CN113354651B - 吡唑并[1,5-a]喹唑啉衍生物及其在药物制备中的用途 - Google Patents
吡唑并[1,5-a]喹唑啉衍生物及其在药物制备中的用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于有机合成药物技术领域,特别涉及一种吡唑并[1,5-a]喹唑啉衍生物及其制备方法和在药物制备中的用途。
背景技术
表观遗传学是生命科学领域研究中最热门的。基因表达的表观遗传学调控主要涉及DNA甲基化、组蛋白修饰、染色质重塑及非编码RNA调控等方面。其中,组蛋白乙酰化修饰最早被发现与基因转录调节有关,并且与很多疾病的发生密切相关,是目前研究的热点。参与去乙酰化的酶类,除了经典的I类和II类组蛋白去乙酰化酶HDAC(Histone deacetylase)外,还有III类HDAC即沉默信息调节蛋白2相关酶类(Sir2-related enzymes)。第III类组蛋白去乙酰化转移酶,通常被称为长寿蛋白(Sirtuins,SIRTs),是一类高度保守的蛋白,与啤酒酵母中的Sir2同源。人类Sirtuins家族中公认的成员有7个:SIRT1~SIRT7。Sirtuins蛋白家族具有不同的亚细胞定位,SIRT1、SIRT 6和SIRT 7主要位于细胞核内,SIRT3、SIRT4和SIRT5定位在线粒体中,它们在不同的亚细胞中进行大量的蛋白质的翻译后修饰,从而发挥不同的功能和作用。
SIRT6作为高度保守的NAD+依赖性脱乙酰酶家族的主要成员,参与调节许多生理过程,如原核生物和真核生物的细胞周期、代谢、应激反应和衰老过程,并且具有多种催化功能,包括去乙酰化(Deacetylation)、单ADP-核糖基化(Mono adenosine diphosphateribosylation)以及去脂肪酰化(De-fatty-acylation)等。SIRT6与多种疾病,如心血管疾病、慢性阻塞性肺病、糖尿病、骨骼相关疾病、视网膜病变、肝病等的发生及演进密切相关。因其在肿瘤发生发展过程中扮演重要角色,尤其是对于癌细胞代谢的关键调节作用,靶向治疗理念逐步加强和药物开发的发展加快的今天,SIRT6作为新的目标引发了新的调节剂的开发热潮。
染色质重塑蛋白在人类癌症中经常失调,但对它们如何控制肿瘤发生知之甚少。比如发表在Cell上的文章里面(Cell 2016,165,1401-1415.),作者揭示了由NAD+依赖的组蛋白去乙酰化酶SIRT6介导的表观遗传程序,该程序对于抑制最致命的恶性肿瘤之一的胰腺导管腺癌(PDAC)至关重要。SIRT6失活后通过上调let-7 microRNA的负调节因子Lin28b来加速PDAC进展和转移。SIRT6缺失导致Lin28b启动子的组蛋白高度乙酰化,Myc募集,以及Lin28b和下游let-7靶基因HMGA2,IGF2BP1和IGF2BP3的显著诱导。该表观程序定义了预后不良的不同子集,占人PDAC的30%-40%,其特征在于SIRT6表达降低和对肿瘤生长的Lin28b的精确依赖性。因此,将SIRT6鉴定为重要的PDAC肿瘤抑制因子,并将Lin28b途径揭示为分子定义的PDAC子集中的潜在治疗靶点。
因此,开发高活性和选择性的SIRT6激动剂是非常必要的。
发明内容
本发明的目的是提供一种吡唑并[1,5-a]喹唑啉衍生物及其制备方法和在药物制备中的用途。
本发明提供了式I所示化合物、或其药学上可接受的盐、或其晶型、或其立体异构体、或其光学异构体:
其中,R1选自H、卤素、C1~6烷基、C1~6烷氧基、C2~6烯基或C2~6炔基;
X选自无、NH、CH2、O、S、CO、NHCO或CONH;
R2选自LaR2a;La为取代或未取代的0~4个亚甲基,所述亚甲基上的取代基选自C1~3烷基、C1~3烷氧基或卤素;
R2a选自被1个或多个取代基取代的NR2bR2c、C1~6烷基、饱和或不饱和3~8元杂环基、饱和或不饱和3~8元环烷基、稠环烷基、杂稠环基、螺环烷基、杂螺环基、桥环烷基或杂桥环基;R2b、R2c各自独立的选自C1~4烷基或C1~4烷氧基;所述取代基各自独立的选自H、卤素、羟基、卤代或未卤代的C1~6烷基、卤代或未卤代的C1~6烷氧基、羧基、饱和或不饱和3~6元杂环基、饱和或不饱和3~6元环烷基、LbR2d、OLcR2e、COOLdR2f、SO2LeR2g或SO2NHR2h,其中,Lb、Lc、Ld、Le各自独立的选自0~4个亚甲基,R2d、R2e、R2f、R2g、R2h各自独立的选自被R2i取代或未取代的以下基团:饱和或不饱和3~6元杂环基、饱和或不饱和3~6元环烷基、C1~6烷基、C1~6烷氧基或卤素,R2i选自卤素、C1~5烷氧基或C1~5烷基。
进一步地,所述R1选自H、卤素、C1~4烷基、C1~4烷氧基、C2~4烯基或C2~4炔基,优选为H、甲基或叔丁基。
进一步地,所述化合物的结构如式II-1、II-2或II-3所示:
其中,R3a、R3b、R3c各自独立的选自L1R3d,其中,L1为0~2个亚甲基,R3d选自被1个或多个取代基取代的饱和或不饱和3~6元杂环基、饱和或不饱和3~6元环烷基、稠环烷基、杂稠环基、螺环烷基或杂螺环基;所述取代基各自独立的选自H、卤素、C1~5烷基、C1~5烷氧基、羧基、OL2R3e、COO L3R3f或SO2L4R3g,其中,L2、L3、L4各自独立的选自0~3个亚甲基,R3e、R3f、R3g各自独立的选自苯环、C1~4烷基、C1~4烷氧基或卤素;
优选的,所述R3d选自被1~3个取代基取代的6元芳基、6元杂芳基、杂稠环基或杂螺环基,且所述杂稠环基或杂螺环基中,至少1个环为不饱和环;所述杂稠环基优选为 所述取代基各自独立的选自H、卤素、C1~4烷基、C1~4烷氧基、羧基、OL2R3e、COOR3f或SO2R3g,其中,L2为0~2个亚甲基,R3e为苯环,R3f为C1~4烷基,R3g为苯环。
进一步地,所述化合物的结构如式III-1、III-2或III-3所示:
其中,R4a、R4b、R4c各自独立的选自L3R4d,其中,L3为被C1~2烷基取代或未取代的0~3个亚甲基,R4d选自被1个或多个取代基取代的NR4eR4f、C1~3烷基、饱和或不饱和3~6元杂环基、饱和或不饱和3~6元环烷基、稠环烷基、杂稠环基、螺环烷基、杂螺环基、桥环烷基或杂桥环基;R4e、R4f各自独立的选自C1~4烷基;所述取代基各自独立的选自H、卤素、苯环、羟基、C1~5烷基、C1~5烷氧基、羧基、L4R4g、OL5R4h、COOL6R4i或SO2NHR4j,其中,L4、L5、L6各自独立的选自0~3个亚甲基,R4g、R4h、R4i各自独立的选自苯环、6元饱和杂环、C1~4烷基、C1~4烷氧基或卤素,R4j选自被0~3个R4k取代的6元杂芳环,所述R4k选自C1~4烷氧基或C1~4烷基;
优选的,所述R4d选自被1~3个取代基取代的NR4eR4f、C1~3烷基、5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基、稠环烷基、杂稠环基或杂桥环基;所述稠环烷基优选为 所述杂桥环基优选为R4e、R4f各自独立的选自C1~2烷基;所述取代基各自独立的选自H、卤素、苯环、羟基、C1~4烷基、C1~4烷氧基、羧基、L4R4g、OL5R4h、COOL6R4i或SO2NHR4j,其中,L4、L5、L6各自独立的选自0~2个亚甲基,R4g、R4h、R4i各自独立的选自苯环、6元饱和杂环、C1~4烷基、C1~4烷氧基或卤素,R4j选自被0~3个R4k取代的所述R4k选自C1~3烷氧基或C1~3烷基。
进一步地,所述化合物的结构如式IV-1、IV-2或IV-3所示:
其中,R5a、R5b、R5c各自独立的选自L7R5e,其中,L7为0~2个亚甲基,R5e选自被1个或多个取代基取代的饱和或不饱和3~6元杂环基、饱和或不饱和3~6元环烷基、稠环烷基、杂稠环基;所述取代基各自独立的选自H、卤素、卤代或未卤代的C1~5烷基、卤代或未卤代的C1~5烷氧基、羧基、芳基或杂芳基;
优选的,L7为1个亚甲基,R5e选自被1~3个取代基取代的5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基或萘基;所述取代基各自独立的选自H、卤素、卤代或未卤代的C1~4烷基、卤代或未卤代的C1~4烷氧基、苯基。
进一步地,所述化合物的结构选自以下结构之一:
本发明还提供了一种药物组合物,所述药物组合物是以上述的化合物、或其药学上可接受的盐、或其晶型、或其立体异构体、或其光学异构体为活性成分,加上药学上可接受的辅料制得的制剂。
本发明还提供了上述化合物、或其药学上可接受的盐、或其晶型、或其立体异构体、或其光学异构体在制备组蛋白去乙酰化酶调节剂中的用途;优选的,所述组蛋白去乙酰化酶优选为SIRT6;更优选的,所述组蛋白去乙酰化酶调节剂为SIRT6激动剂。
进一步地,所述SIRT6激动剂为预防和/或治疗SIRT6介导的相关疾病的药物。
进一步地,所述SIRT6介导的相关疾病选自炎症、衰老、心血管疾病、慢性阻塞性肺病、代谢性疾病、骨骼相关疾病、视网膜病变、白血病、肝病、癌症;优选的,所述肿瘤为胰腺癌或肝癌,所述代谢性疾病为糖尿病或肥胖症。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本文“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换,包括该分子中同位原子或异位原子上的1个、2个或多个取代。
本文碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,C1~6烷基指任何含1~6个碳原子的直链或支链烷基。类似的,C1~6烷氧基指任何含1~6个碳原子的直链或支链烷氧基。
本发明中,“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“杂环基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N)。例如,“3~8元杂环基”指环原子数为3~8的杂环基。
“环烷基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“3-8元环烷基”指环碳原子数为3~8的环烷基。
“稠环烷基”指多环的环烷基,且该多环的环烷基中有两个环共用两个相邻的碳原子。
“杂稠环基”指多环的杂环基,且该多环的杂环基中有两个环共用两个相邻的碳原子或杂原子。
“螺环烷基”指多环的环烷基,且该多环的环烷基中有两个环共用一个碳原子。
“杂螺环基”指多环的杂环基,且该多环的杂环基中有两个环共用一个碳原子或杂原子。
“桥环烷基”指多环的环烷基,且该多环的环烷基中有两个环共用两个不相邻的碳原子。
“杂桥环基”指多环的杂环基,且该多环的杂环基中有两个环共用两个不相邻的碳原子或杂原子。
卤素为氟、氯、溴或碘。
“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
“盐”是将化合物或其立体异构体,与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
本发明中化合物药学上可接受的盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
实验结果表明,本发明提供的吡唑并[1,5-a]喹唑啉衍生物对SIRT6的去肉豆蔻酰化具有优异的活性,对组蛋白去乙酰化酶SIRT6具有优异的激动活性,可以作为高活性和高选择性的SIRT6激动剂。而且,该化合物还能效抑制人胰腺癌细胞的增殖,在制备预防和/或治疗与SIRT6活性有关疾病(特别是胰腺癌)的药物中具有广阔的应用前景。
本发明吡唑并[1,5-a]喹唑啉衍生物的制备方法简单,条件温和,适合扩大化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明中间体化合物的合成路线图。
图2为本发明目标化合物的合成路线图。
图3为化合物21q的的去肉豆蔻酰化的作用的拟合曲线图。
图4为化合物21q的ITC实验的拟合曲线图。
图5为化合物21q和阳性对照化合物MDL-800抗人胰腺癌细胞增殖的结果。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
根据图1所示合成路线,合成本发明的中间体化合物,根据图2所示合成路线,合成本发明的目标化合物。
以下为中间体化合物的具体制备方法:
化合物5-氯吡唑并[1,5-a]喹唑啉(4)的制备
中间体化合物4
将市售的原料化合物2-溴苯甲酸甲酯(1,4.30g,20mmol)和1H-吡唑-5-胺(2,2.0g,24mmol)加入到250mL的双口圆底烧瓶中,再加入CuI(0.76g,4mmol)和Cs2CO3(13.0g,40mmol),最后加入100mL H2O溶解混合物。将得到的混合物在氮气下保护条件下,加热到100℃搅拌,用薄层色谱法(TLC)检测反应,直到反应完全。然后将混合物冷却至室温,并用乙酸乙酯萃取。合并有机相,饱和NaCl溶液洗涤三次,用无水Na2SO4干燥并在真空下浓缩。粗产物通过柱色谱法纯化,用石油醚:乙酸乙酯=3:1洗脱,得到中间体吡唑并[1,5-a]喹唑啉-5(4H)-酮(3)。然后,将中间体3(1.85g,10mmol)加入单口的100mL圆底烧瓶中,加入30mL的POCl3溶液,加热至107℃,搅拌过夜。TLC检测,反应完成后,真空旋出溶剂,0℃条件用水稀释,乙酸乙酯萃取,合并有机相,饱和NaCl溶液洗涤三次,用无水Na2SO4干燥并在真空下浓缩。粗产物通过柱色谱法纯化,用石油醚:乙酸乙酯=3:1洗脱,得到中间体5-氯吡唑并[1,5-a]喹唑啉(4),1.64g,产率81%。1H NMR(400MHz,DMSO-d6)δ8.40(d,J=8.4Hz,1H),8.30-8.17(m,2H),8.08(dd,J=8.5,7.2Hz,1H),7.70(dd,J=8.3,7.1Hz,1H),6.87(d,J=2.1Hz,1H).HRMS m/z(ESI)calcd for C10H7N3Cl[M+H]+204.0323 found:204.0323,calcd forC10H6N3ClNa[M+Na]+226.0142 found:226.0143.
化合物2-甲基吡唑并[1,5-a]喹唑啉-5(4H)-酮(14)的制备
中间体化合物14
将化合物2-肼基苯甲酸盐酸盐(11,3.76g,20mmol)悬浮在40mL水中。然后,向悬浮液中加入化合物氰基丙酮(12,1.86g,22mmol)和4mL浓盐酸。混合物在常温条件下搅拌30分钟,接着将混合物加热回流2-3小时。反应结束后,悬浮液中有固体析出,过滤固体,用水洗涤3次,再用乙醚洗涤,干燥得固体化合物2-甲基吡唑并[1,5-a]喹唑啉-5(4H)-酮(14),产率70%。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.11(dd,J=7.9,1.4Hz,1H),8.00(d,J=8.2Hz,1H),7.84(ddd,J=8.4,7.3,1.5Hz,1H),7.44(td,J=7.7,1.1Hz,1H),5.75(s,1H),2.28(s,3H).HRMS m/z(ESI)calcd for C11H10N3O[M+H]+200.0818 found:200.0827,calcdfor C11H9N3ONa[M+Na]+222.0638 found:222.0640.
化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16)的制备
中间体化合物16
将中间体化合物2-甲基吡唑并[1,5-a]喹唑啉-5(4H)-酮(14,1.99g,10mmol)加入单口的100mL圆底烧瓶中,加入30mL的POCl3溶液,加热至107℃,搅拌过夜。TLC检测,反应完成后,真空旋出溶剂,0℃条件用水稀释,乙酸乙酯萃取,合并有机相,饱和NaCl溶液洗涤三次,用无水Na2SO4干燥并在真空下浓缩。粗产物通过柱色谱法纯化得到中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16),产率79%。1H NMR(400MHz,DMSO-d6)δ8.33(dd,J=8.4,1.1Hz,1H),8.21(dd,J=8.2,1.3Hz,1H),8.05(ddd,J=8.5,7.2,1.3Hz,1H),7.67(ddd,J=8.3,7.2,1.2Hz,1H),6.66(s,1H),2.47(s,3H).HRMS m/z(ESI)calcd for C11H9N3Cl[M+H]+218.0480 found:218.0518,calcd for C11H8N3ClNa[M+Na]+240.0299 found:240.0360.
