CN104844573A - 嘧啶类btk抑制剂、其制备方法及医药用途 - Google Patents
嘧啶类btk抑制剂、其制备方法及医药用途 Download PDFInfo
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Abstract
本发明属于药物领域,具体涉及一种具有式(1)结构的嘧啶类化合物或其药学上可接受的盐、其制备方法以及在制备抗肿瘤药物中的应用。药理实验结果表明,该类化合物对Bruton酪氨酸激酶(BTK)具有良好的抑制作用,并且可以抑制多种B细胞淋巴瘤细胞的增殖,因此可作为BTK抑制剂用于制备抗肿瘤药物。
Description
技术领域
本发明属于药物领域,具体涉及一种嘧啶类化合物、其制备方法以及医药用途,特别是在制备治疗B细胞淋巴瘤的药物中的应用。
技术背景
蛋白激酶是一类能催化三磷酸腺苷(ATP)γ-磷酸基转移到底物蛋白中相应氨基酸残基上的酶家族。蛋白激酶参与几乎所有真核细胞的信号转导通路,在细胞生长、增殖、分化以及凋亡等过程中具有重要的调控作用。蛋白激酶的持续激活会导致其下游信号通路过度活化,引起细胞分化增殖发生紊乱,从而造成如炎症、癌症等许多疾病的发生与发展(Nat Rev Drug Discov,2002,1(4):309-315)。
Bruton酪氨酸激酶(BTK)是非受体酪氨酸蛋白激酶Tec家族中的一员,主要由Pleckstrin homology(PH)结构域、Tec homology(TH)结构域、Src homology 3(SH3)结构域、SH2和SH1结构域组成(Future Med Chem,2014,6(6):675-695)。BTK作为B细胞受体信号转导通路的重要组成部分,在B细胞的发育、成熟、分化和增殖等诸多生理过程中发挥极其重要的作用(Nature,1993,361(6409):226-233)。研究表明,BTK的持续激活与B细胞淋巴瘤及炎症的发生和发展密切相关,因此,BTK已成为目前B细胞淋巴瘤和炎症治疗领域中的一个靶标(Nat Rev Cancer,2005,5(4):251-262)。
Ibrutinib是由Pharmacyclics和强生公司联合开发的一种口服有效、高选择性和高活性的不可逆BTK抑制剂,已分别于2013年11月和2014年2月获得FDA批准用于治疗套细胞淋巴瘤和慢性淋巴性白血病,它是目前唯一一个上市的BTK抑制剂。此外,至今还有CC-292和ONO-4059等BTK抑制剂正在开展治疗B细胞淋巴瘤的临床研究。然而,目前具有良好成药性的BTK抑制剂种类较少,且结构单一,加上Ibrutinib在临床使用过程中已出现耐药现象,因此,研发新的BTK抑制剂具有重要的意义。
发明内容
本发明公开了一种嘧啶类化合物或其药学上可接受的盐、其制备方法以及医药用途。药理实验结果表明,该类化合物对BTK具有良好的抑制作用,并且可以抑制多种B细胞淋巴瘤细胞的增殖,因此可作为BTK抑制剂用于制备抗肿瘤药物。
本发明公开通式(I)所示的嘧啶类化合物或其药学上可接受的盐:
其中:
X为CH2、O、S或NH;
R1为氢、卤素或NR4R5;
R2为(C1-C8)烷基、(C3-C6)环烷基、(C1-C8)烷氧基(C1-C8)烷基、(C6-C10)芳基或(C5-C10)芳杂环基,其中所述的芳基和芳杂环基可任选地用一个至五个以下基团取代:卤素、硝基、氰基、羟基、氨基、(C1-C8)烷基、(C1-C8)烷氧基或(C3-C6)环烷基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、(C1-C6)烷基、(C3-C6)环烷基、或R4和R5与跟它们连接的氮原子一起形成5-7元杂环基团,其中所述的杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子。
进一步地,具有通式(I)所示的嘧啶类化合物或其药学上可接受的盐,其特征在于:
X为CH2、O或NH;
R1为卤素或NR4R5;
R2为(C1-C8)烷基、(C6-C10)芳基或(C5-C10)芳杂环基,其中所述的芳基和芳杂环基可任选地用一个至五个以下基团取代:卤素、硝基、氰基、羟基、氨基、(C1-C8)烷基、(C1-C8)烷氧基或(C3-C6)环烷基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、(C1-C6)烷基、或R4和R5与跟它们连接的氮原子一起形成5-7元杂环基团,其中所述的杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子。
进一步地,具有通式(I)所示的嘧啶类化合物或其药学上可接受的盐,其特征在于:
X为O;
R1为氯、氨基、甲胺基、乙胺基、异丙胺基、二甲胺基或哌啶基;
R2为乙基或苯基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、甲基、乙基、异丙基、或R4和R5与跟它们连接的氮原子一 起形成6元哌啶环。
具体来说,通式(I)所示的嘧啶类化合物优选自下列化合物:
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-1);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-2);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-3);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-4);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-5);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-哌啶基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-6);
