13C NMR(101MHz,CDCl3)δ159.39,156.93,141.73,135.29,135.22,134.97,130.38,125.70,124.44,123.27,123.23,122.49,119.51,119.33,117.62,115.13,114.90,111.92,59.12,33.54,23.61.
HRMS(ESI):m/z 330.1173(M+H)+;计算为C18H18N3FCl:330.1173.
87 DG 402-49680 2-(6-氯-2-氟-3-甲基苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.23-8.08(m,1H),7.56(ddd,J=1.0,1.9,9.1,1H),7.23-7.06(m,3H),6.87-6.72(m,1H),3.54-3.27(m,1H),2.96(d,J=6.4,1H),2.39-2.21(m,3H),1.72-1.51(m,4H),1.51-1.37(m,2H),1.37-1.16(m,2H).
13C NMR(101MHz,CDCl3)δ160.78,158.31,141.64,132.36,132.32,131.52,131.45,129.80,127.90,124.58,124.54,123.93,123.74,123.57,122.61,122.11,121.92,117.83,111.52,59.33,33.16,23.24,14.48,14.44.
HRMS(ESI):m/z 344.1328(M+H)+;计算为C19H20N3FCl:344.1330.
88 DG 402-49681 N-环戊基-2-(4-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.21(d,J=8.0,2H),8.07(d,J=6.9,1H),7.67(d,J=7.9,2H),7.53(d,J=9.1,1H),7.15(dd,J=7.2,8.5,1H),6.79(t,J=6.8,1H),3.75-3.50(m,J=9.6,1H),3.04(d,J=3.2,1H),1.87-1.62(m,4H),1.62-1.51(m,2H),1.50-1.36(m,2H).
13C NMR(101MHz,CDCl3)δ141.81,138.09,138.08,135.39,129.07,128.75,127.10,126.25,125.69,125.33,125.29,125.25,125.22,124.40,122.56,117.66,111.89,59.20,33.51,23.57.
HRMS(ESI):m/z 346.1525(M+H)+;计算为C19H19N3F3:346.1531.
89 DG 402-49686 N-环己基-2-(2,4-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.14(ddd,J=0.9,1.6,6.9,1H),7.64-7.60(m,1H),7.56-7.52(m,1H),7.51-7.48(m,1H),7.38-7.33(m,1H),7.19-7.12(m,1H),6.81(tt,J=1.8,9.2,1H),3.19(d,J=6.0,1H),2.67(dd,J=3.8,9.0,1H),1.65(t,J=11.2,2H),1.59(dd,J=4.6,8.9,2H),1.53-1.42(m,1H),1.17-0.92(m,6H).
13C NMR(101MHz,CDCl3)δ141.75,134.27,134.14,133.34,133.14,132.80,129.29,127.33,126.44,123.93,122.89,117.57,111.70,56.43,33.89,25.62,24.58.
HRMS(ESI):m/z 360.1025(M+H)+;计算为C19H20N3Cl2:360.1034.
90 DG 402-49688 N-(1-金刚烷基)-2-(2-氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.39-8.34(m,1H),7.75-7.68(m,1H),7.52(ddd,J=5.0,6.0,11.0,1H),7.48-7.43(m,1H),7.40-7.29(m,2H),7.17-7.11(m,1H),6.82-6.75(m,1H),3.28-3.11(m,1H),1.95-1.83(m,3H),1.52(d,J=12.2,3H),1.42(t,J=10.7,9H).
13C NMR(101MHz,CDCl3)δ142.21,137.82,134.92,132.85,132.46,129.45,129.04,126.94,124.04,123.94,123.77,117.36,11121,55.83,43.49,36.17,29.61.
HRMS(ESI):m/z 378.1731(M+H)+;计算为C23H25N3Cl:378.1737.
91 DG 402-49690 N-(1-金刚烷基)-2-(5-甲基异噁唑-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.30(dt,J=7.3,15.7,1H),7.50(dt,J=6.1,12.2,1H),7.16-7.07(m,1H),6.80-6.70(m,1H),6.63-6.56(m,1H),4.17-3.98(m,1H),2.60-2.40(m,3H),1.98(d,J=20.6,2H),1.82-1.70(m,5H),1.62-1.47(m,5H).
13C NMR(101MHz,CDCl3)δ168.66,159.46,142.39,128.08,126.54,124.33,124.13,117.50,111.52,101.16,57.60,43.42,36.20,29.78,12.20.
HRMS(ESI):m/z 349.2013(M+H)+;计算为C21H25N4O:349.2028.
92 DG 402-49683 N-环戊基-2-(2,6-二氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.19-8.13(m,1H),7.56(t,J=10.7,1H),7.41-7.29(m,1H),7.19-7.11(m,1H),7.06-6.97(m,2H),6.87-6.75(m,1H),3.48-3.32(m,1H),3.07(d,J=6.1,1H),1.73-1.53(m,4H),1.53-1.38(m,2H),1.38-1.24(m,2H).
13C NMR(101MHz,CDCl3)δ162.09,162.02,159.61,159.54,142.02,129.83,129.72,129.62,128.46,126.59,123.80,122.64,117.88,111.75,111.69,111.66,111.56,111.49,59.42,33.23,23.24.
HRMS(ESI):m/z 314.1462(M+H)+;计算为C18H18N3F2:314.1469.
93 DG 402-49694 N-(1-金刚烷基)-2-(3-甲基噻吩-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.28(dt,J=1.2,7.0,1H),7.51(dt,J=1.1,9.1,1H),7.27(d,J=4.8,1H),7.12(ddd,J=1.3,6.6,9.0,1H),6.93(d,J=5.1,1H),6.76(td,J=1.1,6.8,1H),3.01(s,1H),2.36(s,3H),1.94(s,3H),1.67-1.34(m,12H).
13C NMR(101MHz,CDCl3)δ142.08,135.20,131.03,130.16,127.25,124.57,123.81,123.58,120.05,117.31,111.16,56.25,43.44,36.19,29.68,15.17.
HRMS(ESI):m/z 364.1836(M+H)+;计算为C22H26N3S:364.1847.
94 DG 402-49700 2-(2-氯苯基)-N-(1-金刚烷基)咪唑并[2,1-a]异喹啉-3-胺
1H NMR(400MHz,CDCl3)δ8.66(ddd,J=6.1,6.6,12.7,1H),8.18(d,J=7.4,1H),7.78(dd,J=1.8,7.6,1H),7.73-7.67(m,1H),7.62-7.50(m,2H),7.48-7.44(m,1H),7.42-7.36(m,1H),7.36-7.29(m,1H),7.05(t,J=5.0,1H),3.23(s,1H),1.90(s,3H),1.66(d,J=2.9,3H),1.51(s,2H),1.46(d,J=2.4,8H).
13C NMR(101MHz,CDCl3)δ139.64,135.61,134.88,132.95,132.50,129.60,129.57,129.39,128.86,128.28,127.80,127.76,127.00,126.76,123.88,122.79,121.30,111.80,55.63,43.50,36.12,29.58.
HRMS(ESI):m/z 428.1896(M+H)+;计算为C27H27N3Cl:428.1894.
95 DG 402-49702 6-溴-2-(2-氯苯基)-N-环己基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.71-7.55(m,1H),7.55-7.42(m,1H),7.42-7.29(m,2H),7.25(d,J=4.3,2H),3.18(s,3H),2.55(s,1H),1.53(d,J=17.9,5H),1.16-0.65(m,5H).
13C NMR(50MHz,CDCl3)δ142.05,138.18,137.93,135.11,134.05,132.69,132.49,129.40,129.23,128.26,126.90,116.25,109.91,58.69,33.04,25.68,24.68,17.94.
HRMS(ESI):m/z 418.0676(M+H)+;计算为C20H22N3ClBr:418.0686.
96 DG 402-49704 2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-6-腈
1H NMR(400MHz,CDCl3)δ8.65-8.55(m,1H),7.68-7.63(m,1H),7.61(ddd,J=0.9,3.4,9.3,1H),7.53-7.46(m,1H),7.43-7.32(m,2H),7.27-7.19(m,1H),3.53-3.13(m,1H),2.86-2.55(m,1H),1.60(dd,J=23.5,47.2,5H),1.20-0.95(m,5H).
13C NMR(101MHz,CDCl3)δ140.47,137.48,132.83,132.57,132.30,129.76,129.62,129.36,127.41,127.07,123.24,118.50,117.05,97.81,56.58,33.76,25.44,24.45.
HRMS(ESI):m/z 351.1361(M+H)+;计算为C20H20N4Cl:351.1376.
97 DG 402-49754 2-(2-氯苯基)-N-环己基咪唑并[1,2-a]喹啉-1-胺
1H NMR(400MHz,CDCl3)δ9.44(dt,J=5.7,11.5,1H),7.74(dt,J=4.5,9.0,1H),7.71-7.65(m,1H),7.62-7.55(m,1H),7.52-7.47(m,1H),7.46-7.40(m,3H),7.39-7.36(m,1H),7.36-7.33(m,1H),3.60-3.39(m,1H),2.86-2.67(m,1H),1.74(dd,J=12.6,18.3,2H),1.60-1.36(m,3H),1.11-0.86(m,5H).
13C NMR(101MHz,CDCl3)δ140.68,134.79,132.65,131.29,129.57,129.44,129.34,129.05,128.43,127.66,127.36,127.01,125.69,124.42,124.33,117.52,117.11,56.59,33.10,25.58,24.62.
HRMS(ESI):m/z 376.1576(M+H)+;计算为C23H23N3Cl:376.1581.
98 DG 402-49708 6-溴-2-(2-氯苯基)-N-环己基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.22-8.08(m,1H),7.74-7.59(m,1H),7.53-7.41(m,1H),7.41-7.27(m,2H),7.03(dd,J=1.1,1.8,1H),3.22(d,J=6.9,1H),2.72-2.61(m,1H),2.60(s,3H),1.73-1.40(m,6H),1.17-0.82(m,6H).
13C NMR(101MHz,CDCl3)δ140.39,135.51,133.81,132.77,132.61,129.42,129.25,128.52,126.99,126.84,125.82,120.85,106.62,56.38,33.80,25.59,24.53,16.43.
HRMS(ESI):m/z 418.0676(M+H)+;计算为H22N3ClBr:418.0686.
99 DG 402-49710 6-溴-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.33-8.21(m,1H),7.70-7.56(m,1H),7.52-7.45(m,1H),7.45-7.40(m,1H),7.40-7.29(m,2H),7.20(dd,J=1.9,9.5,1H),3.25(d,J=6.9,1H),2.66(dd,J=3.4,6.5,1H),1.75-1.62(m,2H),1.61-1.52(m,2H),1.52-1.39(m,1H),1.18-0.86(m,5H).
13C NMR(101MHz,CDCl3)δ139.99,136.23,133.61,132.62,132.46,129.52,129.35,127.06,126.97,126.62,123.02,118.30,106.65,56.41,33.81,25.58,24.53.
HRMS(ESI):m/z 404.0512(M+H)+;计算为C19H20N3ClBr:404.0529.
