CN107286134A - 2,4-二取代嘧啶衍生物作为cdk抑制剂及其应用 - Google Patents
2,4-二取代嘧啶衍生物作为cdk抑制剂及其应用 Download PDFInfo
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- CN107286134A CN107286134A CN201610220246.9A CN201610220246A CN107286134A CN 107286134 A CN107286134 A CN 107286134A CN 201610220246 A CN201610220246 A CN 201610220246A CN 107286134 A CN107286134 A CN 107286134A
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- bases
- methyl
- pyridine
- fluoro
- pyrimidine
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Abstract
本发明涉及一类2,4‑二取代嘧啶衍生物、及其作为治疗上有效的周期蛋白依赖性蛋白激酶(CDK)抑制剂的应用。具体的,本发明涉及一种通式(I)所示的新的2,4‑二取代嘧啶衍生物、及其药物组合物,作为选择性CDK4/6抑制剂在预防或治疗与CDK4/6相关疾病中的用途。
Description
技术领域
本发明涉及药物制备技术领域,特别是涉及一种2,4-二取代嘧啶衍生物衍生物作为CDK抑制剂及其应用。
背景技术
周期蛋白依赖性蛋白激酶(cyclin-dependentkinase,CDK)和周期蛋白(cyclin)是细胞周期调控中的重要因子。CDK可以和cyclin结合形成异二聚体,其中CDK为催化亚基,cyclin为调节亚基,形成各种cyclin-CDK复合物,使不同底物磷酸化,对细胞周期不同的时相起推进和转化作用。
在哺乳动物中至少存在9种CDK。细胞由G1期向S期转化主要受G1期CDK激酶控制。与G1期细胞周期蛋白(cyclin)结合的CDK激酶主要包括CDK2、CDK4和CKD6。Cyclin D主要与CDK4和CKD6结合并调节后者活性;cyclin E在G1/S期与CDK2结合,呈现CDK 2的激酶活性促进细胞进入S期。G2/M期主要受CDK1激酶调控,Cyclin A、CyclinB与CDK1结合,CDK1使底物蛋白磷酸化,如将组蛋白H1磷酸化则导致染色体凝缩,如将核纤层蛋白磷酸化则使核膜解体。在M期,M期促发因子(MPF)激活后期促进因子APC,将泛连接在Cyclin A和Cyclin B上,通过多泛素化作用,使它们被蛋白酶体降解,完成一个细胞周期(Malumbres M.etal.NatCell Biol 11:1275,2009;Malumbres M.etal.Nat Rev Cancer 9:153,2009)。
过去十年来,CDK抑制剂作为抗肿瘤新药开发为全球药业的一个热点,有超过20个CDK抑制剂进入临床开发。尽管CDK抑制剂抗肿瘤临床前药效学结果显著,但是早前多数临床试验结果不尽人意。主要问题包括在实体瘤缺乏疗效和毒性较大。(Guha M.Nat RevDrug Dis11:892,2012)。而在分析产生严重毒副作用时发现,部分CDK抑制剂药物对CDK亚型缺乏选择性,因此产生了较大的毒副作用。
CDK4和CDK6是两个密切相关的激酶,在肿瘤细胞周期中与Cyclin D结合促使G1期进入S期,是DNA复制细胞分裂的细胞周期进程必需的。而超过90%的人类肿瘤中,均发现通过各种的基因和生化适应导致G1-S期的过渡控制机制改变。P16和人视网膜母细胞瘤抑制蛋白(retinoblastoma,Rb)是重要的肿痛抑制蛋白,其能调控细胞周期。P16基因蛋白抑制CDK4、Cyclin D1和Rb的反馈回路,并通过调节Rb的蛋白活性,从而防止细胞过度增殖,以达到抑制肿瘤的目的。已经证明在人体肿瘤中(如乳腺癌和骨髓瘤),CDK4和CDK6激活导致细胞周期改变发生。而抑制CDK4和CDK6,可阻止肿瘤抑制蛋白Rb的失活和干扰肿瘤细胞周期进展(Choi YJ and Anders L,Oncogene 33:1890-903,2014)。
由于CDK4/6在各种实体肿瘤和血液肿瘤的细胞周期控制失调中起关键作用。目前,选择性CDK4/6抑制剂目前有多个处于临床阶段(如Palbociclib、LY2835219和LEE011)。这些药物的临床评价还包括转移性乳腺癌、卵巢癌、脂肪肉瘤、非小细胞肺癌、肝癌、胶质母细胞瘤、黑素瘤、多发性骨髓瘤和淋巴瘤等。
虽然有许多CDK抑制剂类化合物已经被公开,但是,由于受CDK介导的病理的原因,仍然需要大量用于治疗与CDK有关的障碍的大量药物,特别是CDK4/6抑制类药物。
发明内容
本发明的目的之一在于提供一种新的2,4-二取代嘧啶衍生物衍生物或其可药用的盐。
本发明的目的之二是提供该类化合物作为新型CDK4/6抑制剂在制备预防或治疗与CDK4/6相关疾病的药物中的用途,所述与CDK4/6所参与的周期控制失调导致的各种疾病,特别是指恶性肿瘤的治疗,包括但不限于乳腺癌、卵巢癌、前列腺癌、结直肠癌、胰腺癌、肝癌、黑色素瘤、胃癌和实体瘤等。
为实现上述目的,本发明提供了如下通式I表示的2,4-二取代嘧啶衍生物或其可药用的盐:
其中:
R1代表氢、C1-C3的烷基、C3-C7的环烷基;
R2代表氢、卤素、甲基、甲氧基、三氟甲基;
n为0或1;
A环为
且当A环为时,n为0;
R3代表C1-C5的烷基、C3-C7的环烷基;
R4,R5分别代表氢、C1-C3的烷基、C3-C5的环烷基、乙酰基、卤素、三氟甲基、氰基或CONR7R8;
R6代表氢、卤素;
R7,R8分别代表氢、甲基;
X为CR6或N;
Y,Z分别为C或N。
本发明还提供了药物组合物,该药物组合物包含至少一种药用载体,和至少一种本申请所述式(I)化合物及其药用盐,以作为CDK4/6抑制剂的应用。
本申请所述的“C1-C3的烷基”是指甲基、乙基、正丙基或异丙基;“C1-C5的烷基”是指甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、1-戊基、2-戊基、3-戊基、2-甲基-3-丁基、1,1-二甲基-1-丙基、2,2-二甲基-1-丙基;所述“卤素”是指F、Cl、Br、I;所述“C3-C7环烷基”是指环丙基、环丁基、环戊基、环己基、环庚基;所述“C3-C5环烷基”是指环丙基、环丁基、环戊基。
本发明的典型化合物包括,但不限于以下表1化合物:
或其可药用的盐。
可药用盐的例子包括无机盐和有机盐,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、扁桃体酸盐和草酸盐。
本发明的化合物可采用如下的合成通法一制备:
根据文献(COATES DAVID ANDREW等WO2010075074A1)中报道的程序制备终产物I,即取代2-氯嘧啶(I1)与胺(I2)经催化反应制得目标产物I。
其中2-氯嘧啶(I1)的制备可按下列通法二和通法三进行。
通法二:
参照文献(B Corbel,FO Michaud等J.Heter.Chem.2007,pp793和MO Frederick,DP Kjell,Tetra.Lett.2015,pp949)方法,原料I3在碱性条件下与溴化物(I4)反应制得I5,I5分别与双联硼酸频那醇酯、2,4-二氯嘧啶(I7)经Suzuki偶联反应制得I1。
按通法二方法还可制备如下I1化合物:
通法三:
参照文献(AJ Majeed,Antonsen,等Tetra.1989,pp993;Gatti Mcarthur,Silvia,Goetschi,Erwin等WO2007110337A1和Chen,Yuzhong;Sharpe,等WO2009061761A2)方法,原料I8在碱性条件下与溴化物(I4)反应制得I9,I9分别与六正丁基二锡、2,4-二氯嘧啶(I7)经偶联反应制得I1。
按通法三方法还可制备如下I1化合物:
本发明涉及所述2,4-二取代嘧啶衍生物为CDK4/6抑制剂,所述化合物可用于CDK4/6所参与的细胞周期控制失调导致的各种临床疾病,如癌症。这类疾病包括但不限于乳腺癌、卵巢癌、前列腺癌、结直肠癌、肝癌、黑色素瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、多发性骨髓瘤、肺癌、胃癌、胰腺癌。
本发明的衍生物在实施疾病治疗过程中,可以组合物的形成通过口服、注射等方式,用于治疗相关癌症及其他疾病。
所述组合物包括治疗有效量的上述化合物或其可药用的盐和医学上可接受的载体。
所述及的载体是指药学领域常规的载体,如:稀释剂、赋形剂如水等;粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等;填充剂如淀粉等;崩裂剂如碳酸钙、碳酸氢钠;另外,还可以在组合物中加入其他辅助剂如香味剂和甜味剂。
用于口服时,可将其制备成常规的固体制剂如片剂、粉剂或胶囊等;用于注射时,可将其制备成注射液。
本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备,其中活性成分的含量为0.1%~99.5%(重量比)。
本发明的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行变化,其日剂量为0.005-30mg/kg体重(口服)或0.005-30mg/kg体重(注射)。
实施例
下面结合具体实施例对本发明作进一步阐述,但这些实施例并不限制本发明的范围。
实施例1
化合物(I-1)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-1H-吲哚-5-基)嘧啶-2-胺
步骤1:5-溴吲哚(1.0g,5.1mmol)、2-溴丙烷(0.94g,7.65mmol)、氢氧化钾(0.43g,7.65mmol)加入N,N-二甲基甲酰胺(DMF,10mL)中,N2保护下70℃反应10h。反应液中加H2O(50mL)/乙酸乙酯(50mL)搅拌萃取,有机层干燥、过滤、浓缩后过硅胶柱(洗脱剂乙酸乙酯/石油醚:1/30-1/10)得白色固体1-异丙基-5-溴-1H-吲哚(0.8g,收率66%)。