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-7);
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-8);
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-9);
1-[4-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-10);
1-[4-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-11);
1-[4-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-12);
1-[4-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-13);
1-[4-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-14);
1-[4-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-15);
1-[4-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-16);
1-[4-[[5-(4-乙氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮)(LX-17);
1-[4-[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-18);
1-[4-[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-19);
1-[4-[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-20);
1-[4-[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-21);
1-[4-[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-22);
1-[4-[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-23);
1-[4-[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-24);
1-[4-[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-25);
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-26);
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基)哌嗪-1-基]-2-丙烯-1-酮(LX-27);
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-28);
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-29);
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-30);
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-31);
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-32);
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-33)。
下面药理实验中涉及的化合物代号等同于此处代号所对应的化合物。
本发明的另一目的在于提供通式(I)所示化合物的制备方法,其特征在于:
a)当R3为时,通式(I)所示化合物的制备方法为:以4,6-二羟基嘧啶为原料,经Vilsmeier-Haack反应和氯代反应一锅法制得4,6-二氯-5-嘧啶甲醛1,1经次氯酸钠氧化制得4,6-二氯-5-嘧啶羧酸2,2与草酰氯反应制得酰氯中间体后分别与二苯醚和苯乙醚进行Friedel-Crafts酰基化反应制得(4,6-二氯嘧啶-5-基)(4-苯氧苯基)甲酮3a和(4,6-二氯嘧啶-5-基)(4-乙氧苯基)甲酮3b,3a-b与(R)-1-Boc-3-氨基哌啶反应制得4a-b,4a-b与胺类化合物反应制得5a-g,5a-g经脱Boc保护基制得6a-g,6a-g与丙烯酰氯反应制得LX-2-LX-6、LX-8和LX-9;其合成路线如下:
其中,R4和R5的定义如权利要求1所述,其中,R4和R5同时为H的化合物除外;
b)当R1为NH2,R3为时,通式(I)所示化合物的制备方法为:中间体3a-b与氨水反应制得7a-b,7a-b与(R)-1-Boc-3-氨基哌啶反应制得8a-b,8a-b脱Boc保护得到9a-b,9a-b与丙烯酰氯反应最后得到LX-1和LX-7;其合成路线如下:
c)当R3为时,通式(I)所示化合物的制备方法为:7a在缚酸剂DIPEA的作用下与1-Boc-4-氨基哌啶反应制得11a;3a-b与1-Boc-4-氨基哌啶反应制得10a-b,10a-b与胺类化合物在乙醇中回流反应制得11b-h,11a-h脱Boc保护基制得12a-h,12a-h与丙烯酰氯反应制得LX-10-LX-17;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