100 DG 402-49692 N-(1-金刚烷基)-2-辛基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.30-8.09(m,1H),7.43(dt,J=1.1,9.0,1H),7.04(ddd,J=1.3,6.6,9.0,1H),6.69(td,J=1.1,6.8,1H),2.77-2.70(m,2H),2.05(d,J=8.4,3H),1.79(dt,J=7.7,15.7,2H),1.72(d,J=2.5,6H),1.64(d,J=12.3,3H),1.57(d,J=12.3,3H),1.45-1.17(m,11H),0.87(t,J=6.9,3H).
13C NMR(101MHz,CDCl3)δ141.92,141.67,123.26,122.92,122.06,116.66,110.52,55.48,44.01,36.27,31.87,29.91,29.73,29.54,29.46,29.25,27.98,22.65,14.06.HRMS(ESI):m/z 380.3053(M+H)+;计算为C25H38N3:380.3066.
101 DG 402-49675 2-(2-溴苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.17(dt,J=1.1,6.9,1H),7.64(ddd,J=1.3,4.4,9.5,2H),7.59-7.49(m,1H),7.40(ddd,J=0.6,1.2,7.5,1H),7.27-7.20(m,1H),7.18-7.08(m,1H),6.80(ddd,J=0.6,1.0,6.7,1H),3.46-3.27(m,1H),3.21(d,J=6.4,1H),1.68-1.48(m,4H),1.48-1.35(m,2H),1.35-1.13(m,2H).
13C NMR(101MHz,CDCl3)δ141.31,136.72,136.11,132.69,132.53,129.32,127.29,126.48,123.65,122.88,122.68,117.54,111.55,59.30,33.16,23.19.
HRMS(ESI):m/z 356.0768(M+H)+;计算为C18H19N3Br:356.0762.
102 DG 402-49682 N-环戊基-2-(2,6-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.16(d,J=6.9,1H),7.67-7.49(m,1H),7.49-7.36(m,2H),7.33-7.21(m,1H),7.19-7.03(m,1H),6.81(dd,J=3.6,10.3,1H),3.50-3.32(m,1H),2.84(d,J=6.0,1H),1.72-1.53(m,4H),1.53-1.40(m,2H),1.40-1.27(m,2H).
13C NMR(101MHz,CDCl3)δ141.46,136.35,132.97,129.88,128.01,127.38,123.61,122.70,117.89,111.60,59.41,33.29,23.34.
HRMS(ESI):m/z 346.0877(M+H)+;计算为C18H18N3Cl2:346.0878.
103 DG 402-49696 N-(1-金刚烷基)-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.18(dt,J=1.2,6.9,1H),7.39(d t,J=1.1,9.0,1H),7.03(ddt,J=1.2,6.7,9.0,1H),6.68(td,J=1.1,6.8,1H),2.77(s,1H),2.19-1.93(m,4H),1.77(d,J=2.5,6H),1.61(q,J=12.2,6H),1.13-1.03(m,2H),0.99-0.91(m,2H).
13C NMR(101MHz,CDCl3)δ142.47,141.73,122.88,122.75,122.49,116.39,110.46,55.60,43.98,36.27,29.73,8.87,8.18.
HRMS(ESI):m/z 308.2128(M+H)+;计算为C20H26N3:308.2127.
104 DG402-49748 5-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ7.63-7.56(m,1H),7.49(dddd,J=1.3,1.8,4.5,5.0,2H),7.39-7.30(m,2H),7.08-6.99(m,1H),6.80-6.73(m,1H),3.31(d,J=6.8,1H),2.81(s,1H),1.67(d,J=12.5,2H),1.52(s,2H),1.45(s,1H),1.06(t,J=10.4,3H),0.89(d,J=10.1,2H).
13C NMR(101MHz,CDCl3)δ143.62,137.52,133.65,133.24,132.59,129.49,129.25,128.24,126.67,125.99,123.55,116.77,114.06,58.58,32.78,25.67,24.50.
HRMS(ESI):m/z 360.1014(M+H)+;计算为C19H20N3Cl2:360.1034.
105 DG 402-49758 2-(2-溴苯基)-N-环己基咪唑并[2,1-a]异喹啉-3-胺
1H NMR(400MHz,CDCl3)δ8.66(d,J=8.0,1H),7.99(dd,J=1.3,7.3,1H),7.75-7.63(m,3H),7.63-7.56(m,1H),7.56-7.48(m,1H),7.42(ddd,J=1.4,4.5,7.6,1H),7.32-7.18(m,1H),7.06(d,J=7.3,1H),3.29(d,J=6.9,1H),2.70(s,1H),1.79-1.64(m,2H),1.57(s,2H),1.51-1.42(m,1H),1.17-0.97(m,4H),0.95-0.75(m,1H).
13C NMR(101MHz,CDCl3)δ138.83,136.11,134.54,132.88,132.55,129.39,129.25,127.85,127.74,127.62,127.50,126.87,123.95,123.13,122.73,120.43,112.28,56.86,33.75,25.62,24.53.
HRMS(ESI):m/z 420.1063(M+H)+;计算为C23H23N3Br:420.1075.
106 SG389-832C N-环己基-2-(2,5-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.15(d,J=7.1,1H),7.69(d,J=2.5,1H),7.52(d,J=9.1,1H),7.46-7.06(m,5H),6.84(d,J=6.7,1H),2.25-2.07(m,5H),1.83-1.43(m,12H),1.41-0.96(m,25H),0.96-0.73(m,16H).
13C NMR(50MHz,CDCl3)δ138.21,132.79,132.26,130.77,130.64,130.58,129.45,129.10,128.52,124.09,122.92,117.54,111.80,56.52,33.93,31.59,24.61.
HRMS(ESI):m/z 360.1037(M+H)+;计算为C19H20N3Cl2:360.1034.
107 SG389-834H N-环戊基-2-(2,4-二氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.15(dt,J=1.0,6.9,1H),7.60(d,J=8.3,1H),7.51(dt,J=0.9,9.0,1H),7.48(d,J=2.1,1H),7.34-7.30(m,1H),7.14(ddd,J=1.2,6.7,9.0,1H),6.79(td,J=0.9,6.7,1H),3.39-3.27(m,1H),3.20(s,1H),1.68-1.48(m,4H),1.48-1.34(m,2H),1.34-1.17(m,2H).
13C NMR(101MHz,CDCl3)δ141.30,134.09,133.50,133.02,132.97,132.30,129.01,127.05,126.87,123.99,122.53,117.06,111.62,58.99,32.94,22.99.
HRMS(ESI):m/z 314.1473(M+H)+;计算为C18H18N3F2:314.1469.
108 SG389-832A 2-(3-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.21-8.10(m,1H),8.07(d,J=6.9,1H),8.01-7.82(m,1H),7.52(d,J=9.1,1H),7.43-7.20(m,2H),7.20-7.02(m,1H),6.78(t,J=6.8,1H),3.20-2.75(m,2H),1.99-1.42(m,6H),1.42-0.92(m,5H).
13C NMR(50MHz,CDCl3)δ141.55,136.30,135.18,134.39,129.55,127.06,127.02,125.17,124.86,124.08,122.60,117.40,111.66,56.90,34.19,25.67,24.78.
HRMS(ESI):m/z 326.1423(M+H)+;计算为C19H21N3Cl:326.1424.
109 SG389-832D N-环己基-2-(2,6-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.15(d,J=6.9,1H),7.56(d,J=9.1,1H),7.48-7.35(m,2H),7.28(dd,J=6.6,8.8,1H),7.21-7.02(m,1H),6.81(td,J=0.7,6.7,1H),3.03-2.55(m,2H),1.93-1.40(m,8H),1.39-0.96(m,14H),0.96-0.65(m,8H).
13C NMR(50MHz,CDCl3)δ141.53,136.31,133.06,129.85,128.90,128.00,126.72,123.56,122.85,117.83,111.55,56.58,33.84,25.69,24.60.
HRMS(ESI):m/z 360.1042(M+H)+;计算为C19H20N3Cl2:360.1034.
110 SG389-832E N-环己基-2-(2,6-二氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.13(dt,J=1.2,6.9,1H),7.57(dt,J=1.1,9.1,1H),7.34(tt,J=6.4,8.3,1H),7.14(ddd,J=1.3,6.6,9.1,1H),7.03(t,J=8.1,2H),6.80(td,J=1.1,6.8,1H),3.12(s,1H),2.71(s,1H),1.84-1.66(m,2H),1.66-1.54(m,2H),1.54-1.42(m,1H),1.21-0.92(m,6H).
13C NMR(101MHz,CDCl3)δ161.92,161.85,159.44,159.37,141.97,129.75,129.64,129.54,127.74,126.45,123.75,122.71,117.69,111.72,111.59,111.46,56.40,33.87,25.53.24.64.
HRMS(ESI):m/z 328.1630(M+H)+;计算为C19H20N3F2:328.1625.
111 DG 402-49756 N-环己基-2-(2-氟苯基)咪唑并[2,1-a]异喹啉-3-胺
1H NMR(400MHz,CDCl3)δ8.66(ddd,J=0.7,1.3,2.6,1H),8.04-7.94(m,2H),7.70(dd,J=0.9,8.0,1H),7.66-7.57(m,1H),7.54(ddd,J=1.4,7.2,7.7,1H),7.40-7.27(m,2H),7.20-7.12(m,1H),7.05(d,J=7.2,1H),3.49(s,1H),2.72(s,1H),1.78(s,2H),1.62(s,2H),1.51(s,1H),1.10(d,J=7.7,5H).
13C NMR(101MHz,CDCl3)δ160.62,158.21,139.52,131.50,129.37,128.88,128.79,127.86,127.82,126.90,124.76,123.94,122.75,120.52,119.88,115.68,115.45,112.25,57.26,33.96,25.63,24.83.
HRMS(ESI):m/z 360.1857(M+H)+;计算为C23H23N3F:360.1876.
112 SG389-816A N-(2-氯-6-甲基苯基)-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.91(d,J=6.8,1H),7.46(d,J=9.0,1H),7.25(d,J=6.8,1H),7.17-7.00(m,1H),6.93(d,J=7.1,1H),6.77(dd,J=6.7,14.2,2H),5.87(s,1H),2.85(s,1H),1.79-1.49(m,3H),1.16-0.85(m,2H),0.85-0.54(m,2H).
13C NMR(50MHz,CDCl3)δ142.56,141.29,139.91,130.63,128.32,127.15,123.48,123.38,121.58,121.34,120.13,116.68,111.66,18.16,7.62,7.17.
HRMS(ESI):m/z 298.1123(M+H)+;计算为C17H17N3Cl:298.111.
113 SG389-832B N-环己基-2-(2-氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.15(d,J=6.9,1H),7.92(td,J=2.3,7.6,1H),7.54(d,J=9.1,1H),7.22(m,4H),6.79(t,J=6.7,1H),3.45(t,J=7.8,1H),2.91-2.46(m,1H),1.88-1.34(m,5H),1.21-0.83(m,5H).
13C NMR(50MHz,CDCl3)δ141.74,131.58,131.49,129.15,128.98,124.60,124.54,123.65,122.88,117.38,115.76,115.29,111.44,56.65,34.01,25.66,24.79.
HRMS(ESI):m/z 310.1724(M+H)+;计算为C19H21N3F:310.1720.