步骤2:1-异丙基-5-溴-1H-吲哚(0.8g,3.36mmol)、双联硼酸频那醇酯(1.02g,4.0mmol)、Pd(dppf)Cl2(0.25g,0.34mmol)、醋酸钾(0.66g,6.72mmol)加入1,4-二氧六环(15mL)中,N2保护下80℃反应5h。浓缩溶剂至干,剩余物中加H2O(50mL)/乙酸乙酯(50mL)搅拌萃取,有机层干燥、过滤、浓缩后得粗品1-异丙基-5-硼酸频哪醇酯-1H-吲哚(0.96g,按100%收率算)。
步骤3:1-异丙基-5-硼酸频哪醇酯-1H-吲哚(0.96g,3.36mmol)、2,4-二氯-5-氟嘧啶(0.62g,3.7mmol)、Pd(PPh3)2Cl2(0.23g,0.34mmol)、K2CO3(0.93g,8.66mmol)加入四氢呋喃(15mL)/H2O(3mL)中,N2保护下80℃反应6h。反应液中加H2O(50mL)/乙酸乙酯(50mL)搅拌萃取,有机层干燥、过滤、浓缩后过硅胶柱(洗脱剂乙酸乙酯/石油醚:1/30-1/20)得白色固体1-异丙基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(0.5g,二步收率51.5%),MS(m/z):291[M+H]+。
步骤4:1-异丙基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(150mg,0.52mmol)、5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺(114mg,0.52mmol)、Pd2(dba)3(50mg,0.052mmol)、Xantphos(45mg,0.05278mmol)和碳酸铯(254mg,0.78mmol)加入1,4-二氧六环(815mL)中,N2保护下100℃反应8h。浓缩溶剂至干,剩余物加H2O(30mL)/二氯甲烷(DCM,50mL)搅拌萃取,有机层干燥、过滤、浓缩得淡黄色固体,过硅胶柱(洗脱剂二氯甲烷/甲醇:1/30-1/20)得淡黄色固体N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-1H-吲哚-5-基)嘧啶-2-胺(I-1,125mg,收率50.9%),MS(m/z):474[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),8.78-8.77(d,J=4.0Hz,1H),8.60(s,1H),8.41(s,1H),8.38-8.36(d,J=8.0Hz,1H),8.03-8.01(d,J=8.0Hz,1H),7.97-7.95(d,J=8.0Hz,1H),7.76-7.74(d,J=8.0Hz,1H),7.67-7.66(d,J=4.0Hz,1H),6.69-6.68(d,J=4.0Hz,1H),4.89-4.82(m,1H),4.42(m,6H),3.17(m,4H),1.50-1.49(d,J=4.0Hz,6H),1.28-1.24(t,J=8.0Hz,3H)。
实施例2
化合物(I-2)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-2的合成按实施例1方法进行,起始原料为1-异丙基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯,按实施例1步骤4反应后得N-(5-(4-羧酸叔丁酯-1-哌嗪基)-吡啶-2-基)-5-氟-4-(1-异丙基-1H-吲哚-5-基)嘧啶-2-胺,该中间体再经3N盐酸乙酸乙酯脱BOC保护后,得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-1H-吲哚-5-基)嘧啶-2-胺盐酸盐(I-2)。MS(m/z):432[M+H]+。1H NMR(DMSO-d6):δ:11.65(br,1H),9.70(br,2H),8.77-8.76(d,J=4.0Hz,1H),8.39(s,1H),8.01-8.00(d,J=4.0Hz,1H),7.96(s,1H),7.93(s,1H),7.85-7.83(d,J=8.0Hz,1H),7.76-7.74(d,J=8.0Hz,1H),7.68-7.67(d,J=4.0Hz,1H),6.69-6.68(d,J=4.0Hz,1H),4.89-4.82(m,1H),3.69-3.46(m,8H),1.51-1.49(d,J=8.0Hz,6H)。
实施例3
化合物(I-3)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-3的合成按实施例1方法进行,起始原料为1-环戊基-3-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-环戊基-3-乙酰基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环戊烷和3-乙酰基-5-溴-1H-吲哚))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺盐酸盐(I-3)。MS(m/z):500[M+H]+。1H NMR(DMSO-d6):δ:11.67(br,1H),9.73(br,2H),9.39(s,1H),8.78(s,1H),8.69-8.67(d,J=8.0Hz,1H),8.00-7.97(m,2H),7.93(s,1H),7.72-7.69(m,2H),4.89-4.83(m,1H),3.69-3.46(m,8H),2.73(s,3H),2.02-1.67(m,8H)。
实施例4
化合物(I-4)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-4的合成按实施例1方法进行,起始原料为1-环戊基-3-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺(I-4)。MS(m/z):542[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.63(br,1H),9.39(s,1H),8.78-8.77(d,J=4.0Hz,1H),8.61(s,1H),8.41(s,1H),8.39-8.36(m,2H),7.97-7.95(d,J=8.0Hz,1H),7.67-7.65(d,J=8.0Hz,1H),4.89-4.82(m,1H),4.57(s,2H),4.41-4.21(m,13H),2.01-1.69(m,8H),1.28-1.24(t,J=8.0Hz,3H)。
实施例5
化合物(I-5)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2,3-二甲基-2H-吲唑-6-基)嘧啶-2-胺
化合物I-5的合成按实施例1方法进行,起始原料为2,3-二甲基-6-(2-氯-5-氟嘧啶-4-基)-2H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和2,3-二甲基-6-溴-2H-吲唑)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2,3-二甲基-2H-吲唑-6-基)嘧啶-2-胺盐酸盐(I-5)。MS(m/z):419[M+H]+。1H NMR(DMSO-d6):δ:11.68(br,1H),9.75(br,2H),9.37(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.75(s,1H),8.00-7.97(m,2H),7.72-7.69(m,2H),4.53(s,3H),4.35-4.21(m,11H)。
实施例6
化合物(I-6)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺
化合物I-6的合成按实施例1方法进行,起始原料为3-异丙基-6-(2-氯-5-氟嘧啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和3-异丙基-6-溴-[1,2,4]三唑并[4,3-a]吡啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺(I-6)。MS(m/z):476[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.61(br,1H),9.67(s,1H),9.37(s,1H),8.83-8.79(m,2H),8.51(s,1H),7.79-7.77(d,J=8.0Hz,1H),7.03-7.01(d,J=8.0Hz,1H),4.88-4.83(m,1H),4.57(s,2H),4.21-4.02(m,9H),1.53-1.51(d,J=8.0Hz,6H),1.28-1.24(t,J=8.0Hz,3H)。
实施例7
化合物(I-7)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺
化合物I-7的合成按实施例1方法进行,起始原料为3-异丙基-6-(2-氯-5-氟嘧啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺盐酸盐(I-7)。MS(m/z):434[M+H]+。1HNMR(DMSO-d6):δ:11.69(br,1H),9.81(br,2H),9.67(s,1H),9.38(s,1H),8.82-8.78(m,2H),8.48(s,1H),7.79-7.75(m,2H),4.33-4.20(m,9H),1.51-1.49(d,J=8.0Hz,6H)。
实施例8
化合物(I-8)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺
2-氯-9-异丙基-8-甲基-9H-嘌呤(合成方法按实施例1步骤1,500mg,2.38mmol)、Pd(PPh3)2Cl2(167mg,0.24mmol)、六正丁基二锡(1.45g,2.50mmol)加入1,4-二氧六环(10mL)中,N2保护下80℃反应5h。浓缩溶剂至干,剩余物过硅胶柱(洗脱剂乙酸乙酯/石油醚:1/30-1/20)得2-三正丁基锡-9-异丙基-8-甲基-9H-嘌呤(700mg,收率63.2%)。