化合物2-叔丁基基吡唑并[1,5-a]喹唑啉-5(4H)-酮(15)的制备
中间体化合物15
使用制备化合物14所述的方法制备化合物15。以化合物2-肼基苯甲酸盐酸盐(11,3.76g,20mmol)和氰基频哪酮(13,1.38g,22mmol)制备目标化合物,收率65%。1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.11(dd,J=7.9,1.1Hz,1H),8.02(d,J=7.9Hz,1H),7.88-7.80(m,1H),7.47-7.39(m,1H),5.80(s,1H),1.32(s,9H).13C NMR(101MHz,DMSO)δ164.38,158.94,139.22,137.97,135.41,128.62,125.12,116.29,114.58,85.71,32.80,30.50.HRMS m/z(ESI)calcd for C14H16N3O[M+H]+242.1288 found:242.1287,calcd forC14H15N3ONa[M+Na]+264.1107 found:264.1296.
化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17)的制备
中间体化合物17
使用制备化合物16所述的方法制备化合物17。1H NMR(400MHz,DMSO-d6)δ8.36(d,J=8.4Hz,1H),8.23(d,J=8.2Hz,1H),8.06(t,J=7.8Hz,1H),7.67(t,J=7.7Hz,1H),6.78(s,1H),1.41(s,9H).13C NMR(101MHz,DMSO)δ165.88,149.88,144.09,136.78,136.27,128.27,126.26,116.36,114.98,96.32,33.11,30.69.HRMS m/z(ESI)calcd for C14H15N3Cl[M+H]+260.0949 found:260.1000,calcd for C14H14N3ClNa[M+Na]+282.0768 found:282.0866.
以下为本发明目标化合物的具体制备实施例:
化合物5-(3,4-二甲氧基苯基)吡唑并[1,5-a]喹唑啉(6a)的制备
目标化合物6a
称量中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)、3,4-二甲氧基苯硼酸(5a,43.4mg,0.24mmol)、Pd(dppf)2Cl2(14.62mg,0.02mmol),Cs2CO3(195mg,0.6mmol)加入25mL双口圆底烧瓶中,然后加入6mL的无水1,4-二氧六环溶液。在氮气保护条件下,搅拌加热至100℃,反应12h。用薄层色谱法(TLC)监测反应过程,反应结束后用旋转蒸发仪浓缩反应液。最后,对浓缩液进行柱层析纯化,得到白色化合物5-(3,4-二甲氧基苯基)吡唑并[1,5-a]喹唑啉(6a),42.1mg,产率69%。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=8.4Hz,1H),8.21(d,J=2.2Hz,1H),8.08(dd,J=8.3,1.3Hz,1H),8.02(ddd,J=8.4,7.2,1.3Hz,1H),7.66-7.54(m,1H),7.35(d,J=2.0Hz,1H),7.30(dd,J=8.2,2.0Hz,1H),7.17(d,J=8.3Hz,1H),6.87(d,J=2.1Hz,1H),3.89(s,3H),3.85(s,3H).13C NMR(101MHz,DMSO)δ159.38,150.53,149.13,144.89,143.52,136.51,134.73,130.07,129.67,125.89,123.10,117.16,114.99,113.49,111.83,99.74,56.15.HRMS m/z(ESI)calcd forC18H16N3O2[M+H]+306.1237 found:306.1245,calcd for C18H15N3O2Na[M+Na]+328.1056found:328.1059.化合物5-(苯并呋喃-2-基)吡唑并[1,5-a]喹唑啉(6b)的制备
目标化合物6b
使用制备化合物6a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和苯并呋喃-2-硼酸(5b,32.4mg,0.2mmol)制备目标化合物,收率68%。1HNMR(400MHz,DMSO-d6)δ8.90(dd,J=8.4,1.2Hz,1H),8.55(dd,J=8.4,1.1Hz,1H),8.28(d,J=2.2Hz,1H),8.10(ddd,J=8.4,7.1,1.3Hz,1H),7.90(d,J=0.9Hz,1H),7.84(t,J=8.5Hz,2H),7.76(ddd,J=8.5,7.2,1.3Hz,1H),7.51(ddd,J=8.3,7.1,1.4Hz,1H),7.44-7.37(m,1H),6.99(d,J=2.2Hz,1H).13C NMR(101MHz,DMSO)δ155.41,153.24,147.31,144.48,143.90,136.48,135.01,128.48,128.00,126.91,126.37,124.25,122.80,115.91,115.13,112.25,111.33,100.47.HRMS m/z(ESI)calcd for C18H12N3O[M+H]+286.0975found:286.0979,calcd for C18H11N3ONa[M+Na]+308.0794 found:308.0802.
化合物5-(苯并[d][1,3]二恶唑-5-基)吡唑并[1,5-a]喹唑啉(6c)的制备
目标化合物6c
使用制备化合物6a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和3,4-亚甲基苯硼酸(5c,33.2mg,0.2mmol)制备目标化合物,收率72%。1H NMR(400MHz,DMSO-d6)δ8.49(dd,J=8.6,1.2Hz,1H),8.21(d,J=2.1Hz,1H),8.08-7.99(m,2H),7.67-7.58(m,1H),7.31(d,J=1.7Hz,1H),7.24(dd,J=8.0,1.7Hz,1H),7.13(d,J=8.0Hz,1H),6.86(d,J=2.1Hz,1H),6.16(s,2H).13C NMR(101MHz,DMSO)δ159.05,148.92,147.89,144.81,143.50,136.46,134.74,131.49,129.46,125.85,124.49,117.10,114.97,110.26,108.71,102.05,99.79.HRMS m/z(ESI)calcd for C17H12N3O2[M+H]+290.0924found:290.0923,calcd for C17H11N3O2Na[M+Na]+312.0743 found:312.0754.
化合物4-(吡唑并[1,5-a]喹唑啉-5-基)苯甲酸(6d)的制备
目标化合物6d
使用制备化合物6a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-羧基苯硼酸(5d,33.2mg,0.2mmol)制备目标化合物,收率61%。1HNMR(400MHz,DMSO-d6)δ13.17(s,1H),8.52(dd,J=8.5,1.1Hz,1H),8.26(d,J=2.2Hz,1H),8.17(d,J=8.3Hz,2H),8.06(ddd,J=8.5,7.2,1.4Hz,1H),7.95(dd,J=8.3,1.3Hz,1H),7.91-7.82(m,2H),7.63(ddd,J=8.4,7.2,1.3Hz,1H),6.94(d,J=2.2Hz,1H).13C NMR(101MHz,DMSO)δ167.44,158.81,144.77,143.66,141.60,136.46,135.05,132.22,130.29,129.85,129.22,126.09,116.93,115.09,100.28.HRMS m/z(ESI)calcd for C17H12N3O2[M+H]+290.0924 found:290.0922,calcd for C17H11N3O2Na[M+Na]+312.0743 found:312.0756.
化合物5-(吡啶-4-基)吡唑并[1,5-a]喹唑啉(6e)的制备
目标化合物6e
使用制备化合物6a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-羧基苯硼酸(5e,24.6mg,0.2mmol)制备目标化合物,收率59%。1HNMR(400MHz,DMSO-d6)δ8.83(d,J=4.9Hz,2H),8.53(d,J=8.4Hz,1H),8.28(s,1H),8.07(t,J=8.0Hz,1H),7.93(d,J=8.1Hz,1H),7.75(d,J=4.9Hz,2H),7.65(d,J=8.1Hz,1H),6.97(s,1H).HRMS m/z(ESI)calcd for C15H11N4[M+H]+247.0978 found:247.0980,calcdfor C15H10N4Na[M+Na]+269.0798 found:269.0808.
化合物5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]喹唑啉(6f)的制备
目标化合物6f
使用制备化合物6a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-羧基苯硼酸(5f,44.2mg,0.2mmol)制备目标化合物,收率46%。1HNMR(400MHz,DMSO-d6)δ8.52(d,J=2.4Hz,1H),8.50-8.44(m,1H),8.20(d,J=2.1Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),8.02(ddd,J=8.4,7.2,1.3Hz,1H),7.96(dd,J=8.9,2.5Hz,1H),7.67-7.57(m,1H),7.03(d,J=8.9Hz,1H),6.84(d,J=2.1Hz,1H),3.65(t,J=5.0Hz,4H),2.45(t,J=5.1Hz,4H),2.25(s,3H).13C NMR(101MHz,DMSO)δ159.44,157.36,149.27,145.06,143.46,139.25,136.50,134.69,129.26,125.90,122.35,117.05,115.02,106.57,99.53,54.79,46.20,44.77.HRMS m/z(ESI)calcd for C20H21N6[M+H]+345.1822 found:345.1822,calcd for C20H20N6Na[M+Na]+367.1642 found:367.1736.
化合物N-(2-甲氧基乙基)吡唑并[1,5-a]喹唑啉-5-胺(8a)的制备
目标化合物8a
将中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol),DIPEA(77.3mg,1.42mmol)和市售的2-甲氧基乙胺(7a,16.5mg,0.24mmol)溶解在DMF溶液中。然后将反应液加热至80℃并在该温度下搅拌2小时。冷却至环境温度后,混合物用水稀释,乙酸乙酯萃取,合并有机层,用饱和NaCl盐水洗涤,用无水Na2SO4干燥,真空浓缩。通过硅胶柱纯化残余物,得到目标化合物N-(2-甲氧基乙基)吡唑并[1,5-a]喹唑啉-5-胺(8a),产率46%。1H NMR(400MHz,DMSO-d6)δ8.32(d,J=8.2Hz,1H),8.23(d,J=8.3Hz,1H),8.00(t,J=5.4Hz,1H),7.92-7.70(m,2H),7.51(t,J=7.7Hz,1H),6.13(s,1H),3.68(d,J=5.7Hz,2H),3.61(d,J=5.9Hz,2H),3.30(s,3H).13C NMR(101MHz,DMSO)δ152.71,146.29,142.88,136.45,133.74,124.94,124.87,114.92,111.81,94.21,70.50,58.47.HRMS m/z(ESI)calcd for C13H15N4O[M+H]+243.1240 found:243.1242,calcd for C13H14N4ONa[M+Na]+265.1060 found:265.1066.
化合物N1,N1-二甲基-N3-(吡唑并[1,5-a]喹唑啉-5-基)丙烷-1,3-二胺(8b)的制备
目标化合物8b
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和N,N-二甲基-1,3-二氨基丙烷(7b,20.4mg,0.2mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.36(d,J=8.1Hz,1H),8.27-8.15(m,2H),7.91-7.75(m,2H),7.51(t,J=7.7Hz,1H),6.12(d,J=2.0Hz,1H),3.56(q,J=6.4Hz,2H),2.78(t,J=7.4Hz,2H),2.48(s,6H),1.96(p,J=7.0Hz,2H).13C NMR(101MHz,DMSO)δ152.76,146.36,142.87,136.43,133.71,125.05,124.88,114.87,111.90,94.15,56.35,44.10,25.37.HRMSm/z(ESI)calcd for C15H20N5[M+H]+270.1713 found:270.1719.化合物N-(3-(吡咯烷-1-基)丙基)吡唑并[1,5-a]喹唑啉-5-胺(8c)的制备
目标化合物8c
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和1-(3-氨基丙基)吡咯烷(7c,25.6mg,0.2mmol)制备目标化合物,收率38%。1H NMR(400MHz,CDCl3)δ8.36(d,J=8.1Hz,1H),8.31(d,J=8.3Hz,1H),7.95(s,1H),7.83(d,J=2.0Hz,1H),7.74(t,J=7.8Hz,1H),7.44(t,J=7.7Hz,1H),6.16(d,J=2.0Hz,1H),3.88(q,J=5.6Hz,3H),3.20(t,J=6.3Hz,3H),2.39-2.25(m,2H),2.16(s,4H),1.27(d,J=10.8Hz,2H).13C NMR(101MHz,CDCl3)δ152.66,145.92,142.53,136.63,133.11,124.81,124.52,114.91,111.68,94.27,53.67,52.73,37.34,24.47,23.20.HRMS m/z(ESI)calcd for C17H22N5[M+H]+296.1870 found:296.1872.
化合物N-(3-吗啉代丙基)吡唑并[1,5-a]喹唑啉-5-胺(8d)的制备
目标化合物8d
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和N-(3-氨丙基)吗啉(7d,28.8mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.28(d,J=8.0Hz,1H),8.22(d,J=8.2Hz,1H),7.94(t,J=5.1Hz,1H),7.85(t,J=7.8Hz,1H),7.80(d,J=1.9Hz,1H),7.51(t,J=7.7Hz,1H),6.09(d,J=2.0Hz,1H),3.68-3.42(m,6H),2.45-2.33(m,6H),1.84(p,J=7.0Hz,2H).13C NMR(101MHz,DMSO)δ152.70,146.44,142.87,136.41,133.64,124.83,114.91,111.88,94.09,66.64,56.68,53.82,25.63.HRMS m/z(ESI)calcd for C17H22N5O[M+H]+312.1819 found:312.1819,calcd for C17H21N5ONa[M+Na]+334.1638 found:334.1653.
化合物N-(2-(4-甲基哌嗪-1-基)乙基)吡唑并[1,5-a]喹唑啉-5-胺(8e)的制备
目标化合物8e
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和2-(4-甲基-哌嗪-1-基)乙胺(7e,28.6mg,0.2mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ8.27(d,J=8.1Hz,1H),8.22(d,J=8.2Hz,1H),7.93-7.74(m,3H),7.51(t,J=7.5Hz,1H),6.11(d,J=1.8Hz,1H),3.63(q,J=6.4Hz,2H),2.65(t,J=6.9Hz,2H),2.53-2.50(m,8H),2.25(s,3H).13C NMR(101MHz,DMSO)δ152.66,146.36,142.89,136.43,133.74,124.89,124.86,114.93,111.83,94.17,56.68,54.74,52.64,45.55,38.62.HRMS m/z(ESI)calcd for C17H23N6[M+H]+311.1979 found:311.1980,calcdfor C17H22N6Na[M+Na]+333.1798 found:333.1861.
化合物N-((1R,3r,5S)-9-甲基-9-氮杂双环[3.3.1]壬南-3-基)吡唑并[1,5-a]喹唑啉-5-胺(8f)的制备
目标化合物8f
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和内向-3-氨基-9-甲基-9-氮杂双环[3,3,1]壬烷(7f,30.8mg,0.2mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.38(dd,J=8.3,1.2Hz,1H),8.21(dd,J=8.4,1.1Hz,1H),7.84(ddd,J=8.4,7.2,1.2Hz,1H),7.80(d,J=2.0Hz,1H),7.54-7.46(m,2H),6.12(d,J=2.0Hz,1H),4.70(dtd,J=14.6,12.2,6.5Hz,1H),3.02(d,J=11.1Hz,2H),2.44(s,3H),2.33(td,J=12.1,6.3Hz,2H),2.10(tt,J=13.0,4.2Hz,1H),1.94(ddt,J=17.4,13.2,3.9Hz,2H),1.59-1.43(m,3H),1.00-0.88(m,2H).HRMS m/z(ESI)calcd for C19H24N5[M+H]+322.2026 found:322.2022,calcd for C19H23N5Na[M+Na]+344.1846 found:344.1991.
化合物N-((1R,3r,5S)-8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)吡唑并[1,5-a]喹唑啉-5-胺(8g)的制备
目标化合物8g
使用制备化合物8a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和(1R,3r,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-胺(7f,28.0mg,0.2mmol)制备目标化合物,收率43%。1H NMR(400MHz,DMSO-d6)δ8.28(d,J=8.2Hz,1H),8.22(d,J=8.2Hz,1H),7.86(t,J=7.8Hz,1H),7.82(d,J=2.0Hz,1H),7.53(t,J=7.7Hz,1H),7.17(d,J=4.2Hz,1H),6.14(d,J=2.0Hz,1H),4.19(dt,J=9.4,4.6Hz,1H),3.47-3.26(m,2H),3.05(br s,2H),2.17(s,3H),2.14-2.08(m,3H),1.99-1.88(m,7H).13C NMR(101MHz,DMSO)δ152.00,146.24,142.86,136.47,133.65,125.41,124.79,114.79,112.09,94.48,59.84,43.01,35.52,26.14.HRMS m/z(ESI)calcd for C18H22N5[M+H]+308.1870found:308.1873,calcd for C18H21N5Na[M+Na]+330.1689 found:330.1722.
