CN117164592A - 吡咯并氨基嘧啶类化合物,其制备方法及制药用途 - Google Patents
吡咯并氨基嘧啶类化合物,其制备方法及制药用途 Download PDFInfo
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- CN117164592A CN117164592A CN202210581667.XA CN202210581667A CN117164592A CN 117164592 A CN117164592 A CN 117164592A CN 202210581667 A CN202210581667 A CN 202210581667A CN 117164592 A CN117164592 A CN 117164592A
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- pyrrolo
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明属于药物化学领域,公开了一类吡咯并氨基嘧啶类化合物,其制备方法及制药用途,具体涉及一类含吡咯并氨基嘧啶类结构的化合物或其药学上可接受盐,其制备方法,含有该类化合物的药物组合物以及该类化合物的医药用途。本发明化合物具有特异性抑制BTK的作用,能够用于制备治疗B细胞恶性肿瘤、自身免疫性疾病等与BTK功能相关的疾病的药物。
Description
技术领域
本发明涉及药物领域,具体涉及一类含吡咯并氨基嘧啶类结构的化合物或其药学上可接受的盐,其制备方法,含有该类化合物的药物组合物以及该类化合物在制备治疗与布鲁顿式酪氨酸激酶(Bruton’s tyrosine kinase,BTK)功能相关的疾病的药物中的应用。
背景技术
酪氨酸蛋白激酶(tyrosine protein kinase,TPK)是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,能催化多种底物蛋白质酪氨酸残基磷酸化,在细胞信号转导通路中占据了十分重要的作用,调节细胞生长、分化、死亡等一系列生理生化过程。酪氨酸蛋白激酶功能失调将引发生物体内一系列疾病。
BTK是酪氨酸蛋白激酶Tec家族的主要成员之一。BTK是B细胞抗原受体(B-cellreceptor,BCR)信号转导通路中的关键激酶,在BCR信号通路中,磷酸化的PI3K(phosphatidylinositol 3-kinase)将膜上的PIP2转化为第二信使PIP3。PIP3结合到BTK的PH结构域,BTK随后会被募集到细胞膜,随后Tyr-551残基被SYK和LYN激酶磷酸化。BTK接着在Tyr-223残基进行自磷酸化反应从而具备生理活性。活化的BTK激活许多下游通路,如下游的蛋白激酶C,核因子kappa-B(NF-κB),MAPK通路等,对B细胞多个细胞过程,如生长、发育、分化、凋亡产生重要影响。
BTK在B细胞相关恶性肿瘤,如急性B淋巴细胞白血病,非霍奇金性淋巴瘤,在自身免疫性疾病,如类风湿关节炎、系统性红斑狼疮等疾病中扮演着重要的角色。这使得BTK成为B细胞恶性肿瘤和自身免疫性疾病的潜在靶点。现有BTK抑制剂选择性差,生物利用度低,导致临床用药量较大,毒副作用较大。因此,亟需发现活性高,成药性好的新型BTK抑制剂。
发明内容
本发明提供了一类含吡咯并氨基嘧啶类结构的化合物或其药学上可接受的盐,其制备方法,含有该类化合物的药物组合物以及该类化合物在制备治疗与BTK功能相关的疾病的药物中的应用。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供如通式(I)所示的化合物或其药学上可接受的盐:
其中,R1选自未取代或被一个或多个选自C1-8直链或支链烷基,C3-8环烷基,C1-8烷氧基,C1-8烷基氨基,卤素,羟基,氨基,氰基取代的芳环或芳杂环;所述芳环、芳杂环选自五元、六元环;所述芳杂环含有1-3个杂原子,所述杂原子选自N;且所述的C1-8直链或支链烷基进一步被一个或多个卤素,羟基,氨基或氰基取代;
R2选自或者-CH2CH2NHR3;且R3选自丙烯酰基,2-丁炔酰基;
n选自0,1,2。
进一步地,根据权利要求1的化合物或其药学上可接受的盐,其特征在于R1选自未取代或被甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,异戊基,环丙基,环丁基,环戊基,甲氧基,乙氧基,丙氧基,甲基氨基,乙基氨基,F,Cl,Br,I,羟基,氨基,氰基取代的芳环或芳杂环基,且所述的甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,异戊基任选被一个或多个卤素取代;所述芳环基选自苯基,萘基;所述芳杂环选自吡啶基,嘧啶基,吡嗪基,吡咯基,吡唑基,噻吩基、噻唑基。
进一步地,根据权利要求1的化合物或其药学上可接受的盐,其特征在于R1选自未取代或被甲基,乙基,三氟甲基,F,Cl,Br或I取代的苯基、萘基或吡啶基。
所述药学上可接受的盐选自有机酸盐或无机酸盐,包括但不限于盐酸盐,氢溴酸盐,硫酸盐,磷酸盐,醋酸盐,柠檬酸盐,苹果酸盐,富马酸盐,酒石酸盐或甲磺酸盐。
作为本发明的优选方案,通式(I)的化合物具有如下的结构:
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐的合成方法,其合成路线如下:
路线(1):
试剂与条件:(a)1-叔丁氧羰基-4-氨甲基哌啶,N,N-二异丙基乙胺,异丙醇,85℃;(b)R1-氧基氮杂环丁烷盐酸盐,1-丙基磷酸酐溶液,N,N-二异丙基乙胺,四氢呋喃溶液,室温;(c);三氟乙酸,二氯甲烷,室温;丙烯酰氯,N,N-二异丙基乙胺,二氯甲烷,室温;
路线(2):
试剂与条件:(a)3-苯氧基氮杂环丁烷盐酸盐,1-丙基磷酸酐溶液,N,N-二异丙基乙胺,四氢呋喃溶液,室温;(b)R2-(CH2)n-NH2,二异丙基乙胺,异丙醇,85℃;
其中R1、R2的定义同前所述。
本发明技术方案的另一方面是提供药物组合物,其特征在于,所述药物组合物中包含前述任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐在制备治疗与BTK功能相关的疾病的药物中的应用。
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐在制备治疗类风湿性关节炎,系统性红斑狼疮的药物中的应用。
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐在制备治疗非霍奇金性淋巴瘤,优选套细胞淋巴瘤、弥漫大B细胞淋巴瘤药物中的用途。
本发明技术方案的另一方面是提供如通式(I)所示的化合物或其药学上可接受的盐在制备治疗华式巨球蛋白血症,慢性淋巴细胞白血病或原发性中枢神经系统淋巴瘤药物中的用途。
有益技术效果
本发明技术方案中的实施例,对BTK有明显的抑制活性,优于上市药物依鲁替尼,该类化合物可抑制BCR相关信号通路,从而抑制B细胞淋巴瘤的生长,达到对B细胞淋巴瘤的治疗作用,
具体实施方式
实施例1
1-(4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮的制备
将4-氯-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.5g,2.53mmol),3-苯氧基氮杂环丁烷盐酸盐(0.564g,3.04mmol),N,N-二异丙基乙胺(0.981g,7.59mmol)溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.967g,3.04mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得520mg,收率63%,熔点182-183℃.