d)当R3为时,通式(I)所示化合物的制备方法为:中间体3a-b与胺反应制得13b-d和13f-h,13b-d或13f-h与无水哌嗪反应制得14a-h,14a-h与丙烯酰氯反应制得LX-18-LX-25;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
e)当R3为时,通式(I)所示化合物的制备方法为:以邻溴硝基苯为起始原料,与无水哌嗪反应制得15,15经Boc保护制得化合物16,16经过还原得到芳胺17,17与中间体3a-b发生反应制得化合物18a-b,18a-b与胺类化合物反应得到化合物19a-g,19a-g脱Boc保护基制得化合物20a-g,20a-g与丙烯酰氯反应制得LX-27-LX-33;此外,18a直接脱Boc得到另一中间体21,21与丙烯酰氯反应制得LX-26;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
制备18a-b所示化合物的特征在于,所用溶剂为二甲基亚砜或N,N-二甲基甲酰胺,温度为100-120℃,反应时间为3-6小时。
本发明的进一步目的在于提供一种药物组合物,由治疗上有效量的权利要求1-4中任一项的化合物或其药学上可接受的载体或者辅料组成。
本发明的再一目的是提供具有通式(I)的化合物或其药学上可接受的盐在抗肿瘤和炎症方面的应用,其中所述的肿瘤为B细胞淋巴瘤,其中包括慢性淋巴性白血病、套细胞淋巴瘤、小淋巴细胞性肿瘤、弥漫性大B细胞淋巴瘤或多发性骨髓瘤。
本发明化合物的药理实验方法与结果如下:
1.BTK酶抑制活性测试
实验方法:采用Z-Lyte荧光共振能量转移法进行BTK抑制活性测试,阳性对照药为Ibrutinib。
实验材料:蛋白激酶BTK及其相应的底物试剂盒(Life technologies,USA);Envision Multilabel Reader多功能酶标仪(PerkinElmer,USA);Echo520超声波微量液体转移系统(Labcyte,USA)。
实验步骤:
1)在384微孔板内加入5μL适量的蛋白激酶与5μL相应底物(反应终浓度为2μM)的混合液,然后用Echo520超声波微量液体转移系统加入一系列梯度稀释的化合物,最后加入相应浓度的ATP,振荡混匀5min后,置于29℃恒温箱内反应1.5h;
2)加入5μL相应浓度的检测液,振荡混匀5min,置于29℃恒温箱内反应1h;
3)加入5μL终止液,振荡混匀后用Envision Multilabel Reader多功能酶标仪进行检测,激发光波长为400nm,发射光波长分别为445nm和520nm;
4)根据荧光比值计算化合物对酶反应的抑制率;
5)根据初筛结果,选择抑制率大于50%的目标化合物,梯度稀释10个浓度双孔复筛。GraphPad Prism5.0软件计算各化合物的IC50值。实验结果如表1和表2所示。
表1 本发明化合物对BTK的抑制率(10μM)
表2 本发明部分化合物对BTK半数抑制浓度
实验结果表明,本发明化合物对BTK激酶具有不同程度的抑制活性,其中化合物LX-1的活性最强。
2.细胞增殖的抑制活性
采用四甲基氮唑蓝比色法(MTT)评价本发明部分化合物对4种人B细胞淋巴瘤细胞株增殖的抑制活性。MTT法已广泛用于大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感测定等。
B细胞淋巴瘤细胞株:人弥漫性大B细胞淋巴瘤(Pfeiffer细胞)、人滤泡性淋巴瘤(DoHH2细胞)、套细胞淋巴瘤(JeKo-1细胞)和生发中心B细胞样弥漫性大B细胞淋巴瘤(WSU-NHL细胞)。
实验方法:取对数生长期的细胞配成4.5×105/mL细胞悬液,接种至96孔培养板中,每孔180μL,每组设5个平行孔,分别加入不同浓度受试物各20μL。置于恒温CO2培养箱中培养48小时,将四甲基氮唑蓝加入96孔板中,每孔20μL,继续培养4小时。吸去上清液,加入DMSO,每孔150μL,平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度,以上实验各重复3次。计算细胞增殖抑制率(抑制率%=(阴性对照组OD值-受试组OD值)/阴性对照组OD值×100%),根据抑制率建立直线回归方程求得半数抑制浓度IC50值。结果见表3。
表3 本发明部分化合物对BTK细胞抑制活性(IC50:μM)
实验结果表明,本发明化合物对B细胞淋巴瘤具有不同程度的抑制活性,其中化合物LX-1对所有测试的人源性B细胞淋巴瘤增殖均有良好的抑制作用。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
实施例1
4,6-二氯-5-嘧啶甲醛(1)的制备
将DMF(5.50mL,71.34mmol)于冰浴下缓慢滴入POCl3(17.00mL,185.71mmol),搅拌反应1h,撤去冰浴,加入4,6-二羟基嘧啶(4.00g,35.68mmol),升温回流3h,冷却至室温,倒入冰水中,二氯甲烷萃取,减压浓缩,石油醚-乙酸乙酯(P∶E=4∶1(V∶V))重结晶,得黄色固体4.74g,收率75.4%,mp 68-70℃。ESI-MS:177[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):8.89(s,1H),10.43(s,1H)。
4,6-二氯-5-嘧啶羧酸(2)的制备
1(4.00g,22.72mmol)和NaH2PO4(9.55g,79.58mmol)溶于60mL叔丁醇和10mL水混合溶剂中,冰浴下加入NaClO2(7.66g,84.69mmol),反应1h,减压蒸去叔丁醇,倒入水中,盐酸调pH至5,乙酸乙酯萃取减压浓缩,得黄色固体3.12g,收率71.5%,mp 131-133℃。ESI-MS:190.9[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):9.00(s,1H).