化合物N-(呋喃-2-基甲基)吡唑并[1,5-a]喹唑啉-5-胺(8h)的制备
目标化合物8h
称量中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)、原料化合物2-呋喃甲胺(7h,23.3mg,0.24mmol)、Pd(OAc)2(4.5mg,0.02mmol),Xant-phos(16.6mg,0.02mmol),Cs2CO3(195mg,0.6mmol)加入25mL双口圆底烧瓶中,然后加入6mL的无水1,4-二氧六环溶液。在氮气保护条件下,搅拌加热至100℃,反应12h。用薄层色谱法(TLC)监测反应过程,反应结束后用旋转蒸发仪浓缩反应液。最后,对浓缩液进行柱层析纯化,得到白色化合物N-(呋喃-2-基甲基)吡唑并[1,5-a]喹唑啉-5-胺(8h),产率69%。1H NMR(400MHz,DMSO-d6)δ8.41(t,J=5.5Hz,1H),8.34(dd,J=8.3,1.2Hz,1H),8.24(dd,J=8.3,1.2Hz,1H),7.91-7.80(m,2H),7.62-7.57(m,1H),7.51(t,J=7.7Hz,1H),6.40(dd,J=3.3,1.8Hz,1H),6.34(d,J=3.1Hz,1H),6.15(d,J=2.0Hz,1H),4.73(d,J=5.5Hz,2H).13C NMR(101MHz,DMSO)δ152.89,152.41,146.07,142.94,142.38,136.48,133.90,124.97,114.93,111.74,110.97,107.57,94.47,37.82.HRMS m/z(ESI)calcd for C15H13N4O[M+H]+265.1084found:265.1090,calcd for C15H12N4ONa[M+Na]+287.0903 found:287.0881.化合物(R)-N-(1-苯乙基)吡唑并[1,5-a]喹唑啉-5-胺(8i)的制备
目标化合物8i
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和R(+)-alpha-甲基苄胺(7i,29.1mg,0.24mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ8.54(dd,J=8.2,1.2Hz,1H),8.22(dd,J=8.4,1.2Hz,1H),8.13(d,J=7.8Hz,1H),7.87(ddd,J=8.3,7.2,1.2Hz,1H),7.78(d,J=2.0Hz,1H),7.54(ddd,J=8.4,7.2,1.3Hz,1H),7.50-7.40(m,2H),7.37-7.27(m,2H),7.25-7.15(m,1H),6.05(d,J=2.0Hz,1H),5.54(p,J=7.1Hz,1H),1.59(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ151.88,146.13,145.42,142.87,136.48,133.81,128.66,126.98,126.59,125.21,124.84,114.87,111.74,94.31,49.68,22.86.HRMS m/z(ESI)calcd for C18H17N4[M+H]+289.1448 found:289.1449,calcd for C18H16N4Na[M+Na]+311.1267 found:311.1270.
化合物(S)-N-(1-苯乙基)吡唑并[1,5-a]喹唑啉-5-胺(8j)的制备
目标化合物8j
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和S(-)-alpha-甲基苄胺(7j,29.1mg,0.24mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ8.54(d,J=7.7Hz,1H),8.26-8.19(m,1H),8.13(d,J=7.8Hz,1H),7.93-7.84(m,1H),7.79(d,J=2.0Hz,1H),7.59-7.49(m,1H),7.46(d,J=7.3Hz,2H),7.31(t,J=7.6Hz,2H),7.20(t,J=7.3Hz,1H),6.05(d,J=2.0Hz,1H),5.54(p,J=7.1Hz,1H),1.59(d,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ151.87,146.13,145.42,142.87,136.48,133.81,128.66,126.97,126.59,125.21,124.84,114.87,111.74,94.31,49.68,22.86.HRMS m/z(ESI)calcd for C18H17N4[M+H]+289.1448 found:289.1451,calcdfor C18H16N4Na[M+Na]+311.1267 found:311.1276.
化合物(R)-N-(1-(4-甲氧基苯基)乙基)吡唑并[1,5-a]喹唑啉-5-胺(8k)的制备
目标化合物8k
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和(R)-(+)-1-(4-甲氧基苯)乙胺(7k,36.2mg,0.24mmol)制备目标化合物,收率56%。1H NMR(400MHz,DMSO-d6)δ8.51(dd,J=8.3,1.2Hz,1H),8.21(dd,J=8.4,1.2Hz,1H),8.08-8.03(m,1H),7.86(ddd,J=8.4,7.2,1.2Hz,1H),7.79(t,J=2.1Hz,1H),7.56-7.49(m,1H),7.41-7.35(m,2H),6.91-6.83(m,2H),6.06(d,J=2.0Hz,1H),5.49(p,J=7.1Hz,1H),3.71(s,3H),1.57(d,J=7.0Hz,3H).HRMS m/z(ESI)calcd for C19H19N4O[M+H]+319.1553 found:319.1553,calcd for C19H18N4ONa[M+Na]+341.1373 found:341.1376.
化合物(S)-N-(1-(4-甲氧基苯基)乙基)吡唑并[1,5-a]喹唑啉-5-胺(8l)的制备
目标化合物8l
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和(S)-(-)-1-(4-甲氧基苯)乙胺(7l,36.2mg,0.24mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.51(dd,J=8.4,1.2Hz,1H),8.21(dd,J=8.4,1.2Hz,1H),8.09-8.03(m,1H),7.86(ddd,J=8.3,7.2,1.2Hz,1H),7.79(d,J=2.0Hz,1H),7.52(ddt,J=9.8,7.3,2.0Hz,1H),7.42-7.36(m,2H),6.89-6.85(m,2H),6.06(d,J=2.0Hz,1H),5.49(p,J=7.2Hz,1H),3.71(s,3H),1.57(d,J=7.0Hz,3H).HRMS m/z(ESI)calcd for C19H19N4O[M+H]+319.1553 found:319.1554,calcd for C19H18N4ONa[M+Na]+341.1373 found:341.1375.
化合物N-(4-(吗啉代甲基)苯基)吡唑并[1,5-a]喹唑啉-5-胺(8m)的制备
目标化合物8m
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-吗啉甲基苯胺(7m,46.1mg,0.24mmol)制备目标化合物,收率60%。1HNMR(400MHz,DMSO-d6)δ9.49(s,1H),8.60(d,J=8.2Hz,1H),8.31(d,J=8.2Hz,1H),8.00-7.88(m,2H),7.83(d,J=8.4Hz,2H),7.61(t,J=7.7Hz,1H),7.32(d,J=8.3Hz,2H),6.25(d,J=2.0Hz,1H),3.59(t,J=4.6Hz,4H),3.46(s,2H),2.38(t,J=4.5Hz,4H).13C NMR(101MHz,DMSO)δ150.45,145.17,143.12,139.02,136.79,134.15,132.94,129.55,125.35,125.11,122.06,115.03,112.10,95.39,66.68,62.56,53.62.HRMS m/z(ESI)calcd forC21H22N5O[M+H]+360.1819 found:360.1822,calcd for C21H21N5ONa[M+Na]+382.1638found:382.1682.
化合物N-(4-苯氧基苯基)吡唑并[1,5-a]喹唑啉-5-胺(8n)的制备
目标化合物8n
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-氨基二苯醚(7n,44.4mg,0.24mmol)制备目标化合物,收率65%。1HNMR(400MHz,DMSO-d6)δ9.53(s,1H),8.63-8.56(m,1H),8.32(dd,J=8.3,1.1Hz,1H),7.97-7.85(m,4H),7.61(ddd,J=8.4,7.2,1.2Hz,1H),7.43-7.35(m,2H),7.16-7.00(m,5H),6.24(d,J=2.1Hz,1H).HRMS m/z(ESI)calcd for C22H17N4O[M+H]+353.1397 found:353.1399,calcd for C22H16N4ONa[M+Na]+375.1216 found:375.1226.
化合物N-二苯甲基吡唑并[1,5-a]喹唑啉-5-胺(8o)的制备
目标化合物8o
使用制备化合物8h所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和二苯甲胺(7o,44.4mg,0.24mmol)制备目标化合物,收率69%。1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.2Hz,1H),8.50(d,J=8.3Hz,1H),8.24(d,J=8.3Hz,1H),7.93-7.85(m,1H),7.82(d,J=2.0Hz,1H),7.59-7.49(dd,J=8.3,1.2Hz,1H),7.43(t,J=7.3Hz,4H),7.35(t,J=7.5Hz,4H),7.27(t,J=7.2Hz,2H),6.81(d,J=8.3Hz,1H),6.11(d,J=2.0Hz,1H).13C NMR(101MHz,DMSO)δ151.98,145.91,142.93,142.77,136.55,133.94,128.75,128.33,127.44,125.54,124.86,114.86,111.72,94.59,57.63.HRMS m/z(ESI)calcd for C23H19N4[M+H]+351.1604 found:351.1606,calcd for C23H18N4Na[M+Na]+373.1424 found:373.1425.
化合物5-(呋喃-2-基甲氧基)吡唑并[1,5-a]喹唑啉(10a)的制备
目标化合物10a
将中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol),DIPEA(77.3mg,1.42mmol)和市售的2-羟甲基呋喃(9a,23.5mg,0.24mmol)溶解在DMF溶液中。然后将反应液加热至80℃并在该温度下搅拌2小时。冷却至环境温度后,混合物用水稀释,乙酸乙酯萃取,合并有机层,用饱和NaCl盐水洗涤,用无水Na2SO4干燥,真空浓缩。通过硅胶柱纯化残余物,得到目标化合物5-(呋喃-2-基甲氧基)吡唑并[1,5-a]喹唑啉(10a),产率50%。1H NMR(400MHz,DMSO-d6)δ8.30(d,J=8.3Hz,1H),8.13(dd,J=8.1,1.3Hz,1H),8.04(d,J=2.1Hz,1H),7.98(ddd,J=8.5,7.3,1.4Hz,1H),7.94-7.89(m,1H),7.72(t,J=1.8Hz,1H),7.58(ddd,J=8.2,7.3,1.1Hz,1H),6.75-6.66(m,1H),6.54(d,J=2.1Hz,1H),5.47(s,2H).HRMS m/z(ESI)calcd for C15H12N3O2[M+H]+266.0924 found:266.0931,calcd forC15H11N3O2Na[M+Na]+288.0743 found:288.0779.
化合物5-(环己基甲氧基)吡唑并[1,5-a]喹唑啉(10b)的制备
目标化合物10b
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和环己基甲醇(9b,27.4mg,0.24mmol)制备目标化合物,收率49%。1H NMR(400MHz,CDCl3)δ8.37(d,J=8.3Hz,1H),8.16(d,J=8.0Hz,1H),7.95(d,J=2.0Hz,1H),7.83(t,J=7.8Hz,1H),7.46(t,J=7.6Hz,1H),6.43(d,J=1.8Hz,1H),4.35(d,J=6.2Hz,2H),1.96-1.91(m,1H),1.38-1.16(m,10H).13C NMR(101MHz,CDCl3)δ142.54,133.84,125.58,124.72,114.66,112.25,96.72,72.16,37.31,29.90,26.47,25.80.HRMS m/z(ESI)calcd for C17H20N3O[M+H]+282.1601 found:282.1601,calcd for C17H19N3ONa[M+Na]+304.1420 found:304.1416.
化合物5-(吡啶-2-基甲氧基)吡唑并[1,5-a]喹唑啉(10c)的制备
目标化合物10c
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和2-吡啶甲醇(9c,26.2mg,0.24mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ8.61(dt,J=4.7,1.5Hz,1H),8.33(d,J=8.2Hz,1H),8.25(dd,J=8.1,1.5Hz,1H),8.09-7.97(m,2H),7.87(td,J=7.7,1.8Hz,1H),7.70-7.54(m,2H),7.38(ddd,J=7.6,4.8,1.2Hz,1H),6.52(d,J=2.1Hz,1H),5.68(s,2H).13C NMR(101MHz,DMSO)δ157.77,156.23,149.66,144.00,143.23,137.51,137.35,135.23,125.94,125.84,123.53,122.07,114.73,111.56,97.35,69.07.HRMS m/z(ESI)calcd for C16H13N4O[M+H]+277.1084found:266.0931,calcd for C15H11N3O2Na[M+Na]+288.0743 found:288.0779.
化合物5-((3,5,6-三甲基吡嗪-2-基)甲氧基)吡唑并[1,5-a]喹唑啉(10d)的制备
目标化合物10d
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和(3,5,6-三甲基吡嗪-2-基)甲醇(9d,36.5mg,0.24mmol)制备目标化合物,收率39%。1H NMR(400MHz,DMSO-d6)δ8.40-8.26(m,1H),8.21-8.02(m,2H),7.98(t,J=7.8Hz,1H),7.56(t,J=7.7Hz,1H),6.54(d,J=2.3Hz,1H),5.64(s,2H),2.57(s,3H),2.47(s,3H),2.44(s,3H).HRMS m/z(ESI)calcd for C18H18N5O[M+H]+320.1506 found:320.1511,calcd for C18H17N5ONa[M+Na]+342.1325 found:342.1328.
化合物5-((3,4-二甲氧基苄基)氧基)吡唑并[1,5-a]喹唑啉(10e)的制备
目标化合物10e
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和3,4-二甲氧基苄醇(9e,40.3mg,0.24mmol)制备目标化合物,收率45%。1HNMR(400MHz,DMSO-d6)δ8.31(d,J=8.2Hz,1H),8.13(dd,J=8.2,1.3Hz,1H),8.04(d,J=2.1Hz,1H),7.98(ddd,J=8.4,7.2,1.4Hz,1H),7.62-7.53(m,1H),7.21(d,J=1.9Hz,1H),7.12(dd,J=8.1,1.9Hz,1H),6.99(d,J=8.2Hz,1H),6.53(d,J=2.1Hz,1H),5.51(s,2H),3.79(s,3H),3.77(s,3H).13C NMR(101MHz,DMSO)δ158.03,149.35,149.20,144.17,143.21,137.29,135.08,128.79,125.88,125.77,121.53,114.69,112.97,112.18,111.68,97.16,68.87,56.02.HRMS m/z(ESI)calcd for C19H18N3O3[M+H]+336.1343 found:336.1342,calcd for C19H17N3O3Na[M+Na]+358.1162 found:358.1166.
化合物5-((2-(三氟甲氧基)苄基)氧基)吡唑并[1,5-a]喹唑啉(10f)的制备
目标化合物10f
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和2-三氟甲氧基苯甲醇(9f,46.1mg,0.24mmol)制备目标化合物,收率52%。1H NMR(400MHz,DMSO-d6)δ8.32(d,J=8.2Hz,1H),8.13(dd,J=8.2,1.3Hz,1H),8.05(d,J=2.1Hz,1H),8.00(ddd,J=8.5,7.3,1.4Hz,1H),7.82(dd,J=7.7,1.8Hz,1H),7.63-7.53(m,2H),7.52-7.45(m,2H),6.56(d,J=2.1Hz,1H),5.67(s,2H).HRMS m/z(ESI)calcdfor C18H13F3N3O2[M+H]+360.0954 found:360.0960,calcd for C18H12F3N3O2Na[M+Na]+382.0774 found:382.0788.
化合物5-(萘-2-基甲氧基)吡唑并[1,5-a]喹唑啉(10g)的制备
目标化合物10g
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和2-萘甲醇(9g,37.9mg,0.24mmol)制备目标化合物,收率43%。1H NMR(400MHz,DMSO-d6)δ8.13(dd,J=8.0,1.2Hz,1H),8.01(d,J=2.0Hz,1H),7.89(ddd,J=8.3,7.5,1.8Hz,1H),7.82(dd,J=7.6,1.6Hz,1H),7.55-7.49(m,4H),7.52-7.45(m,4H),6.56(d,J=2.1Hz,1H),5.27(s,2H).HRMS m/z(ESI)calcd for C21H16N3O[M+H]+326.1288found:326.1111.