2-三正丁基锡-9-异丙基-8-甲基-9H-嘌呤(700mg,1.51mmol)、2,4-二氯-5-氟嘧啶(276mg,1.65mmol)、Pd(PPh3)2Cl2(110mg,0.15mmol)、K2CO3(415mg,3.01mmol)加入1,4-二氧六环(10mL)中,N2保护下80℃反应6h。反应液中加H2O(50mL)/乙酸乙酯(50mL)搅拌萃取,有机层干燥、过滤、浓缩后过硅胶柱(洗脱剂乙酸乙酯/石油醚:1/30-1/20)得白色固体9-异丙基-8-甲基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤(350mg,收率76.1%),MS(m/z):308[M+H]+。
化合物I-8的制备按实施例1和2的方法,以9-异丙基-8-甲基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯为原料,得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺盐酸盐(I-8)。MS(m/z):449[M+H]+。1H NMR(DMSO-d6):δ:11.68(br,1H),9.83(br,2H),9.81(s,1H),9.39(s,1H),8.85(s,1H),8.02-8.00(d,J=8.0Hz,1H),7.93-7.91(d,J=8.0Hz,1H),5.86-5.81(m,1H),4.32-4.20(m,8H),2.85(s,3H),1.55-1.54(d,J=4.0Hz,6H)。
实施例9
化合物(I-9)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-9的合成按实施例1方法进行,起始原料为9-异丙基-8-甲基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺(I-9)。MS(m/z):491[M+H]+。1H NMR(DMSO-d6):δ:11.95(br,1H),11.64(br,1H),9.82(s,1H),9.38(s,1H),8.84(s,1H),8.05-8.03(d,J=8.0Hz,1H),7.03-7.01(d,J=8.0Hz,1H),5.88-5.83(m,1H),4.58(s,2H),4.21-4.02(m,13H),1.54-1.53(d,J=4.0Hz,6H),1.28-1.24(t,J=8.0Hz,3H)。
实施例10
化合物(I-10)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(5-氟-6-甲酸二甲酰胺基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺
化合物I-10的合成按实施例1方法进行,起始原料为5-氟-6-甲酸二甲酰胺基-7-异丙基-4-(2-氯-5-氟嘧啶-4-基)-7H-吡咯并[2,3-d]嘧啶(合成方法类似于实施例8,起始原料为2,4-二氯-5-氟嘧啶和2-氯-5-氟-6-甲酸二甲酰胺基-7-异丙基-7H-吡咯并[2,3-d]嘧啶)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(5-氟-6-甲酸二甲酰胺基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺盐酸盐(I-10)。MS(m/z):523[M+H]+。1H NMR(DMSO-d6):δ:11.67(br,1H),9.82(br,2H),9.83(s,1H),9.37(s,1H),8.83(s,1H),8.02-8.00(d,J=8.0Hz,1H),7.94-7.92(d,J=8.0Hz,1H),5.85-5.82(m,1H),4.32-4.20(m,14H),1.56-1.55(d,J=4.0Hz,6H)。
实施例11
化合物(I-11)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(6-甲基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺
化合物I-11的合成按实施例1方法进行,起始原料为6-甲基-7-环戊基-4-(2-氯-5-氟嘧啶-4-基)-7H-吡咯并[2,3-d]嘧啶(合成方法类似于实施例10,起始原料为2,4-二氯-5-氟嘧啶和6-甲基-7-环戊基-4-溴-7H-吡咯并[2,3-d]嘧啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(6-甲基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺(I-11)。MS(m/z):516[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.62(br,1H),9.84(s,1H),9.38(s,1H),8.83(s,1H),8.04-8.02(d,J=8.0Hz,1H),7.00-6.98(d,J=8.0Hz,1H),6.63(s,1H),4.89-4.83(m,1H),4.59(s,2H),4.21-4.03(m,10H),2.10-1.68(m,11H),1.26-1.22(t,J=8.0Hz,3H)。
实施例12
化合物(I-12)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-环戊基-2H-7-氮杂吲唑-6-基)嘧啶-2-胺
化合物I-12的合成按实施例1方法进行,起始原料为2-甲基-3-环戊基-6-(2-氯-5-氟嘧啶-4-基)-2H-7-氮杂吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和2-甲基-3-环戊基-6-溴-2H-吲唑)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-环戊基-2H-7-氮杂吲唑-6-基)嘧啶-2-胺盐酸盐(I-12)。MS(m/z):474[M+H]+。1H NMR(DMSO-d6):δ:11.71(br,1H),9.79(br,2H),9.38(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.73(s,1H),7.58(s,1H),7.23-7.19(m,2H),4.47(s,3H),4.36-4.21(m,8H),1.57-1.29(m,8H)。
实施例13
化合物(I-13)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-3-甲酰胺基-4-氟-1H-吲唑-5-基)嘧啶-2-胺
化合物I-13的合成按实施例1方法进行,起始原料为1-异丙基-3-甲酰胺基-4-氟-5-(2-氯-5-氟嘧啶-4-基)-1H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-异丙基-3-甲酰胺基-4-氟-5-溴-1H-吲唑(起始原料为溴代异丙烷和3-甲酰胺基-4-氟-5-溴-1H-吲唑))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡白色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-3-甲酰胺基-4-氟-1H-吲唑-5-基)嘧啶-2-胺盐酸盐(I-13)。MS(m/z):494[M+H]+。1H NMR(DMSO-d6):δ:12.11(br,2H),11.68(br,1H),9.71(br,2H),9.39(s,1H),8.68-8.66(d,J=8.0Hz,1H),8.02-8.00(d,J=8.0Hz,1H),7.95(s,1H),7.73-7.69(m,2H),4.87-4.82(m,1H),3.67-3.46(m,8H),1.24-1.20(d,J=8.0Hz,6H)。
实施例14
化合物(I-14)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-2-甲酸二甲酰胺基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-14的合成按实施例1方法进行,起始原料为1-环戊基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-环戊基-2-甲酸二甲酰胺基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环戊烷和2-甲酸二甲酰胺基-5-溴-1H-吲哚))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡白色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-2-甲酸二甲酰胺基-1H-吲哚-5-基)嘧啶-2-胺盐酸盐(I-14)。MS(m/z):529[M+H]+。1H NMR(DMSO-d6):δ:11.66(br,1H),9.71(br,2H),9.38(s,1H),8.78(s,1H),8.67-8.65(d,J=8.0Hz,1H),8.01-7.97(m,2H),7.93(s,1H),7.71-7.69(m,2H),4.88-4.82(m,1H),3.68-3.46(m,14H),2.01-1.68(m,8H)。
实施例15