(4,6-二氯嘧啶-5-基)(4-苯氧苯基)甲酮(3a)的制备
2(3.00g,15.63mmol)溶于20mL无水THF中,滴加草酰氯(4.00mL,46.87mmol)和2滴DMF,室温反应4h,减压蒸去溶剂和剩余的草酰氯,无水CH2Cl2溶解,移至恒压滴液漏斗,冰浴下滴加至二苯醚(12.40mL,8.31mmol)和AlCl3(3.12g,23.46mmol)的无水CH2Cl2中,滴毕,回流反应3h,倒入冰水,浓盐酸调pH至2,CH2Cl2萃取,无水硫酸镁干燥,柱层析纯化[石油醚∶乙酸乙酯(P∶E)=5∶1(V∶V)],得白色固体3.82g,收率71.1%,mp 91-93℃。ESI-MS:345[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):7.07(d,J=8.97Hz,2H),7.13(d,J=9.72Hz,2H),7.26(t,J=6.27Hz,1H),7.44(t,J=7.53Hz,2H),7.80(d,J=9.72Hz,2H),8.91(s,1H).
(4-氨基-6-氯嘧啶-5-基)(4-苯氧苯基)甲酮(7a)的制备
3a(1.0g,2.91mmol)加入25mL乙醇和氨水(8mL,52.0mmol),室温反应24h,冰浴冷却,抽滤,干燥,得白色固体0.51g,收率53.9%,mp 264-266℃。ESI-MS:324[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):7.07(d,J=8.82Hz,2H),7.16(d,J=7.68Hz,2H),7.28(t,J=7.35Hz,1H),7.35(br s,2H),7.49(t,J=7.86Hz,2H),7.84(d,J=8.79Hz,2H),8.32(s,1H).
(R)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8a)的制备
7a(0.27g,0.818mmol)溶于30mL乙醇中,加入(R)-1-Boc-3-氨基哌啶(0.25g,1.23mmol)和DIPEA(0.16mL,0.90mmol),回流反应48h,乙酸乙酯溶解,抽滤,柱层析纯化[P∶E=1∶1(V∶V)],得淡黄色固体0.27g,收率67.5%,mp 68-70℃。ESI-MS:512[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.16(t,J=6.96Hz,2H),1.22~1.24(m,2H),1.32(s,9H),1.49~1.51(m,1H),1.70~1.72(m,1H),2.24~2.26(m,1H),4.00~4.02(m,1H),6.76(s,2H),7.01(d,J=8.70Hz,2H),7.16(d,J=7.68Hz,3H),7.22(t,J=7.41Hz,1H),7.44(t,J=8.19Hz,2H),7.65(d,J=8.64Hz,2H),8.02(s,1H).
(R)-[4-氨基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(9a)的制备
8a(196mg,0.40mmol)溶于20mL CH2Cl2中,冰浴下加入TFA(0.3mL,4.0mmol),滴毕室温反应12h,减压浓缩,干燥,制得黄色固体140mg,收率92.5%,mp 90-92℃。ESI-MS:390[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.37~1.41(m,4H),2.23~2.25(m,1H),2.54(t,J=9.15Hz,1H),2.92(d,J=12.06Hz,1H),3.07(d,J=11.55Hz,1H),4.22(m,1H),6.78(s,2H),7.03(d,J=6.75Hz,2H),7.09(d,J=8.28Hz,2H),7.25(t,J=7.17Hz,1H),7.45(t,J=7.50Hz,2H),7.67(d,J=8.22Hz,2H),8.02(s,1H).
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-1)的制备
9a(0.19g,0.5mmol)溶于20mL CH2Cl2中,滴加丙烯酰氯(0.07mL,0.75mmol),室温反应3h,无水硫酸镁干燥,粗品加入适量硅胶搅拌30min,抽滤,滤液减压浓缩,得黄色固体0.14g,收率62.2%,mp 78-79℃。ESI-MS:444[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.23~1.25(m,2H),1.43~1.46(m,3H),1.77~1.79(m,1H),3.67~3.69(m,1H),3.74~3.76(m,1H),4.14~4.15(m,2H),5.62(d,J=9.23Hz,1H),6.03(d,J=16.32Hz,1H),6.55(dd,J1=6.96Hz,J2=15.38Hz,1H),6.76(s,2H),7.00(d,J=8.34Hz,2H),7.09(d,J=6.75Hz,2H),7.22(t,J=7.08Hz,1H),7.45(t,J=6.48Hz,2H),7.64(d,J=6.21Hz,2H),8.04(s,1H).