化合物5-([1,1'-联苯]-4-基甲氧基)吡唑并[1,5-a]喹唑啉(10h)的制备
目标化合物10h
使用制备化合物10a所述的方法,以中间体化合物5-氯吡唑并[1,5-a]喹唑啉(4,40.6mg,0.2mmol)和4-联苯甲醇(9h,44.2mg,0.24mmol)制备目标化合物,收率39%。1H NMR(400MHz,DMSO-d6)δ8.15(dd,J=8.1,1.2Hz,1H),8.01(d,J=2.0Hz,1H),7.89(ddd,J=8.4,7.5,1.4Hz,1H),7.83(dd,J=7.6,1.6Hz,1H),7.63-7.53(m,2H),7.48-7.39(m,4H),7.52-7.45(m,4H),6.54(d,J=2.3Hz,1H),5.23(s,2H).HRMS m/z(ESI)calcd for C23H18N3O[M+H]+352.1444 found:352.1466.
化合物5-(3,4-二甲氧基苯基)-2-甲基吡唑并[1,5-a]喹唑啉(19a)的制备
目标化合物19a
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和3,4-二甲氧基苯硼酸(18a,43.7mg,0.24mmol)制备目标化合物,收率65%。1H NMR(400MHz,DMSO-d6)δ8.40(dd,J=8.4,1.1Hz,1H),8.04(dd,J=8.3,1.2Hz,1H),7.97(ddd,J=8.4,7.2,1.3Hz,1H),7.55(ddd,J=8.3,7.1,1.2Hz,1H),7.32(d,J=2.0Hz,1H),7.28(dd,J=8.2,2.1Hz,1H),7.16(d,J=8.3Hz,1H),6.65(s,1H),3.88(s,3H),3.84(s,3H),2.49(s,3H).13C NMR(101MHz,DMSO)δ159.11,152.64,150.48,149.11,145.50,136.28,134.61,130.13,129.57,125.27,123.07,116.81,114.77,113.48,111.81,99.08,56.14,14.84.HRMS m/z(ESI)calcd for C19H18N3O2[M+H]+320.1394 found:320.1394,calcd for C19H17N3O2Na[M+Na]+342.1213 found:342.1223.
化合物5-(苯并[d][1,3]二恶唑-5-基)-2-甲基吡唑并[1,5-a]喹唑啉(19b)的制备
目标化合物19b
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和3,4-亚甲基苯硼酸(18b,39.8mg,0.24mmol)制备目标化合物,收率61%。1H NMR(400MHz,CDCl3)δ8.84(dd,J=8.4,1.3Hz,1H),8.57(dd,J=8.5,1.2Hz,1H),7.91(ddd,J=8.5,7.2,1.3Hz,1H),7.74(dt,J=7.6,1.0Hz,1H),7.69(dq,J=8.4,0.9Hz,1H),7.65(d,J=1.0Hz,1H),7.57(ddd,J=8.4,7.2,1.2Hz,1H),7.44(ddd,J=8.4,7.2,1.3Hz,1H),7.34(td,J=7.5,1.0Hz,1H),6.68(s,1H),2.61(s,3H).13C NMR(101MHz,CDCl3)δ155.68,153.53,153.29,147.73,145.38,136.56,133.94,128.24,127.92,126.17,124.90,123.65,122.07,116.03,115.03,111.93,110.72,99.75,14.62.HRMS m/z(ESI)calcd for C19H14N3O[M+H]+300.1131 found:300.1139,calcd for C19H13N3ONa[M+Na]+322.0951 found:322.0959.
化合物4-(2-甲基吡唑并[1,5-a]喹唑啉-5-基)苯甲酸(19d)的制备
目标化合物19d
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-羧基苯硼酸(18d,39.8mg,0.24mmol)制备目标化合物,收率55%。1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.43(dd,J=8.4,1.1Hz,1H),8.20-8.12(m,2H),8.01(ddd,J=8.4,7.2,1.3Hz,1H),7.91(dd,J=8.3,1.2Hz,1H),7.89-7.82(m,2H),7.56(ddd,J=8.3,7.1,1.2Hz,1H),6.72(s,1H),2.50(s,3H).13C NMR(101MHz,DMSO)δ167.40,158.51,152.85,145.38,141.70,136.22,134.98,132.05,130.29,129.84,129.13,125.51,116.57,114.88,99.61,14.84.HRMS m/z(ESI)calcd for C18H14N3O2[M+H]+304.1081 found:304.1087,calcd for C18H13N3O2Na[M+Na]+326.0900 found:326.0907.
化合物5-(4-(苄氧基)苯基)-2-甲基吡唑并[1,5-a]喹唑啉(19e)的制备
目标化合物19e
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-苄氧基苯硼酸(18e,54.7mg,0.24mmol)制备目标化合物,收率45%。1H NMR(400MHz,CDCl3)δ8.57-8.50(m,1H),7.93(dd,J=8.3,1.2Hz,1H),7.85(ddd,J=8.4,7.1,1.3Hz,1H),7.50-7.43(m,3H),7.43-7.35(m,4H),7.32(ddd,J=6.3,2.9,1.6Hz,2H),7.20-7.14(m,1H),6.63(s,1H),5.16(s,2H),2.60(s,3H).13C NMR(101MHz,CDCl3)δ159.52,158.82,152.98,145.58,138.91,136.75,136.55,133.80,129.71,129.15,128.64,128.05,127.51,124.35,122.29,116.92,116.43,115.86,114.83,99.36,70.18.HRMS m/z(ESI)calcd for C24H20N3O[M+H]+366.1601 found:366.1607,calcd forC24H19N3ONa[M+Na]+388.1420 found:388.1418.
化合物2-甲基-5-(吡啶-4-基)吡唑并[1,5-a]喹唑啉(19f)的制备
目标化合物19f
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和吡啶-4-硼酸(18f,29.5mg,0.24mmol)制备目标化合物,收率54%。1H NMR(400MHz,CDCl3)δ8.93-8.81(m,2H),8.54(dd,J=8.4,1.1Hz,1H),7.90(ddd,J=11.6,7.7,2.2Hz,2H),7.74-7.63(m,2H),7.46(ddd,J=8.3,7.1,1.2Hz,1H),6.66(s,1H),2.60(s,3H).13C NMR(101MHz,CDCl3)δ156.53,153.40,149.74,145.76,145.42,136.62,134.24,128.04,124.68,124.16,116.18,116.18,115.18,99.96,14.66.HRMS m/z(ESI)calcd for C16H13N4[M+H]+261.1135 found:261.1137,calcd for C16H12N4Na[M+Na]+283.0954 found:283.0955.
化合物5-(2-甲氧基吡啶-4-基)-2-甲基吡唑并[1,5-a]喹唑啉(19g)的制备
目标化合物19g
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-甲氧基吡啶-4-硼酸(18g,36.7mg,0.24mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.41(dd,J=14.2,6.8Hz,2H),8.02(ddd,J=8.4,7.1,1.3Hz,1H),7.89(d,J=8.2Hz,1H),7.57(t,J=7.9Hz,1H),7.30(dd,J=5.2,1.4Hz,1H),7.12(s,1H),6.74(s,1H),3.96(s,3H),2.50(s,3H).13C NMR(101MHz,DMSO)δ164.21,157.09,152.92,148.13,147.78,145.20,136.14,135.17,128.86,125.62,118.00,116.33,114.85,111.34,99.82,53.95,14.83.HRMS m/z(ESI)calcd for C17H15N4O[M+H]+291.1240found:291.1240,calcd for C17H14N4ONa[M+Na]+313.1060 found:313.1071.
化合物5-(4-氯-3-甲氧基苯基)-2-甲基吡唑并[1,5-a]喹唑啉(19h)的制备
目标化合物19h
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-氯-3-甲基苯硼酸(18h,40.8mg,0.24mmol)制备目标化合物,收率47%。1H NMR(400MHz,CDCl3)δ8.50(dd,J=8.4,1.1Hz,1H),7.95(dd,J=8.2,1.2Hz,1H),7.87(ddd,J=8.4,7.0,1.4Hz,1H),7.54(d,J=8.0Hz,1H),7.43(ddd,J=8.3,7.2,1.2Hz,1H),7.31(d,J=1.9Hz,1H),7.22(dd,J=8.0,1.9Hz,1H),6.63(s,1H),3.97(s,3H),2.59(s,3H).HRMS m/z(ESI)calcd for C18H15ClN3O[M+H]+324.0898 found:324.0885,calcd for C18H14ClN3ONa[M+Na]+346.0718 found:346.0725.
化合物5-(2-氟-6-甲氧基苯基)-2-甲基吡唑并[1,5-a]喹唑啉(19i)的制备
目标化合物19i
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-氟-6-甲氧基苯硼酸(18i,40.8mg,0.24mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ8.41(d,J=8.4Hz,1H),7.99(tt,J=6.8,1.7Hz,1H),7.66-7.58(m,1H),7.56-7.47(m,2H),7.12(d,J=8.4Hz,1H),7.05(t,J=8.7Hz,1H),6.72(s,1H),3.71(s,3H),2.51(s,3H).HRMS m/z(ESI)calcd for C18H15FN3O[M+H]+308.1194 found:308.1885,calcd for C18H14FN3ONa[M+Na]+330.1013 found:330.1015.
化合物5-(2,5-二甲氧基苯基)-2-甲基吡唑并[1,5-a]喹唑啉(19j)的制备
目标化合物19j
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2,5-二甲氧基苯硼酸(18j,43.7mg,0.24mmol)制备目标化合物,收率41%。1H NMR(400MHz,DMSO-d6)δ8.37(dd,J=8.3,1.0Hz,1H),7.95(ddd,J=8.5,6.5,2.0Hz,1H),7.56-7.44(m,2H),7.17(d,J=9.0Hz,1H),7.12(dd,J=9.0,3.0Hz,1H),7.01(d,J=3.0Hz,1H),6.67(s,1H),3.76(s,3H),3.63(s,3H),2.50(s,3H).13C NMR(101MHz,DMSO)δ158.25,153.68,152.54,151.20,145.61,135.59,134.68,129.45,127.41,125.24,117.68,116.29,116.24,114.43,113.31,99.30,56.39,56.08,14.81.HRMS m/z(ESI)calcdfor C19H18N3O2[M+H]+320.1394 found:320.1407,calcd for C19H17N3ONa[M+Na]+342.1213found:342.1216.
化合物3-(2-甲基吡唑并[1,5-a]喹唑啉-5-基)-1H-吲哚-1-甲酸叔丁酯(19k)的制备
目标化合物19k
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和1-BOC-吲哚-3-硼酸(18k,62.6mg,0.24mmol)制备目标化合物,收率45%。1H NMR(400MHz,CDCl3)δ8.53(d,J=8.4Hz,1H),8.26(d,J=8.4Hz,1H),8.17(dd,J=8.3,1.2Hz,1H),8.09(s,1H),7.88(ddd,J=8.5,7.2,1.3Hz,1H),7.78(d,J=7.9Hz,1H),7.43(dddd,J=9.7,8.4,7.1,1.2Hz,2H),7.30(ddd,J=8.1,7.1,1.0Hz,1H),6.63(s,1H),2.60(s,3H),1.72(s,9H).13C NMR(101MHz,CDCl3)δ153.48,152.96,149.47,145.86,136.49,135.51,133.92,129.30,128.66,127.36,125.22,124.46,123.49,121.10,118.31,117.51,115.37,114.92,99.21,84.62,28.21,14.62.HRMS m/z(ESI)calcd for C24H23N4O2[M+H]+399.1816 found:399.1816,calcd for C24H22N4O2Na[M+Na]+421.1635 found:421.1641.
化合物5-(1H-吲哚-3-基)-2-甲基吡唑并[1,5-a]喹唑啉(19l)的制备
目标化合物19l
1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.41(ddd,J=9.8,8.4,1.2Hz,2H),8.09(d,J=2.8Hz,1H),8.05(d,J=7.9Hz,1H),7.97(ddd,J=8.4,7.2,1.3Hz,1H),7.58(ddd,J=8.3,7.2,1.3Hz,1H),7.56-7.52(m,1H),7.24(ddd,J=8.2,7.0,1.3Hz,1H),7.16(ddd,J=8.0,7.0,1.2Hz,1H),6.58(s,1H),2.48(s,3H).13C NMR(101MHz,DMSO)δ154.77,152.45,146.03,136.91,136.38,134.22,129.69,129.40,126.86,125.21,122.76,121.46,120.80,117.15,114.73,112.86,112.39,98.25,14.87.HRMS m/z(ESI)calcd for C19H15N4[M+H]+299.1291 found:299.1301,calcd for C19H14N4Na[M+Na]+321.1111 found:321.1114.化合物2-甲基-5-(1-(苯磺酰基)-1H-吲哚-3-基)吡唑并[1,5-a]喹唑啉(19m)的制备
目标化合物19m
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和1-(苯磺酰基)-3-吲哚硼酸(18m,72.1mg,0.24mmol)制备目标化合物,收率42%。1H NMR(400MHz,DMSO-d6)δ8.45(d,J=1.1Hz,1H),8.43(s,1H),8.20-8.12(m,3H),8.08(d,J=8.3Hz,1H),8.04(ddd,J=8.5,7.2,1.3Hz,1H),7.85(d,J=7.9Hz,1H),7.78-7.71(m,1H),7.69-7.59(m,3H),7.48(ddd,J=8.4,7.1,1.2Hz,1H),7.40-7.32(m,1H),6.69(s,1H),2.51(s,3H).13C NMR(101MHz,CDCl3)δ153.02,152.64,145.51,137.88,136.53,135.09,134.30,134.22,129.53,128.29,127.57,127.05,125.72,124.80,124.28,121.73,119.31,117.26,115.10,113.55,99.31,14.59.HRMS m/z(ESI)calcd forC25H19N4O2[M+H]+439.1223 found:439.1227,calcd for C25H18N4O2Na[M+Na]+461.1043found:461.1046.
化合物2-甲基-5-(1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-3-基)吡唑并[1,5-a]喹唑啉(19n)的制备
目标化合物19n
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和1-苯磺酰基吡咯并吡啶-3-硼酸酯(18n,92.2mg,0.24mmol)制备目标化合物,收率39%。1H NMR(400MHz,CDCl3)δ8.59-8.50(m,2H),8.35-8.19(m,5H),7.92(ddd,J=8.5,7.2,1.3Hz,1H),7.65-7.58(m,1H),7.56-7.48(m,3H),7.30(dd,J=8.0,4.7Hz,1H),6.58(s,1H),2.59(s,3H).13C NMR(101MHz,CDCl3)δ153.14,151.92,147.23,146.05,145.55,137.89,136.62,134.45,134.20,130.69,129.17,128.32,127.86,127.36,124.90,122.07,119.82,116.89,116.22,115.20,99.28,14.62.HRMS m/z(ESI)calcd forC24H18N5O2S[M+H]+440.1176 found:440.1183,calcd for C24H17N5O2SNa[M+Na]+462.0995found:462.1006.
化合物2-甲基-5-苯乙基吡唑并[1,5-a]喹唑啉(19o)的制备
目标化合物19o
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-苯基乙基-1-硼酸频哪醇酯(18o,23.2mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.32(dd,J=8.4,1.1Hz,1H),8.27(dd,J=8.2,1.2Hz,1H),7.94(ddd,J=8.4,7.1,1.3Hz,1H),7.56(ddd,J=8.3,7.1,1.2Hz,1H),7.39-7.33(m,2H),7.29(t,J=7.6Hz,2H),7.23-7.16(m,1H),6.56(s,1H),3.56-3.47(m,2H),3.15(dd,J=9.3,6.7Hz,2H),2.45(s,3H).13C NMR(101MHz,DMSO)δ160.77,152.21,145.41,141.74,135.53,134.51,128.94,128.76,127.52,126.42,125.25,117.15,114.61,98.47,36.12,33.51,14.78.HRMS m/z(ESI)calcd for C19H18N3[M+H]+288.1495 found:288.1494,calcd for C19H17N3Na[M+Na]+310.1315 found:310.1324.
化合物N-(2-甲氧基乙基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21a)的制备
目标化合物21a
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-甲氧基乙胺(20a,15.0mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.27(dd,J=8.2,1.2Hz,1H),8.13(dd,J=8.3,1.2Hz,1H),7.93(t,J=5.4Hz,1H),7.81(ddd,J=8.4,7.2,1.2Hz,1H),7.44(ddd,J=8.3,7.1,1.3Hz,1H),5.93(s,1H),3.74-3.63(m,2H),3.61-3.58(m,2H),3.30(s,3H),2.31(s,3H).13C NMR(101MHz,DMSO)δ152.66,151.65,146.90,136.32,133.62,124.87,124.17,114.65,111.42,93.99,70.52,58.45,14.81.HRMS m/z(ESI)calcd for C14H17N4O[M+H]+257.1397 found:257.1397,calcd for C14H16N4ONa[M+Na]+279.1216 found:279.1211.