1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),8.65(s,1H),8.09(s,1H),7.34–7.24(m,2H),7.03–6.93(m,1H),6.91–6.79(m,2H),5.09(tt,J=6.5,4.1Hz,1H),4.54(ddd,J=10.2,6.6,1.3Hz,2H),4.15(s,1H),3.99(s,1H).
MS(ESI)m/z 329.08(M+H)+
(2)4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.52g,1.58mmol),1-叔丁氧羰基-4-氨甲基哌啶(0.406g,1.9mmol),N,N-二异丙基乙胺(0.613g,4.74mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得618mg,收率77%,熔点174-176℃.
1H NMR(500MHz,DMSO-d6)δ12.21(s,1H),9.48(t,J=5.7Hz,1H),8.10(s,1H),7.62(s,1H),7.30(t,J=7.8Hz,2H),6.97(t,J=7.4Hz,1H),6.85(d,J=8.1Hz,2H),5.09(s,1H),4.88(s,1H),4.52(s,2H),3.92(d,J=13.2Hz,3H),3.37(s,2H),2.66(s,2H),1.72(s,1H),1.67(d,J=13.7Hz,2H),1.35(s,9H),1.06(q,J=10.7Hz,2H).MS(ESI)m/z 507.27(M+H)+.
(3)标题化合物的制备
将4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丙烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体70mg,收率50.1%,熔点178-181℃。
1H NMR(500MHz,DMSO-d6)δ12.24(s,1H),9.53(s,1H),8.13(s,1H),7.66(s,1H),7.33(t,J=7.7Hz,2H),7.01(t,J=7.5Hz,1H),6.88(d,J=8.0Hz,2H),6.79(dd,J=16.7,10.5Hz,1H),6.13–6.00(m,1H),5.63(d,J=10.3Hz,1H),5.12(s,1H),4.97–4.87(m,1H),4.55(s,2H),4.43(d,J=13.1Hz,1H),4.06(d,J=14.2Hz,2H),3.41(d,J=15.8Hz,2H),3.03(t,J=13.2Hz,1H),2.63(t,J=12.8Hz,1H),1.93–1.71(m,3H),1.13(s,2H).
HRMS calcd.For C25H29N6O3(M+H)+461.22983,found 461.22957
实施例2
1-(4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丁-2-炔-1-酮
(1)标题化合物的制备
将4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丁炔酰氯(0.037g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体65mg,收率45.8%,熔点230-232℃。
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.49(t,J=5.8Hz,1H),8.09(s,1H),7.62(s,1H),7.29(t,J=7.8Hz,2H),6.96(t,J=7.3Hz,1H),6.84(d,J=8.1Hz,2H),5.08(dt,J=6.5,2.9Hz,1H),4.87(s,1H),4.51(s,2H),4.37–4.14(m,2H),3.98(q,J=7.1Hz,1H),3.37(q,J=6.9Hz,2H),3.05(td,J=12.8,2.6Hz,1H),2.60(td,J=12.8,3.0Hz,1H),1.95(d,J=7.3Hz,3H),1.79(ddd,J=39.7,22.3,10.9Hz,3H),1.23–1.10(m,1H),1.02(dq,J=20.2,7.9,6.1Hz,1H).
HRMS calcd.For C26H29N6O3(M+H)+473.23077,found 473.22957
实施例3
1-(3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-
基)丙-2-烯-1-酮
(1)3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯的制备
将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.5g,1.52mmol),3-氨基哌啶-1-羧酸叔丁酯(0.36g,1.8mmol),N,N-二异丙基乙胺(0.589g,4.56mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得450mg,收率60%,熔点128-130℃.
1H NMR(500MHz,DMSO-d6)δ12.25(s,1H),9.56(d,J=7.1Hz,1H),8.15(d,J=2.4Hz,1H),7.66(s,1H),7.33(t,J=7.4Hz,2H),7.00(t,J=7.2Hz,1H),6.88(d,J=8.2Hz,2H),5.12(s,1H),4.90(s,1H),4.53(d,J=10.5Hz,2H),4.04(d,J=34.7Hz,2H),3.55(d,J=84.2Hz,2H),3.19(s,1H),1.93(s,1H),1.78(s,1H),1.65(s,1H),1.49(s,1H),1.41–1.02(m,9H),0.86(t,J=6.3Hz,1H).
MS(ESI)m/z 493.16(M+H)+
(2)标题化合物的制备
将3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丙烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体68mg,收率50.8%,熔点228-230℃。
1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),9.38(s,1H),7.99(s,1H),7.48(s,1H),7.13(d,J=7.9Hz,2H),6.81(t,J=7.6Hz,1H),6.69(d,J=8.0Hz,2H),6.37(s,1H),5.79(d,J=17.4Hz,1H),5.37(d,J=68.1Hz,1H),4.93(s,1H),4.71(s,1H),4.35(s,2H),4.05–3.64(m,3H),3.47(d,J=30.8Hz,1H),3.23(d,J=45.2Hz,2H),1.82(s,1H),1.69–1.26(m,3H).
HRMS calcd.For C24H27N6O3(M+H)+447.21524,found 447.21392
实施例4
1-(3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-
基)丁-2-炔-1-酮
(1)标题化合物的制备
将3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丁烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体63mg,收率45.8%,熔点153-155℃。
1H NMR(500MHz,DMSO-d6)δ12.36(s,1H),9.76(s,1H),8.20(d,J=18.0Hz,1H),7.71(s,1H),7.33(t,J=7.8Hz,2H),7.01(t,J=7.5Hz,1H),6.88(d,J=8.0Hz,2H),5.13(s,1H),4.92(s,1H),4.56(s,2H),4.12(s,1H),4.07–3.75(m,3H),3.58(d,J=26.8Hz,1H),3.31(d,J=71.3Hz,1H),2.00(d,J=13.4Hz,3H),1.80(d,J=53.6Hz,1H),1.64(s,2H),1.53(s,1H).
HRMS calcd.For C25H27N6O3(M+H)+459.21402,found 459.21392
实施例5
1-(4-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-
基)丙-2-烯-1-酮
(1)4-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯的制备
将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.5g,1.52mmol),4-氨基哌啶-1-羧酸叔丁酯(0.36g,1.8mmol),N,N-二异丙基乙胺(0.589g,4.56mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得460mg,收率61%,熔点135-136℃.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.52(d,J=7.4Hz,1H),8.09(s,1H),7.62(d,J=2.2Hz,1H),7.31–7.23(m,2H),6.95(tt,J=7.4,1.1Hz,1H),6.87–6.78(m,2H),5.07(tt,J=6.7,3.8Hz,1H),4.86(s,1H),4.51(s,2H),4.25–4.07(m,1H),3.96(s,1H),3.73(d,J=13.3Hz,2H),3.04(s,2H),1.95–1.81(m,2H),1.36(s,9H),1.33–1.13(m,2H).