化合物(I-15)N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氯-4-(1-(3-戊基)-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-15的合成按实施例1方法进行,起始原料为1-(3-戊基)-2-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-(3-戊基)-2-乙酰基-5-硼酸频哪醇酯-1H-吲哚(起始原料为3-溴戊烷和2-乙酰基-5-溴-1H-吲哚))和5-[(4-甲基哌嗪-1-基)甲基]吡啶-2-胺。得白色固体目标产物N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氯-4-(1-(3-戊基)-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺(I-15)。MS(m/z):547[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.38(s,1H),8.76-8.75(d,J=4.0Hz,1H),8.60(s,1H),8.40(s,1H),8.37-8.34(m,2H),7.97-7.95(d,J=8.0Hz,1H),7.66-7.64(d,J=8.0Hz,1H),4.87-4.82(m,1H),4.56(s,2H),4.40-4.21(m,8H),2.42(s,3H),2.37(s,3H),2.03-1.98(m,4H),1.02-0.98(m,6H)。
实施例16
化合物(I-16)N-(5-(4-异丙基哌嗪-1-甲基)-吡啶-2-基)-4-(1,2-二甲基-3-三氟甲基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-16的合成按实施例1方法进行,起始原料为1,2-二甲基-3-三氟甲基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-嘧啶和1,2-二甲基-3-三氟甲基-5-硼酸频哪醇酯-1H-吲哚(起始原料为碘甲烷和2-甲基-3-三氟甲基-5-溴-1H-吲哚))和5-[(4-异丙基哌嗪-1-基)甲基]吡啶-2-胺。得白色固体目标产物N-(5-(4-异丙基哌嗪-1-甲基)-吡啶-2-基)-4-(1,2-二甲基-3-三氟甲基-1H-吲哚-5-基)嘧啶-2-胺(I-16)。MS(m/z):524[M+H]+。1H NMR(DMSO-d6):δ:11.90(br,1H),11.63(br,1H),9.35(s,1H),8.78-8.77(d,J=4.0Hz,1H),8.58(s,1H),8.38-8.35(m,2H),7.93-7.88(m,2H),7.35(s,1H),4.57(s,2H),4.52(s,3H),4.42-4.19(m,12H),1.25-1.21(d,J=8.0Hz,6H)。
实施例17
化合物(I-17)N-(5-(4-环丙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环丙基-2-氰基-3-异丙基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-17的合成按实施例1方法进行,起始原料为1-环丙基-2-氰基-3-异丙基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟-嘧啶和1-环丙基-2-氰基-3-异丙基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环丙烷和1-环丙基-2-氰基-5-溴-1H-吲哚))和5-[(4-环丙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-环丙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环丙基-2-氰基-3-异丙基-1H-吲哚-5-基)嘧啶-2-胺(I-17)。MS(m/z):552[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.33(s,1H),8.78-8.75(m,2H),8.39-8.36(m,2H),7.91-7.88(m,1H),7.37(s,1H),4.56(s,2H),4.43-4.19(m,10H),1.25-1.20(m,7H),0.95-0.82(m,8H)。
实施例18
化合物(I-18)N-(5-(4-环庚基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环丁基-3-环丙基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-18的合成按实施例1方法进行,起始原料为1-环丁基-3-环丙基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟-嘧啶和1-环丁基-3-环丙基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环丁烷和3-环丙基-5-溴-1H-吲哚))和5-[(4-环庚基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-环庚基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环丁基-3-环丙基-1H-吲哚-5-基)嘧啶-2-胺(I-18)。MS(m/z):594[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.35(s,1H),8.79-8.76(m,2H),8.57(s,1H),8.39-8.36(m,2H),7.90-7.88(d,J=8.0Hz,1H),7.35(s,1H),4.88-4.82(m,1H),4.57(s,2H),4.43-4.13(m,15H),1.25-1.01(m,17H)。
实施例19
化合物(I-19)N-(5-(4-环己基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环己基-3-环丁基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-19的合成按实施例1方法进行,起始原料为1-环己基-3-环丁基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟-嘧啶和1-环己基-3-环丁基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环己烷和3-环丁基-5-溴-1H-吲哚))和5-[(4-环己基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-环己基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环己基-3-环丁基-1H-吲哚-5-基)嘧啶-2-胺(I-19)。MS(m/z):622[M+H]+。1H NMR(DMSO-d6):δ:11.92(br,1H),11.63(br,1H),9.37(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.57(s,1H),8.39-8.36(m,2H),7.90-7.88(d,J=8.0Hz,1H),7.67-7.65(d,J=8.0Hz,1H),7.37(s,1H),4.83-4.68(m,3H),4.60-4.56(m,1H),4.45-4.11(m,15H),1.27-1.01(m,20H)。
实施例20
化合物(I-20)N-(5-(4-环戊基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环庚基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-20的合成按实施例1方法进行,起始原料为1-环庚基-3-乙酰基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟-嘧啶和1-环庚基-3-乙酰基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代环庚烷和3-乙酰基-5-溴-1H-吲哚))和5-[(4-环戊基哌嗪-1-基)甲基]吡啶-2-胺。得白色固体目标产物N-(5-(4-环戊基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环庚基-3-乙酰基-1H-吲哚-5-基)嘧啶-2-胺(I-20)。MS(m/z):610[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.63(br,1H),9.57(s,1H),9.35(s,1H),8.81-8.79(d,J=8.0Hz,1H),8.57(s,1H),8.41-8.37(m,2H),7.90-7.88(d,J=8.0Hz,1H),7.66-7.65(d,J=4.0Hz,1H),4.81-4.69(m,3H),4.43-4.21(m,12H),1.29-1.03(m,20H)。
实施例21
化合物(I-21)N-(5-(4-环丁哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-环戊基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-21的合成按实施例1方法进行,起始原料为1-异丙基-2-环戊基-5-(2-氯-嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟-嘧啶和1-异丙基-2-环戊基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代异丙烷和2-环戊基-5-溴-1H-吲哚))和5-(4-环丁哌嗪-1-基)吡啶-2-胺。得白色固体目标产物N-(5-(4-环丁哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-环戊基-1H-吲哚-5-基)嘧啶-2-胺(I-21)。MS(m/z):554[M+H]+。1H NMR(DMSO-d6):δ:11.92(br,1H),11.65(br,1H),9.38(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.56(s,1H),8.40-8.37(m,2H),7.90-7.88(d,J=8.0Hz,1H),7.67-7.65(d,J=8.0Hz,1H),7.37(s,1H),5.81-5.70(m,1H),4.41-4.21(m,10H),1.57-1.02(m,20H)。