化合物N1,N1-二甲基-N3-(2-甲基吡唑并[1,5-a]喹唑啉-5-基)丙烷-1,3-二胺(21b)的制备
目标化合物21b
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和N,N-二甲基-1,3-二氨基丙烷(20b,20.4mg,0.2mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ8.22(dd,J=8.3,1.2Hz,1H),8.12(dd,J=8.4,1.1Hz,1H),8.00(t,J=5.4Hz,1H),7.81(ddd,J=8.3,7.1,1.2Hz,1H),7.44(ddd,J=8.4,7.2,1.2Hz,1H),5.91(s,1H),3.51(td,J=7.0,5.3Hz,2H),2.55(t,J=7.1Hz,2H),2.33(s,6H),2.30(s,3H),1.86(p,J=7.1Hz,2H).13C NMR(101MHz,DMSO)δ152.69,151.65,146.99,136.30,133.62,124.79,124.22,114.66,111.48,93.91,56.96,56.49,44.84,26.04,19.02,14.82.HRMS m/z(ESI)calcd for C16H22N5[M+H]+284.1870 found:284.1870.
化合物2-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)吡唑并[1,5-a]喹唑啉-5-胺(21c)的制备
目标化合物21c
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-(4-甲基-哌嗪-1-基)乙胺(20c,28.6mg,0.2mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.22(dd,J=8.3,1.2Hz,1H),8.13(dd,J=8.4,1.1Hz,1H),7.86-7.72(m,2H),7.44(ddd,J=8.3,7.2,1.2Hz,1H),5.91(s,1H),3.60(q,J=6.4Hz,2H),3.50(t,J=5.2Hz,1H),3.46-3.27(m,4H),2.61(t,J=6.9Hz,2H),2.37(br s,3H),2.31(s,3H),2.18(s,3H).13C NMR(101MHz,DMSO)δ152.59,151.65,146.98,136.29,133.61,124.77,124.19,114.66,111.44,93.94,56.84,55.08,53.09,46.03,38.68,14.82.HRMS m/z(ESI)calcd for C18H25N6[M+H]+325.2135 found:325.2133,calcd forC18H24N6Na[M+Na]+347.1955 found:347.2012.
化合物2-甲基-N-(3-吗啉代丙基)吡唑并[1,5-a]喹唑啉-5-胺(21d)的制备
目标化合物21d
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和N-(3-氨丙基)吗啉(20d,28.8mg,0.2mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ8.23(d,J=8.2Hz,1H),8.12(d,J=8.3Hz,1H),7.88(t,J=5.3Hz,1H),7.83-7.75(m,1H),7.48-7.39(m,1H),5.90(s,1H),3.58(t,J=4.6Hz,4H),3.51(q,J=6.6Hz,2H),2.41-2.38(m,6H),2.30(s,3H),1.82(p,J=7.1Hz,2H).13C NMR(101MHz,DMSO)δ152.65,151.62,147.06,136.29,133.52,124.78,124.11,114.65,111.50,93.86,66.68,56.70,53.84,25.66,14.82.HRMS m/z(ESI)calcd for C18H24N5O[M+H]+326.1975 found:326.1974,calcd for C18H24N5ONa[M+Na]+348.1795 found:348.1807.
化合物2-甲基-N-((1R,3r,5S)-9-甲基-9-氮杂双环[3.3.1]壬南-3-基)吡唑并[1,5-a]喹唑啉-5-胺(21e)的制备
目标化合物21e
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和内向-3-氨基-9-甲基-9-氮杂双环[3,3,1]壬烷(20e,30.8mg,0.2mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.32(d,J=8.3Hz,1H),8.12(d,J=8.4Hz,1H),7.81(q,J=9.7,7.9Hz,1H),7.44(q,J=7.5,7.0Hz,2H),5.92(s,1H),4.69(d,J=8.2Hz,1H),3.07(br s,2H),2.50(s,3H),2.32(s,3H),2.10(t,J=13.3Hz,1H),2.04-1.89(m,2H),1.53-1.49(m,3H),1.23-1.16(m,2H),0.98(d,J=12.9Hz,2H).13CNMR(101MHz,DMSO)δ152.06,151.65,147.08,136.34,133.56,124.98,124.04,114.62,111.50,99.98,93.71,51.35,32.36,23.60,14.85.HRMS m/z(ESI)calcd for C20H26N5[M+H]+336.2183 found:336.2085,calcd for C20H25N5Na[M+Na]+358.2002 found:358.2096.
化合物2-甲基-N-((1R,3r,5S)-8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)吡唑并[1,5-a]喹唑啉-5-胺(21f)的制备
目标化合物21f
使用制备化合物8a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(1R,3r,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-胺(20f,28.0mg,0.2mmol)制备目标化合物,收率43%。1H NMR(400MHz,DMSO-d6)δ8.23(dd,J=8.3,1.3Hz,1H),8.12(dd,J=8.3,1.2Hz,1H),7.81(ddd,J=8.3,7.2,1.2Hz,1H),7.46(ddd,J=8.3,7.2,1.2Hz,1H),7.12(d,J=4.2Hz,1H),5.94(s,1H),4.21-4.11(m,1H),3.08(br s,2H),2.31(s,3H),2.18(s,3H),2.12(ddd,J=14.3,6.7,4.4Hz,2H),1.98-1.94(m,3H),1.92(d,J=2.3Hz,1H),1.23(d,J=2.6Hz,2H).13C NMR(101MHz,DMSO)δ151.96,151.64,146.82,136.33,133.58,125.33,124.13,114.54,111.70,94.27,59.90,42.87,35.35,26.04,14.82.HRMS m/z(ESI)calcd for C19H24N5[M+H]+322.2026 found:322.2027.HRMS m/z(ESI)calcd for C19H24N5[M+H]+322.2026 found:322.2027.
化合物N-(4-氟苄基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21g)的制备
目标化合物21g
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-氟苄胺(20g,15.1mg,0.2mmol)制备目标化合物,收率56%。1HNMR(400MHz,DMSO-d6)δ8.45(t,J=5.9Hz,1H),8.31(dd,J=8.3,1.3Hz,1H),8.14(dd,J=8.4,1.2Hz,1H),7.83(ddd,J=8.4,7.2,1.2Hz,1H),7.44(dddd,J=17.6,8.9,6.2,2.2Hz,3H),7.17-7.09(m,2H),5.90(s,1H),4.71(d,J=5.7Hz,2H),2.30(s,3H).13C NMR(101MHz,DMSO)δ152.51,151.70,146.78,136.38,136.31,136.29,133.76,129.70,129.62,124.85,124.29,115.48,115.27,114.70,111.38,94.13,43.49,14.80.HRMS m/z(ESI)calcd forC18H16FN4[M+H]+307.1354 found:307.1355,calcd for C18H15FN4Na[M+Na]+329.11731found:329.1175.
化合物2-甲基-N-(4-甲基苄基)吡唑并[1,5-a]喹唑啉-5-胺(21h)的制备
目标化合物21h
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-甲基苄胺(20h,24.2mg,0.2mmol)制备目标化合物,收率56%。1HNMR(400MHz,DMSO-d6)δ8.40(t,J=5.8Hz,1H),8.32(dd,J=8.3,1.2Hz,1H),8.14(dd,J=8.4,1.1Hz,1H),7.82(ddd,J=8.3,7.2,1.2Hz,1H),7.45(ddd,J=8.3,7.2,1.2Hz,1H),7.27(d,J=7.8Hz,2H),7.12(d,J=7.8Hz,2H),5.89(s,1H),4.69(d,J=5.7Hz,2H),2.30(s,3H),2.26(s,3H).13C NMR(101MHz,DMSO)δ152.55,151.67,146.87,137.09,136.38,136.09,133.66,129.22,127.68,124.86,124.24,114.68,111.44,94.04,43.92,21.12,14.80.HRMS m/z(ESI)calcd for C19H19N4[M+H]+303.1604 found:303.1614,calcd forC19H18N4Na[M+Na]+325.1424 found:325.1423.
化合物N-(3,4-二氯苄基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21i)的制备
目标化合物21i
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和3,4-二氯苄胺(20i,35.2mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.49(t,J=5.9Hz,1H),8.30(d,J=8.2Hz,1H),8.15(dd,J=8.4,1.2Hz,1H),7.84(ddd,J=8.4,7.2,1.2Hz,1H),7.64(d,J=2.0Hz,1H),7.57(d,J=8.3Hz,1H),7.48(td,J=7.7,7.1,1.2Hz,1H),7.37(dd,J=8.3,2.0Hz,1H),5.91(s,1H),4.72(d,J=5.7Hz,2H),2.30(s,3H).13C NMR(101MHz,DMSO)δ152.44,151.72,146.62,141.54,136.38,133.83,131.27,130.85,129.70,129.60,128.07,124.84,124.33,114.72,111.30,94.26,43.26,14.78.HRMS m/z(ESI)calcd for C18H15Cl2N4[M+H]+357.0668found:357.0672,calcd for C18H14Cl2N4Na[M+Na]+379.0488 found:379.0501.
化合物(R)-2-甲基-N-(1-苯乙基)吡唑并[1,5-a]喹唑啉-5-胺(21j)的制备
目标化合物21j
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和R(+)-alpha-甲基苄胺(20j,29.1mg,0.24mmol)制备目标化合物,收率61%。1H NMR(400MHz,DMSO-d6)δ8.56-8.43(m,1H),8.13(dd,J=8.4,1.2Hz,1H),8.06(d,J=7.9Hz,1H),7.82(ddd,J=8.5,7.1,1.3Hz,1H),7.52-7.40(m,3H),7.31(t,J=7.6Hz,2H),7.24-7.16(m,1H),5.86(s,1H),5.52(p,J=7.1Hz,1H),2.28(s,3H),1.59(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ151.83,151.64,146.74,145.47,136.35,133.68,128.62,126.94,126.60,125.14,124.12,114.61,111.36,94.08,49.62,22.83,14.78.HRMSm/z(ESI)calcd for C19H19N4[M+H]+303.1604 found:303.1607,calcd for C19H18N4Na[M+Na]+325.1424 found:325.2129.
化合物(S)-2-甲基-N-(1-苯乙基)吡唑并[1,5-a]喹唑啉-5-胺(21k)的制备
目标化合物21k
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和S(-)-alpha-甲基苄胺(20k,29.1mg,0.24mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ8.50(dd,J=8.3,1.3Hz,1H),8.12(dd,J=8.4,1.2Hz,1H),8.06(d,J=7.9Hz,1H),7.82(ddd,J=8.4,7.2,1.2Hz,1H),7.51-7.42(m,3H),7.31(t,J=7.6Hz,2H),7.24-7.15(m,1H),5.86(s,1H),5.52(p,J=7.2Hz,1H),2.28(s,3H),1.58(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ151.83,151.64,146.74,145.47,136.35,133.68,128.62,126.94,126.60,125.14,124.12,114.61,111.36,94.08,49.62,22.83,14.78.HRMS m/z(ESI)calcd for C19H19N4[M+H]+303.1604 found:303.1609,calcdfor C19H18N4Na[M+Na]+325.1424 found:325.1433.
化合物(R)-N-(1-(4-甲氧基苯基)乙基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21l)的制备
目标化合物21l
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(R)-(+)-1-(4-甲氧基苯)乙胺(20l,36.2mg,0.24mmol)制备目标化合物,收率57%。1H NMR(400MHz,DMSO-d6)δ8.47(dd,J=8.3,1.2Hz,1H),8.12(dd,J=8.3,1.2Hz,1H),7.99(d,J=7.9Hz,1H),7.81(ddd,J=8.3,7.2,1.2Hz,1H),7.46(ddd,J=8.3,7.2,1.2Hz,1H),7.41-7.33(m,2H),6.94-6.81(m,2H),5.87(s,1H),5.47(t,J=7.3Hz,1H),3.71(s,3H),2.29(s,3H),1.56(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ158.42,151.78,151.64,146.81,137.35,136.36,133.62,127.77,125.12,124.08,114.60,113.99,111.39,94.04,55.46,49.01,22.76,14.79.HRMS m/z(ESI)calcd for C20H21N4O[M+H]+333.1710 found:333.1708,calcd for C20H20N4ONa[M+Na]+355.1529 found:355.1534.
化合物(S)-N-(1-(4-甲氧基苯基)乙基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21m)的制备
目标化合物21m
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(S)-(-)-1-(4-甲氧基苯)乙胺(20m,36.2mg,0.24mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=8.2Hz,1H),8.12(dd,J=8.3,1.2Hz,1H),7.99(d,J=7.9Hz,1H),7.81(ddd,J=8.3,7.2,1.2Hz,1H),7.55-7.41(m,1H),7.42-7.30(m,2H),6.94-6.77(m,2H),5.86(s,1H),5.47(p,J=7.1Hz,1H),3.71(s,3H),2.28(s,3H),1.56(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ158.42,151.78,151.64,146.81,137.35,136.36,133.62,127.77,125.12,124.08,114.60,113.99,111.40,94.04,55.46,49.01,22.76,14.79.HRMS m/z(ESI)calcd for C20H21N4O[M+H]+333.1710 found:333.1709,calcd for C20H20N4ONa[M+Na]+355.1529 found:355.1530.
化合物(R)-N-(1-(4-氟苯基)乙基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21n)的制备
目标化合物21n
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(R)-1-(4-氟苯基)乙胺(20n,33.4mg,0.24mmol)制备目标化合物,收率55%。1H NMR(400MHz,DMSO-d6)δ8.47(dd,J=8.3,1.2Hz,1H),8.12(dd,J=8.4,1.1Hz,1H),8.06(d,J=7.7Hz,1H),7.82(ddd,J=8.3,7.2,1.2Hz,1H),7.48(dt,J=8.0,6.0Hz,3H),7.17-7.07(m,2H),5.86(s,1H),5.50(p,J=7.2Hz,1H),2.28(s,3H),1.57(d,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ151.76,151.66,146.68,141.62,141.59,136.35,133.72,128.55,128.47,125.13,124.14,115.38,115.17,114.61,111.32,94.13,49.09,22.82,14.78.HRMS m/z(ESI)calcd for C19H18N4F[M+H]+321.1510 found:321.1509,calcdfor C19H17N4FNa[M+Na]+343.1329 found:343.1337.
化合物(S)-N-(1-(4-氟苯基)乙基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21o)的制备
目标化合物21o
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(S)-1-(4-氟苯基)乙胺(20o,33.4mg,0.24mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.47(dd,J=8.3,1.3Hz,1H),8.12(dd,J=8.4,1.2Hz,1H),8.06(d,J=7.8Hz,1H),7.82(ddd,J=8.3,7.2,1.2Hz,1H),7.53-7.43(m,3H),7.17-7.07(m,2H),5.86(s,1H),5.50(p,J=7.1Hz,1H),2.28(s,3H),1.57(d,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ151.76,151.66,146.68,141.63,141.60,136.35,133.72,128.55,128.47,125.13,124.14,115.38,115.17,114.61,111.32,94.13,49.09,22.82,14.78.HRMS m/z(ESI)calcd for C19H18N4F[M+H]+321.1510 found:321.1510,calcd forC19H17N4FNa[M+Na]+343.1329 found:343.1331.
化合物N-(2-甲基吡唑并[1,5-a]喹唑啉-5-基)苯并[d]噻唑-5-胺(21p)的制备
目标化合物21p
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和1,3-苯并噻唑-5-胺(20p,30.0mg,0.2mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.40(s,1H),8.77(d,J=2.0Hz,1H),8.61(d,J=8.2Hz,1H),8.25(d,J=8.3Hz,1H),8.14(d,J=8.7Hz,1H),7.99-7.87(m,2H),7.58(t,J=7.7Hz,1H),6.13(s,1H),2.37(s,3H).13C NMR(101MHz,DMSO)δ157.14,154.07,152.09,150.46,145.60,138.91,136.66,134.19,128.27,125.30,124.52,122.35,121.10,115.61,114.82,111.70,95.34,14.82.HRMS m/z(ESI)calcd for C18H14N5S[M+H]+332.0964found:332.0974,calcd for C18H13N5SNa[M+Na]+354.0784 found:354.0784.