MS(ESI)m/z 493.23(M+H)+.
(2)标题化合物的制备
将4-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丙烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体58mg,收率43.3%,熔点148-150℃。
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),9.61(d,J=7.4Hz,1H),8.16(s,1H),7.68(d,J=2.3Hz,1H),7.33(dd,J=8.6,7.4Hz,2H),7.00(tt,J=7.3,1.1Hz,1H),6.92–6.86(m,2H),6.86–6.79(m,1H),6.10(dd,J=16.7,2.4Hz,1H),5.67(dd,J=10.5,2.5Hz,1H),5.11(dt,J=6.5,2.8Hz,1H),4.91(s,1H),4.56(s,2H),4.38–4.21(m,1H),4.18–3.83(m,3H),3.38(t,J=12.0Hz,1H),3.14(t,J=11.5Hz,1H),2.00(d,J=12.6Hz,2H),1.40(q,J=10.2Hz,2H).
HRMS calcd.For C24H27N6O3(M+H)+447.21570,found 447.21392
实施例6
1-(4-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-
基)丁-2-炔-1-酮
(1)标题化合物的制备
将4-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丁烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体60mg,收率43.6%,熔点243-245℃。
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),9.62(d,J=7.2Hz,1H),8.16(s,1H),7.68(s,1H),7.33(t,J=8.0Hz,2H),7.00(t,J=7.5Hz,1H),6.87(d,J=8.0Hz,2H),5.11(s,1H),4.91(s,1H),4.56(s,2H),4.31(s,1H),4.05(dd,J=28.2,13.0Hz,3H),3.48(t,J=11.6Hz,1H),3.17(d,J=12.0Hz,1H),2.03(s,5H),1.55–1.11(m,2H).HRMS calcd.ForC25H27N6O3(M+H)+459.21548,found 459.21392
实施例7
1-(3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷
-1-基)丙-2-烯-1-酮
(1)3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯的制备
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将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.5g,1.52mmol),3-氨基吡咯烷-1-羧酸叔丁酯(0.335g,1.8mmol),N,N-二异丙基乙胺(0.589g,4.56mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得500mg,收率68.8%,熔点76-78℃.
1H NMR(400MHz,DMSO-d6)δ9.70(t,J=6.7Hz,1H),8.18(s,1H),7.69(s,1H),7.33(t,J=7.8Hz,2H),7.00(t,J=7.4Hz,1H),6.88(d,J=8.0Hz,2H),5.11(d,J=7.2Hz,1H),4.92(s,1H),4.57(s,3H),4.09(d,J=61.2Hz,1H),3.61(d,J=10.5Hz,1H),3.41(s,2H),3.19(s,1H),2.21(s,1H),1.87(s,1H),1.39(d,J=5.1Hz,9H).MS(ESI)m/z 479.13(M+H)+.
(2)标题化合物的制备
将3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(150mg,0.31mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.159g,1.23mmol),在-10℃条件下逐滴加入丙烯酰氯(0.033g,0.37mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体60mg,收率44.8%,熔点138-140℃。
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),9.78(s,1H),8.20(s,1H),7.70(s,1H),7.42–7.25(m,2H),7.00(t,J=7.3Hz,1H),6.87(d,J=8.1Hz,2H),6.59(ddd,J=29.9,16.8,10.3Hz,1H),6.13(ddd,J=16.8,8.8,2.5Hz,1H),5.66(ddd,J=17.5,10.3,2.4Hz,1H),5.11(dt,J=6.5,2.9Hz,1H),4.91(s,1H),4.70(q,J=5.6Hz,1H),4.65–4.43(m,2H),4.09–3.87(m,1H),3.79–3.68(m,1H),3.56(t,J=7.1Hz,1H),3.51–3.36(m,2H),2.37–2.11(m,1H),2.05–1.80(m,1H).
HRMS calcd.For C23H25N6O3(M+H)+433.20181,found 433.19827
实施例8
1-(3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丁-2-炔-1-酮
(1)标题化合物的制备
将3-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(150mg,0.31mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.159g,1.23mmol),在-10℃条件下逐滴加入丁烯酰氯(0.033g,0.37mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体58mg,收率42.1%,熔点155-157℃。
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),9.69(t,J=7.1Hz,1H),8.15(d,J=7.2Hz,1H),7.65(t,J=2.4Hz,1H),7.33–7.18(m,2H),6.95(t,J=7.4Hz,1H),6.83(d,J=8.1Hz,2H),5.07(dt,J=6.6,2.9Hz,1H),4.86(s,1H),4.57(dt,J=11.3,5.8Hz,3H),4.04–3.86(m,1H),3.66(dt,J=13.9,6.7Hz,1H),3.44(t,J=7.2Hz,2H),2.23(dq,J=12.1,6.1Hz,1H),1.95(d,J=17.1Hz,4H).
HRMS calcd.For C24H25N6O3(M+H)+445.20261,found 445.19827
实施例9
N-(2-((5-(3-苯氧氮杂环丁烷--1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)乙基)
丙烯酰胺
(1)(2-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)乙基)氨基甲酸叔丁酯的制备
将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.5g,1.52mmol),(2-氨基乙基)氨基甲酸叔丁酯(0.288g,1.8mmol),N,N-二异丙基乙胺(0.589g,4.56mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得430mg,收率62.5%,熔点135-136℃.
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.45(t,J=5.9Hz,1H),8.15(s,1H),7.67(s,1H),7.34(dd,J=8.7,7.3Hz,2H),7.07–6.97(m,1H),6.92–6.82(m,2H),5.13(dt,J=6.5,2.7Hz,1H),4.91(s,1H),4.54(s,2H),4.09(d,J=60.9Hz,1H),3.56–3.46(m,2H),3.15(t,J=6.3Hz,2H),1.36(s,9H).
MS(ESI)m/z 453.12(M+H)+.
(2)标题化合物的制备
将(2-((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)乙基)氨基甲酸叔丁酯(150mg,0.33mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.17g,1.32mmol),在-10℃条件下逐滴加入丙烯酰氯(0.036g,0.4mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体56mg,收率41.8%,熔点139-140℃。
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),9.48(s,1H),8.27(s,1H),8.16(s,1H),7.67(d,J=2.6Hz,1H),7.33(t,J=7.8Hz,2H),7.01(t,J=7.3Hz,1H),6.88(d,J=8.0Hz,2H),6.21(dd,J=17.0,10.1Hz,1H),6.07(dd,J=17.2,2.3Hz,1H),5.57(dd,J=10.1,2.3Hz,1H),5.13(d,J=7.0Hz,1H),4.89(s,1H),4.54(s,2H),4.01(s,1H),3.66–3.52(m,2H),3.36(t,J=6.4Hz,2H).