实施例22
化合物(I-22)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-2-甲酸二甲酰胺基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-22的合成按实施例1方法进行,起始原料为1-环戊基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-2-甲酸二甲酰胺基-1H-吲哚-5-基)嘧啶-2-胺(I-22)。MS(m/z):572[M+H]+。1HNMR(DMSO-d6):δ:11.92(br,1H),11.65(br,1H),9.37(s,1H),8.78-8.76(d,J=8.0Hz,1H),8.59(s,1H),8.39-8.36(m,2H),7.98-7.96(m,2H),7.67-7.65(d,J=8.0Hz,1H),4.89-4.83(m,1H),4.57(s,2H),4.21(s,6H),3.68-3.48(m,10H),2.02-1.69(m,8H),1.26-1.22(t,J=8.0Hz,3H)。
实施例23
化合物(I-23)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-23的合成按实施例1方法进行,起始原料为1-异丙基-2-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-异丙基-2-乙酰基-5-硼酸频哪醇酯-1H-吲哚(起始原料为溴代异丙烷和2-乙酰基-5-溴-1H-吲哚))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺盐酸盐(I-23)。MS(m/z):474[M+H]+。1H NMR(DMSO-d6):δ:11.69(br,1H),9.75(br,2H),9.38(s,1H),8.82(s,1H),8.69-8.67(d,J=8.0Hz,1H),8.01-7.97(m,2H),7.92(s,1H),7.73-7.69(m,2H),4.89-4.83(m,1H),3.69-3.48(m,8H),2.75(s,3H),1.67-1.65(d,J=8.0Hz,6H)。
实施例24
化合物(I-24)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺
化合物I-24的合成按实施例1方法进行,起始原料为1-异丙基-2-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲哚和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-乙酰基-1H-吲哚-5-基)嘧啶-2-胺(I-24)。MS(m/z):516[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.67(br,1H),9.36(s,1H),8.78-8.76(d,J=8.0Hz,1H),8.58(s,1H),8.39-8.36(m,2H),7.98-7.95(m,2H),7.67-7.65(d,J=8.0Hz,1H),4.89-4.82(m,1H),4.58(s,2H),3.68-3.51(m,10H),2.67(s,3H),1.67-1.65(d,J=8.0Hz,6H),1.27-1.23(t,J=8.0Hz,3H)。
实施例25
化合物(I-25)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氮杂吲哚-5-基)嘧啶-2-胺
化合物I-25的合成按实施例1方法进行,起始原料为1-异丙基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-4-氮杂吲哚(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-异丙基-2-甲酸二甲酰胺基-5-硼酸频哪醇酯-1H-4-氮杂吲哚(起始原料为溴代异丙烷和2-甲酸二甲酰胺基-5-溴-1H-4-氮杂吲哚))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氮杂吲哚-5-基)嘧啶-2-胺盐酸盐(I-25)。MS(m/z):504[M+H]+。1H NMR(DMSO-d6):δ:11.69(br,1H),9.77(br,2H),9.39(s,1H),8.82(s,1H),8.69-8.67(d,J=8.0Hz,1H),8.01-7.98(m,1H),7.92(s,1H),7.73-7.69(m,1H),6.87(s,1H),4.82-4.51(m,15H),1.67-1.65(d,J=8.0Hz,6H)。
实施例26
化合物(I-26)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氮杂吲哚-5-基)嘧啶-2-胺
化合物I-26的合成按实施例1方法进行,起始原料为1-异丙基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-4-氮杂吲哚和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氮杂吲哚-5-基)嘧啶-2-胺(I-26)。MS(m/z):546[M+H]+。1H NMR(DMSO-d6):δ:11.92(br,1H),11.68(br,1H),9.38(s,1H),8.78-8.76(d,J=8.0Hz,1H),8.57(s,1H),8.39-8.36(m,2H),7.98-7.97(m,1H),7.67-7.65(d,J=8.0Hz,1H),4.89-4.83(m,1H),4.59(s,2H),4.21(s,6H),3.68-3.53(m,10H),2.67(s,3H),1.67-1.66(d,J=4.0Hz,6H),1.29-1.25(t,J=8.0Hz,3H)。
实施例27
化合物(I-27)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氟吲哚-5-基)嘧啶-2-胺
化合物I-27的合成按实施例1方法进行,起始原料为1-异丙基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-4-氟吲哚和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氟-吲哚-5-基)嘧啶-2-胺(I-27)。MS(m/z):563[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.69(br,1H),9.37(s,1H),8.78-8.76(d,J=8.0Hz,1H),8.58(s,1H),8.39-8.36(m,2H),7.99-7.97(d,J=8.0Hz,1H),7.67-7.65(d,J=8.0Hz,1H),4.89-4.83(m,1H),4.57(s,2H),4.23(s,6H),3.68-3.52(m,10H),2.67(s,3H),1.69-1.67(d,J=4.0Hz,6H),1.29-1.25(t,J=8.0Hz,3H)。
实施例28
化合物(I-28)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氟吲哚-5-基)嘧啶-2-胺
化合物I-28的合成按实施例1方法进行,起始原料为1-异丙基-2-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-4-氟吲哚和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-异丙基-2-甲酸二甲酰胺基-1H-4-氟吲哚-5-基)嘧啶-2-胺盐酸盐(I-28)。MS(m/z):521[M+H]+。1H NMR(DMSO-d6):δ:11.67(br,1H),9.76(br,2H),9.41(s,1H),8.85(s,1H),8.69-8.67(d,J=8.0Hz,1H),8.00-7.98(d,J=8.0Hz,1H),7.92(s,1H),7.73-7.69(m,2H),4.89-4.82(m,1H),4.77-4.62(m,14H),1.68-1.66(d,J=8.0Hz,6H)。
实施例29
化合物(I-29)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-环丙基-3-乙酰基-2H-7-氮杂吲唑-6-基)嘧啶-2-胺
化合物I-29的合成按实施例1方法进行,起始原料为2-环丙基-3-乙酰基-6-(2-氯-5-氟嘧啶-4-基)-2H-7-氮杂吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和2-环丙基-3-乙酰基-6-溴-2H-7-氮杂吲唑)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-环丙基-3-乙酰基-2H-7-氮杂吲唑-6-基)嘧啶-2-胺盐酸盐(I-29)。MS(m/z):474[M+H]+。1H NMR(DMSO-d6):δ:11.69(br,1H),9.78(br,2H),9.35(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.76(s,1H),8.00-7.98(d,J=8.0Hz,1H),7.71-7.68(m,2H),4.41-4.21(m,8H),3.58-3.52(m,1H),2.87(s,3H),1.02-0.88(m,4H)。
实施例30
化合物(I-30)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-异丙基-2H-7-氯-吲唑-6-基)嘧啶-2-胺