化合物2-甲基-N-(4-苯氧基苯基)吡唑并[1,5-a]喹唑啉-5-胺(21q)的制备
目标化合物21q
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-氨基二苯醚(20q,37.0mg,0.2mmol)制备目标化合物,收率68%。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.56(d,J=7.9Hz,1H),8.25-8.19(m,1H),7.93-7.86(m,3H),7.58-7.51(m,1H),7.40(td,J=7.4,2.0Hz,2H),7.12(t,J=7.4Hz,1H),7.10-7.05(m,2H),7.05-7.00(m,2H),6.05(s,1H),2.35(s,3H).13C NMR(101MHz,DMSO)δ157.85,152.28,151.99,150.39,145.76,136.64,136.03,134.08,130.44,125.26,124.46,123.89,123.47,119.62,118.45,114.79,111.65,95.08,14.84.HRMS m/z(ESI)calcd forC23H19N4O[M+H]+367.1553 found:367.1560,calcd for C23H18N4ONa[M+Na]+389.1373found:389.1384.
化合物N-(2,6-二甲氧基嘧啶-4-基)-4-((2-甲基吡唑并[1,5-a]喹唑啉-5-基)氨基)苯磺酰胺(21r)的制备
目标化合物21r
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和磺胺二甲氧嘧碇(20r,62.0mg,0.2mmol)制备目标化合物,收率65%。1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),9.81(s,1H),8.60-8.52(m,1H),8.25(dd,J=8.4,1.2Hz,1H),8.17-8.09(m,2H),7.98-7.88(m,3H),7.58(ddd,J=8.4,7.2,1.3Hz,1H),6.19(s,1H),6.00(s,1H),3.81(s,3H),3.79(s,3H),2.38(s,3H).13C NMR(101MHz,DMSO)δ172.16,160.45,152.20,149.79,145.02,144.91,136.68,134.44,133.09,128.60,125.43,124.59,120.74,114.81,111.64,95.94,85.04,54.99,54.26,14.79.HRMS m/z(ESI)calcdfor C23H22N7O4S[M+H]+492.1448 found:492.1451,calcd for C23H21N7O4SNa[M+Na]+514.1268 found:514.1276.
化合物N-(6-甲氧基嘧啶-4-基)-4-((2-甲基吡唑并[1,5-a]喹唑啉-5-基)氨基)苯磺酰胺(21s)的制备
目标化合物21s
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和磺胺间甲氧嘧啶(20s,56.0mg,0.2mmol)制备目标化合物,收率55%。1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.79(s,1H),8.56(d,J=8.3Hz,1H),8.42(s,1H),8.25(d,J=8.3Hz,1H),8.17-8.09(m,2H),7.93(dd,J=8.4,6.0Hz,3H),7.58(t,J=7.6Hz,1H),6.37(s,1H),6.18(s,1H),3.85(s,3H),2.37(s,3H).13C NMR(101MHz,DMSO)δ170.36,159.25,152.20,149.81,145.05,144.65,136.69,134.44,128.31,125.45,124.59,120.78,114.82,111.66,95.91,91.39,54.55,14.81.HRMS m/z(ESI)calcd for C22H20N7O3S[M+H]+462.1343 found:462.1353,calcd for C22H19N7O3SNa[M+Na]+484.1162 found:484.1169.
化合物N-(4,6-二甲基嘧啶-2-基)-4-((2-甲基吡唑并[1,5-a]喹唑啉-5-基)氨基)苯磺酰胺(21t)的制备
目标化合物21t
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和磺胺二甲嘧啶(20t,55.6mg,0.2mmol)制备目标化合物,收率58%。1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.75(s,1H),8.56(dd,J=8.4,1.2Hz,1H),8.25(dd,J=8.4,1.2Hz,1H),8.06(d,J=8.9Hz,2H),7.99(d,J=8.9Hz,2H),7.92(ddd,J=8.4,7.2,1.2Hz,1H),7.57(ddd,J=8.4,7.2,1.2Hz,1H),6.77(s,1H),6.16(s,1H),2.37(s,3H),2.27(s,6H).13C NMR(101MHz,DMSO)δ156.78,152.19,149.88,145.12,144.24,136.68,134.41,129.38,125.40,124.60,120.30,114.81,111.65,95.83,23.41,14.79.HRMS m/z(ESI)calcd for C23H22N7O2S[M+H]+460.1550 found:460.1554,calcd for C23H21N7O2SNa[M+Na]+482.1370 found:482.1378.
化合物2-((2-甲基吡唑并[1,5-a]喹唑啉-5-基)氨基)噻唑-4,5-二羧酸二乙酯(21u)的制备
目标化合物21u
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-氨基噻唑-4,5-二羧酸二乙酯(20u,48.8mg,0.2mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.76(d,J=8.3Hz,1H),8.28(dd,J=8.4,1.2Hz,1H),7.96(ddd,J=8.3,7.1,1.2Hz,1H),7.56(ddd,J=8.3,7.1,1.2Hz,1H),6.42(s,1H),4.34(dq,J=21.6,7.1Hz,4H),2.41(s,3H),1.34-1.28(m,6H).13C NMR(101MHz,DMSO)δ163.97,161.74,161.12,152.61,146.95,143.42,136.57,135.06,125.37,125.02,119.64,114.87,110.48,96.25,62.14,61.81,14.75,14.52,14.39.HRMS m/z(ESI)calcd for C20H20N5O4S[M+H]+426.1231 found:421.1233,calcd for C20H19N5O4SNa[M+Na]+448.1050 found:448.1058.
化合物(R)-2-((2-甲基吡唑并[1,5-a]喹唑啉-5-基)氨基)-1,1-二苯丙烷-1-醇(21v)的制备
目标化合物21v
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(R)-2-氨基-1,2-联苯-1-丙醇(20v,45.4mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=8.3Hz,1H),8.18(dd,J=17.8,7.8Hz,3H),8.11-7.94(m,4H),7.86(t,J=7.8Hz,1H),7.54(td,J=7.6,3.9Hz,2H),7.46(t,J=7.6Hz,1H),7.28(d,J=5.0Hz,1H),6.85(s,1H),6.08(s,1H),5.67(s,1H),4.81-4.78(m,1H),2.55(s,3H),1.23(d,J=8.2Hz,3H).HRMS m/z(ESI)calcd for C26H25N4O[M+H]+409.2023 found:409.2029.
化合物N-(1,2,3,5,6,7-六氢-S-茚满-4-基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21w)的制备
目标化合物21w
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和1,2,3,5,6,7-六氢-S-茚满-4-胺(20w,34.6mg,0.2mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.50(dd,J=8.3,1.3Hz,1H),8.19(dd,J=8.4,1.2Hz,1H),7.87(ddd,J=8.4,7.2,1.2Hz,1H),7.52(ddd,J=8.3,7.2,1.3Hz,1H),7.03(s,1H),5.87(s,1H),2.87(t,J=7.4Hz,4H),2.71(t,J=7.4Hz,4H),2.29(s,3H),1.98(p,J=7.5Hz,4H).HRMS m/z(ESI)calcd for C23H23N4[M+H]+355.1917 found:355.1919,calcd for C23H22N4Na[M+Na]+377.1737 found:377.1735.
化合物N-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21x)的制备
目标化合物21x
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和5-氨基-3-叔丁基-1-甲基吡唑(20x,30.6mg,0.2mmol)制备目标化合物,收率55%。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.41(d,J=8.2Hz,1H),8.22(dd,J=8.4,1.1Hz,1H),7.91(ddd,J=8.4,7.2,1.2Hz,1H),7.54(ddd,J=8.3,7.2,1.2Hz,1H),6.11(s,1H),6.05(s,1H),3.58(s,3H),2.33(s,3H),1.27(s,9H).13C NMR(101MHz,DMSO)δ159.08,152.02,151.42,145.85,137.47,136.60,134.39,125.27,124.67,114.83,110.96,98.18,95.24,36.01,32.41,30.89,14.79.HRMS m/z(ESI)calcd for C19H23N6[M+H]+335.1979 found:335.1975,calcd for C19H22N6Na[M+Na]+357.1798 found:357.1802.
化合物N-(3-(叔丁基)-1-苯基-1H-吡唑-5-基)-2-甲基吡唑并[1,5-a]喹唑啉-5-胺(21y)的制备
目标化合物21y
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和5-氨基-3-叔丁基-1-苯基吡唑(20y,43.0mg,0.2mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.32(d,J=8.1Hz,1H),8.19(dd,J=8.4,1.1Hz,1H),7.89(ddd,J=8.3,7.1,1.2Hz,1H),7.57-7.53(m,3H),7.32(t,J=7.9Hz,2H),7.23-7.16(m,1H),6.42(s,1H),5.97(s,1H),2.29(s,3H),1.35(s,9H).13C NMR(101MHz,DMSO)δ161.26,152.00,151.70,145.75,139.89,137.35,136.50,134.45,129.29,127.06,125.01,124.76,123.12,114.83,110.88,101.78,95.26,32.69,30.71,14.76.HRMSm/z(ESI)calcd for C24H25N6[M+H]+397.2135 found:397.2139,calcd for C24H24N6Na[M+Na]+419.1955 found:419.1966.
化合物5-(呋喃-2-基甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22a)的制备
目标化合物22a
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-羟甲基呋喃(9a,23.5mg,0.24mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.3Hz,1H),8.12-8.05(m,1H),8.00-7.87(m,2H),7.71(t,J=1.7Hz,1H),7.51(ddd,J=8.1,7.3,1.0Hz,1H),6.70(dd,J=1.9,0.8Hz,1H),6.34(s,1H),5.45(s,2H),2.40(s,3H).13C NMR(101MHz,DMSO)δ157.78,152.19,144.64,144.25,142.47,137.13,135.04,125.81,125.11,120.93,114.43,111.35,111.18,96.85,60.66,14.79.HRMS m/z(ESI)calcd for C16H14N3O2[M+H]+280.1081 found:280.1090,calcd for C16H13N3O2Na[M+Na]+302.0900 found:302.0895.
化合物5-(环己基甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22b)的制备
目标化合物22b
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和环己基甲醇(9b,27.4mg,0.24mmol)制备目标化合物,收率50%。1H NMR(400MHz,CDCl3)δ8.31(d,J=8.3Hz,1H),8.12(dd,J=8.1,1.4Hz,1H),7.79(ddd,J=8.5,7.2,1.4Hz,1H),7.46-7.33(m,1H),6.22(s,1H),4.33(d,J=6.1Hz,2H),2.50(s,3H),2.00-1.88(m,3H),1.86-1.76(m,2H),1.76-1.68(m,1H),1.31(ddt,J=29.0,15.2,3.2Hz,3H),1.15(qd,J=12.4,3.3Hz,2H).13C NMR(101MHz,CDCl3)δ152.39,145.30,133.78,125.55,124.11,114.39,111.85,96.48,72.07,37.33,29.90,26.47,25.80,14.54.HRMS m/z(ESI)calcd for C18H22N3O[M+H]+296.1757 found:296.1766,calcd forC18H21N3ONa[M+Na]+318.1577 found:318.1579.
化合物5-(吡啶-2-基甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22c)的制备
目标化合物22c
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-吡啶甲醇(9c,26.2mg,0.24mmol)制备目标化合物,收率49%。1H NMR(400MHz,DMSO-d6)δ8.61(dt,J=4.8,1.4Hz,1H),8.21(ddd,J=9.8,8.3,1.1Hz,2H),7.95(ddd,J=8.5,7.2,1.4Hz,1H),7.86(td,J=7.7,1.8Hz,1H),7.63(d,J=7.8Hz,1H),7.55(ddd,J=8.3,7.3,1.2Hz,1H),7.38(ddd,J=7.6,4.8,1.1Hz,1H),6.31(s,1H),5.65(s,2H),2.39(s,3H).13C NMR(101MHz,DMSO)δ157.70,156.28,152.25,149.66,144.55,137.51,137.21,135.21,125.91,125.25,123.53,122.09,114.51,111.16,97.00,69.01,14.80.HRMS m/z(ESI)calcd for C17H15N4O[M+H]+291.1240 found:291.1248,calcdfor C17H14N4ONa[M+Na]+313.1060 found:313.1066.
化合物5-((3,5,6-三甲基吡嗪-2-基)甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22d)的制备
目标化合物22d
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和(3,5,6-三甲基吡嗪-2-基)甲醇(9d,36.5mg,0.24mmol)制备目标化合物,收率56%。1H NMR(400MHz,CDCl3)δ8.29(d,J=8.4Hz,1H),8.06(d,J=8.0Hz,1H),7.84-7.74(m,1H),7.36(t,J=7.6Hz,1H),6.25(s,1H),5.66(s,2H),2.66(s,3H),2.57(s,3H),2.54(s,3H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ157.81,152.59,151.22,149.49,149.31,145.49,144.83,137.42,133.94,125.56,124.12,114.37,111.34,96.77,67.65,21.58,21.46,20.58,14.58.HRMS m/z(ESI)calcd for C19H20N5O[M+H]+334.1662found:334.1666,calcd for C19H19N5ONa[M+Na]+356.1482 found:356.1488.
化合物5-((3,4-二甲氧基苄基)氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22e)的制备
目标化合物22e
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和3,4-二甲氧基苄醇(9e,40.3mg,0.24mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ8.21(dd,J=8.2,1.0Hz,1H),8.09(dd,J=8.1,1.3Hz,1H),7.93(ddd,J=8.5,7.2,1.4Hz,1H),7.51(ddd,J=8.2,7.2,1.1Hz,1H),7.20(d,J=2.0Hz,1H),7.11(dd,J=8.2,2.0Hz,1H),6.99(d,J=8.2Hz,1H),6.33(s,1H),5.49(s,2H),3.78(s,3H),3.77(s,3H),2.40(s,3H).13C NMR(101MHz,DMSO)δ157.97,152.21,149.33,149.18,144.73,137.15,135.06,128.84,125.85,125.18,121.51,114.46,112.96,112.18,111.29,96.81,68.80,56.02,14.81.HRMS m/z(ESI)calcd for C20H20N3O3[M+H]+350.1499found:350.1508,calcd for C20H19N3O3Na[M+Na]+372.1319 found:372.1323.
化合物5-((2-(三氟甲氧基)苄基)氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22f)的制备
目标化合物22f
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-三氟甲氧基苯甲醇(9f,46.1mg,0.24mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.26-8.20(m,1H),8.08(dd,J=8.2,1.3Hz,1H),7.94(ddd,J=8.5,7.2,1.4Hz,1H),7.81(dd,J=7.8,1.8Hz,1H),7.60-7.45(m,4H),6.35(s,1H),5.64(s,2H),2.40(s,3H).13C NMR(101MHz,DMSO)δ157.58,152.29,147.30,144.49,137.18,135.23,131.54,130.94,129.09,128.17,125.66,125.25,121.11,114.52,111.02,97.03,63.33,14.80.HRMS m/z(ESI)calcd for C19H15F3N3O2[M+H]+374.1111 found:374.1111,calcd for C19H14F3N3O2Na[M+Na]+396.0930 found:396.0945.
化合物5-(萘-2-基甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22g)的制备
目标化合物22g
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和2-萘甲醇(9g,37.9mg,0.24mmol)制备目标化合物,收率41%。1HNMR(400MHz,CDCl3)δ8.33(d,J=8.4Hz,1H),8.17(d,J=8.1Hz,1H),7.98(s,1H),7.88(m,3H),7.83-7.77(m,1H),7.64(dd,J=8.4,1.4Hz,1H),7.54-7.47(m,2H),7.40(t,J=7.7Hz,1H),6.28(s,1H),5.74(s,2H),2.52(s,3H).13C NMR(101MHz,CDCl3)δ158.27,152.52,145.05,137.37,133.96,133.67,133.27,133.18,128.40,128.00,127.76,127.27,126.33,126.26,125.92,125.62,124.21,114.42,111.64,96.73,68.75,14.55.HRMS m/z(ESI)calcd for C22H18N3O[M+H]+340.1444 found:340.1444,calcd for C22H17N3ONa[M+Na]+362.1264 found:362.1269.
化合物5-([1,1'-联苯]-4-基甲氧基)-2-甲基吡唑并[1,5-a]喹唑啉(22h)的制备
目标化合物22h
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-甲基吡唑并[1,5-a]喹唑啉(16,43.4mg,0.2mmol)和4-联苯甲醇(9h,44.2mg,0.24mmol)制备目标化合物,收率37%。1H NMR(400MHz,CDCl3)δ8.30(d,J=8.4Hz,1H),8.17(d,J=8.1Hz,1H),7.83-7.76(m,1H),7.63(dd,J=14.9,7.4Hz,6H),7.45(t,J=7.5Hz,2H),7.38(dt,J=13.5,7.7Hz,2H),6.27(s,1H),5.63(s,2H),2.51(s,3H).13C NMR(101MHz,CDCl3)δ158.15,152.59,145.04,141.24,140.73,137.46,135.28,133.88,128.82,128.68,127.44,127.35,127.15,125.61,124.10,114.35,111.62,96.65,68.28,14.62.HRMS m/z(ESI)calcd for C24H20N3O[M+H]+366.1601 found:366.1600,calcd for C24H19N3ONa[M+Na]+388.1420 found:388.1425.