HRMS calcd.For C21H23N6O3(M+H)+407.18204,found 407.18262
实施例10
1-(4-羟基-4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)4-羟基-4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将(4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)(3-苯氧氮杂环丁烷-1-基)甲酮(0.5g,1.52mmol),4-(氨基甲基)-4-羟基哌啶-1-羧酸叔丁酯(0.415g,1.8mmol),N,N-二异丙基乙胺(0.589g,4.56mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得530mg,收率66.8%,熔点118-120℃.
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.57(t,J=5.8Hz,1H),8.12(s,1H),7.67(s,1H),7.38–7.28(m,2H),7.00(t,J=7.4Hz,1H),6.88(d,J=8.1Hz,2H),5.12(s,1H),4.91(s,1H),4.81(s,1H),4.56(s,2H),4.08(d,J=61.3Hz,1H),3.65(d,J=13.0Hz,2H),3.54(d,J=5.7Hz,2H),3.08(s,2H),1.46(t,J=4.5Hz,4H),1.37(s,9H).
MS(ESI)m/z 523.27(M+H)+.
(2)标题化合物的制备
将4-羟基-4-(((5-(3-苯氧氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.29mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.15g,1.16mmol),在-10℃条件下逐滴加入丙烯酰氯(0.032g,0.35mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体50mg,收率36.2%,熔点140-141℃。
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.58(t,J=5.8Hz,1H),8.11(s,1H),7.67(d,J=2.3Hz,1H),7.33(dd,J=8.6,7.3Hz,2H),7.01(dd,J=7.9,6.8Hz,1H),6.91–6.86(m,2H),6.79(dd,J=16.7,10.5Hz,1H),6.06(dd,J=16.7,2.5Hz,1H),5.62(dd,J=10.4,2.5Hz,1H),5.20–5.09(m,1H),4.89(s,2H),4.55(s,2H),4.11(d,J=13.2Hz,1H),4.03(d,J=7.1Hz,1H),3.81(d,J=13.4Hz,1H),3.58–3.50(m,2H),3.38(d,J=12.4Hz,1H),3.11–2.91(m,1H),1.50(dd,J=24.8,11.0Hz,4H).HRMS calcd.For C25H29N6O4(M+H)+477.22543,found 477.22448
实施例11
1-(4-(((5-(3-(4-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸的制备
将4-氯-7H-吡咯并[2,3-d]嘧啶-5-羧酸(1g,5.06mmol),1-叔丁氧羰基-4-氨甲基哌啶(1.3g,6.07mmol),N,N-二异丙基乙胺(1.96g,15.18mmol)溶于异丙醇溶液中,85℃条件下反应5h。反应结束后加水淬灭,稀盐酸溶液调节pH至酸性,有白色固体析出,减压抽滤,干燥得白色固体1.2g,收率63.2%,熔点158-160℃.
1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),12.42(s,1H),9.00(s,1H),8.18(s,1H),7.86(s,1H),3.95(d,J=13.1Hz,2H),3.43(t,J=6.1Hz,2H),2.74–2.62(m,2H),1.79(dt,J=7.0,3.9Hz,1H),1.75–1.68(m,2H),1.38(s,9H),1.11(tt,J=12.4,6.0Hz,2H).
MS(ESI)m/z 376.11(M+H)+.
(2)3-(4-氟苯氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将4-氟苯酚(600mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.1g,收率76.9%。
1H NMR(400MHz,Chloroform-d)δ7.01–6.86(m,2H),6.74–6.58(m,2H),4.82(tt,J=6.4,4.2Hz,1H),4.27(ddt,J=8.8,6.4,1.1Hz,2H),3.98(ddd,J=9.6,4.1,1.1Hz,2H),1.45(s,9H).
MS(ESI)m/z 267.97(M+H)+.
(3)4-((((5-(3-(4-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(4-氟苯氧基)氮杂环丁烷-1-羧酸叔丁酯(0.171g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(4-氟苯氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得210mg,收率75.5%,熔点187-188℃.
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.51(t,J=5.7Hz,1H),8.13(s,1H),7.66(s,1H),7.16(dd,J=9.8,7.8Hz,2H),7.03–6.84(m,2H),5.09(dt,J=6.6,2.9Hz,1H),4.89(s,1H),4.54(s,2H),4.06–3.85(m,3H),3.40(s,2H),2.69(s,2H),1.79–1.74(m,1H),1.70(d,J=13.6Hz,2H),1.38(s,9H),1.11(dtt,J=23.4,12.3,5.7Hz,2H).
MS(ESI)m/z 525.26(M+H)+.
(4)标题化合物的制备
将4-((((5-(3-(4-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.29mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.15g,1.16mmol),在-10℃条件下逐滴加入丙烯酰氯(0.032g,0.35mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体55mg,收率40.4%,熔点184-186℃。
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.52(t,J=5.7Hz,1H),8.14(s,1H),7.66(s,1H),7.16(t,J=8.8Hz,2H),6.90(dd,J=9.1,4.2Hz,2H),6.79(dd,J=16.7,10.5Hz,1H),6.07(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.4,2.5Hz,1H),5.09(tt,J=6.7,3.8Hz,1H),4.89(s,1H),4.54(s,2H),4.43(d,J=13.2Hz,1H),4.12–3.95(m,2H),3.50–3.35(m,2H),3.02(t,J=12.8Hz,1H),2.62(t,J=12.6Hz,1H),1.91–1.84(m,1H),1.78(s,2H),1.13(q,J=13.7,10.4Hz,2H).
HRMS calcd.For C25H28FN6O3(M+H)+479.22079,found 479.22014
实施例12
1-(4-(((5-(3-(3-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(3-氟苯氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将3-氟苯酚(600mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.15g,收率80.4%。
1H NMR(400MHz,Chloroform-d)δ7.27–7.17(m,1H),6.69(tdd,J=8.3,2.4,0.8Hz,1H),6.54–6.49(m,1H),6.46(dt,J=10.5,2.4Hz,1H),4.85(tt,J=6.4,4.1Hz,1H),4.29(ddd,J=9.7,6.4,1.1Hz,2H),3.99(ddd,J=9.6,4.1,1.1Hz,2H),1.45(s,9H).
MS(ESI)m/z 267.97(M+H)+.
(2)4-((((5-(3-(3-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(4-氟苯氧基)氮杂环丁烷-1-羧酸叔丁酯(0.171g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(3-氟苯氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得215mg,收率77.3%,熔点194-196℃.