化合物I-30的合成按实施例1方法进行,起始原料为2-甲基-3-异丙基-7-氯-6-(2-氯-5-氟嘧啶-4-基)-2H-吲唑和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-异丙基-2H-7-氯-吲唑-6-基)嘧啶-2-胺盐酸盐(I-30)。MS(m/z):482[M+H]+。1H NMR(DMSO-d6):δ:11.71(br,1H),9.80(br,2H),9.37(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.77(s,1H),8.00-7.98(d,J=8.0Hz,1H),7.71-7.67(m,2H),4.79(s,3H),4.41-4.20(m,9H),1.68-1.66(d,J=8.0Hz,6H)。
实施例31
化合物(I-31)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-甲酸二甲酰胺基-2H-7-氟-吲唑-6-基)嘧啶-2-胺
化合物I-31的合成按实施例1方法进行,起始原料为2-甲基-3-甲酸二甲酰胺基-7-氟-6-(2-氯-5-氟嘧啶-4-基)-2H-吲唑和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(2-甲基-3-甲酸二甲酰胺基-2H-7-氟-吲唑-6-基)嘧啶-2-胺盐酸盐(I-31)。MS(m/z):494[M+H]+。1H NMR(DMSO-d6):δ:11.70(br,1H),9.81(br,2H),9.37(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.79(s,1H),8.00-7.98(d,J=8.0Hz,1H),7.72-7.69(m,2H),4.78(s,3H),4.41-4.18(m,14H)。
实施例32
化合物(I-32)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-乙酰基-3-环丙基-8-氟-咪唑并[1,5-a]吡啶-6-基)嘧啶-2-胺
化合物I-32的合成按实施例1方法进行,起始原料为1-乙酰基-3-环丙基-8-氟-6-(2-氯-5-氟嘧啶-4-基)-咪唑并[1,5-a]吡啶-6-基)嘧啶和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-乙酰基-3-环丙基-8-氟-咪唑并[1,5-a]吡啶-6-基)嘧啶-2-胺盐酸盐(I-32)。MS(m/z):491[M+H]+。1H NMR(DMSO-d6):δ:11.71(br,1H),9.79(br,2H),9.71(s,1H),9.38(s,1H),8.21(s,1H),7.79-7.75(m,2H),7.21(s,1H),4.32-4.20(m,8H),2.79(s,3H),2.01-1.51(m,5H)。
实施例33
化合物(I-33)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺
化合物I-33的合成按实施例1方法进行,起始原料为3-三氟甲基-6-(2-氯-5-氟嘧啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和3-三氟甲基-6-溴-[1,2,4]三唑并[4,3-a]吡啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺(I-33)。MS(m/z):502[M+H]+。1HNMR(DMSO-d6):δ:11.91(br,1H),11.63(br,1H),9.68(s,1H),9.38(s,1H),8.83-8.79(m,2H),8.45(s,1H),7.80-7.78(d,J=8.0Hz,1H),7.02-7.00(d,J=8.0Hz,1H),4.55(s,2H),3.58-3.42(m,10H),1.28-1.24(t,J=8.0Hz,3H)。
实施例34
化合物(I-34)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-氰基-咪唑并[1,2-a]吡啶-6-基)嘧啶-2-胺
化合物I-34的合成按实施例1方法进行,起始原料为3-氰基-6-(2-氯-5-氟嘧啶-4-基)-咪唑并[1,2-a]吡啶(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和3-氰基-6-溴-咪唑并[1,2-a]吡啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-氰基-咪唑并[1,2-a]吡啶-6-基)嘧啶-2-胺(I-34)。MS(m/z):458[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.67(br,1H),9.71(s,1H),9.58(s,1H),9.37(s,1H),8.82-8.78(m,3H),7.80-7.78(d,J=8.0Hz,1H),7.04-7.02(d,J=8.0Hz,1H),4.57(s,2H),3.59-3.42(m,10H),1.26-1.22(t,J=8.0Hz,3H)。
实施例35
化合物(I-35)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-乙酰基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺
化合物I-35的合成按实施例1方法进行,起始原料为3-乙酰基-6-(2-氯-5-氟嘧啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和3-乙酰基-6-溴-[1,2,4]三唑并[4,3-a]吡啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-乙酰基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺(I-35)。MS(m/z):476[M+H]+。1H NMR(DMSO-d6):δ:11.93(br,1H),11.68(br,1H),9.71(s,1H),9.43(s,1H),8.81-8.77(m,2H),8.47(s,1H),7.79-7.77(d,J=8.0Hz,1H),6.89-6.87(d,J=8.0Hz,1H),4.57(s,2H),4.01(s,3H),3.55-3.42(m,10H),1.29-1.25(t,J=8.0Hz,3H)。
实施例36
化合物(I-36)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-环丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺
化合物I-36的合成按实施例1方法进行,起始原料为3-环丙基-6-(2-氯-5-氟嘧啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和3-环丙基-6-溴-[1,2,4]三唑并[4,3-a]吡啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(3-环丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基)嘧啶-2-胺(I-36)。MS(m/z):474[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.69(br,1H),9.69(s,1H),9.39(s,1H),8.80-8.76(m,2H),8.45(s,1H),7.78-7.76(d,J=8.0Hz,1H),6.89-6.87(d,J=8.0Hz,1H),4.56(s,2H),3.58-3.47(m,10H),2.02-1.57(m,8H)。
实施例37
化合物(I-37)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-环戊基-8-甲酸二甲酰胺基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-37的合成按实施例1方法进行,起始原料为9-环戊基-8-甲酸二甲酰胺基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤(合成方法类似于实施例8,起始原料为2,4-二氯-5-氟嘧啶和9-环戊基-8-甲酸二甲酰胺基-2-溴-9H-嘌呤)和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡黄色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-环戊基-8-甲酸二甲酰胺基-9H-嘌呤-2-基)嘧啶-2-胺盐酸盐(I-37)。MS(m/z):546[M+H]+。1H NMR(DMSO-d6):δ:11.75(br,1H),11.60(br,1H),9.83(s,1H),9.36(s,1H),8.82(s,1H),8.00-7.96(m,2H),4.89-4.83(m,1H),4.33-4.28(m,4H),3.61(s,6H),3.15-3.06(m,4H),2.77(s,3H),2.30-2.18(m,8H)。
实施例38
化合物(I-38)N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-乙酰基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-38的合成按实施例1方法进行,起始原料为9-异丙基-8-乙酰基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤(合成方法类似于实施例8,起始原料为2,4-二氯-5-氟嘧啶和9-异丙基-8-乙酰基-2-溴-9H-嘌呤)和5-[(4-甲基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-乙酰基-9H-嘌呤-2-基)嘧啶-2-胺(I-38)。MS(m/z):505[M+H]+。1H NMR(DMSO-d6):δ:11.92(br,1H),11.62(br,1H),9.83(s,1H),9.37(s,1H),8.85(s,1H),8.04-8.02(d,J=8.0Hz,1H),7.03-7.01(d,J=8.0Hz,1H),5.88-5.83(m,1H),4.59(s,2H),4.51(s,3H),4.23-4.04(m,11H),2.24-2.23(d,J=4.0Hz,6H)。