实施例2
(R)-3-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(4a)的制备
3a(6.00g,17.44mmol)和(R)-1-Boc-3-氨基哌啶(4.18g,20.88mmol)加入40mL乙醇和DIPEA(3.00mL,17.40mmol),室温反应24h。旋干溶剂,加水充分搅拌,抽滤,水洗,干燥得淡黄色固体8.67g,收率98.1%,mp 65-67℃。ESI-MS:531[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.21~1.23(m,4H),1.37(s,9H),1.56~1.58(m,1H),1.78~1.80(m,1H),2.69~2.72(m,2H),3.78~3.80(m,1H),7.06(d,J=7.32Hz,2H),7.16(d,J=7.62Hz,2H),7.29(t,J=6.51Hz,1H),7.47(t,J=7.32Hz,2H),7.83(d,J=7.38Hz,2H),8.44(s,1H).
(R)-3-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5a)的制备
4a(401mg,0.79mmol)、甲胺盐酸盐(167mg,2.47mmol)和DIPEA(0.15mL,0.87mmol)溶于25mL乙醇中,回流反应5h。旋干溶剂,乙酸乙酯溶解,抽滤,柱层析纯化[P∶E=1.5∶1(V∶V)],得黄色固体210 mg,收率52.9%,mp 58-60℃。ESI-MS:504[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.85(d,J=7.02Hz,1H),1.17~1.19(m,4H),1.32(s,9H),1.69~1.71(m,1H),2.24~2.26(m,1H),2.79(d,J=4.14,3H),3.48~3.50(m,1H),3.92~3.94(m,1H),6.76(s,2H),7.01(d,J=8.70Hz,2H),7.16(d,J=7.68Hz,3H),7.22(t,J=7.41Hz,1H),7.44(t,J=8.19Hz,2H),7.65(d,J=8.64Hz,2H),8.02(s,1H).
(R)-[4-甲胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(6a)的制备
参照9a的制备方法,由5a反应制得黄色固体,收率93.1%,mp 70-72℃。ESI-MS:404[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.10~1.12(m,2H),1.55~1.58(m,4H),2.43~2.46(m,1H),2.79(d,J=3.99Hz,3H),2.89(d,J=12.06Hz,1H),2.99(d,J=10.83Hz,1H),4.14~4.16(m,1H),6.81(d,J=7.29Hz,1H),7.01(d,J=8.07Hz,2H),7.08(d,J=7.62Hz,2H),7.24~7.26(m,2H),7.45(t,J=7.62Hz,2H),7.64(d,J=8.19Hz,2H),8.12(s,1H).
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-2)的制备
参照LX-1的制备方法,由6a与丙烯酰氯反应制得黄色固体,收率64.7%,mp 207-209℃。ESI-MS:458[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.19~1.21(m,2H),1.43~1.46(m,3H),1.74~1.76(m,1H),2.81(d,J=9.96Hz,3H),3.61~3.63(m,1H),3.73~3.75(m,1H),3.99~4.02(m,2H),5.60(d,J=10.44Hz,1H),6.03(d,J=16.65Hz,1H),6.59(dd,J1=6.60Hz,J2=9.78Hz,1H),6.75~6.77(m,1H),7.00(d,J=8.49Hz,2H),7.08(d,J=7.86Hz,2H),7.22(t,J=7.02Hz,1H),7.45(t,J=7.80Hz,2H),7.61(d,J=7.38Hz,2H),8.16(s,1H).
实施例3
(R)-3-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5b)的制备
参照5a的制备方法,由4a和乙胺盐酸盐反应制得黄色固体,收率60.0%,mp 63-65℃。ESI-MS:518[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.84~0.86(m,1H),0.99(t,J=7.02Hz,3H),1.22~1.24(m,4H),1.32(s,9H),1.47~1.49(m,1H),1.70~1.72(m,1H),2.24~2.26(m,1H),3.94~3.96(m,1H),7.01(d,J=8.67Hz,2H),7.07(d,J=7.86Hz,3H),7.21(t,J=6.93Hz,1H),7.44(t,J=7.68Hz,2H),7.62(d,J=8.25Hz,2H),8.11(s,1H).