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),9.56(t,J=5.7Hz,1H),8.19(s,1H),7.72(s,1H),7.42(q,J=7.9Hz,1H),6.90(t,J=8.7Hz,1H),6.86–6.75(m,2H),5.21(s,1H),4.98(s,1H),4.62(s,2H),4.01(d,J=13.3Hz,3H),3.46(s,2H),2.75(s,2H),1.76(d,J=13.5Hz,3H),1.44(s,9H),1.21–1.07(m,2H).
MS(ESI)m/z 525.26(M+H)+.
(3)标题化合物的制备
将4-((((5-(3-(3-氟苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.29mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.15g,1.16mmol),在-10℃条件下逐滴加入丙烯酰氯(0.032g,0.35mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体62mg,收率44.7%,熔点170-171℃。
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.51(t,J=5.7Hz,1H),8.13(s,1H),7.66(s,1H),7.42–7.27(m,1H),6.91–6.61(m,4H),6.06(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.4,2.5Hz,1H),5.14(dt,J=6.5,2.9Hz,1H),4.92(s,1H),4.56(s,2H),4.43(d,J=13.0Hz,1H),4.04(t,J=12.9Hz,2H),3.40(s,2H),3.02(t,J=12.9Hz,1H),2.62(s,1H),1.92–1.82(m,1H),1.77(s,2H),1.20–1.01(m,2H).
HRMS calcd.For C25H28FN6O3(M+H)+479.21948,found 479.22014
实施例13
1-(4-(((5-(3-(间甲苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(间甲苯氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将间甲苯酚(580mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.1g,收率78%。
1H NMR(500MHz,Chloroform-d)δ7.10(dddd,J=13.5,10.6,6.4,3.0Hz,1H),6.74(q,J=6.6,5.9Hz,1H),6.57–6.36(m,2H),4.79(dtt,J=8.9,4.6,2.1Hz,1H),4.30–4.14(m,2H),3.93(p,J=6.2,5.7Hz,2H),2.44–2.16(m,3H),1.58–0.98(m,9H).MS(ESI)m/z264.00(M+H)+.
(2)4-((((5-(3-(间甲苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(间甲苯氧基)氮杂环丁烷-1-羧酸叔丁酯(0.168g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(间甲苯氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得220mg,收率79.7%,熔点94-96℃.
1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),9.52(t,J=5.7Hz,1H),8.13(s,1H),7.66(s,1H),7.20(t,J=7.8Hz,1H),6.82(d,J=7.6Hz,1H),6.74–6.61(m,2H),5.08(d,J=6.4Hz,1H),4.91(s,1H),4.54(s,2H),3.98(dd,J=24.1,10.3Hz,3H),3.40(s,2H),2.68(s,2H),2.29(s,3H),1.78-1.67(m,J=13.6Hz,3H),1.39(s,9H),1.15–1.05(m,2H).
MS(ESI)m/z 521.29(M+H)+.
(3)标题化合物的制备
将4-((((5-(3-(间甲苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.29mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.15g,1.16mmol),在-10℃条件下逐滴加入丙烯酰氯(0.032g,0.35mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体63mg,收率45.8%,熔点117-118℃。
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),9.48(t,J=5.7Hz,1H),8.08(s,1H),7.61(d,J=2.1Hz,1H),7.15(t,J=7.8Hz,1H),6.81–6.71(m,2H),6.68–6.58(m,2H),6.02(dd,J=16.7,2.5Hz,1H),5.58(dd,J=10.5,2.5Hz,1H),5.04(tt,J=6.7,3.8Hz,1H),4.86(s,1H),4.48(s,2H),4.38(d,J=13.2Hz,1H),4.00(dd,J=15.4,10.2Hz,2H),3.42–3.32(m,2H),2.98(t,J=12.8Hz,1H),2.57(t,J=12.5Hz,1H),2.24(s,3H),1.87–1.79(m,1H),1.75(d,J=13.2Hz,2H),1.14–0.98(m,2H).
HRMS calcd.For C26H31N6O3(M+H)+475.24646,found 475.24522
实施例14
1-(4-(((5-(3-(3-氯苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(3-氯苯氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将3-氯苯酚(689mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.3g,收率85.5%。
1H NMR(400MHz,Chloroform-d)δ7.18(t,J=8.2Hz,1H),6.95(ddd,J=8.0,2.0,0.9Hz,1H),6.71(t,J=2.2Hz,1H),6.61(ddd,J=8.4,2.5,1.0Hz,1H),4.83(ddd,J=6.4,4.2,2.3Hz,1H),4.27(ddd,J=9.7,6.4,1.2Hz,2H),4.01–3.76(m,2H),1.43(s,J=1.2Hz,9H).
MS(ESI)m/z 283.89(M+H)+.
(2)4-((((5-(3-(3-氯苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(3-氯苯氧基)氮杂环丁烷-1-羧酸叔丁酯(0.182g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(3-氯苯氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得223mg,收率76.7%,熔点129-131℃.
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),9.45(t,J=5.7Hz,1H),8.08(s,1H),7.62(s,1H),7.30(t,J=8.1Hz,1H),7.02(ddd,J=8.0,2.0,0.9Hz,1H),6.92(t,J=2.2Hz,1H),6.83(ddd,J=8.4,2.5,0.9Hz,1H),5.11(tt,J=6.4,3.6Hz,1H),4.90(d,J=24.3Hz,1H),4.51(s,2H),3.94(dd,J=31.2,10.2Hz,3H),3.35(s,2H),2.64(s,2H),1.67(t,J=13.4Hz,3H),1.33(s,9H),1.03(td,J=12.2,4.1Hz,2H).
MS(ESI)m/z 541.23(M+H)+.
(3)标题化合物的制备
将4-((((5-(3-(3-氯苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.28mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.145g,1.12mmol),在-10℃条件下逐滴加入丙烯酰氯(0.031g,0.34mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体61mg,收率44%,熔点120-121℃。
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),9.52(t,J=5.7Hz,1H),8.14(s,1H),7.67(s,1H),7.35(t,J=8.2Hz,1H),7.12–7.02(m,1H),6.97(t,J=2.2Hz,1H),6.88(dd,J=8.3,2.5Hz,1H),6.80(dd,J=16.7,10.5Hz,1H),6.07(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.4,2.5Hz,1H),5.16(s,1H),4.92(s,1H),4.55(s,2H),4.43(d,J=13.1Hz,1H),4.12–3.91(m,2H),3.48–3.37(m,2H),3.02(t,J=13.1Hz,1H),2.62(t,J=12.6Hz,1H),1.86(s,1H),1.78(s,2H),1.19–0.97(m,2H).