化合物2-(叔丁基)-5-(3,4-二甲氧基苯基)吡唑并[1,5-a]喹唑啉(24a)的制备
目标化合物24a
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和3,4-二甲氧基苯硼酸(23a,36.4mg,0.2mmol)制备目标化合物,收率60%。1H NMR(400MHz,CDCl3)δ8.55(d,J=8.3Hz,1H),8.03(d,J=8.0Hz,1H),7.85(dd,J=11.4,4.1Hz,1H),7.40(t,J=7.6Hz,1H),7.28(d,J=13.5Hz,2H),7.03(d,J=8.0Hz,1H),6.67(s,1H),3.98(s,3H),3.96(s,3H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ165.98,158.93,150.28,149.17,145.14,136.97,133.52,130.32,129.10,124.07,122.74,117.01,115.20,112.68,110.85,95.81,56.10,32.95,30.59.HRMS m/z(ESI)calcd forC22H24N3O2[M+H]+362.1863 found:362.1866,calcd for C22H23N3O2Na[M+Na]+384.16821found:384.1686.
化合物2-(叔丁基)-5-(3,4,5-三甲氧基苯基)吡唑并[1,5-a]喹唑啉(24b)的制备
目标化合物24b
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和3,4,5-三甲氧基苯硼酸(23b,42.4mg,0.2mmol)制备目标化合物,收率62%。1H NMR(400MHz,CDCl3)δ8.55(d,J=8.4Hz,1H),8.01(d,J=8.1Hz,1H),7.85(t,J=7.8Hz,1H),7.42(t,J=7.7Hz,1H),6.92(s,2H),6.66(s,1H),3.94(s,3H),3.92(s,6H),1.48(s,9H).13C NMR(101MHz,CDCl3)δ166.03,159.06,153.31,145.15,139.22,136.90,133.59,133.25,128.90,124.12,116.95,115.22,106.94,95.99,60.99,56.35,32.96,30.59.HRMS m/z(ESI)calcd for C23H26N3O3[M+H]+392.1969 found:392.1970,calcd for C23H25N3O3Na[M+Na]+414.1788 found:414.1790.
化合物2-(叔丁基)-5-(1-(苯磺酰基)-1H-吲哚-3-基)吡唑并[1,5-a]喹唑啉(24c)的制备
目标化合物24c
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和1-(苯磺酰基)-3-吲哚硼酸(23c,60.2mg,0.2mmol)制备目标化合物,收率51%。1H NMR(400MHz,DMSO-d6)δ8.45(dd,J=8.5,1.1Hz,1H),8.42(s,1H),8.22-8.12(m,3H),8.08(d,J=8.4Hz,1H),8.03(ddd,J=8.4,7.2,1.3Hz,1H),7.86(d,J=7.9Hz,1H),7.78-7.72(m,1H),7.68-7.59(m,3H),7.48(ddd,J=8.4,7.2,1.3Hz,1H),7.35(ddd,J=8.1,7.2,1.0Hz,1H),6.79(s,1H),1.43(s,9H).13C NMR(101MHz,CDCl3)δ166.07,151.96,145.18,137.93,136.90,135.10,134.26,133.88,129.65,129.51,128.08,127.35,127.02,125.65,124.50,124.22,121.79,119.53,117.25,115.34,113.54,96.06,32.98,30.60.HRMS m/z(ESI)calcd for C28H25N4O2S[M+H]+481.1693 found:481.1696,calcd forC28H24N4O2SNa[M+Na]+503.1512 found:503.1512.
化合物2-(叔丁基)-5-(1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-3-基)吡唑并[1,5-a]喹唑啉(24d)的制备
目标化合物24d
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和1-苯磺酰基吡咯并吡啶-3-硼酸酯(23d,76.8mg,0.2mmol)制备目标化合物,收率45%。1H NMR(400MHz,DMSO-d6)δ8.51-8.49(m,2H),8.46(d,J=8.4Hz,1H),8.35(dt,J=8.3,2.2Hz,2H),8.31-8.24(m,2H),8.08-8.00(m,1H),7.81-7.74(m,1H),7.72-7.61(m,3H),7.43(dd,J=8.0,4.7Hz,1H),6.81(s,1H),1.43(s,9H).13C NMR(101MHz,CDCl3)δ166.15,151.33,147.25,145.99,145.22,137.94,136.95,134.41,133.92,130.72,129.16,128.29,127.67,127.15,124.65,122.16,119.77,116.90,116.40,115.49,96.06,32.97,30.58.HRMS m/z(ESI)calcd for C27H24N5O2S[M+H]+482.1645 found:482.1644,calcd for C27H23N5O2SNa[M+Na]+504.1465 found:504.1465.
化合物2-(叔丁基)-5-苯乙基吡唑并[1,5-a]喹唑啉(24e)的制备
目标化合物24e
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和2-苯基乙基-1-硼酸频哪醇酯(23e,46.4mg,0.2mmol)制备目标化合物,收率56%。1H NMR(400MHz,CDCl3)δ8.49(dd,J=8.4,1.1Hz,1H),7.99(dd,J=8.2,1.3Hz,1H),7.81(ddd,J=8.4,7.1,1.3Hz,1H),7.43(ddd,J=8.3,7.1,1.2Hz,1H),7.32(d,J=4.4Hz,4H),7.25-7.19(m,1H),6.60(s,1H),3.54-3.46(m,2H),3.26-3.19(m,2H),1.46(s,9H).13C NMR(101MHz,CDCl3)δ165.60,159.91,145.21,141.40,136.33,133.32,128.56,128.46,126.23,126.09,124.16,117.21,115.31,95.21,36.82,34.24,32.89,30.59.HRMS m/z(ESI)calcd for C22H24N3[M+H]+330.1965 found:330.1966,calcdfor C22H23N3Na[M+Na]+352.1784 found:352.1791.
化合物5-(4-(苄氧基)苯基)-2-(叔丁基)吡唑并[1,5-a]喹唑啉(24f)的制备
目标化合物24f
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和4-苄氧基苯硼酸(23f,45.6mg,0.2mmol)制备目标化合物,收率62%。1H NMR(400MHz,CDCl3)δ8.54(dd,J=8.4,1.1Hz,1H),7.90(dd,J=8.2,1.2Hz,1H),7.83(ddd,J=8.4,7.1,1.3Hz,1H),7.50-7.43(m,3H),7.42-7.27(m,6H),7.15(dd,J=8.3,2.5Hz,1H),6.67(s,1H),5.15(s,2H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ165.94,159.00,158.82,145.24,139.12,136.85,136.79,133.50,129.67,128.95,128.65,128.05,127.52,124.10,122.31,116.92,116.29,115.87,115.11,96.11,70.18,32.98,30.65.HRMSm/z(ESI)calcd for C27H26N3O[M+H]+408.2070 found:408.2078,calcd for C27H25N3ONa[M+Na]+430.1890 found:430.1899.
化合物2-(叔丁基)-5-(吡啶-4-基)吡唑并[1,5-a]喹唑啉(24g)的制备
目标化合物24g
使用制备化合物6a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和吡啶-4-硼酸(23g,24.4mg,0.2mmol)制备目标化合物,收率70%。1H NMR(400MHz,DMSO-d6)δ8.86-8.79(m,2H),8.45(dd,J=8.4,1.1Hz,1H),8.01(ddd,J=8.5,7.2,1.3Hz,1H),7.88(dd,J=8.3,1.2Hz,1H),7.77-7.69(m,2H),7.56(ddd,J=8.3,7.1,1.2Hz,1H),6.85(s,1H),1.44(s,9H).13C NMR(101MHz,DMSO)δ165.82,157.03,150.40,145.05,136.32,135.11,128.81,125.61,124.46,116.36,114.94,96.85,33.09,30.80.HRMS m/z(ESI)calcd for C19H19N4[M+H]+303.1604 found:303.1604,calcd forC19H18N4Na[M+Na]+325.1424 found:325.1420.
化合物2-(叔丁基)-N-(萘-1-基)吡唑并[1,5-a]喹唑啉-5-胺(26a)的制备
目标化合物26a
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和1-萘胺(25a,28.6mg,0.2mmol)制备目标化合物,收率65%。1HNMR(400MHz,DMSO-d6)δ9.71(s,1H),8.64(dd,J=8.3,1.3Hz,1H),8.25(dd,J=8.3,1.2Hz,1H),8.03-7.98(m,1H),7.95-7.88(m,3H),7.62-7.59(m,2H),7.58-7.51(m,2H),7.47(ddd,J=8.2,6.8,1.4Hz,1H),5.88(s,1H),1.28(s,9H).13C NMR(101MHz,DMSO)δ164.79,152.78,145.94,136.83,135.91,134.48,134.05,130.76,128.59,126.82,126.49,126.45,126.27,125.44,124.52,124.13,114.84,111.57,91.66,32.77,30.70.HRMS m/z(ESI)calcd forC24H23N4[M+H]+367.1917 found:367.1916,calcd for C24H22N4Na[M+Na]+389.1737 found:389.1738.
化合物N-(2-(叔丁基)吡唑并[1,5-a]喹唑啉-5-基)苯并[d]噻唑-5-胺(26b)的制备
目标化合物26b
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和1,3-苯并噻唑-5-胺(25b,30.0mg,0.2mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.40(s,1H),8.80(d,J=2.0Hz,1H),8.62(dd,J=8.4,1.3Hz,1H),8.27(dd,J=8.4,1.2Hz,1H),8.14(d,J=8.8Hz,1H),7.99-7.88(m,2H),7.58(ddd,J=8.4,7.1,1.2Hz,1H),6.26(s,1H),1.37(s,9H).13C NMR(101MHz,DMSO)δ165.05,157.11,154.09,150.30,145.28,138.98,136.82,134.12,128.17,125.29,124.48,122.32,121.02,115.50,114.88,111.81,92.34,32.89,30.76.HRMS m/z(ESI)calcd for C21H20N5S[M+H]+374.1434 found:374.1434,calcd for C21H19N5SNa[M+Na]+396.1253 found:396.1255.
化合物2-(叔丁基)-N-(吡啶-2-基)吡唑并[1,5-a]喹唑啉-5-胺(26c)的制备
目标化合物26c
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和吡啶-2-胺(25c,18.8mg,0.2mmol)制备目标化合物,收率67%。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.68(dd,J=8.3,1.2Hz,1H),8.47-8.36(m,2H),8.27(dd,J=8.3,1.2Hz,1H),7.91(ddd,J=8.4,7.2,1.2Hz,1H),7.85(ddd,J=9.0,7.3,1.9Hz,1H),7.52(ddd,J=8.3,7.2,1.3Hz,1H),7.12(ddd,J=7.3,5.0,0.9Hz,1H),6.30(s,1H),1.37(s,9H).13C NMR(101MHz,DMSO)δ165.11,153.34,149.64,148.25,144.84,138.17,136.84,134.32,125.80,124.65,119.13,115.54,114.72,111.73,92.77,32.90,30.76.HRMS m/z(ESI)calcd for C19H20N5[M+H]+318.1713 found:318.1712,calcd forC19H19N5Na[M+Na]+340.1533 found:340.1549.
化合物4-((2-(叔丁基)吡唑并[1,5-a]喹唑啉-5-基)氨基)-N-(2,6-二甲氧基嘧啶-4-基)苯磺酰胺(26e)的制备
目标化合物26e
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和磺胺二甲氧嘧碇(25e,62.0mg,0.2mmol)制备目标化合物,收率53%。1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),9.80(s,1H),8.61-8.51(m,1H),8.28(dd,J=8.4,1.2Hz,1H),8.19-8.10(m,2H),7.94(dd,J=8.9,2.4Hz,2H),7.62-7.51(m,2H),6.31(s,1H),6.01(s,1H),3.81(s,3H),3.80(s,3H),1.37(s,9H).13C NMR(101MHz,DMSO)δ172.16,165.13,160.49,153.82,149.64,144.97,144.72,136.85,134.37,129.80,128.56,125.43,124.54,120.66,114.87,112.93,111.76,92.93,85.05,54.98,54.25,32.89,30.73.HRMS m/z(ESI)calcd for C26H28N7O4S[M+H]+534.1918 found:534.1923,calcd forC26H27N7O4SNa[M+Na]+556.1737 found:556.1740.
化合物4-((2-(叔丁基)吡唑并[1,5-a]喹唑啉-5-基)氨基)-N-(6-甲氧基嘧啶-4-基)苯磺酰胺(26f)的制备
目标化合物26f
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和磺胺间甲氧嘧啶(25f,56.0mg,0.2mmol)制备目标化合物,收率56%。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),9.78(s,1H),8.56(dd,J=8.4,1.2Hz,1H),8.43(d,J=1.0Hz,1H),8.27(dd,J=8.4,1.2Hz,1H),8.16-8.10(m,2H),7.97-7.87(m,3H),7.57-7.52(m,1H),6.38(d,J=1.0Hz,1H),6.30(s,1H),3.85(s,3H),1.37(s,9H).13C NMR(101MHz,DMSO)δ170.37,165.13,159.26,159.14,153.80,149.66,144.74,136.86,134.37,129.64,128.30,125.44,124.55,120.71,114.87,113.01,111.77,92.91,91.39,54.56,32.90,30.75.HRMS m/z(ESI)calcd for C25H26N7O3S[M+H]+504.1812 found:502.1813,calcd for C25H25N7O3SNa[M+Na]+526.1632 found:526.1639.
化合物4-((2-(叔丁基)吡唑并[1,5-a]喹唑啉-5-基)氨基)-N-(4,6-二甲基嘧啶-2-基)苯磺酰胺(26g)的制备
目标化合物26g
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和磺胺二甲嘧啶(25g,55.6mg,0.2mmol)制备目标化合物,收率69%。1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.73(s,1H),8.56(d,J=8.3Hz,1H),8.27(dd,J=8.4,1.2Hz,1H),8.09(d,J=8.9Hz,2H),8.03-7.96(m,2H),7.66-7.62(m,1H),6.74(s,1H),6.59-6.53(m,1H),6.28(s,1H),2.28(s,3H),2.25(s,3H),1.36(s,9H).13C NMR(101MHz,DMSO)δ165.10,157.13,153.33,149.72,144.81,136.85,134.34,130.75,129.36,125.42,124.55,120.17,114.87,112.30,111.77,92.83,32.90,30.75,23.57.HRMS m/z(ESI)calcd for C26H28N7O2S[M+H]+502.2020 found:502.2017,calcd for C26H27N7O2SNa[M+Na]+524.1839 found:524.1852.
化合物2-((2-(2-叔丁基)吡唑并[1,5-a]喹唑啉-5-基)氨基)噻唑-4,5-二羧酸二乙酯(26h)的制备
目标化合物26h
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和2-氨基噻唑-4,5-二羧酸二乙酯(25h,48.8mg,0.2mmol)制备目标化合物,收率59%。1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.78(d,J=8.2Hz,1H),8.32(d,J=8.4Hz,1H),7.97(dd,J=8.7,7.1Hz,1H),7.57(ddd,J=8.4,7.1,1.2Hz,1H),6.57(s,1H),4.34(dq,J=19.8,7.1Hz,4H),1.40(s,9H),1.36-1.28(m,6H).13C NMR(101MHz,DMSO)δ165.53,163.99,161.82,161.13,146.91,143.25,136.78,135.09,125.43,125.06,119.57,114.95,110.64,93.40,62.15,61.82,33.03,30.72,14.56,14.39.HRMS m/z(ESI)calcd for C23H26N5O4S[M+H]+468.1700 found:468.1703,calcd for C23H25N5O4SNa[M+Na]+490.1519 found:490.1533.