实施例39
化合物(I-39)N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-(3-戊基)-8-异丙基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-39的合成按实施例1方法进行,起始原料为9-(3-戊基)-8-异丙基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤(合成方法类似于实施例8,起始原料为2,4-二氯-5-氟嘧啶和9-(3-戊基)-8-异丙基-2-溴-9H-嘌呤)和5-[(4-甲基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-甲基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-(3-戊基)-8-异丙基-9H-嘌呤-2-基)嘧啶-2-胺(I-39)。MS(m/z):533[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.81(s,1H),9.37(s,1H),8.82(s,1H),8.06-8.04(d,J=8.0Hz,1H),7.01-6.99(d,J=8.0Hz,1H),4.89-4.83(m,1H),4.58-4.55(m,3H),4.20-4.03(m,11H),2.15-2.10(m,4H),1.55-1.54(d,J=4.0Hz,6H),1.26-1.24(d,J=8.0Hz,6H)。
实施例40
化合物(I-40)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-甲基-8-甲酸二甲酰胺基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-40的合成按实施例1方法进行,起始原料为9-甲基-8-甲酸二甲酰胺基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤(合成方法类似于实施例8,起始原料为2,4-二氯-5-氟嘧啶和9-甲基-8-甲酸二甲酰胺基-2-溴-9H-嘌呤)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(9-甲基-8-甲酸二甲酰胺基-9H-嘌呤-2-基)嘧啶-2-胺(I-40)。MS(m/z):520[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.83(s,1H),9.39(s,1H),8.84(s,1H),8.02-8.00(d,J=8.0Hz,1H),7.00-6.98(d,J=8.0Hz,1H),4.89(s,3H),4.58(s,2H),4.22-4.02(m,16H),1.28-1.24(t,J=8.0Hz,3H)。
实施例41
化合物(I-41)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(6-乙酰基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺
化合物I-41的合成按实施例1方法进行,起始原料为6-乙酰基-7-环丙基-4-(2-氯-5-氟嘧啶-4-基)-7H-吡咯并[2,3-d]嘧啶(合成方法类似于实施例10,起始原料为2,4-二氯-5-氟嘧啶和6-乙酰基-7-环丙基-4-溴-7H-吡咯并[2,3-d]嘧啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(6-乙酰基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺(I-41)。MS(m/z):516[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.62(br,1H),9.83(s,1H),9.39(s,1H),8.83(s,1H),8.04-8.02(d,J=8.0Hz,1H),7.01-6.99(d,J=8.0Hz,1H),6.68(s,1H),4.59(s,2H),4.23-4.04(m,11H),3.57(s,3H),1.28-1.24(t,J=8.0Hz,3H),2.08-1.68(m,4H)。
实施例42
化合物(I-42)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(5-氰基-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺
化合物I-42的合成按实施例1方法进行,起始原料为5-氰基-7-甲基-4-(2-氯-5-氟嘧啶-4-基)-7H-吡咯并[2,3-d]嘧啶(合成方法类似于实施例10,起始原料为2,4-二氯-5-氟嘧啶和5-氰基-7-甲基-4-溴-7H-吡咯并[2,3-d]嘧啶)和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(5-氰基-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-2-胺(I-42)。MS(m/z):473[M+H]+。1H NMR(DMSO-d6):δ:11.91(br,1H),11.63(br,1H),9.85(s,1H),9.39(s,1H),8.84(s,1H),8.03-8.01(d,J=8.0Hz,1H),7.05(s,1H),6.636.61(d,J=8.0Hz,1H),4.59(s,2H),4.52(s,3H),4.21-4.03(m,10H),1.25-1.21(t,J=8.0Hz,3H)。
实施例43
化合物(I-43)N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-甲酸二甲酰胺基-1H-吲唑-5-基)嘧啶-2-胺
化合物I-43的合成按实施例1方法进行,起始原料为1-环戊基-3-甲酸二甲酰胺基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-环戊基-3-甲酸二甲酰胺基-5-溴-1H-吲唑(起始原料为溴代环戊烷和3-甲酸二甲酰胺基-5-溴-1H-吲唑))和4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。得淡白色固体目标产物N-(5-(哌嗪-1-基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-甲酸二甲酰胺基-1H-吲唑-5-基)嘧啶-2-胺盐酸盐(I-43)。MS(m/z):530[M+H]+。1H NMR(DMSO-d6):δ:11.67(br,1H),9.70(br,2H),9.38(s,1H),8.69-8.65(m,2H),8.02-8.00(d,J=8.0Hz,1H),7.97(s,1H),7.72-7.69(m,2H),4.88-4.82(m,1H),3.69-3.47(m,14H),2.10-1.57(m,8H)。
实施例44
化合物(I-44)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-3-乙酰基-1H-吲唑-5-基)嘧啶-2-胺
化合物I-44的合成按实施例1方法进行,起始原料为1-异丙基-3-乙酰基-5-(2-氯-5-氟嘧啶-4-基)-1H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-异丙基-3-乙酰基-5-溴-1H-吲唑(起始原料为溴代异丙烷和3-乙酰基-5-溴-1H-吲唑))和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得米白色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-异丙基-3-乙酰基-1H-吲唑-5-基)嘧啶-2-胺(I-44)。MS(m/z):517[M+H]+。1H NMR(DMSO-d6):δ:11.90(br,1H),11.69(br,1H),9.38(s,1H),8.80-8.77(m,2H),8.50(s,1H),8.04-8.02(d,J=8.0Hz,1H),7.79-7.77(d,J=8.0Hz,1H),6.88-6.86(d,J=8.0Hz,1H),4.65-4.60(m,1H),4.56(s,2H),3.59-3.47(m,10H),2.79(s,3H),1.69-1.67(d,J=4.0Hz,6H),1.29-1.25(t,J=8.0Hz,3H)。
实施例45
化合物(I-45)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-甲基-4-氟-1H-吲唑-5-基)嘧啶-2-胺
化合物I-45的合成按实施例1方法进行,起始原料为1-环戊基-3-甲基-4-氟-5-(2-氯-5-氟嘧啶-4-基)-1H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-环戊基-3-甲基-4-氟-5-溴-1H-吲唑(起始原料为溴代环戊烷和3-甲基-4-氟-5-溴-1H-吲唑))和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得白色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-甲基-4-氟-1H-吲唑-5-基)嘧啶-2-胺(I-45)。MS(m/z):533[M+H]+。1H NMR(DMSO-d6):δ:11.89(br,1H),11.71(br,1H),9.39(s,1H),8.81-8.79(d,J=8.0Hz,1H),8.50(s,1H),8.03-8.01(d,J=8.0Hz,1H),7.78-7.76(d,J=8.0Hz,1H),6.91-6.89(d,J=8.0Hz,1H),4.66-4.60(m,1H),4.57(s,2H),3.61-3.49(m,10H),2.15-1.67(m,11H),1.28-1.24(t,J=8.0Hz,3H)。