114 SG389-834A 2-(3-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.13(t,J=1.9,1H),8.04(dt,J=1.1,6.9,1H),7.94(dt,J=1.4,7.7,1H),7.50(dt,J=1.0,9.0,1H),7.33(t,J=7.8,1H),7.25(ddd,J=1.1,2.1,8.0,1H),7.15-7.07(m,1H),6.75(td,J=1.1,6.8,1H),3.70-3.52(m,1H),3.03(d,J=3.2,1H),1.84-1.61(m,4H),1.59-1.49(m,2H),1.49-1.32(m,2H).
13C NMR(101MHz,CDCl3)δ141.48,136.13,135.21,134.29,129.53,127.09,126.98,125.72,124.90,124.28,122.49,117.31,111.74,59.01,33.40,23.49.
HRMS(ESI):m/z 312.1273(M+H)+;计算为C18H19N3Cl:312.1268.
115 SG389-834C 2-(4-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.08(dt,J=1.2,6.9,1H),8.04-7.98(m,2H),7.52(dt,J=1.0,9.1,1H),7.42-7.37(m,2H),7.14(ddd,J=1.3,6.7,9.0,1H),6.79(td,J=1.1,6.8,1H),3.62(s,1H),3.02(s,1H),1.83-1.62(m,4H),1.62-1.50(m,2H),1.50-1.38(m,2H).
13C NMR(101MHz,CDCl3)δ141.49,135.58,133.05,132.74,128.58,128.33,125.47,124.38,122.54,117.29,111.85,59.05,33.45,23.56.
HRMS(ESI):m/z 312.1273(M+H)+;计算为C18H19N3Cl:312.1268.
116 CW23836 2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-5-腈
1H NMR(400MHz,CDCl3)δ7.80(dd,J=0.9,9.0,1H),7.62(dt,J=3.1,5.4,1H),7.54-7.47(m,1H),7.45-7.34(m,3H),7.17(dd,J=7.1,8.9,1H),3.33(d,J=7.1,1H),2.79(d,J=3.3,1H),1.73(d,J=10.2,2H),1.55(d,J=3.8,3H),1.44(d,J=13.8,1H),1.04(dd,J=10.2,19.7,5H).
13C NMR(101MHz,CDCl3)δ141.06,138.44,133.09,132.37,129.80,129.66,128.09,127.08,124.31,124.30,122.94,121.90,113.97,108.02,57.24,32.67,25.60,24.54.
117 SG389-812 N-(3-氯苯基)-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.78(d,J=6.8,1H),7.56(d,J=9.0,1H),7.25-7.11(m,1H),7.06(t,J=8.0,1H),6.86-6.61(m,2H),6.51(t,J=2.0,1H),6.37(dd,J=2.2,8.1,1H),5.81(s,1H),3.27-2.83(m,1H),1.29(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ148.27,146.94,142.60,135.34,130.53,124.27,122.19,119.44,117.33,116.27,113.16,111.83,111.28,26.71,22.22.
HRMS(ESI):m/z 286.1118(M+H)+;计算为C16H17N3Cl:286.111.
118 SG389-834B 2-(2-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.23-8.13(m,1H),7.76-7.62(m,1H),7.62-7.42(m,2H),7.42-7.23(m,2H),7.15(ddd,J=1.3,6.8,9.1,1H),6.81(td,J=1.0,6.8,1H),3.34(dt,J=5.0,10.2,1H),3.21(d,J=6.4,1H),2.21-1.82(m,1H),1.72-1.04(m,7H).
13C NMR(50MHz,CDCl3)δ141.55,134.01,132.66,132.57,129.44,129.11,127.00,126.87,123.74,122.71,117.56,111.60,59.42,33.24,23.28.
HRMS(ESI):m/z312.1270(M+H)+;计算为C18H19N3Cl:312.1268.
119 SG389-816B N-(2-氯-6-甲基苯基)-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.02(dd,J=1.1,6.8,1H),7.56(d,J=9.0,1H),7.26(d,J=7.8,1H),7.20-6.99(m,1H),6.93(d,J=6.7,1H),6.88-6.63(m,2H),5.77(s,1H),2.85(dt,J=6.9,13.8,1H),1.61(s,3H),1.23(dd,J=7.3,14.5,6H).
13C NMR(50MHz,CDCl3)δ146.67,141.52,140.23,130.59,128.13,127.27,123.44,123.32,122.01,121.38,118.58,117.02,111.81,26.15,21.73(br),18.03.
HRMS(ESI):m/z 300.1271(M+H)+;计算为C17H19N3Cl:300.1268.
120 SG389-816C N-(2-氯-6-甲基苯基)-2-乙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14-7.91(m,1H),7.52(d,J=9.0,1H),7.26(d,J=6.1,1H),7.21-7.03(m,1H),6.94(d,J=7.1,1H),6.81(t,J=7.6,2H),5.76(s,1H),2.50(dd,J=7.6,15.1,2H),1.62(s,3H),1.14(t,J=7.6,3H).
13C NMR(50MHz,CDCl3)δ142.86,141.53,140.10,130.61,128.49,127.27,123.58,123.46,122.01,121.58,119.58,117.02,111.86,20.34,18.11,12.84.
HRMS(ESI):m/z 286.1117(M+H)+;计算为C16H17N3Cl:286.1111.
121 SG389-834G N-环戊基-2-(2,5-二氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.16(dt,J=1.2,6.9,1H),7.67(d,J=2.6,1H),7.49(dt,J=1.1,9.1,1H),7.39(d,J=8.6,1H),7.29(dd,J=2.6,8.6,1H),7.17(ddd,J=1.3,6.7,9.1,1H),6.82(tt,J=3.2,6.5,1H),3.37(d,J=25.1,1H),3.18(s,1H),2.02-1.88(m,1H),1.70-1.50(m,4H),1.50-1.37(m,2H),1.37-1.19(m,2H).
13C NMR(101MHz,CDCl3)δ141.47,135.21,132.65,132.04,130.71,130.45,129.10,128.93,128.48,124.32,122.70,117.19,111.87,59.24,33.10,23.10.
HRMS(ESI):m/z 346.0878(M+H)+;计算为C18H18N3Cl2:346.0878.
122 SG389-832F N-环己基-2-(2,4,5-三氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.14(dt,J=1.1,6.9,1H),7.57(dt,J=1.1,9.1,1H),7.35(tt,J=6.4,8.4,1H),7.15(ddd,J=1.3,6.6,9.1,1H),7.03(t,J=8.1,1H),6.81(td,J=1.1,6.8,1H),3.11(s,1H),2.67(m,1H),1.75(m,2H),1.69-1.56(m,2H),1.56-1.38(m,1H),1.07(m,5H).
13C NMR(101MHz,CDCl3)δ161.95,161.88,159.48,159.41,142.03,129.69,123.82,122.76,117.76,111.78,111.65,111.52,56.46,34.04,25.58,24.70.
HRMS(ESI):m/z 346.1534(M+H)+;计算为C19H19N3F3:346.1531.
123 SG389-834E N-环戊基-2-(2-氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.15(d,J=6.9,1H),7.92(td,J=2.2,7.5,1H),7.53(d,J=9.0,1H),7.29(ddd,J=4.8,8.8,13.0,2H),7.13(dd,J=9.4,16.2,2H),6.75(t,J=6.3,1H),3.55-3.15(m,2H),1.77-1.09(m,8H).
13C NMR(50MHz,CDCl3)δ161.82,156.95,141.45,131.43,131.35,129.31,129.14,124.53,124.46,124.17,122.70,116.93,115.65,115.18,111.70,59.30,33.09,23.16.
HRMS(ESI):m/z 296.1566(M+H)+;计算为C18H19N3F:296.1563.
124 SM60 N,2-二环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.07-7.97(m,1H),7.53-7.43(m,1H),7.04(ddd,J=1.2,6.5,8.9,1H),6.71(td,J=0.8,6.6,1H),3.02-2.59(m,2H),2.03-1.51(m,13H),1.51-1.00(m,8H).
13C NMR(50MHz,CDCl3)δ144.01,141.36,138.21,122.68,122.43,116.98,110.93,57.21,36.47,34.28,33.02,26.91,26.04,25.86,24.95.
HRMS(ESI):m/z 298.2261(M+H)+;计算为C19H28N3:298.2283.
125 SM2 N-环己基-2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.13-7.92(m,2H),7.52(dt,J=1.0,9.1,1H),7.22-6.97(m,2H),6.77(td,J=1.1,6.8,1H),3.31-2.47(m,2H),1.93-1.40(m,4H),1.40-0.86(m,4H).
13C NMR(50MHz,CDCl3)δ164.7,160.0,142.1,131.3,129.6,129.4,124.9,124.0,123.4,117.9,116.4,115.7,112.2,57.3,35.3,26.1,25.0.
HRMS(ESI):m/z 310.1721(M+H)+;计算为C19H21N3F:310.1720.
126 SM61 N,2-二环己基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.89(dd,J=0.9,7.0,1H),6.83(d,J=6.8,1H),6.61(t,J=6.8,1H),3.01-2.65(m,2H),2.57(s,3H),2.05-1.52(m,15H),1.52-1.32(m,4H),1.32-1.02(m,6H).
13C NMR(50MHz,CDCl3)δ143.45,138.22,126.60,123.69,121.57,120.35,110.81,57.34,37.09,34.29,32.90,26.95,25.96,25.89,24.99,16.93.
HRMS(ESI):m/z 312.2404(M+H)+;计算为C20H30N3:312.2440.
127 SM62 N,2-二环己基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.89(d,J=7.2,1H),7.23(s,1H),6.54(dd,J=1.3,6.8,1H),2.98-2.55(m,2H),2.35(s,3H),1.96-1.66(m,10H),1.66-1.48(m,3H),1.48-1.30(m,3H),1.30-1.00(m,5H).
13C NMR(50MHz,CDCl3)δ137.08,133.51,128.81,126.28,121.76,115.49,113.53,57.35,36.49,34.25,33.00,26.94,26.06,25.89,24.96,21.23.
HRMS(ESI):m/z 312.2409(M+H)+;计算为C20H30N3:312.2440.
128 SM63 N,2-二环己基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.77(s,1H),7.37(d,J=9.1,1H),6.89(dd,J=1.7,9.1,1H),2.97-2.78(m,2H),2.31(s,3H),2.06-1.49(m,13H),1.34(m,8H).
13C NMR(50MHz,CDCl3)δ143.91,140.49,125.77,123.03,120.41,120.11,116.36,57.13,36.46,34.26,33.04,26.94,26.06,25.88,24.97,18.38.
HRMS(ESI):m/z 312.2408(M+H)+;计算为C20H30N3:312.2440.
129 SM64 N,2-二环己基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.32(d,J=8.2,1H),7.07-6.74(m,1H),6.34(d,J=6.8,1H),2.88(s,3H),2.70(m,2H),2.00-1.53(m,13H),1.52-0.98(m,8H).
13C NMR(50MHz,CDCl3)δ146.00,143.08,135.88,124.67,122.94,115.28,112.64,59.65,36.23,33.44,32.87,26.93,25.96,25.15,19.76.
HRMS(ESI):m/z 312.2428(M+H)+;计算为C20H30N3:312.2440.