化合物2-(叔丁基)-N-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)吡唑并[1,5-a]喹唑啉-5-胺(26i)的制备
目标化合物26i
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和5-氨基-3-叔丁基-1-甲基吡唑(25i,30.6mg,0.2mmol)制备目标化合物,收率71%。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.41(dd,J=8.2,1.2Hz,1H),8.24(dd,J=8.4,1.1Hz,1H),7.91(ddd,J=8.3,7.2,1.1Hz,1H),7.54(ddd,J=8.3,7.2,1.2Hz,1H),6.17(s,1H),6.12(s,1H),3.60(s,3H),1.33(s,9H),1.28(s,9H).13C NMR(101MHz,DMSO)δ164.95,159.08,151.30,145.54,137.52,136.77,134.25,125.25,124.57,114.87,111.07,98.07,92.20,35.97,32.82,32.39,30.89,30.71.HRMS m/z(ESI)calcdfor C22H29N6[M+H]+377.2448 found:377.2450,calcd for C22H28N6Na[M+Na]+399.2268found:399.2278.
化合物2-(叔丁基)-N-(3-(叔丁基)-1-苯基-1H-吡唑-5-基)吡唑并[1,5-a]喹唑啉-5-胺(26j)的制备
目标化合物26j
使用制备化合物8h所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和5-氨基-3-叔丁基-1-苯基吡唑(25j,43.0mg,0.2mmol)制备目标化合物,收率68%。1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.32(d,J=8.2Hz,1H),8.21(d,J=8.4Hz,1H),7.89(t,J=7.8Hz,1H),7.61-7.55(m,2H),7.51(t,J=7.7Hz,1H),7.35(t,J=7.9Hz,2H),7.25-7.18(m,1H),6.42(s,1H),6.11(s,1H),1.35(s,9H),1.31(s,9H).13C NMR(101MHz,DMSO)δ164.95,161.30,151.71,145.50,139.82,137.35,136.69,134.34,129.39,129.33,127.04,125.00,124.68,123.09,114.89,111.01,101.89,92.30,32.81,32.68,30.70.HRMS m/z(ESI)calcd for C27H31N6[M+H]+439.2605 found:439.2614,calcdfor C27H30N6Na[M+Na]+461.2424 found:461.2426.
化合物2-(叔丁基)-5-(呋喃-2-基甲氧基)吡唑并[1,5-a]喹唑啉(27a)的制备
目标化合物27a
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和2-羟甲基呋喃(9a,23.5mg,0.24mmol)制备目标化合物,收率61%。1H NMR(400MHz,CDCl3)δ8.32(d,J=8.2Hz,1H),8.05(dd,J=8.1,0.9Hz,1H),7.81-7.66(m,1H),7.38-7.29(m,2H),6.42-6.40(m,2H),6.33(s,1H),5.64(s,2H),1.43(s,9H).HRMS m/z(ESI)calcd for C19H20N3O2[M+H]+322.1550 found:322.1557.
化合物2-(叔丁基)-5-(吡啶-2-基甲氧基)吡唑并[1,5-a]喹唑啉(27c)的制备
目标化合物27c
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和2-吡啶甲醇(9c,26.2mg,0.24mmol)制备目标化合物,收率43%。1H NMR(400MHz,CDCl3)δ8.34(d,J=8.2Hz,1H),8.07(dd,J=8.0,1.4Hz,1H),7.98(dd,J=8.2,1.0Hz,1H),7.86-7.64(m,1H),7.49-7.38(m,2H),7.21-7.03(m,2H),6.43(s,1H),5.54(s,2H),1.26(s,9H).HRMS m/z(ESI)calcd for C20H21N4O[M+H]+333.1710 found:333.1831.
化合物2-(叔丁基)-5-((3,5,6-三甲基吡嗪-2-基)甲氧基)吡唑并[1,5-a]喹唑啉(27d)的制备
目标化合物27d
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和(3,5,6-三甲基吡嗪-2-基)甲醇(9d,36.5mg,0.24mmol)制备目标化合物,收率45%。1H NMR(400MHz,CDCl3)δ8.33(d,J=8.3Hz,1H),8.05(dd,J=8.1,0.9Hz,1H),7.82-7.69(m,1H),7.39-7.28(m,1H),6.33(s,1H),5.64(s,2H),2.65(s,3H),2.56(s,3H),2.54(s,3H),1.43(s,9H).13C NMR(101MHz,CDCl3)δ165.50,157.60,151.31,149.63,149.11,145.41,144.36,137.72,133.73,125.43,123.91,114.70,111.39,93.53,67.60,32.85,30.50,21.68,21.46,20.68.HRMS m/z(ESI)calcd for C22H26N5O[M+H]+376.2132 found:376.2131,calcd for C22H25N5ONa[M+Na]+398.1951 found:398.1950.
化合物2-(叔丁基)-5-(萘-2-基甲氧基)吡唑并[1,5-a]喹唑啉(27g)的制备
目标化合物27g
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和2-萘甲醇(9g,37.9mg,0.24mmol)制备目标化合物,收率41%。1H NMR(400MHz,CDCl3)δ8.35(d,J=8.3Hz,1H),8.15(dd,J=8.1,0.9Hz,1H),7.98(s,1H),7.87(dt,J=7.2,6.7Hz,3H),7.82-7.75(m,1H),7.64(dd,J=8.4,1.5Hz,1H),7.54-7.45(m,2H),7.37(dd,J=11.3,4.0Hz,1H),6.35(s,1H),5.74(s,2H),1.44(s,9H).13C NMR(101MHz,CDCl3)δ165.52,157.95,144.56,137.77,133.83,133.70,133.28,133.17,128.38,128.00,127.76,127.17,126.30,126.22,125.91,125.47,123.92,114.71,111.66,93.46,68.58,32.87,30.52.HRMS m/z(ESI)calcd for C25H24N3O[M+H]+382.1914 found:382.1922,calcd for C25H23N3ONa[M+Na]+404.17230 found:404.1733.
化合物2-(叔丁基)-5-([1,1'-联苯]-4-基甲氧基)吡唑并[1,5-a]喹唑啉(27h)的制备
目标化合物27h
使用制备化合物10a所述的方法,以中间体化合物5-氯-2-叔丁基吡唑并[1,5-a]喹唑啉(17,51.8mg,0.2mmol)和4-联苯甲醇(9h,44.2mg,0.24mmol)制备目标化合物,收率37%。1H NMR(400MHz,CDCl3)δ8.37(d,J=8.3Hz,1H),8.15(dd,J=8.1,1.0Hz,1H),7.81-7.75(m,1H),7.62(ddd,J=8.3,5.6,2.1Hz,6H),7.45(dd,J=10.3,4.8Hz,2H),7.40-7.33(m,2H),6.34(s,1H),5.62(s,2H),1.44(s,9H).13C NMR(101MHz,CDCl3)δ165.50,157.96,144.57,141.20,140.76,137.74,135.40,133.72,128.83,128.81,128.66,127.44,127.35,127.16,125.48,123.95,114.74,111.66,93.49,68.19,32.89,30.55.HRMS m/z(ESI)calcdfor C27H26N3O[M+H]+408.2070 found:408.2070,calcd for C27H25N3ONa[M+Na]+430.1890found:430.1907.
以下通过实验例证明本发明化合物的有益效果。
实施例1化合物的酶活性激动实验
本实验的目的是检测化合物在体外对组蛋白去乙酰化酶SIRT6的激动活性。本实验采用荧光强度检测方法,对SIRT6进行体外活性激动测试。受试化合物的SIRT6激动活性用EC1.5(半数激动浓度或受试化合物在40μM浓度下对SIRT6活性的激活率)来表示。EC1.5值可通过受试化合物在一系列不同浓度下对SIRT6的激活率计算获得。
1.1实验材料
人源SIRT6酶(用载体pQE80L.1在大肠杆菌M15[pREP4]中构建)、缓冲液为改进的Buffer、100%DMSO(二甲基亚砜)、NAD(烟酰胺腺嘌呤二核苷酸)、乙酰化的多肽底物、胰蛋白酶和酶标仪(Synergy MX),CM5传感器芯片,Biacore X100仪器(GE Healthcare),RT-PCR检测系统(BIO-RAD CFX96),MicroCal iTC200仪器,以上实验仪器均为四川大学生物治疗国家重点实验室提供。
所有的受试吡唑并[1,5-a]喹唑啉衍生物以及阳性化合物MDL-800为发明合成所得。其中,化合物21q和MDL-800的结构式为:
体外实验时将待测化合物用100%DMSO配制成10mM储存液,置-20℃冰箱避光保存备用,临用时用完全培养液稀释至所需浓度。
1.2测试方法
1.2.1蛋白的表达和纯化
在大肠杆菌M15[pREP4]中使用载体pQE80L.1表达N末端his标记的人SIRT6构建体。基本上如文献所述的方法表达和纯化蛋白质。将纯化的SIRT6蛋白质储存在缓冲液中,温度-80℃。
1.2.2体外测试化合物对SIRT6的激动活性(FDL实验)
SIRT6去乙酰化,在黑色半体积96孔板中,将内部重组SIRT6与测定缓冲液在37℃保持15分钟。向混合物中加入底物S5(Ac-RYQK(Ac)-AMC)。然后加入NAD,开始反应并在37℃下孵育120分钟。接下来,添加含有胰蛋白酶,烟酰胺的显影剂溶液,并在室温下孵育30分钟,并使用Bio-Tek(Bio-Tek)分别测量激发和发射波长380和440nm的荧光。对于SIRT6去肉豆蔻酰化,将内部重组SIRT6与缓冲液和二硫苏糖醇混合物置于黑色半体积96孔板中于37℃保持20分钟。该混合物含有MAcALPK(MyrK)-AMC肽,加入NAD。开始反应并在37℃下孵育120分钟。接下来,添加含有胰蛋白酶,烟酰胺的显影剂溶液,并在37℃下孵育120分钟,并使用Bio-Tek(Bio,激发和发射波长分别为380和440nm测量荧光)。将实验数据拟合在GraphPad Prism中以使用以下等式获得抑制或活性值:抑制%=(max-信号)/(max-min)*100或活性%=信号/(max-min)*100。
1.2.3等温滴定量热法(ITC)测定
在25℃条件下,等温滴定量热法的实验在MicroCal iTC200仪器中进行。将蛋白质注射到含有活化剂的反应池中进行滴定。通过结合等温线的非线性回归分析提取热力学结合参数(MicroCal Origin软件)。应用单点结合模型产生焓变,反应熵变,化学计量和平衡解离常数(Kd)。
1.3化合物的激动能力测试结果
表1化合物6a-f的结构和活性
表2化合物8a-o的结构和活性
表3化合物10a-h的结构和活性
表4化合物19a-o的结构和活性
表5化合物21a-y的结构和活性
表6化合物22a-h的结构和活性
表7化合物24a-g的结构和活性
表8化合物26a-j的结构和活性
表9化合物27a-h的结构和活性
表1~9中,“/”前的值为%Effect@40μM,“/”后的值为EC1.5;“%Effect@40μM”表示待测化合物在40μM浓度下对SIRT6活性的激活率;“EC1.5”表示半数激动浓度,单位为μM。
上述实验结果表明,本发明制得的化合物在体外对组蛋白去乙酰化酶SIRT6具有优异的激动活性。
本发明利用ITC实验和细胞MTT实验对优选化合物21q进行初步药理活性验证的结果如图3和图4所示。在FDL实验中(见1.2.2),使用肉豆蔻酰化的底物Ac-EALPKK(Myr)-AMC测定化合物21q对SIRT6的去肉豆蔻酰化的活性,EC1.5的值为0.78μM(图3);在ITC实验中,化合物21q的KD值为20μM(图4)。
上述结果说明,本发明的提供的吡唑并[1,5-a]喹唑啉衍生物对SIRT6的去肉豆蔻酰化具有优异的活性,对组蛋白去乙酰化酶SIRT6具有优异的激动活性,可以作为高活性和高选择性的SIRT6激动剂。
实施例2化合物21q对人胰腺癌细胞株PANC-1细胞的体外活性
本实验的目的是检测化合物21q在体外细胞上的抗恶性细胞增殖的活性。本实验采用实验室培养的人胰腺癌PANC-1细胞,加药处理一定时间后,用MTT(四甲基偶氮唑盐)比色法检测。
3.1实验材料
3.2实验方法
3.2.1细胞系及培养
人胰腺癌细胞系PANC-1购自American Type Culture Collection(ATCC,Rockville,MD,USA)。将其在补充有10%FBS(Gibco,Eggenstein,Germany),100单位/mL青霉素(Sigma-Aldrich)和链霉素(Sigma)的DMEM中培养,并在具有湿润的5%CO2气氛的37℃培养箱中维持。
3.2.2 MTT法
将多种人胰腺癌细胞一式三份接种在96孔板中(3000细胞/孔,用于人PANC-1细胞),用指定浓度的21q或其他试剂处理72小时,用MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物)测定细胞存活率(Sigma-Aldrich,St.Louis,MO)测定。通过Graph PadPrism软件计算IC50值。
3.3实验结果
本发明进一步验证了化合物21q在胰腺癌细胞中的活性。在细胞实验中,化合物21q对胰腺癌细胞PANC-1有良好的抑制作用,其IC50值为19.36μM(图5),抑制作用优于阳性对照化合物MDL-800(IC50值为35.19μM)。
上述实验结果表明,本发明提供的吡唑并[1,5-a]喹唑啉骨架类衍生物能够有效抑制人胰腺癌细胞的增殖。
综上,本发明提供了一种式I所示的吡唑并[1,5-a]喹唑啉类骨架衍生物。该吡唑并[1,5-a]喹唑啉衍生物对组蛋白去乙酰化酶SIRT6的去肉豆蔻酰化具有优异的活性,对SIRT6具有优异的激动活性,可以作为高活性和高选择性的SIRT6激动剂。而且,该化合物还能效抑制人胰腺癌细胞的增殖,在制备预防和/或治疗与SIRT6活性有关疾病(特别是胰腺癌)的药物中具有广阔的应用前景。
Claims (5)
1.一种化合物、或其药学上可接受的盐,其特征在于:所述化合物的结构如式II-1、II-2或II-3所示:
其中,R3a、R3b、R3c各自独立的选自L1R3d,其中,L1为0~2个亚甲基,R3d选自被1~3个取代基取代的6元芳基、6元杂芳基、杂稠环基或杂螺环基,且所述杂稠环基或杂螺环基中,至少1个环为不饱和环;所述杂稠环基为所述取代基各自独立的选自H、卤素、C1~4烷基、C1~4烷氧基、羧基、OL2R3e、COOR3f或SO2R3g,其中,L2为0~2个亚甲基,R3e为苯环,R3f为C1~4烷基,R3g为苯环;
当R3d选自被1~3个取代基取代的6元芳基时,所述取代基不为H;
或者,所述化合物的结构如式III-1、III-2或III-3所示:
其中,R4a、R4b、R4c各自独立的选自L3R4d,其中,L3为被C1~2烷基取代或未取代的0~3个亚甲基,R4d选自被1~3个取代基取代的NR4eR4f、C1~3烷基、5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基、稠环烷基、杂稠环基或杂桥环基;所述稠环烷基为所述杂桥环基为R4e、R4f各自独立的选自C1~2烷基;所述取代基各自独立的选自H、卤素、苯环、羟基、C1~4烷基、C1~4烷氧基、羧基、L4R4g、OL5R4h、COOL6R4i或SO2NHR4j,其中,L4、L5、L6各自独立的选自0~2个亚甲基,R4g、R4h、R4i各自独立的选自苯环、6元饱和杂环、C1~4烷基、C1~4烷氧基或卤素,R4j选自被0~3个R4k取代的所述R4k选自C1~3烷氧基或C1~3烷基;
当R4d为被1~3个取代基取代的NR4eR4f时,L3不为0个亚甲基;
或者,所述化合物的结构如式IV-1、IV-2或IV-3所示:
其中,R5a、R5b、R5c各自独立的选自L7R5e,其中,L7为1个亚甲基,R5e选自被1~3个取代基取代的5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基或萘基;所述取代基各自独立的选自H、卤素、卤代或未卤代的C1~4烷基、卤代或未卤代的C1~4烷氧基、苯基。
3.一种药物组合物,其特征在于:所述药物组合物是以权利要求1~2任一项所述的化合物、或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制得的制剂。
4.权利要求1~2任一项所述化合物、或其药学上可接受的盐在制备SIRT6激动剂中的用途。
5.根据权利要求4所述的用途,其特征在于:所述SIRT6激动剂为预防和/或治疗SIRT6介导的相关疾病的药物,所述SIRT6介导的相关疾病选自胰腺癌或肝癌。
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