实施例46
化合物(I-46)N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-三氟甲基-4-氮杂-1H-吲唑-5-基)嘧啶-2-胺
化合物I-46的合成按实施例1方法进行,起始原料为1-环戊基-3-三氟甲基-4-氮杂-5-(2-氯-5-氟嘧啶-4-基)-1H-吲唑(合成方法类似于实施例1,起始原料为2,4-二氯-5-氟嘧啶和1-环戊基-3-三氟甲基-4-氮杂-5-溴-1H-吲唑(起始原料为溴代环戊烷和3-三氟甲基-4-氮杂-5-溴-1H-吲唑))和5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺。得白色固体目标产物N-(5-(4-乙基哌嗪-1-甲基)-吡啶-2-基)-5-氟-4-(1-环戊基-3-三氟甲基-4-氮杂-1H-吲唑-5-基)嘧啶-2-胺(I-46)。MS(m/z):570[M+H]+。1H NMR(DMSO-d6):δ:11.88(br,1H),11.68(br,1H),9.38(s,1H),8.80-8.78(d,J=8.0Hz,1H),8.51-8.47(m,2H),8.03-8.01(d,J=8.0Hz,1H),6.90-6.88(d,J=8.0Hz,1H),4.67-4.60(m,1H),4.58(s,2H),3.62-3.53(m,10H),2.10-1.67(m,8H),1.26-1.22(t,J=8.0Hz,3H)。
实施例47
化合物(I-47)N-(5-(4-甲基哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-47的制备按实施例1和2的方法,以9-异丙基-8-甲基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤和5-(4-甲基哌嗪-1-基)吡啶-2-胺为原料,得淡黄色固体目标产物N-(5-(4-甲基哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺(I-47)。MS(m/z):463[M+H]+。1H NMR(DMSO-d6):δ:11.89(br,1H),11.65(br,1H),9.83(s,1H),9.38(s,1H),8.86(s,1H),8.02-8.00(d,J=8.0Hz,1H),7.95-7.93(d,J=8.0Hz,1H),5.87-5.83(m,1H),4.33-4.30(m,4H),3.15(s,3H),3.05-3.02(m,4H),2.85(s,3H),1.57-1.56(d,J=4.0Hz,6H)。
实施例48
化合物(I-48)N-(5-(4-乙基哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺
化合物I-48的制备按实施例1和2的方法,以9-异丙基-8-甲基-2-(2-氯-5-氟嘧啶-4-基)-9H-嘌呤和5-(4-乙基哌嗪-1-基)吡啶-2-胺为原料,得淡黄色固体目标产物N-(5-(4-乙基哌嗪-1-基)-吡啶-2-基)-5-氟-4-(9-异丙基-8-甲基-9H-嘌呤-2-基)嘧啶-2-胺(I-48)。MS(m/z):477[M+H]+。1H NMR(DMSO-d6):δ:11.88(br,1H),11.64(br,1H),9.82(s,1H),9.38(s,1H),8.84(s,1H),8.01-7.99(d,J=8.0Hz,1H),7.93-7.91(d,J=8.0Hz,1H),5.88-5.83(m,1H),4.33-4.25(m,8H),3.17(s,3H),2.67-2.61(q,J=8.0Hz,2H),2.01-2.00(d,J=4.0Hz,6H),1.67-1.63(t,J=8.0Hz,3H)。
实施例49
生物测试
CDK4活性测试:采用Caliper迁移率变动检测技术(Caliper mobility shiftassay)测定CDK4蛋白激酶活性(参见J.Biomol.Screen,2009,PP31)。将待测化合物以DMSO溶解后用激酶缓冲溶液(20mM HEPES-pH 7.5,0.01%Triton X-100,10mM MgCl2,2mM DTT)稀释,在384孔板中加入5μL的10%DMSO溶解的5倍反应终浓度的化合物,无化合物对照孔是5μL的10%DMSO,无没活性对照孔是5μL的激酶缓冲液。加入10μL稀释2.5倍后的CDK4酶溶液(GST-CDK4(1-303end))后在室温下孵育10min,再加入10μL的稀释2.5倍后的底物溶液Peptide FAM-P8。28℃下孵育3h后加25μL终止液终止反应,Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据,按照上述方法把转化率转化成抑制率数据。其中,抑制率%=(max-转化)/(max-min)×100%。
CDK6活性测试:采用Caliper迁移率变动检测技术(Caliper mobility shiftassay)测定CDK6蛋白激酶活性(参见J.Biomol.Screen,2009,PP31)。将待测化合物以DMSO溶解后用激酶缓冲溶液(20mM HEPES-pH 7.5,0.01%Triton X-100,10mM MgCl2,2mM DTT)稀释,在384孔板中加入5μL的10%DMSO溶解的5倍反应终浓度的化合物,无化合物对照孔是5μL的10%DMSO,无没活性对照孔是5μL的激酶缓冲液。加入10μL稀释2.5倍后的CDK6酶溶液(GST-CDK6(1-326end))后在室温下孵育10min,再加入10μL的稀释2.5倍后的底物溶液Peptide FAM-P8。28℃下孵育40min后加25μL终止液终止反应,Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据,按照上述方法把转化率转化成抑制率数据。其中,抑制率%=(max-转化)/(max-min)×100%。
上述实验结果如表2所示。
表2.测试结果:
注:A表示IC50>500nM,B表示500nM≥IC50>100nM,C表示100nM≥IC50>20nM,D表示IC50≤20nM。
Claims (7)
1.一类2,4-二取代嘧啶衍生物,其特征在于,为具有如下通式(I)所示化合物或其可药用的盐:
其中:
R1代表氢、C1-C3的烷基、C3-C7的环烷基;
R2代表氢、卤素、甲基、甲氧基、三氟甲基;
n为0或1;
A环为
且当A环为时,n为0;
R3代表C1-C5的烷基、C3-C7的环烷基;
R4,R5分别代表氢、C1-C3的烷基、C3-C5的环烷基、乙酰基、卤素、三氟甲基、氰基或CONR7R8;
R6代表氢、卤素;
R7,R8分别代表氢、甲基;
X为CR6或N;
Y,Z分别为C或N。
2.根据权利要求1所述的2,4-二取代嘧啶衍生物,其特征在于,所述的C1-C3的烷基为甲基、乙基、正丙基或异丙基;所述的C1-C5的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、1-戊基、2-戊基、3-戊基、2-甲基-3-丁基、1,1-二甲基-1-丙基、2,2-二甲基-1-丙基。
3.根据权利要求1所述的2,4-二取代嘧啶衍生物,其特征在于,所述的C3-C7环烷基为环丙基、环丁基、环戊基、环己基、环庚基;所述的C3-C5环烷基为环丙基、环丁基、环戊基;所述卤素指F、Cl、Br、I。
4.根据权利要求1所述的2,4-二取代嘧啶衍生物,其特征在于,一种选自下组的化合物:
或其可药用的盐。
5.权利要求1-4中任一项所述的2,4-二取代嘧啶衍生物及其可药用的盐作为CDK4/6抑制剂,并用于预防或治疗与CDK4/6相关的疾病。
6.权利要求5中所述的疾病治疗用途,主要是指与CDK4/6相关的癌症。
7.一种药物组合物,其特征在于,包含治疗有效量的权利要求1-4任一项所述的2,4-二取代嘧啶衍生物和药学上可接受的载体或赋形剂。
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WO2024051702A1 (zh) * | 2022-09-05 | 2024-03-14 | 浙江同源康医药股份有限公司 | 用作cdk4激酶抑制剂的化合物及其应用 |
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WO2022257568A1 (zh) * | 2021-06-10 | 2022-12-15 | 中国药科大学 | 氮杂吲哚嘧啶胺杂环化合物及其制备方法和应用 |
CN115703760A (zh) * | 2021-08-11 | 2023-02-17 | 山东大学 | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 |
CN115703760B (zh) * | 2021-08-11 | 2024-05-31 | 山东大学 | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 |
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US20190071427A1 (en) | 2019-03-07 |
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JP6661048B2 (ja) | 2020-03-11 |
EP3444246A4 (en) | 2019-04-03 |
US10464927B2 (en) | 2019-11-05 |
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