130 SM66 2-环己基-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.03(dd,J=0.8,6.7,1H),7.47(dd,J=0.9,9.0,1H),7.13-6.90(m,1H),6.70(t,J=6.7,1H),3.59(m,1H),3.00-2.49(m,1H),2.25-0.94(m,19H).
13C NMR(50MHz,CDCl3)δ144.25,141.35,123.99,122.73,122.30,117.01,110.94,59.92,36.53,33.53,33.00,26.91,26.03,23.60.
HRMS(ESI):m/z 284.2106(M+H)+;计算为C18H26N3:284.2127.
131 SM67 2-环己基-N-环戊基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.91(d,J=6.3,1H),6.84(d,J=6.8,1H),6.62(t,J=6.7,1H),3.59(m,1H),2.99-2.64(m,1H),2.57(s,3H),2.16-0.77(m,19H).
13C NMR(50MHz,CDCl3)δ143.58,126.58,124.38,123.88,121.70,120.19,110.86,60.00,37.06,33.52,32.84,26.92,25.94,23.60,16.88.
HRMS(ESI):m/z 298.2234(M+H)+;计算为C19H28N3:298.2283.
132 SM68 2-环己基-N-环戊基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.92(d,J=6.5,1H),7.26(d,J=6.4,1H),6.57(t,J=6.6,1H),2.88-2.61(m,1H),2.29(s,3H),2.08-1.31(m,12H),1.31-1.00(m,7H).
13C NMR(50MHz,CDCl3)δ144.2,142.6,134.4,123.3,122.6,116.1,115.3,60.8,37.4,35.38,34.3,27.2,26.5,25.7,21.6.
HRMS(ESI):m/z 298.2247(M+H)+;计算为C19H28N3:298.2283.
133 SM69 2-环己基-N-环戊基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.81(s,1H),7.42(d,J=9.1,1H),6.92(d,J=9.3,1H),3.69-3.48(m,1H),2.91-2.58(m,1H),2.32(s,3H),2.00-0.98(m,19H).
13C NMR(50MHz,CDCl3)δ143.87,140.64,139.16,138.19,125.96,123.66,120.80,119.99,116.31,114.35,59.76,36.47,33.48,32.97,29.29,26.92,26.02,25.64,23.60,18.33.
HRMS(ESI):m/z 298.2250(M+H)+;计算为C19H28N3:298.2283.
134 SM70 2-环己基-N-环戊基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.36(t,J=7.4,1H),7.03-6.78(m,1H),6.35(t,J=7.3,1H),4.01-3.24(m,4H),2.92(s,2H),2.71-2.50(m,2H),2.50-2.07(m,4H),2.04-0.96(m,27H).
13C NMR(50MHz,CDCl3)δ145.55,136.00,125.97,123.29,122.79,122.74,115.31,115.22,115.09,112.86,112.52,112.28,62.69,36.24,32.94,32.89,26.99,26.87,26.01,23.71,19.74.
HRMS(ESI):m/z 298.2251(M+H)+;计算为C19H28N3:298.2283.
135 SM52 N-环己基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.06-7.95(m,1H),7.58-7.44(m,1H),7.44-7.11(m,5H),7.05(ddd,J=1.2,6.7,8.8,1H),6.71(t,J=6.7,1H),4.33(q,J=7.1,1H),2.87-2.28(m,2H),1.98-1.43(m,8H),1.43-0.78(m,6H).
13C NMR(50MHz,CDCl3)δ145.64,142.00,141.09,128.41,128.35,127.97,127.43,126.01,122.77,122.43,117.07,111.08,57.20,37.99,34.13,25.75,24.90,24.80,21.71.
HRMS(ESI):m/z 320.2073(M+H)+;计算为C21H26N3:320.2127.
136 SM53 N-环己基-8-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98-7.83(m,1H),7.62-7.10(m,5H),6.95-6.83(m,1H),6.64(t,J=6.8,1H),4.42(q,J=7.1,1H),2.65(s,3H),2.52-2.23(m,1H),1.84(d,J=7.2,3H),1.77-1.47(m,5H),1.36-0.90(m,5H).
13C NMR(50MHz,CDCl3)δ145.60,141.51,141.35,128.28,127.57,126.75,125.95,124.79,121.56,120.39,110.91,57.38,38.31,34.02,25.79,24.92,21.71,16.74.
HRMS(ESI):m/z 334.2242(M+H)+:计算为C22H28N3:334.2283.
137 SM54 N-环己基-7-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.92(m,1H),7.42-7.14(m,6H),6.65(dd,1H),4.32(q,1H),2.78(s,1H),2.31(s,1H),1.83(d,3H),1.88-1.54(m,5H),1.29-1.04(m,5H).
13C NMR(50MHz,CDCl3)δ146.8,142.0,134.7,129.3,128.4,128.0,127.5,126.8,123.1,121.8,116.7,115.6,59.8,39.5,34.8,26.6,25.3,23.9,22.2.
HRMS(ESI):m/z 334.2255(M+H)+;计算为C22H28N3:334.2283.
138 SM55 N-环己基-6-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.84-7.67(m,1H),7.54-7.00(m,6H),6.99-6.78(m,1H),4.30(q,J=7.1,1H),2.89-2.44(m,2H),2.30(s,3H),1.74(d,J=3.7,3H),1.72-1.48(m,6H),1.44-0.83(m,5H).
13C NMR(50MHz,CDCl3)δ159.24,145.78,141.86,140.19,128.31,127.41,125.93,125.85,120.57,120.08,116.43,57.10,37.98,34.09,25.76,24.91,21.72,18.32.
HRMS(ESI):m/z 334.2257(M+H)+;计算为C22H28N3:334.2283.
139 SM56 N-环己基-5-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.59-7.02(m,8H),6.92(dd,J=6.8,8.9,1H),6.42-6.29(m,1H),4.30(q,J=7.1,1H),3.68(s,1H),2.84(s,3H),1.76(d,J=7.2,3H),1.72-1.46(m,4H),1.46-0.83(m,6H).
13C NMR(50MHz,CDCl3)δ145.91,143.89,142.83,136.00,128.24,127.41,125.83,123.11,115.40,112.92,59.27,37.67,33.57,33.44,25.88,25.18,24.95,21.97,19.81.
HRMS(ESI):m/z 334.2255(M+H)+;计算为C22H28N3:334.2283.
140 SM51 N-环戊基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.08-7.90(m,1H),7.60-7.43(m,1H),7.43-7.11(m,5H),7.06(ddd,J=1.4,6.7,9.0,1H),6.71(td,J=1.2,6.8,1H),4.35(q,J=7.1,1H),3.61-3.22(m,1H),2.65-1.98(m,2H),1.86-1.75(m,3H),1.75-1.05(m,9H).
13C NMR(50MHz,CDCl3)δ145.64,142.08,141.11,128.74,128.34,127.42,122.79,122.28,117.18,111.11,59.75,37.93,33.57,33.41,23.55,21.77.
HRMS(ESI):m/z306.1950(M+H)+;计算为C20H24N3:306.1970.
141 SM72 N-环戊基-8-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.91(d,J=7.3,1H),7.51-7.10(m,5H),6.89(d,J=6.8,1H),6.65(t,J=6.7,1H),4.43(q,J=7.2,1H),3.44(dt,J=5.1,10.2,1H),2.65(s,3H),1.83(d,J=7.2,3H),1.79-1.11(m,8H).
13C NMR(50MHz,CDCl3)δ145.54,141.38,128.27,127.54,126.79,125.94,125.54,121.71,120.22,111.01,59.93,38.19,33.46,33.36,23.57,21.75,16.74.
HRMS(ESI):m/z 320.2105(M+H)+;计算为C21H26N3:320.2127.
142 SM73 N-环戊基-7-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.89(d,J=6.9,1H),7.52-7.01(m,5H),6.54(dd,J=1.6,6.9,1H),4.32(q,J=7.2,1H),3.45(dt,J=5.6,11.0,1H),2.35(s,3H),1.77(d,J=7.2,3H),1.73-1.44(m,5H),1.44-1.04(m,3H).
13C NMR(50MHz,CDCl3)δ145.76,141.63,141.59,133.64,128.30,127.43,125.92,124.63,121.61,115.65,113.71,59.86,37.88,33.51,33.38,23.57,21.75,21.19.
HRMS(ESI):m/z320.2121(M+H)+;计算为C21H26N3:320.2127.
143 SM74 N-环戊基-6-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.81-7.73(m,1H),7.55-7.06(m,5H),6.91(dd,J=1.7,9.1,1H),4.32(q,J=7.2,1H),3.58-3.31(m,1H),2.30(s,3H),1.77(d,J=7.2,3H),1.72-1.09(m,8H).
13C NMR(50MHz,CDCl3)δ145.81,141.83,140.20,138.23,128.37,127.46,127.31,126.00,120.72,120.02,116.59,59.67,37.97,33.60,23.62,21.83,18.40.
HRMS(ESI):m/z 320.2095(M+H)+;计算为C21H26N3:320.2127.
144 SM75 N-环戊基-5-甲基-2-(1-苯基乙基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.46-7.03(m,6H),6.93(dd,J=6.9,8.9,1H),6.36(d,J=6.7,1H),4.34(q,J=7.1,1H),3.49(dt,J=5.7,11.2,1H),2.85(s,3H),1.77(d,J=7.2,3H),1.73-1.07(m,8H).
13C NMR(50MHz,CDCl3)δ145.96,143.65,142.86,136.02,128.27,127.42,127.01,125.86,123.16,115.49,112.93,62.31,37.53,33.15,32.74,23.74,23.61,22.04,19.68.
HRMS(ESI):m/z 320.2106(M+H)+;计算为C21H26N3:320.2127.
145 SM3 N-环己基-2-(2,3,6-三氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.23-8.07(m,1H),7.62-7.50(m,1H),7.47(d,J=8.7,1H),7.36(d,J=8.7,1H),7.18(dd,J=1.3,6.7,1H),6.82(td,J=0.9,6.7,1H),2.77(m,2H),1.85-1.35(m,3H),1.35-0.71(m,3H).
13C NMR(50MHz,CDCl3)δ141.56,134.79,134.48,133.04,131.85,130.54,128.27,126.61,123.79,122.90,117.81,111.69,56.63,33.84,25.63,24.58.
HRMS(ESI):m/z 394.0645(M+H)+;计算为C19H19N3Cl3:394.0645.
146 SM4 N-环己基-2-(2-氟-3-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.29-8.03(m,1H),7.60-7.39(m,2H),7.33-7.05(m,2H),6.97(td,J=1.6,8.2,1H),6.77(td,J=1.1,6.8,1H),3.93(s,3H),3.72-3.26(m,1H),2.91-2.54(m,1H),1.94-1.36(m,5H),1.33-0.81(m,5H).
13C NMR(50MHz,CDCl3)δ152.17,148.23,147.99,147.32,142.22,127.26,124.54,123.96,123.56,117.67,112.66,111.74,56.95,56.67,34.31,25.93,25.14.
HRMS(ESI):m/z 340.1824(M+H)+;计算为C20H23N30F:340.1825.
