CN118184629A - 一种嘧啶喹喔啉cdk抑制剂及其制备方法和应用 - Google Patents
一种嘧啶喹喔啉cdk抑制剂及其制备方法和应用 Download PDFInfo
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- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 title claims abstract description 6
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title claims abstract description 6
- FEOZRVMIWAJUCM-UHFFFAOYSA-N pyrimidine quinoxaline Chemical compound N1=CN=CC=C1.N1=CC=NC2=CC=CC=C12 FEOZRVMIWAJUCM-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 108091007914 CDKs Proteins 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
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- 239000002253 acid Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种嘧啶喹喔啉CDK抑制剂及其制备方法和应用,所述化合物如式(S)所示。本发明的化合物能抑制癌症细胞的持续增殖,可用于制备治疗癌症或肿瘤相关疾病药物。
Description
技术领域
本发明涉及药物化学领域,特别涉及一种嘧啶喹喔啉CDK抑制剂及其制备方法和应用。
背景技术
细胞周期的进展对细胞增殖有巨大的影响,细胞周期蛋白依赖性激酶(Cyclin-dependent kinases,CDKs)在细胞周期的进程中发挥着重要的调控作用,在致癌因素的诱导下,CDKs会被上调,细胞周期的进程加快,癌症细胞进行持续增殖,导致癌症的发生。近年来,通过抑制CDKs的活性来治疗癌症被广泛关注,CDK2和CDK6在细胞周期的进程中都有着重要的调节作用。因此,抑制CDK2或CDK6是一个有效的癌症治疗策略。
发明内容
发明目的:本发明提供了一种嘧啶喹喔啉CDK抑制剂,对CDK2或CDK6产生抑制作用。本发明还提供了该化合物的制备方法和应用。
技术方案:本发明所述的如式(S)所示的化合物或其药学上可接受的盐:
其中,
R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
R2选自卤素;
R3选自氢、-C(O)C1-C3烷基或-S(O)2R6,其中,R6选自C1-C3烷基或C3-C5环烷基。
优选地:
所述R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自C1-C3烷基或环丙基。
优选地:
所述R1选自氢或NR4R5,其中,R4、R5选自甲基或乙基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自C1-C3烷基或环丙基。
优选地:
所述R1选自氢或NR4R5,其中,R4、R5选自甲基或乙基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自甲基、异丙基或环丙基。
在本发明的一些具体的实施例中,本发明还提供选自S-1至S-44所示的化合物或其药学上可接受的盐,选自以下化合物:
上述药学上可接受的盐为通式(S)化合物的酸加成盐,其中用于成盐的酸包括无机酸及有机酸,所述无机酸包括:盐酸、硫酸、磷酸和甲磺酸,有机酸包括乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
优选地,本发明中所述的药学上可接受的盐为盐酸盐。
本发明通式(S)化合物的制备方法,化合物A与化合物B在钯催化剂的作用下经偶联反应制备化合物S;
或化合物C与化合物D在碱的作用下反应制备化合物S;
R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
R2选自卤素;
R3选自氢、-C(O)C1-C3烷基或-S(O)2R6,其中,R6选自C1-C3烷基或C3-C5环烷基。
本发明还提供了如式(S)所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药,以及药学上可接受的载体的药物组合物。
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。
本发明还提供了一种式(S)化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药或本发明所述的组合物在制备药物中的用途。