HRMS calcd.For C25H28ClN6O3(M+H)+495.18909,found 495.19059
实施例15
1-(4-(((5-(3-(3-(三氟甲基)苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(3-(三氟甲基)苯氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将3-(三氟甲基)苯酚(869mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.4g,收率82.4%。
1H NMR(400MHz,Chloroform-d)δ7.39(t,J=8.0Hz,1H),7.24(d,J=0.6Hz,1H),6.95(t,J=2.1Hz,1H),6.89(dd,J=8.4,2.6Hz,1H),4.89(tt,J=6.4,4.1Hz,1H),4.31(ddd,J=9.6,6.4,1.1Hz,2H),4.07–3.92(m,2H),1.44(s,9H).
MS(ESI)m/z 317.89(M+H)+.
(2)4-((((5-(3-(3-(三氟甲基)苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(3-(三氟甲基)苯氧基)氮杂环丁烷-1-羧酸叔丁酯(0.203g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(3-(三氟甲基)苯氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得240mg,收率78.8%,熔点192-194℃.
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),9.50(t,J=5.7Hz,1H),8.14(s,1H),7.68(s,1H),7.58(t,J=7.9Hz,1H),7.37(d,J=7.7Hz,1H),7.24–7.17(m,2H),5.25(dq,J=6.6,3.4Hz,1H),4.95(s,1H),4.59(s,2H),4.12–3.85(m,3H),3.40(s,2H),2.70(s,2H),1.73(t,J=13.8Hz,3H),1.39(s,9H),1.19–1.05(m,2H).
MS(ESI)m/z 575.26(M+H)+
(3)标题化合物的制备
将4-((((5-(3-(3-(三氟甲基)苯氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.26mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.134g,1.04mmol),在-10℃条件下逐滴加入丙烯酰氯(0.028g,0.31mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体53mg,收率38.7%,熔点108-110℃。
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.50–9.37(m,1H),8.09(s,1H),7.63(d,J=2.6Hz,1H),7.53(t,J=7.9Hz,1H),7.32(d,J=7.7Hz,1H),7.21–7.03(m,2H),6.75(dd,J=16.7,10.5Hz,1H),6.02(dd,J=16.7,2.5Hz,1H),5.59(dd,J=10.4,2.5Hz,1H),5.20(dt,J=6.3,2.9Hz,1H),4.89(s,1H),4.54(s,2H),4.38(d,J=13.2Hz,1H),4.08–3.91(m,2H),3.36(s,2H),2.98(t,J=12.9Hz,1H),2.57(t,J=12.7Hz,1H),1.82(d,J=3.6Hz,1H),1.73(s,2H),1.16–1.00(m,2H).
HRMS calcd.For C26H28F3N6O3(M+H)+529.21783,found 529.21695
实施例16
1-(4-((((5-(3-(萘-1-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(萘-1-基氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将萘-1-醇(773mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.2g,收率75%。
1H NMR(400MHz,Chloroform-d)δ8.28–8.19(m,1H),7.81–7.75(m,1H),7.54–7.42(m,3H),7.31(dd,J=8.3,7.6Hz,1H),6.44(dd,J=7.6,1.0Hz,1H),5.05(ttd,J=6.2,4.2,1.8Hz,1H),4.39(ddd,J=9.8,6.4,1.1Hz,2H),4.13(ddd,J=9.6,4.2,1.1Hz,2H),1.45(s,J=1.1Hz,9H).
MS(ESI)m/z 299.94(M+H)+
(2)4-((((5-(3-(3-(萘-1-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)
甲基)哌啶-1-羧酸叔丁酯的制备
将3-(萘-1-基氧基)氮杂环丁烷-1-羧酸叔丁酯(0.192g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(萘-1-基氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得230mg,收率78%,熔点82-84℃.
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),9.67–9.41(m,1H),8.25(dd,J=7.1,2.7Hz,1H),8.14(s,1H),7.90(dd,J=6.8,3.5Hz,1H),7.70(d,J=2.4Hz,1H),7.55(dd,J=7.5,3.1Hz,3H),7.47–7.40(m,1H),6.77(dd,J=8.0,3.2Hz,1H),5.35–5.25(m,1H),5.03(s,1H),4.69(s,2H),4.19(s,1H),3.95(d,J=12.9Hz,2H),3.41(s,2H),2.69(s,2H),1.73(t,J=13.3Hz,3H),1.38(d,J=2.7Hz,9H),1.17–0.98(m,2H).MS(ESI)m/z 557.22(M+H)+
(3)标题化合物的制备
将4-((((5-(3-(3-(萘-1-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.27mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.14g,1.08mmol),在-10℃条件下逐滴加入丙烯酰氯(0.029g,0.32mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体54mg,收率39.1%,熔点128-130℃。
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),9.48(d,J=7.3Hz,1H),8.18(d,J=7.7Hz,1H),8.08(s,1H),7.83(d,J=7.3Hz,1H),7.63(s,1H),7.47(d,J=7.9Hz,3H),7.35(t,J=8.1Hz,1H),6.72(dd,J=18.6,9.3Hz,2H),6.00(d,J=16.6Hz,1H),5.56(d,J=10.5Hz,1H),5.24(s,1H),4.95(s,1H),4.62(s,2H),4.36(d,J=12.8Hz,1H),4.20–3.88(m,2H),3.33(s,2H),2.95(s,1H),2.55(s,1H),1.79(s,1H),1.71(s,2H),1.14–0.95(m,2H).
HRMS calcd.For C29H31N6O3(M+H)+511.24661,found 511.24522
实施例17
1-(4-((((5-(3-(萘-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(4)3-(萘-2-基氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将萘-2-醇(773mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.2g,收率75%。
1H NMR(400MHz,Chloroform-d)δ7.76(d,J=9.2Hz,2H),7.68(d,J=8.2Hz,1H),7.49–7.40(m,1H),7.38–7.28(m,1H),7.10(ddd,J=9.0,2.7,1.2Hz,1H),6.82(d,J=2.5Hz,1H),5.00(ddd,J=6.7,4.7,2.3Hz,1H),4.37(ddt,J=11.0,6.6,1.1Hz,2H),4.16–3.97(m,2H),1.64–1.15(s,9H).
MS(ESI)m/z 299.81(M+H)+
(5)4-((((5-(3-(3-(萘-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将3-(萘-2-基氧基)氮杂环丁烷-1-羧酸叔丁酯(0.192g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(萘-2-基氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得232mg,收率78.6%,熔点82-84℃.
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.49(t,J=5.7Hz,1H),8.09(s,1H),7.87–7.73(m,3H),7.66–7.60(m,1H),7.44(ddd,J=8.1,6.8,1.3Hz,1H),7.33(ddd,J=8.1,6.8,1.2Hz,1H),7.19–7.07(m,2H),5.21(tt,J=6.8,3.8Hz,1H),4.96(s,1H),4.59(s,2H),4.04(s,1H),3.91(d,J=13.0Hz,2H),3.36(s,2H),2.65(s,2H),1.68(t,J=13.5Hz,3H),1.33(s,9H),1.11–0.98(m,2H).