147 SM6 2-(3-氯-2-氟苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.27-8.03(m,1H),7.81(ddd,J=1.8,6.6,8.4,1H),7.64-7.47(m,1H),7.40(ddd,J=1.8,7.1,8.0,1H),7.31-7.03(m,2H),6.80(td,J=1.2,6.8,1H),3.56-3.17(m,1H),2.87-2.50(m,1H),1.89-1.33(m,5H),1.10(d,J=7.0,5H).
13C NMR(50MHz,CDCl3)δ157.31,152.40,142.05,129.94,129.87,129.58,127.10,124.93,124.84,124.01,122.99,117.47,111.64,56.74,34.04,25.62,24.79.
HRMS(ESI):m/z 344.1329(M+H)+;计算为C19H20N3FCl:344.1330.
148 SM7 2-(4-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.13-7.98(m,3H),7.53(d,J=9.0,1H),7.46-7.37(m,2H),7.14(dd,J=7.8,9.1,1H),6.79(t,J=6.8,1H),3.13-2.84(m,2H),1.95-1.46(m,6H),1.22(m,4H).
13C NMR(50MHz,CDCl3)δ141.65,133.09,132.93,128.58,128.26,123.99,122.60,117.45,111.62,56.87,34.23,25.72,24.82.
HRMS(ESI):m/z 326.1422(M+H)+;计算为C19H21N3Cl:326.1424.
149 SM8 N-环己基-2-(2-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.28-7.99(m,1H),7.85-7.71(m,1H),7.66-7.40(m,4H),7.13(ddd,J=1.3,6.7,9.0,1H),6.80(td,J=1.1,6.8,1H),3.28-2.83(m,1H),2.66(m,1H),1.90-1.35(m,5H),1.23-0.80(m,5H).
13C NMR(50MHz,CDCl3)δ141.06,138.17,135.28,132.83,131.21,128.11,126.85,126.14(q,J=5.1,1H),123.49,122.77,121.40,117.59,111.50,56.25,33.81,25.63,24.51.
HRMS(ESI):m/z 360.1688(M+H)+;计算为C20H21N3F3:360.1688.
150 SM11 N-环戊基-2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.21-7.90(m,3H),7.55(dt,J=1.0,9.1,1H),7.22-6.97(m,3H),6.78(td,J=1.0,6.8,1H),3.63(m,1H),1.93-1.27(m,9H).
13C NMR(50MHz,CDCl3)δ164.68,159.78,141.48,138.21,129.01,128.85,124.17,122.53,117.36,115.57,115.15,111.77,59.20,33.55,23.64.
HRMS(ESI):m/z 296.1560(M+H)+;计算为C18H19N3F:296.1563.
151 SM12 N-环戊基-2-辛基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.03(d,J=6.8,1H),7.45(d,J=9.0,1H),7.05(ddd,J=1.2,6.5,8.7,1H),6.71(td,J=1.0,6.8,1H),3.71-3.45(m,1H),2.88-2.51(m,2H),1.92-1.67(m,7H),1.67-1.42(m,5H),1.42-1.11(m,10H),0.87(m,2H).
13C NMR(50MHz,CDCl3)δ141.31,139.81,126.46,122.81,122.24,116.83,110.95,59.79,33.55,31.90,29.86,29.67,29.49,29.28,27.51,23.60,22.67,14.08.
HRMS(ESI):m/z 314.2595(M+H)+;计算为C20H32N3:314.2596.
152 SM13 N-环戊基-2-(2,3,6-三氯苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.21-8.10(m,1H),7.59-7.50(m,1H),7.50-7.41(m,1H),7.41-7.33(m,1H),7.16(ddd,J=1.0,6.5,8.0,1H),6.82(td,J=0.8,6.7,1H),3.56-3.28(m,2H),2.79(d,J=5.6,1H),1.79-1.40(m,7H),1.40-1.04(m,4H).
13C NMR(50MHz,CDCl3)δ148.09,141.46,137.64,134.80,134.78,134.50,131.85,130.56,130.01,128.88,128.25,127.27,123.88,122.73,117.79,114.22,111.76,107.50,59.43,33.38,23.41.
HRMS(ESI):m/z 380.0490(M+H)+;计算为C18H17N3Cl3:380.0488.
153 SM14 N-环戊基-2-(2-氟-3-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14(d,J=6.9,1H),7.65-7.35(m,2H),7.26-7.03(m,2H),6.95(td,J=1.6,8.2,1H),6.75(t,J=6.8,1H),3.91(s,3H),3.53-3.22(m,2H),1.76-1.07(m,8H).
13C NMR(50MHz,CDCl3)δ151.87,147.84,147.60,147.01,141.78,131.51,127.51,124.16,124.07,123.62,122.67,117.29,112.37,111.37,59.40,56.29,33.13,23.24.
HRMS(ESI):m/z 326.1668(M+H)+;计算为C19H21N3OF:326.1669.
154 SM15 N-环戊基-2-异丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.18-7.92(m,1H),7.49(m,1H),7.14-6.94(m,1H),6.82-6.61(m,1H),3.80-3.47(m,1H),3.32-3.02(m,1H),2.90-2.66(m,1H),1.931.68(m,4H),1.68-1.43(m,4H),1.38(d,J=9.0,6H).
13C NMR(50MHz,CDCl3)δ160.21,155.76,138.10,126.18,116.34,105.78,105.24,58.19,37.28,37.04,34.17,25.09,18.18,17.96.
HRMS(ESI):m/z 244.1812(M+H)+;计算为C15H22N3:244.1814.
155 SM16 2-(3-氯-2-氟苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.23(d,1H),7.92-7.86(m,1H),7.55(d,1H),7.48-7.30(d,1H),7.28-7.07(m,2H),6.92-6.76(m,1H),6.56-3.22(m,2H),1.80-1.12(m,8H).
13C NMR(50MHz,CDCl3)δ157.39,152.48,142.01,138.19,129.87,129.62,127.73,124.93,124.50,124.08,122.87,117.52,111.50,59.58,33.30,23.31.
HRMS(ESI):m/z 330.1173(M+H)+;计算为C18H18N3FCI:330.1173.
156 SM17 N-环戊基-2-(戊-3-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.06(dt,J=1.0,6.8,1H),7.49(d,J=9.1,1H),7.04(ddd,J=1.2,6.6,8.9,1H),6.71(td,J=0.9,6.8,1H),3.64(dt,J=5.3,10.8,1H),3.02-2.73(m,1H),2.62(ddd,J=6.4,8.2,14.6,1H),1.96-1.68(m,8H),1.68-1.41(m,4H),
1.37(d,J=6.8,1H),0.82(t,J=7.4,6H).
13C NMR(50MHz,CDCl3)δ142.09,141.51,126.28,122.65,122.26,116.94,110.72,60.03,40.98,33.58,28.25,23.65,12.60.
HRMS(ESI):m/z272.2125(M+H)+;计算为C17H26N3:272.2127.
157 SM18 N-环戊基-2-(2-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.13(d,J=6.9,1H),7.78(d,J=7.5,1H),7.66-7.41(m,
4H),7.23-7.03(m,1H),6.81(td,J=0.9,6.7,1H),3.52-3.21(m,1H),3.06-2.78(m,1H),1.40(m,8H).
13C NMR(50MHz,CDCl3)δ141.03,135.34,132.87,131.23,129.95,128.14,126.72,126.17(q,J=5.1),123.60,122.64,121.42,117.65,111.59,59.16,33.33,23.35.
HRMS(ESI):m/z 346.1531(M+H)+;计算为C19H19N3F3:346.1531.
158 SM19 N-环戊基-2-(3-甲基噻吩-2-基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.15-8.06(m,1H),7.52(dt,J=1.0,9.0,1H),7.26(d,J=5.1,1H),7.11(ddd,J=1.3,6.7,9.0,1H),6.94(d,J=5.1,1H),6.77(td,J=1.1,6.8,1H),3.82-3.25(m,1H),3.22-2.92(m,1H),2.43(s,4H),1.88-1.56(m,5H),1.55-1.31(m,4H).
13C NMR(50MHz,CDCl3)δ141.36,135.77,130.47,129.73,126.57,124.33,124.21,123.50,122.49,117.47,111.46,59.35,33.32,23.50.
HRMS(ESI):m/z 298.1383(M+H)+;计算为C17H20N3S:298.1378.
159 SM20 N-环戊基-2-环丙基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.01(d,J=6.7,1H),7.40(d,J=8.9,1H),7.21-6.91(m,1H),6.91-6.47(m,1H),3.85-3.53(m,1H),3.14-2.48(m,1H),2.21-1.69(m,4H),1.69-1.40(m,4H),1.23-0.79(m,5H).
13C NMR(50MHz,CDCl3)δ141.47,140.87,138.47,123.06,122.12,116.94,111.17,60.15,33.82,23.86,8.45,8.00.
HRMS(ESI):m/z 242.1659(M+H)+;计算为C15H20N3:242.1657.
160 SM21 2-仲丁基-N-环戊基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.13-7.98(m,1H),7.57-7.42(m,1H),7.14-6.98(m,1H),6.85-6.59(m,1H),4.55-3.84(m,1H),3.61(m,1H),2.86(m,1H),2.11-1.40(m,11H),1.34(d,J=6.9,3H),0.85(t,J=7.4,2H).
13C NMR(50MHz,CDCl3)δ143.56,141.42,124.80,122.89,122.29,116.86,110.94,59.92,33.54,33.51,29.84,23.58,20.73,12.61.
HRMS(ESI):m/z 258.1970(M+H)+;计算为C16H24N3:258.1970.
161 SM24 2-仲丁基-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.14-7.93(m,1H),7.48(m,1H),7.04(ddd,J=1.2,6.7,8.8,1H),6.71(td,J=1.1,6.9,1H),3.10-2.63(m,2H),2.12-1.48(m,8H),1.48-1.06(m,8H),0.85(t,J=7.3,3H).
13C NMR(50MHz,CDCl3)δ143.77,141.75,124.39,123.01,122.71,117.13,111.12,57.58,34.55,33.63,30.16,26.09,25.23,21.07,12.87.
HRMS(ESI):m/z 272.2127(M+H)+;计算为C17H26N3:272.2127.
162 SM26 6-溴-2-(2-氯苯基)-N-环己基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.30(s,1H),7.71-7.54(m,1H),7.52-7.12(m,4H),3.22(d,J=5.6,1H),2.78-2.51(m,1H),2.45(s,3H),1.87-1.33(m,5H),1.23-0.78(m,5H).
13C NMR(50MHz,CDCl3)δ140.87,135.76,134.14,133.78,132.60,132.42,129.45,129.16,126.86,125.74,122.98,116.60,110.69,56.52,33.79,25.64,24.56,22.53.
HRMS(ESI):m/z 418.0686(M+H)+;计算为C20H22N3ClBr:418.0686.
163 SM27 2-(2-氯苯基)-N-环己基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.91(s,1H),7.74-7.54(m,1H),7.52-7.40(m,2H),7.40-7.18(m,2H),6.98(dd,J=1.7,9.2,1H),3.40-3.07(m,1H),2.82-2.51(m,1H),2.35(s,3H),1.91-1.31(m,5H),1.23-0.80(m,5H).
13C NMR(50MHz,CDCl3)δ140.71,135.00,134.20,132.48,129.31,128.86,126.74,125.92,121.02,120.30,116.84,56.26,33.80,25.64,24.55,18.37.