本发明还提供了一种式(S)化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药或本发明所述的组合物在制备CDK2或CDK6抑制剂中的应用;所述CDK2或CDK6激酶抑制剂用于治疗癌症或肿瘤相关疾病。
本发明所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药或本发明所述的组合物在制备治疗癌症或肿瘤相关疾病药物中的应用。癌症或肿瘤是CDK2或CDK6相关的癌症或肿瘤。癌症或肿瘤相关疾病包括但不限于白血病、乳腺癌、前列腺癌、肺癌、多发性骨髓瘤、肝癌、胃癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌、食管癌、脂肪肉瘤子宫内膜癌等。
本发明所述的通式(S)化合物或其药学上可接受的盐,具有CDK2或CDK6靶点抑制活性,对细胞恶性增殖肿瘤具有治疗效果。
有益效果:本发明通式(S)所示的化合物,能抑制癌症细胞的恶性增殖,治疗效果好、毒性低,具有良好药物代谢特性、不易产生耐药性,可用于制备治疗癌症或肿瘤相关疾病药物。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。下面结合具体实施例对本申请作出详细说明。
一、中间反应物的合成
自主研发中间反应物(M)的具体制备方法如下:
(1)6-(2-氯-5-氟嘧啶-4-基)喹喔啉(M1)的合成
将6-溴喹喔啉(4.18 g,20 mmol),联硼酸频那醇酯(5.58 g,22 mmol),溶于1,4-二氧六环(100 mL),然后加入Pd(dppf)Cl2(731 mg,1 mmol),醋酸钾(5.88 g,60mmol),置换氩气三次,加热至100℃,反应12 h。反应完毕后,加水淬灭,用乙酸乙酯,减压蒸发浓缩得到化合物M1-1,无需纯化,直接用于后续的反应。将2,4-二氯-5-氟嘧啶(4.01 g,24 mmol)、Pd(PPh3)2Cl2(702 mg,1 mmol)、碳酸钠(5.30 g,50 mmol)、水(20 ml)和乙二醇二甲醚(20mL)加入三颈烧瓶中,置换氩气三次。将溶解在乙二醇二甲醚(80 mL)的化合物M1-1缓慢加入三颈烧瓶中,加热至80℃,反应12 h,快速硅胶柱纯化得到化合物M1(3.54 g,产率为68%)。1H NMR(400 MHz,Chloroform-d)δ8.97-8.95(m,3H),8.65(d,J=2.9 Hz,1H),8.60-8.57(m,1H),8.30-8.27(m,1H).
(2)7-溴-N,N-二甲基喹喔啉-2-胺(M2)的合成
化合物7-溴-2-氯喹喔啉(4.87g,20mmol)和二甲胺(1.13g,25mmol)溶于四氢呋喃(100mL),加热至50℃,反应18h。快速硅胶柱纯化得到化合物M2(4.13g,产率为82%)。MS(M+H)+:found,252.1.
(3)7-(2-氯-5-氟嘧啶-4-基)-N,N-二甲基喹喔啉-2-胺(M3)的合成
参照化合物M1的合成方法,产率为60%。1H NMR(400MHz,Chloroform-d)δ7.34-7.32(m,2H),7.24(s,1H),6.87-6.84(m,1H),6.75(d,J=8.7Hz,1H),2.07(s,3H).
(4)7-溴-N,N-二乙基喹喔啉-2-胺(M4)的合成
参照化合物M2的合成方法,产率为83%。MS(M+H)+:found,280.1.
(5)7-(2-氯-5-氟嘧啶-4-基)-N,N-二乙基喹喔啉-2-胺(M5)的合成
参照化合物M1的合成方法,产率为62%。1H NMR(400MHz,Chloroform-d)δ8.48(d,J=3.0Hz,1H),8.41(s,1H),8.36(s,1H),7.99-7.96(m,1H),7.88(d,J=8.6Hz,1H),3.63(q,J=7.1Hz,4H),1.23(t,J=7.1Hz,6H).
二、化合物S-1-S-11的合成
实施例1:5-氟-N-(1-(甲基磺酰基)哌啶-4-基)-4-(喹喔啉-6-基)嘧啶-2-胺(S-1)的合成
将化合物M1(521mg,2mmol)和1-Boc-4-氨基哌啶(445mg,2.5mmol)溶于二氧六环(6mL),然后加入Pd2(dba)3(92mg,0.1mmol),Xantphos(116mg,0.2mmol),碳酸铯(1.3g,4mmol),置换氩气三次,加热至105℃,反应12h。冷却过滤浓缩柱层析得到化合物S-1(386mg,48%收率),白色固体。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.68(s,1H),8.57(d,J=3.6Hz,1H),8.45(d,J=9.1Hz,1H),8.27(d,J=8.8Hz,1H),7.50(d,J=7.8Hz,1H),3.95-3.90(m,1H),3.58-3.53(m,2H),2.96-2.92(m,2H),2.89(s,3H),2.06-2.01(m,2H),1.65-1.56(m,2H).