MS(ESI)m/z 557.22(M+H)+
(6)标题化合物的制备
将4-((((5-(3-(3-(萘-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.27mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.14g,1.08mmol),在-10℃条件下逐滴加入丙烯酰氯(0.029g,0.32mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体58mg,收率42%,熔点121-122℃。
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),9.55(t,J=6.0Hz,1H),8.15(s,1H),7.96–7.80(m,3H),7.69(s,1H),7.49(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.25–7.04(m,2H),6.79(dd,J=16.7,10.4Hz,1H),6.07(d,J=16.6Hz,1H),5.63(d,J=10.5Hz,1H),5.25(s,1H),5.00(s,1H),4.64(s,2H),4.50–4.32(m,1H),4.06(d,J=14.4Hz,2H),3.41(s,2H),3.03(t,J=12.3Hz,1H),2.62(t,J=12.7Hz,1H),1.92–1.69(m,3H),1.25–0.93(m,2H).
HRMS calcd.For C29H31N6O3(M+H)+511.24719,found 511.24522
实施例18
1-(4-(((5-(3-(吡啶-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)3-(吡啶-2-基氧基)氮杂环丁烷-1-羧酸叔丁酯的制备
将吡啶-2-醇(509mg,5.36mmol),3-碘吖丁啶-1-羧酸叔丁酯(1.82g,6.43mmol)溶于N,N-二甲基酰胺溶液中,加入碳酸铯(5.24g,16.08mmol),140℃条件下反应3h。反应结束后,加水淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为石油醚:乙酸乙酯=10:1。得黄色油状化合物1.05g,收率78.4%。
1H NMR(400MHz,Chloroform-d)δ8.09(ddd,J=5.1,2.0,0.8Hz,1H),7.58(ddd,J=8.3,7.1,2.0Hz,1H),6.88(ddd,J=7.1,5.0,1.0Hz,1H),6.76(dd,J=8.3,1.0Hz,1H),5.31(tt,J=6.6,4.3Hz,1H),4.31(ddd,J=9.9,6.6,1.2Hz,2H),3.96(ddd,J=9.9,4.3,1.2Hz,2H),1.44(s,9H).
MS(ESI)m/z 251.01(M+H)+.
(2)4-((((5-(3-(吡啶-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)
甲基)哌啶-1-羧酸叔丁酯的制备
将3-(吡啶-2-基氧基)氮杂环丁烷-1-羧酸叔丁酯(0.16g,0.64mmol)溶于盐酸的乙醇溶液中,室温搅拌5h,反应结束后减压浓缩待用。将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(吡啶-2-基氧基)氮杂环丁烷盐酸盐溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得201mg,收率74.7%,熔点93-95℃.
1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),9.54(t,J=5.8Hz,1H),8.18(dd,J=5.2,1.9Hz,1H),8.13(s,1H),7.78(ddd,J=8.7,7.1,1.9Hz,1H),7.65(s,1H),7.05(dd,J=7.2,5.1Hz,1H),6.92(d,J=8.3Hz,1H),5.44(t,J=3.9Hz,1H),4.90(s,1H),4.52(s,2H),4.14–4.01(m,1H),3.95(d,J=12.8Hz,2H),3.40(s,2H),2.71(d,J=15.1Hz,2H),1.83–1.68(m,3H),1.39(s,9H),1.16–1.04(m,2H).
MS(ESI)m/z 508.27(M+H)+.
(3)标题化合物的制备
将4-((((5-(3-(吡啶-2-基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.3mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.155g,1.2mmol),在-10℃条件下逐滴加入丙烯酰氯(0.033g,0.36mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体67mg,收率48.6%,熔点128-129℃。
1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),9.55(s,1H),8.15(d,J=17.1Hz,2H),7.77(s,1H),7.65(s,1H),7.05(s,1H),7.00–6.89(m,1H),6.79(s,1H),6.07(d,J=16.6Hz,1H),5.63(d,J=10.4Hz,1H),5.43(s,1H),4.89(s,1H),4.64–4.41(m,3H),4.06(s,2H),3.55–3.37(m,2H),3.02(s,1H),2.62(s,1H),1.78(s,3H),1.17(d,J=44.1Hz,2H).
HRMS calcd.For C24H28N7O3(M+H)+462.22632,found 462.22481
实施例19
1-(4-(((5-(3-(苄氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(1)4-((((5-(3-(苄氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(苄氧基)氮杂环丁烷盐酸盐(0.128g,0.64mmol)溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得210mg,收率76.1%,熔点224-225℃.
(4)标题化合物的制备
将4-((((5-(3-(苄氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.29mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.15g,1.16mmol),在-10℃条件下逐滴加入丙烯酰氯(0.032g,0.35mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体50mg,收率36.3%,熔点87-89℃。
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.53(t,J=5.7Hz,1H),8.08(s,1H),7.55(s,1H),7.35–7.22(m,5H),6.73(dd,J=16.8,10.5Hz,1H),6.02(dd,J=16.7,2.5Hz,1H),5.58(dd,J=10.4,2.5Hz,1H),4.61(s,1H),4.48–4.29(m,5H),4.22(s,1H),4.00(d,J=13.7Hz,1H),3.84(s,1H),3.35(dt,J=11.6,6.4Hz,2H),2.96(t,J=12.8Hz,1H),2.56(t,J=12.5Hz,1H),1.87–1.77(m,1H),1.73(d,J=13.4Hz,2H),1.06(t,J=12.9Hz,2H).
HRMS calcd.For C26H31N6O3(M+H)+475.24628,found 475.24522
实施例20
1-(4-(((5-(3-(异丙基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-基)丙-2-烯-1-酮
(2)4-((((5-(3-(异丙基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的制备
将将4-((((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-羧酸(0.2g,0.53mmol)和3-(异丙基氧基)氮杂环丁烷盐酸盐(0.097g,0.64mmol)溶于四氢呋喃溶液中,冰浴5分钟后,逐滴加入1-丙基磷酸酐溶液(0.204g,0.64mmol),室温搅拌反应8h。反应结束后加水淬灭,乙酸乙酯萃取三次,饱和氯化钠溶液洗两次,无水硫酸钠干燥,浓缩得180mg,收率71.9%,熔点198-199℃.