HRMS(ESI):m/z 340.1582(M+H)+;计算为C20H23N3Cl:340.1581.
164 SM28 2-(2-氯苯基)-N-环己基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MH z,CDCl3)δ8.11(d,1H),7.72-7.68(m,1H),7.53-7.26(m,4H),6.72(dd,1H),3.24(s,1H),2.78(s,1H),2.45(s,3H),1.80-1.42(m,5H),1.23-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ142.4,135.2,134.4,134.7,133.9,130.2,129.3,127.7,126.2123.3,116.6,115.3,57.4,34.7,26.4,25.2,21.8.
HRMS(ESI):m/z340.1581(M+H)+;计算为C20H23N3Cl:340.1581.
165 SM29 2-(2-氯苯基)-N-环己基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.92(s,1H),7.73-7.67(m,1H),7.58-7.22(m,4H),7.03-6.92(dd,1H),3.37(s,1H),2.72(s,1H),2.38(s,3H),1.85-1.42(m,5H),1.22-1.08(m,5H).
13C NMR(50MHz,CDCl3)δ146.1,142.8,141.3,139.5,135.9,133.3,130.2,129.6,127.2,122.7,121.3,118.6,57.0,34.2,26.5,25.9,19.5.
HRMS(ESI):m/z 340.1581(M+H)+;计算为C20H23N3Cl:340.1581.
166 SM30 2-(2-氯苯基)-N-环己基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.71-7.68(m,1H),7.52-7.26(m,4H),7.12-7.08(m,1H),6.53-6.46(d,1H),3.25-3.18(m,1H),3.03(s,3H),2.65(s,1H),1.80-1.45(m,5H),1.26-0.81(m,5H).
13C NMR(50MHz,CDCl3)δ143.15,137.29,136.64,134.56,132.65,132.48,129.22,128.87,128.05,126.71,123.78,115.74,113.16,58.72,33.39,25.67,24.95,19.84.
HRMS(ESI):m/z340.1581(M+H)+;计算为C20H23N3Cl:340.1581.
167 SM32 6-溴-2-(2-氯苯基)-N-环戊基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.31(s,1H),7.65(dd,J=2.5,6.9,1H),7.53-7.11(m,4H),3.50-3.25(m,1H),3.24-3.07(m,1H),2.44(s,3H),1.77-1.04(m,8H).
13C NMR(50MHz,CDCl3)δ140.72,135.51,134.08,133.66,132.60,132.36,129.39,129.15,126.81,126.38,122.80,116.51,110.69,59.33,33.13,23.20,22.47.
HRMS(ESI):m/z 404.0528(M+H)+:计算为C19H20N3ClBr:404.0529.
168 SM33 2-(2-氯苯基)-N-环戊基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.98-7.90(m,1H),7.67(dd,J=2.2,7.2,1H),7.52-7.38(m,2H),7.38-7.28(m,2H),7.00(dd,J=1.8,9.2,1H),3.49-2.94(m,2H),2.36(s,3H),1.73-0.94(m,8H).
13C NMR(50MHz,CDCl3)δ142.02,135.00,134.23,132.63,132.55,129.39,128.97,126.87,126.82,121.16,120.27,116.94,108.37,59.32,33.22,23.28,18.24
HRMS(ESI):m/z 326.1422(M+H)+;计算为C19H21N3Cl:326.1424.
169 SM34 2-(2-氯苯基)-N-环戊基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.05(d,J=6.9,1H),7.75-7.60(m,1H),7.46(dd,J=2.1,7.2,1H),7.41-7.16(m,3H),6.64(dd,J=1.5,7.0,1H),3.49-3.01(m,2H),2.40(s,3H),1.72-1.10(m,8H).
13C NMR(50MHz,CDCl3)δ142.19,138.27,134.80,134.49,132.88,132.79,129.65,129.28,129.20,127.06,122.22,116.13,114.50,59.76,33.45,23.54,21.56.
HRMS(ESI):m/z 326.1422(M+H)+;计算为C19H21N3Cl:326.1424.
170 SM35 2-(2-氯苯基)-N-环戊基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.03(ddd,J=0.5,1.0,2.4,1H),7.74-7.64(m,1H),7.50-7.42(m,1H),7.41-7.26(m,2H),6.94(d,J=6.7,1H),6.72(t,J=6.7,1H),3.47-3.25(m,1H),3.26-3.00(m,1H),2.62(s,3H),1.71-1.41(m,6H),1.41-1.01(m,3H).
13C NMR(50MHz,CDCl3)δ141.93,138.20,134.64,134.32,132.84,132.75,129.35,129.00,127.31,126.90,122.49,120.58,111.62,59.43,33.26,23.29,16.71.
HRMS(ESI):m/z 326.1424(M+H)+;计算为C19H21N3Cl:326.1424.
171 SM36 2-(2-氯苯基)-N-环戊基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.76-7.61(m,1H),7.56-7.21(m,4H),7.01(dd,J=6.9,8.9,1H),6.49(d,J=8.6,1H),3.37-3.00(m,2H),2.97(s,3H),1.71-1.28(m,6H),1.28-0.93(m,2H).
13C NMR(50MHz,CDCl3)δ143.47,138.45,137.04,134.89,133.05,132.97,132.86,129.60,129.29,127.11,124.22,116.12,113.55,62.36,32.95,23.56,20.16.
HRMS(ESI):m/z 326.1426(M+H)+;计算为C19H21N3Cl:326.1424.
172 SM38 6-溴-N-环戊基-2-异丙基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.18(s,1H),7.33(s,1H),3.69-3.44(m,1H),3.27-2.96(m,1H),2.88-2.53(m,1H),2.41(s,3H),1.97-1.38(m,8H),1.34(d,J=6.8,6H).
13C NMR(50MHz,CDCl3)δ145.57,133.02,123.33,122.61,116.30,109.91,109.74,59.91,33.56,26.32,23.61,22.73,22.44.
HRMS(ESI):m/z 336.1077(M+H)+;计算为C16H23N3Br:336.1075.
173 SM39 N-环戊基-2-异丙基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.86-7.74(m,1H),7.39(d,J=9.1,1H),6.90(dd,J=1.8,9.1,1H),3.71-3.41(m,1H),3.29-3.00(m,1H),2.31(s,3H),1.91-1.41(m,8H),1.36(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ144.70,140.54,125.88,123.17,120.44,120.04,116.42,59.75,33.55,26.23,23.64,22.85,18.37.
HRMS(ESI):m/z 258.1972(M+H)+;计算为C16H24N3:258.1970.
174 SM40 N-环戊基-2-异丙基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.91(d,J=7.1,1H),7.24(s,1H),6.54(dd,J=1.4,7.1,1H),3.68-3.46(m,1H),3.24-2.99(m,1H),2.35(s,3H),1.90-1.40(m,8H),1.36(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ144.35,141.78,133.46,121.96,121.53,115.42,113.42,59.85,33.41,26.15,23.52,22.71,21.09.
HRMS(ESI):m/z 258.1969(M+H)+;计算为C16H24N3:258.1970.
175 SM41 N-环戊基-2-异丙基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.00-7.82(m,1H),6.97-6.75(m,1H),6.62(t,J=6.8,1H),3.72-3.43(m,1H),3.33-2.99(m,1H),2.58(s,3H),1.93-1.67(m,4H),1.67-1.43(m,4H),1.39(d,J=6.9,6H).
13C NMR(50MHz,CDCl3)δ144.27,141.65,126.67,124.17,121.68,120.23,110.86,59.99,33.59,26.71,23.65,22.82,16.87.
HRMS(ESI):m/z 258.1969(M+H)+;计算为C16H24N3:258.1970.
176 SM42 N-环戊基-2-异丙基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.35(d,J=8.9,1H),6.91(dd,J=6.8,9.0,1H),6.39-6.30(m,1H),3.63-3.38(m,1H),3.15(q,J=6.8,1H),2.96-2.76(m,3H),1.93-1.67(m,4H),1.67-1.41(m,4H),1.41-1.26(m,6H).
13C NMR(50MHz,CDCl3)δ146.39,143.09,135.91,123.02,115.29,115.29,112.63,62.55,32.91,25.88,23.65,22.75,19.68.
HRMS(ESI):m/z 258.1971(M+H)+;计算为C16H24N3:258.1970.
177 SM44 6-溴-N-环己基-2-异丙基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.17(s,1H),7.33(s,1H),3.08(q,J=6.7,1H),2.96-2.59(m,2H),2.41(s,3H),2.02-1.46(m,6H),1.34(d,J=6.9,6H),1.29-1.07(m,4H).
13C NMR(50MHz,CDCl3)δ145.76,138.45,133.21,122.96,116.48,110.14,100.21,57.62,34.47,26.54,26.07,25.16,22.97,22.68.
HRMS(ESI):m/z 350.1236(M+H)+;计算为C17H25N3Br:350.1232.
178 SM45 N-环己基-2-异丙基-6-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.78(s,1H),7.38(d,J=9.2,1H),6.89(dd,J=1.7,9.1,1H),3.23-3.00(m,1H),2.97-2.74(m,1H),2.31(s,3H),1.98-1.47(m,5H),1.35(d,J=6.9,6H),1.22-1.09(m,5H).
13C NMR(50MHz,CDCl3)δ144.63,140.56,138.22,125.82,120.41,120.14,116.41,57.17,34.30,26.22,25.89,24.98,22.86,18.39.
HRMS(ESI):m/z 272.2126(M+H)+;计算为C17H26N3:272.2127.
179 SM46 N-环己基-2-异丙基-7-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ8.00-7.79(m,1H),7.26(s,1H),6.55(dd,J=1.5,7.0,1H),3.23-2.93(m,2H),2.93-2.73(m,1H),2.35(s,3H),1.99-1.44(m,5H),1.35(d,J=6.9,6H),1.30-0.99(m,5H).
13C NMR(50MHz,CDCl3)δ144.44,142.08,139.90,133.86,122.00,115.73,113.81,57.62,34.51,26.47,26.14,25.20,23.03,21.47.
HRMS(ESI):m/z 272.2126(M+H)+;计算为C17H26N3:272.2127.
180 SM47 N-环己基-2-异丙基-8-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.89(d,J=6.8,1H),7.02-6.73(m,1H),6.61(t,J=6.7,1H),3.28-3.04(m,1H),2.98-2.66(m,2H),2.57(s,3H),1.97-1.50(m,5H),1.38(d,J=6.9,6H),1.31-1.04(m,5H).
13C NMR(50MHz,CDCl3)δ153.93,144.41,141.95,126.89,121.84,120.62,111.05,57.61,34.57,26.94,26.14,25.24,23.08,17.13.
HRMS(ESI):m/z 272.2123(M+H)+;计算为C17H26N3:272.2127.
181 SM48 N-环己基-2-异丙基-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.36(d,J=8.8,1H),6.92(dd,J=6.7,8.9,1H),6.42-6.29(m,1H),3.24-3.00(m,1H),2.89(s,3H),1.97-1.51(m,5H),1.35(d,J=6.9,6H),1.31-0.97(m,5H).
13C NMR(50MHz,CDCl3)δ144.26,141.87;139.92,138.47,123.30,115.64,112.96,59.90,33.82,26.27,26.23,25.46,23.01,20.09.