实施例2:7-(5-氟-2-(哌啶-4-基氨基)嘧啶-4-基)-N,N-二甲基喹喔啉-2-胺(S-2)的合成
化合物S-2-1的合成参考实施例1的合成方法,产率为45%,白色固体,MS(M+H)+:found,468.6;
将化合物S-2-1(420mg,0.9mmol)溶于二氯甲烷(10mL),加入2N氯化氢-乙酸乙酯溶液(5mL),室温反应4h。调节反应液pH值至中性,柱层析得到化合物S-2(314mg,95%收率),白色固体。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.52(d,J=3.7Hz,1H),8.20(s,1H),7.96-7.93(m,2H),7.59(d,J=7.2Hz,1H),4.05-3.95(m,1H),3.31-3.27(m,2H),3.26(s,6H),3.03-2.97(m,2H),2.12-2.06(m,2H),1.76-1.68(m,2H).
实施例3:1-(4-((4-(3-(二甲基氨基)喹喔啉-6-基)-5-氟嘧啶-2-基)氨基)哌啶-1-基)乙烷-1-酮(S-3)的合成
参考实施例1的合成方法,产率为45%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.39(s,1H),8.28(d,J=3.6Hz,1H),8.02(d,J=8.7Hz,1H),7.96(d,J=8.7Hz,1H),5.07(d,J=7.7Hz,1H),4.54-4.50(m,1H),4.12-4.10(m,1H),3.86-3.82(m,1H),3.32(s,6H),3.29-3.25(m,1H),2.96-2.89(m,1H),2.23-2.20(m,1H),2.14(s,3H),2.12-2.10(m,1H),1.52-1.41(m,2H).
实施例4:7-(5-氟-2-((1-(甲基磺酰基)哌啶-4-基)氨基)嘧啶-4-基)-N,N-二甲基喹喔啉-2-胺(S-4)的合成
参考实施例1的合成方法,产率为44%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.32(d,J=2.5Hz,1H),8.16(d,J=4.1Hz,1H),8.10-8.07(m,1H),6.64(d,J=9.6Hz,1H),5.35-5.29(m,1H),5.02(d,J=7.6Hz,1H),3.98-3.90(m,1H),3.81-3.75(m,2H),2.98-2.91(m,2H),2.82(s,3H),2.22-2.18(m,2H),1.72-1.65(m,2H),1.42(d,J=6.8Hz,6H).
实施例5:7-(2-((1-(环丙基磺酰基)哌啶-4-基)氨基)-5-氟嘧啶-4-基)-N,N-二甲基喹喔啉-2-胺(S-5)的合成
将化合物S-2(147mg,0.4mmol),三乙胺(122mg,1.2mmol)溶于二氯甲烷(5mL),冰浴,滴加异丙基磺酰氯(172mg,1.2mmol),恢复至室温,搅拌2h,浓缩柱层析得到化合物S-5(160mg,85%收率),白色固体。1H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.27(d,J=3.6Hz,1H),8.05(d,J=8.7Hz,1H),7.98(d,J=8.7Hz,1H),5.46(s,1H),4.16-4.06(m,1H),3.81-3.75(m,2H),3.37(s,6H),3.20-3.14(m,2H),2.34-
2.30(m,1H),2.24-2.19(m,2H),1.73-1.64(m,2H),1.22-1.18(m,2H),1.04-1.00(m,2H).
实施例6:7-(5-氟-2-((1-(异丙基磺酰基)哌啶-4-基)氨基)嘧啶-4-基)-N,N-二甲基喹喔啉-2-胺(S-6)的合成
参考实施例5的合成方法,产率为88%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.39(s,1H),8.27(d,J=3.6Hz,1H),8.02(d,J=8.9Hz,1H),7.96(d,J=8.9Hz,1H),5.08(d,J=7.8Hz,1H),4.04(d,J=9.9Hz,1H),3.86-3.82(m,2H),3.32(s,6H),3.25-3.11(m,3H),2.20-2.16(m,2H),1.66-1.60(m,2H),1.37(d,J=6.8Hz,6H).