(5)标题化合物的制备
将4-((((5-(3-(异丙基氧基)氮杂环丁烷-1-羰基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(150mg,0.32mmol)溶于2ml的二氯甲烷溶液中,加入1ml三氟乙酸溶液,室温搅拌1h。反应结束后浓缩,加入2ml二氯甲烷溶液和N,N-二异丙基乙胺(0.17g,1.28mmol),在-10℃条件下逐滴加入丙烯酰氯(0.034g,0.38mmol),室温搅拌3h。反应结束后,加水淬灭,二氯甲烷萃取混合物三次,饱和氯化钠溶液洗2次,无水硫酸钠干燥。浓缩,柱层析分离,洗脱剂为二氯甲烷:甲醇=20:1,得白色固体55mg,收率40.4%,熔点175-178℃。
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.59(t,J=5.7Hz,1H),8.12(s,1H),7.59(s,1H),6.79(dd,J=16.7,10.5Hz,1H),6.07(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.5,2.5Hz,1H),4.65(s,1H),4.44(tt,J=6.6,4.2Hz,2H),4.32(s,2H),4.06(d,J=13.6Hz,1H),3.82(s,1H),3.64(p,J=6.2Hz,1H),3.49–3.34(m,2H),3.02(t,J=12.8Hz,1H),2.62(t,J=12.5Hz,1H),1.96–1.65(m,3H),1.11(d,J=6.1Hz,8H).HRMS calcd.ForC22H31N6O3(M+H)+427.24432,found 427.24522
药理实验
实验例1、对BTK的抑制活性
实验目的:对本发明化合物进行体外BTK的抑制活性评价。
实验方法:实验使用来自Promega Corporation的ADP-GloTM检测试剂盒。共设置了11个浓度(10μM至1nM)。将50μL化合物添加到384孔稀释板中,并使用Echo将每行0.05μL稀释的化合物溶液转移到384测定板中,每列包含2个重复。将2.5μL酶工作液加入384孔检测板中,与化合物在25℃孵育15分钟。加入2.5μL底物工作液引发反应,60min后加入4μL ADPGlo试剂。60min后,加入8μL激酶检测试剂,25℃孵育60min。用envision Perkin Elmer读板器(Envision,PE,USA)读取发光信号。
实验结果:如表1所示,本发明化合物具有较高的BTK抑制活性,半数抑制浓度IC50大部分小于10nM。如表1-2所示,多个化合物的活性与阳性对照依鲁替尼相当。
表1-1本发明化合物对BTK蛋白的抑制活性范围
注:抑制活性分级:“A”表示IC50值小于10nM,“B”表示IC50值在10nM与100nM之间,“C”表示IC50值在100nM与1000nM之间,“D”表示IC50值大于1000nM。
表1-2本发明化合物对BTK蛋白的抑制活性数值
实验例2、对TMD-8细胞的的增殖抑制活性
实验目的:本实验通过检测化合物在TMD8细胞系中对体外细胞活性的影响而研究化合物抑制细胞增殖的作用。
实验方法:实验采用了96孔板的体外筛选体系,在每孔中加入95μL细胞悬液,在Min对照孔中加入不含细胞(含0.1%DMSO)的培养液。取5μL的20×化合物工作液加入到细胞培养板中。在Max对照中加入5μL DMSO细胞培养液混合液。DMSO终浓度为0.1%。将培养板在37℃,5%CO2培养箱中培养72小时。用CellTiter-Glo发光法进行细胞活性检测。SpectraMax Paradigm读数得出对应的每孔荧光值RLU。细胞增殖抑制率(InhibitionRate)数据采用下列公式来处理:Inhibition Rate(Inh%)=100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%。在EXCEL中计算不同浓度化合物对应的抑制率,然后用GraphPadPrism软件作抑制率曲线图并计算相关参数,参数包括细胞最大和最小抑制率,IC50值。
实验结果:如表2-1所示,本发明化合物具有较高的TMD-8增殖抑制活性。如表2-2所示,多个化合物的活性与阳性对照依鲁替尼相当。
表2-1本发明化合物对TMD-8增殖抑制活性范围
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注:抑制活性分级:“A”表示IC50值小于10nM,“B”表示IC50值在10nM与100nM之间,“C”表示IC50值在100nM与1000nM之间,“D”表示IC50值大于1000nM。
表2-2本发明化合物对TMD-8增殖抑制活性数值
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Claims (10)
1.如通式(I)所示的化合物或其药学上可接受的盐:
其中,R1选自未取代或被一个或多个选自C1-8直链或支链烷基,C3-8环烷基,C1-8烷氧基,C1-8烷基氨基,卤素,羟基,氨基,氰基取代的芳环或芳杂环;所述芳环、芳杂环选自五元、六元环;所述芳杂环含有1-3个杂原子,所述杂原子选自N;且所述的C1-8直链或支链烷基进一步被一个或多个卤素,羟基,氨基或氰基取代;
R2选自或者-CH2CH2NHR3;且R3选自丙烯酰基,2-丁炔酰基;
n选自0,1,2。
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,R1选自未取代或被甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,异戊基,环丙基,环丁基,环戊基,甲氧基,乙氧基,丙氧基,甲基氨基,乙基氨基,F,Cl,Br,I,羟基,氨基,氰基取代的芳环或芳杂环基,且所述的甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,异戊基任选被一个或多个卤素取代;所述芳环基选自苯基,萘基;所述芳杂环选自吡啶基,嘧啶基,吡嗪基,吡咯基,吡唑基,噻吩基,噻唑基。
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,R1选自未取代或被甲基,乙基,三氟甲基,F,Cl,Br或I取代的苯基、萘基或吡啶基。
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,所述的化合物结构为:
5.权利要求1-4任一项的化合物或其药学上可接受的盐的制备方法,其特征在于,步骤如下:
路线(1):
试剂与条件:(a)1-叔丁氧羰基-4-氨甲基哌啶,N,N-二异丙基乙胺,异丙醇,85℃;(b)R1-氧基氮杂环丁烷盐酸盐,1-丙基磷酸酐溶液,N,N-二异丙基乙胺,四氢呋喃溶液,室温;(c);三氟乙酸,二氯甲烷,室温;丙烯酰氯,N,N-二异丙基乙胺,二氯甲烷,室温;
路线(2):
试剂与条件:(a)3-苯氧基氮杂环丁烷盐酸盐,1-丙基磷酸酐溶液,N,N-二异丙基乙胺,四氢呋喃溶液,室温;(b)R2-(CH2)n-NH2,二异丙基乙胺,异丙醇,85℃;
其中R1、R2的定义同权利要求1-4任一项所述。
6.一种药物组合物,其特征在于,所述药物组合物中包含权利要求1-4中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
7.权利要求1-4中任一项所述的化合物或其药学上可接受的盐在制备治疗与BTK功能相关的疾病的药物中的应用。
8.权利要求1-4任一项所述的化合物或其药学上可接受的盐在制备治疗类风湿性关节炎、系统性红斑狼疮的药物中的应用。
9.权利要求1-4任一项所述的化合物或其药学上可接受的盐在制备治疗非霍奇金性淋巴瘤药物中的应用。
10.权利要求1-4任一项所述的化合物或其药学上可接受的盐在制备治疗华式巨球蛋白血症、慢性淋巴细胞白血病或原发性中枢神经系统淋巴瘤药物中的应用。
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