HRMS(ESI):m/z 272.2128(M+H)+;计算为C17H26N3:272.2127.
182 SM81 N,2-双(2-氯苯基)-5-甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.68-7.49(m,2H),7.49-7.34(m,1H),7.34-7.20(m,2H),7.14(dd,J=6.8,9.1,1H),7.03-6.84(m,1H),6.65(td,J=1.2,7.6,1H),6.52(d,J=6.7,1H),6.19(s,1H),6.09(dd,J=1.1,8.3,1H),2.67(s,3H).
13C NMR(50MHz,CDCl3)δ144.65,143.60,140.64,138.21,136.14,133.24,132.70,131.97,129.61,129.48,129.38,127.82,126.70,125.31,119.47,118.64,116.22,113.90,113.60,18.59.
HRMS(ESI):m/z 368.0733(M+H)+;计算为C20H16N3Cl2:368.0721.
183 SM83 2-(2-氯苯基)-N-环己基-5,7-二甲基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.71-7.53(m,1H),7.52-7.39(m,1H),7.39-7.20(m,2H),7.14(s,1H),6.29(s,1H),2.91(s,3H),2.54(m,1H),2.31(s,3H),1.58(m,5H),1.11-0.68(m,5H).
13C NMR(50MHz,CDCl3)δ143.77,138.20,135.88,134.77,134.58,132.74,132.57,129.31,128.86,127.69,126.79,116.02,114.18,58.77,33.16,25.80,24.76,20.87,19.72.
HRMS(ESI):m/z 354.1715(M+H)+;计算为C21H25N3Cl:354.1737.
184 SM92 2-(2-氯苯基)-N-环己基-5-苯氧基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.68-7.61(m,1H),7.56-7.41(m,3H),7.39-7.28(m,3H),7.28-7.19(m,3H),7.08-6.89(m,1H),5.91(d,J=7.2,1H),2.89-2.80(m,1H),1.78-1.41(m,6H),1.11-0.81(m,5H).
13C NMR(50MHz,CDCl3)δ156.34,149.94,143.46,138.28,134.05,133.85,131.01,129.96,129.24,128.01,127.34,124.91,120.04,113.84,97.02,57.96,33.95,25.74,25.07.
HRMS(ESI):m/z418.1635(M+H)+;计算为C25H25N3OCl:418.1686.
185 SM93 2-(2-氯苯基)-N-环己基-5-乙氧基咪唑并[1,2-a]吡啶-3-胺
1H NMR(200MHz,CDCl3)δ7.57(dd,J=3.3,6.0,1H),7.51-7.39(m,1H),7.38-7.19(m,2H),7.13(d,J=8.9,1H),7.04-6.88(m,1H),5.89(d,J=7.3,1H),4.26(q,J=7.0,2H),4.11(s,1H),2.74(s,1H),1.83-1.63(m,2H),1.63-1.31(m,6H),1.21-0.75(m,5H).
13C NMR(50MHz,CDCl3)δ150.94,142.66,134.48,134.05,132.58,129.41,128.73,128.48,126.29,123.89,110.70,88.54,65.45,57.15,33.42,25.88,24.57,14.46.
HRMS(ESI):m/z 370.1658(M+H)+;计算为C21H25N3OCl:370.1686.
186 DG402-49720 4-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)苯甲腈
1H NMR(400MHz,CDCl3)δ8.24(dd,J=1.7,8.5,2H),8.05(dt,J=1.0,6.9,1H),7.69(dd,J=1.7,8.5,2H),7.53(dt,J=1.0,9.1,1H),7.17(ddd,J=1.2,6.7,9.1,1H),6.81(td,J=1.0,6.8,1H),3.06(d,J=4.9,1H),2.95(ddd,J=4.6,10.0,14.4,1H),1.87-1.76(m,2H),1.76-1.64(m,2H),1.64-1.51(m,1H),1.33-1.03(m,5H).
13C NMR(101MHz,CDCl3)δ141.94,139.17,134.70,132.16,127.17,126.06,124.61,122.63,119.18,117.75,112.04,110.20,56.96,34.22,25.59,24.77.
HRMS(ESI):m/z 317.1765(M+H)+;计算为C20H21N4:317.1766.
187 DG402-49722 3-(3-(环己基氨基)咪唑并[1,2-a]吡啶-2-基)苯甲腈
1H NMR(400MHz,CDCl3)δ8.48(t,J=1.6,1H),8.37(dt,J=1.5,7.6,1H),8.14-7.94(m,1H),7.62-7.45(m,3H),7.16(ddd,J=1.1,6.7,9.0,1H),6.81(td,J=1.0,6.8,1H),3.04(d,J=4.7,1H),2.94(ddd,J=4.4,10.0,14.3,1H),1.88-1.75(m,2H),1.75-1.63(m,2H),1.63-1.49(m,1H),1.42-0.92(m,5H).
13C NMR(101MHz,CDCl3)δ141.85,135.91,134.59,130.95,130.44,130.33,129.11,125.29,124.46,122.58,118.98,117.64,112.48,111.96,56.91,34.21,25.58,24.76.
HRMS(ESI):m/z 317.1775(M+H)+;计算为C20H21N4:317.1766.
188 DG402-49744 7-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.07(d,J=7.3,1H),7.64(d,J=5.5,1H),7.52(s,1H),7.47(d,J=6.3,1H),7.35(dd,J=7.1,12.4,2H),6.79(d,J=7.2,1H),3.26(s,1H),2.64(s,1H),1.75-1.61(m,2H),1.56(s,2H),1.47(s,1H),1.15-0.91(m,5H).
13C NMR(101MHz,CDCl3)δ141.08,135.68,133.40,132.41,132.35,130.20,129.44,129.28,126.93,126.56,123.19,116.16,113.23,56.41,33.71,25.49,24.46.
189 CW23828a 2-(2-氯苯基)-N-环己基-6-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.70(dd,J=1.9,7.5,1H),7.60(dd,J=0.7,9.3,1H),7.54(d,J=8.8,2H),7.48(dd,J=1.5,7.7,1H),7.43-7.29(m,3H),7.03(d,J=8.8,2H),3.86(s,3H),3.31(d,J=6.8,1H),2.80-2.59(m,1H),1.78-1.63(m,2H),1.63-1.51(m,2H),1.51-1.40(m,1H),1.17-0.89(m,5H).
13C NMR(101MHz,CDCl3)δ159.32,140.83,135.58,133.97,132.48,130.28,129.41,129.07,127.99,126.88,126.56,125.70,124.48,119.32,117.26,114.43,56.42,55.32,33.79,25.55,24.53.
190 CW23828b 2-(2-氯苯基)-N-环己基-5-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ7.62(dd,J=2.1,7.3,1H),7.60-7.53(m,1H),7.46(d+m,J=8.7,3H),7.37-7.26(m,2H),7.14(dd,J=6.8,8.9,1H),6.98(d,J=8.6,2H),6.61(dd,J=1.0,6.8,1H),3.88(s,3H),2.64(s,1H),2.00(m,1H),0.82(m,8H),0.37(m,2H).
13C NMR(101MHz,CDCl3)δ159.88,142.70,138.01,135.45,134.19,133.32,132.69,130.78,129.40,128.92,127.99,127.08,126.62,122.99,116.73,115.26,112.64,56.36,55.50,32.47,25.59,24.34.
191 CW23825 2-(2-氯苯基)-N-环己基-5-邻甲苯基咪唑并[1,2-a]吡啶-3-胺
192 CW23828c 2-(2-氯苯基)-N-环己基-6-邻甲苯基咪唑并[1,2-a]吡啶-3-胺
1H NMR(400MHz,CDCl3)δ7.65-7.60(m,1H),7.58(dd,J=1.2,9.0,1H),7.46-7.19(m,7H),7.15(dd,J=6.8,9.0,1H),6.57(dd,J=1.2,6.8,1H),2.45(d,J=7.8,1H),2.07(s,3H),2.01(ddd,J=3.6,8.5,10.1,1H),1.41-0.98(m,5H),0.89-0.65(m,2H),0.58(d,J=12.4,1H),0.41-0.27(m,1H),0.27-0.11(m,1H).
13C NMR(101MHz,CDCl3)δ142.26,138.77,137.87,134.92,134.19,133.22,132.68,129.34,129.24,129.00,128.97,128.94,128.53,127.75,127.34,126.66,125.06,122.97,116.94,114.82,56.76,32.63,32.50,25.55,19.77.
193 DG402-49750 2-(2-氯苯基)-N-环己基咪唑并[1,2-a]嘧啶-3-胺
1H NMR(400MHz,CDCl3)δ8.53(dd,J=2.1,4.1,1H),8.46(dd,J=2.1,6.8,1H),7.81-7.70(m,1H),7.55-7.43(m,1H),7.38(dqd,J=1.8,7.4,14.8,2H),6.90(dd,J=4.1,6.8,1H)3.34(d,J=6.9,1H),2.64(dd,J=3.4,6.7,1H),1.73-1.61(m,2H),1.61-1.52(m,2H),1.47(s,1H),1.19-0.91(m,5H).
13C NMR(101MHz,CDCl3)δ149.13,144.56,136.60,133.27,132.79,132.24,130.42,129.45,129.42,127.01,124.75,108.09,56.60,33.72,25.47,24.46.
HRMS(ESI):m/z 327.1380(M+H)+;计算为C18H20N4Cl:327.1376.
194 DG 402-49752 2-(2-氯苯基)-N-环己基咪唑并[2,1-a]异喹啉-3-胺
1H NMR(400MHz,CDCl3)δ8.66(d,J=8.0,1H),8.00(d,J=7.3,1H),7.75(dd,J=1.6,7.5,1H),7.71(d,J=7.0,1H),7.62-7.57(m,1H),7.57-7.51(m,1H),7.48(dd,J=1.2,7.9,1H),7.39(td,J=1.4,7.5,1H),7.36-7.30(m,1H),7.07(d,J=7.2,1H),3.29(d,J=7.1,1H),2.78-2.62(m,1H),1.77-1.66(m,2H),1.63-1.51(m,2H),1.51-1.44(m,1H),1.16-0.98(m,5H).
13C NMR(101MHz,CDCl3)δ139.07,134.03,132.69,132.61,129.61,129.43,129.38,128.97,128.12,127.88,127.78,127.05,126.89,123.95,122.72,120.44,112.30,56.93,33.80,25.62,24.60.
HRMS(ESI):m/z376.1587(M+H)+;计算为C23H23N3Cl;376.1581.