实施例7:N、N-二乙基-7-(5-氟-2-(哌啶-4-基氨基)嘧啶-4-基)喹喔啉-2-胺(S-7)的合成
化合物S-7-1的合成参考实施例1的合成方法,产率为43%,白色固体,MS(M+H)+:found,496.7。
将化合物S-7-1(446mg,0.9mmol)溶于二氯甲烷(10mL),加入2N氯化氢-乙酸乙酯溶液(5mL),室温反应4h。调节反应液pH值至中性,柱层析得到化合物S-7(335mg,94%收率),白色固体。1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.51(d,J=3.7Hz,1H),8.18(s,1H),7.97-7.91(m,2H),7.60(d,J=7.1Hz,1H),4.04-3.92(m,1H),3.71(q,J=7.0Hz,4H),3.29-3.24(m,2H),3.00-2.94(m,2H),2.10-2.05(m,2H),1.80-1.71(m,2H),1.22(t,J=7.0Hz,6H).
实施例8:1-(4-((4-(3-(二乙基氨基)喹喔啉-6-基)-5-氟嘧啶-2-基)氨基)哌啶-1-基)乙烷-1-酮(S-8)的合成
参考实施例1的合成方法,产率为43%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.34(s,1H),8.27(d,J=3.6Hz,1H),7.98(d,J=8.7Hz,1H),7.93(d,J=8.7Hz,1H),5.07(d,J=7.7Hz,1H),4.54-4.49(m,1H),4.13-4.10(m,1H),3.85-3.81(m,1H),3.71(q,J=7.1Hz,4H),3.32-3.25(m,1H),2.96-2.89(m,1H),2.23-2.19(m,1H),2.13(s,3H),2.12-2.10(m,1H),1.52-1.41(m,2H),1.30(t,J=7.1Hz,6H).
实施例9:N、N-二乙基-7-(5-氟-2-((1-(甲基磺酰基)哌啶-4-基)氨基)嘧啶-4-基)喹喔啉-2-胺(S-9)的合成
参考实施例1的合成方法,产率为46%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.34(s,1H),8.27(d,J=3.6Hz,1H),7.98(d,J=9.0Hz,1H),7.93(d,J=8.6Hz,1H),5.10(d,J=7.6Hz,1H),4.06-3.99(m,1H),3.80-3.76(m,2H),3.71(q,J=7.1Hz,4H),3.01-2.95(m,2H),2.83(s,3H),2.26-2.21(m,2H),1.74-1.67(m,2H),1.30(t,J=7.1Hz,6H).
实施例10:7-(2-((1-(环丙基磺酰基)哌啶-4-基)氨基)-5-氟嘧啶-4-基)-N,N-二乙基喹喔啉-2-胺(S-10)的合成
参考实施例5的合成方法,产率为82%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.35(d,J=1.7Hz,1H),8.18(d,J=4.1Hz,1H),8.06(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,1H),4.98(d,J=7.8Hz,1H),4.11-3.96(m,3H),3.62(q,J=7.1Hz,4H),3.03-2.96(m,2H),2.10-2.05(m,2H),1.48(s,9H),1.44-1.34(m,2H),1.32(t,J=7.1Hz,6H).
实施例11:N、N-二乙基-7-(5-氟-2-((1-(异丙基磺酰基)哌啶-4-基)氨基)嘧啶-4-基)喹喔啉-2-胺(S-11)的合成
参考实施例5的合成方法,产率为43%,白色固体。1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.34(s,1H),8.27(d,J=3.6Hz,1H),7.98(d,J=8.5Hz,1H),7.93(d,J=8.5Hz,1H),5.09(d,J=7.7Hz,1H),4.08-4.01(m,1H),3.86-3.83(m,2H),3.72(q,J=7.1Hz,4H),3.25-3.14(m,3H),2.20-2.16(m,2H),1.66-1.62(m,2H),1.37(d,J=6.8Hz,6H),1.31(t,J=7.1Hz,6H).
三、生物学评价实验
(1)CDK2激酶活性分析检测方法
a)用激酶反应缓冲液制备ATP/底物溶液和CDK2激酶溶液。
b)将化合物稀释液转移到384孔板中;离心并向384孔板中加入CDK2激酶溶液,继续离心1分钟,然后在25℃下孵育10分钟。
c)向384孔板中加入ATP/底物溶液,离心1分钟,然后在25℃下孵育60分钟。
d)向384孔板中加入ADP-Glo,离心1分钟,然后在25℃下孵育40分钟。
e)将反应溶液转移到另一个384孔板中,以1000rpm的速度离心1分钟,然后在25℃下孵育40分钟。
f)用多功能酶标仪读取发光信号,计算化合物对CDK2激酶的抑制率和IC50值。
(2)CDK6激酶活性分析检测方法
a)用激酶反应缓冲液制备ATP/底物溶液和CDK6激酶溶液。
b)将化合物稀释液转移到384孔板中;离心并向384孔板中加入CDK6激酶溶液,继续离心1分钟,然后在25℃下孵育10分钟。
c)向384孔板中加入ATP/底物溶液,离心1分钟,然后在25℃下孵育60分钟。
d)向384孔板中加入ADP-Glo,离心1分钟,然后在25℃下孵育40分钟。
e)将反应溶液转移到另一个384孔板中,以1000rpm的速度离心1分钟,然后在25℃下孵育40分钟。
f)用多功能酶标仪读取发光信号,计算化合物对CDK6激酶的抑制率和IC50值。
表1本发明化合物对CDK激酶抑制活性
实施例 | CDK2激酶抑制活性 | CDK6激酶抑制活性 |
1 | A | B |
2 | C | - |
3 | A | C |
4 | A | A |
5 | A | A |
6 | A | A |
7 | B | C |
8 | B | C |
9 | A | A |
10 | A | A |
11 | A | B |
A:IC50≤100nM;B:100nM<IC50≤200nM;C:200nM<IC50≤1000nM;“-”:未测试。
Claims (10)
1.一种如式(S)所示的化合物或其药学上可接受的盐,其特征在于:
其中,
R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
R2选自卤素;
R3选自氢、-C(O)C1-C3烷基或-S(O)2R6,其中,R6选自C1-C3烷基或C3-C5环烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:
所述R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自C1-C3烷基或环丙基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:
所述R1选自氢或NR4R5,其中,R4、R5选自甲基或乙基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自C1-C3烷基或环丙基。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:
所述R1选自氢或NR4R5,其中,R4、R5选自甲基或乙基;
所述R2选自F;
所述R3选自氢、-C(O)CH3或-S(O)2R6,其中,R6选自甲基、异丙基或环丙基。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:选自以下任一化合物:
6.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为通式(S)化合物的酸加成盐,其中用于成盐的酸包括无机酸及有机酸,所述无机酸包括盐酸、硫酸、磷酸和甲磺酸,有机酸包括乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
7.一种权利要求1所述的化合物的制备方法,其特征在于:
化合物A与化合物B在钯催化剂的作用下经偶联反应制备化合物S;
或化合物C与化合物D在碱的作用下反应制备化合物S;
R1选自氢或NR4R5,其中,R4、R5选自C1-C3烷基;
R2选自卤素;
R3选自氢、-C(O)C1-C3烷基或-S(O)2R6,其中,R6选自C1-C3烷基或C3-C5环烷基。
8.一种药用组合物,其特征在于:包含权利要求1-6中任一所述的化合物或其药学上可接受的盐或其异构体,以及药学上可接受的载体。
9.一种根据权利要求1-6中任一所述的化合物或其药学上可接受的盐在制备CDK抑制剂中的应用。
10.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗肿瘤药物中的应用,所述肿瘤是与CDK相关的肿瘤。
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