生物活性
表1给出了在酶试验(enzymatic assay)和/或全细胞抗-HIV试验(wholecell anti-HIV assay)中,本发明的化合物抗HIV-1逆转录酶经选择的结果。
表1.在酶试验和/或全细胞抗-HIV试验中得到的、化合物抗HIV-1逆转录酶的IC50值。
ND:未进行测试
用于测定抗逆转录酶活性的酶法
该试验根据夹心-ELISA实验方案,采用ROCHE逆转录酶显色试剂盒(colorimetric reverse transcriptase kit)(cat# 11468120910)进行。将生物素和DIG-标记的核苷酸引入cDNA链,所述cDNA链通过HIV-1逆转录酶的作用在RNA模板上聚合而成。将cDNA产物固定到包被有链霉抗生素蛋白的96-孔细胞培养***板的孔中,通过与缀合到辣根过氧化物酶(HRP)的抗-DIG抗体进行培养来检测它们连接的DIG部分。通过用显色HRP底物培养后多孔分光光度计(multiwell spectrophotometer)上405nm处的吸光度读数表示固定抗体的量。
为了评价测试化合物的抑制活性,可进行单一浓度筛选(通常为50μM)或IC50测定。在单一浓度筛选中,用HIV-1逆转录酶和底物培养化合物,残留酶的活性用相对于对照(没有抑制剂)的百分数表示。对于IC50测定,用HIV-1逆转录酶和底物培养所述化合物四倍的连续稀释液(4-fold serialdilutions),所述酶的活性用相对于对照(没有抑制剂)的百分数表示,将所述酶的活性相对于抑制剂浓度绘制曲线,得到在达到50%酶抑制作用时的浓度(IC50)。
用于测定抗-HIV活性的细胞法
PBMC
新鲜的人PBMC(对于HIV和HBV是血清反应阴性的)分离自经筛选的提供者(Interstate Blood Bank,Inc.Memphis,TN)。通过低速离心使细胞沉淀/洗涤2-3次,再在PBS中重悬以除去会造成污染的血小板。然后将白细胞保有血(Leukophoresed blood)用Dulbecco磷酸盐缓冲盐水(DPBS)按1∶1稀释,再将稀释后的白细胞保有血覆盖到处于50ml离心管中的14ml淋巴细胞分离培养基(LSM;Mediatech公司生产的Cellgro;密度为1.078±0.002g/ml;Cat.# 85-072-CL)中,然后再以600×g离心30分钟。从产生的界面轻轻地吸出带状PBMC,随后通过低速离心用PBS洗涤2次。最后一次洗涤完后,用台盼蓝排除法对细胞进行计数,再以1×107细胞/ml的密度重悬于RPMI 1640中,所述RPMI 1640补充有15%的胎牛血清(FBS)、2mM L-谷氨酰胺和4μg/ml植物血球凝集素(PHA-P,Sigma)。在37℃,将重悬的细胞培养48-72小时。培养后,将PBMC离心,然后使它们重悬于含有15%FBS、2mM L-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素、10μg/ml庆大霉素和20U/ml重组人IL-2(R&D Systems,Inc)的RPMI 1640中。将IL-2包含在培养基中,来保持由PHA促细胞***刺激引起的细胞***。PBMC在此培养基中的浓度保持在1×106-2×106细胞/mL,每两周更换一次培养基直到在试验方案中使用。细胞在培养物中最多保持两周,之后会被视为太老不能在试验中使用而被弃置。单核细胞由于附着到组织培养瓶上而使其在培养物中的量减少。
对于标准的PBMC试验,将来自于至少两位正常提供者的PHA-P受激细胞合并(混合在一起),在新鲜的培养基中稀释到终浓度为1×106细胞/mL,再按Infectious Disease Research Department,Southern Research Institute)开发的标准格式(standard format),以50μl/孔(5×104细胞/孔)的量铺于96孔圆底微孔板的内孔中。将来自于超过一位提供者的单核细胞合并(混合),以使各个提供者之间观察到的差异最小,所述差异由HIV感染和原始淋巴细胞群(primary lymphocyte populations)对PHA和IL-2总应答中定量和定性的不同造成。每个板包括病毒/细胞对照孔(细胞+病毒)、试验孔(药物+细胞+病毒)和化合物对照孔(药物+没有细胞的培养基,对MTS监测细胞毒性是必要的)。因为HIV-1不导致PBMC细胞病变,这使得能够用同样的试验板测量抗病毒活性和细胞毒性。在微量管中制备2×浓度的试验药物的稀释液,采用所述标准格式,将100μl各个浓度的稀释液置于合适的孔中。将50μl病毒储备液的预定稀释液置于各个测试孔(最终MOI≈0.1)中。将所述PBMC培养物在感染后于37℃、5%CO2中保持七天。此后,收集无细胞的上清液样品用于分析逆转录酶活性。除去上清液样品后,通过将MTS添加到所述板中测定细胞的活力,来测量化合物的细胞毒性。还通过显微镜对孔进行检察,并注意任何异常情况。
MAGI
MAGI-R5细胞天然地表达CXCR4辅助受体,因而将它设计用来表达CD4(HIV-1细胞表面受体)、CCR5辅助受体,并且还将它设计成包含LTR-β-半乳糖苷酶报道基因构建体(reporter construct)。设计MAGI抗病毒试验用于鉴别在Tat反式激活(transactivation)及其之前的病毒生命周期(例如,病毒附着/融合/进入、脱壳、逆转录、核输入、整合、LTR反式激活)内,对通过靶标进行的HIV-1复制进行阻止的化合物。在添加病毒之前,将MAGI细胞用化合物处理15-30分钟。然后将HIV-1添加到所述细胞/化合物中,再将培养物培养48小时。如果所述病毒能够感染所述细胞,那么它会进行逆转录和整合,并且从整合后的前病毒开始转录。产生的第一病毒蛋白之一为HIV-1Tat,它反式激活驱使β-半乳糖苷酶表达的HIV-1LTR启动子。结果,感染的细胞开始生产过多的β-半乳糖苷酶。感染48小时后,所述细胞被溶解,再用化学发光检测法(Perkin ElmerApplied Biosystems)测量β-半乳糖苷酶的酶活性。在复制板(replicate plates)上,用MTS染料还原(MTS dyereduction)(CellTiter 96Reagent,Promega,Madison,WI)监测化合物毒性。
因此,本发明表明:所述通式A化合物和通式B化合物抑制HIV-1逆转录酶,因而具有作为抗HIV药剂的用途。
PCT/US2008/082531要求USSN 60/986,990的优先权。然而,在提交本申请时,无法从从美国专利局获得所述优先权文件。如果PCT/US2008/082531公开的任何化合物的优先权日晚于本说明书公开的化合物的优先权日,那么有必要修改但书部分。因此,将如下内容归入本说明书,为这些可能发生的事件作准备。
本发明还提供了选自于式A化合物和式B化合物的化合物在制造用于治疗已感染HIV的受试者的药剂方面的用途;用于治疗已感染HIV的受试者的组合物,所述组合物包含用于治疗受到HIV感染的受试者、选自于式A化合物或式B化合物的化合物;通过给予选自于式A化合物或式B化合物的化合物治疗受到HIV感染的受试者的方法;并且对于式A化合物或式B化合物,其中,对于式A:
R选自烷基、支链烷基、环烷基、芳基、取代芳基、萘基、苄基和二环烷基;
R1选自烷基、环烷基、取代烷基、支链烷基、苯基、杂芳基、氧杂环烷基、二环烷基、呋喃基、取代呋喃基、噻吩基和取代噻吩基;
R2-R5各自独立地选自H、卤素、氰基、烷基和取代烷基;或R2和R3一起形成碳环;或独立地,R4和R5一起形成碳环,
R6为H、烷基或烷酰基;
并且其中,对于式B:
R为环烷基,并且R1为取代芳基,但排除USSN 60/986,990中公开的化合物。
Claims (8)
2.如权利要求1所述的化合物,所述化合物选自:
2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺;
5-溴-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺;
5-氯-2-(2-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺;
2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-6-腈;
5-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺;
2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-5-腈。
3.如权利要求2所述的化合物,所述化合物选自:
5-氯-2-(2-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺;
5-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺;
2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-5-腈。
4.如权利要求3所述的化合物,所述化合物为5-氯-2-(2-氯苯基)-N-环戊基咪唑并[1,2-a]吡啶-3-胺。
5.如权利要求3所述的化合物,所述化合物为5-氯-2-(2-氯苯基)-N-环己基咪唑并[1,2-a]吡啶-3-胺。
6.如权利要求3所述的化合物,所述化合物为2-(2-氯苯基)-3-(环己基氨基)咪唑并[1,2-a]吡啶-5-腈。
7.一种用于治疗已感染HIV的受试者的药物组合物,所述组合物包含如权利要求1所述的化合物。
8.如权利要求1所述的化合物在制备用于治疗HIV感染的药剂方面的用途。
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PCT/IB2009/054021 WO2010032195A1 (en) | 2008-09-16 | 2009-09-15 | Imidazopyridines and imidazopyrimidines as hiv-i reverse transcriptase inhibitors |
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US (1) | US8501767B2 (zh) |
EP (1) | EP2334675B1 (zh) |
CN (1) | CN102216298B (zh) |
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EP2417136B1 (en) * | 2009-04-07 | 2016-01-06 | University Of Witwatersrand, Johannesburg | Imidazo [1,2-a] pyridine-6-carboxamide derivatives, their use for the treatment of colon cancer and their method of manufacture |
CN103140488A (zh) * | 2010-08-03 | 2013-06-05 | 加利福尼亚大学董事会 | 缓和组织损伤和坏死的化合物和组合物 |
US8633200B2 (en) * | 2010-09-08 | 2014-01-21 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
KR20150082308A (ko) | 2012-11-14 | 2015-07-15 | 에프. 호프만-라 로슈 아게 | 이미다조피리딘 유도체 |
ES2623777T3 (es) * | 2013-03-13 | 2017-07-12 | VIIV Healthcare UK (No.5) Limited | Inhibidores de la replicación del virus de la inmunodeficiencia humana |
RU2016105108A (ru) * | 2013-07-25 | 2017-08-30 | Дана-Фарбер Кэнсер Инститьют, Инк. | Ингибиторы факторов транскрипции и их применение |
EP3307728A4 (en) | 2015-06-12 | 2019-07-17 | Dana Farber Cancer Institute, Inc. | ASSOCIATION THERAPY USING TRANSCRIPTION INHIBITORS AND KINASE INHIBITORS |
WO2017044792A1 (en) | 2015-09-11 | 2017-03-16 | Dana-Farber Cancer Institute, Inc. | Acetamide thienotriazoldiazepines and uses thereof |
WO2017044849A1 (en) | 2015-09-11 | 2017-03-16 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
SG11201803210YA (en) | 2015-11-25 | 2018-05-30 | Dana Farber Cancer Inst Inc | Bivalent bromodomain inhibitors and uses thereof |
WO2017192228A1 (en) * | 2016-05-06 | 2017-11-09 | Albert Einstein College Of Medicine, Inc. | Pak1 inhibitors and uses thereof |
US11098043B2 (en) | 2017-07-14 | 2021-08-24 | University Of Massachusetts | Certain imidazopyridines as cyclic AMP response element binding (CREB) binding protein (CBP) inhibitors and uses thereof |
CN111518044A (zh) * | 2019-02-01 | 2020-08-11 | 华东师范大学 | 烷氧基异噁唑类衍生物及其制备方法与应用 |
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EP2334675B1 (en) | 2014-03-26 |
ZA201101975B (en) | 2011-12-28 |
US20110312957A1 (en) | 2011-12-22 |
WO2010032195A1 (en) | 2010-03-25 |
EP2334675A1 (en) | 2011-06-22 |
US8501767B2 (en) | 2013-08-06 |
CN102216298A (zh) | 2011-10-12 |
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