(R)-[4-乙胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(6b)的制备
参照9a的制备方法,由5b反应制得黄色固体,收率95.3%,mp 67-69℃。ESI-MS:418[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.99(t,J=7.17Hz,3H),1.10~1.12(m,2H),1.47~1.50(m,6H),2.35(dd,J1=3.15Hz,J2=8.46Hz,1H),2.77~2.79(m,1H),2.91(dd,J1=3.04Hz,J2=9.18Hz,1H),4.06~4.08(m,2H),7.01(d,J=8.22Hz,2H),7.07~7.09(m,3H),7.25~7.27(m,2H),7.45(t,J=7.62Hz,2H),7.63(d,J=8.79Hz,2H),8.09(s,1H).
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-3)的制备
参照LX-1的制备方法,由6b与丙烯酰氯反应制得黄色固体,收率58.6%,mp 51-53℃。ESI-MS:472[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.98(t,J=6.96Hz,3H),1.21~1.23(m,2H),1.47~1.50(m,3H),1.75~1.76(m,1H),3.64~3.66(m,1H),3.72~3.75(m,1H),3.97~4.00(m,2H),5.62(d,J=10.28Hz,1H),6.03(d,J=16.02Hz,1H),6.60(dd,J1=6.14Hz,J2=10.05Hz,1H),6.74~6.76(m,1H),6.99(d,J=8.25Hz,2H),7.07(d,J=7.98Hz,2H),7.21~7.22(m,1H),7.44(t,J=7.62Hz,2H),7.61(d,J=7.50Hz,2H),8.14(s,1H).
实施例4
(R)-3-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5c)的制备
参照5a的制备方法,由4a和异丙胺反应制得黄色固体,收率53.2%,mp 57-59℃。ESI-MS:532[M+H]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):0.88~0.90(m,1H),1.12(d,J=6.99Hz,6H),1.23~1.26(m,4H),1.37(s,9H),1.50~1.52(m,1H),1.61~1.63(m,1H),2.24~2.26(m,1H),3.94~3.96(m,1H),7.01(d,J=8.67Hz,2H),7.04(d,J=6.46Hz,3H),7.21(t,J=6.85Hz,1H),7.42(t,J=7.35Hz,2H),7.82(d,J=7.26Hz,2H),8.25(s,1H).
(R)-[4-异丙胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(6c)的制备
参照9a的制备方法,由5c反应制得黄色固体,收率95.4%,mp 102-103℃。ESI-MS:432[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.01(d,J=7.23Hz,6H),1.21~1.23(m,1H),1.65~1.67(m,3H),2.44~2.46(m,1H),2.61~2.63(m,1H),3.09(dd,J1=3.36Hz,J2=6.15Hz,2H),4.22~4.24(m,2H),7.01~7.04(m,4H),7.20~7.21(m,1H),7.45(t,J=7.01Hz,2H),7.63(d,J=6.63Hz,2H),8.11(s,1H),8.89(br s,2H).
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-4)的制备
参照LX-1的制备方法,由6c与丙烯酰氯反应制得,收率57.4%,mp 57-59℃。ESI-MS:486[M+H]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.00(d,J=6.15Hz,6H),1.21~1.24(m,2H),1.42~1.46(m,4H),1.77~1.79(m,1H),3.67~3.69(m,2H),4.00~4.02(m,2H),4.22~4.24(m,1H),5.60(d,J=8.64Hz,1H),5.91(d,J=11.01Hz,1H),6.56(dd,J1=8.94Hz,J2=10.89Hz,1H),6.75~6.77(m,1H),7.00(d,J=8.07Hz,2H),7.05(d,J=7.44Hz,2H),7.18~7.20(m,1H),7.43(t,J=7.77Hz,2H),7.58(d,J=7.56Hz,2H),8.12(s,1H).
实施例5
(R)-3-[[5-(4-苯氧苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5d)的制备
参照5a的制备方法,由4a和二甲胺盐酸盐反应制得黄色固体,收率50.1%,mp 51-53℃。ESI-MS:540[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.40(s,9H),1.69~1.72(m,3H),1.99~2.01(m,1H),2.72(s,6H),3.20~3.22(m,2H),3.54~3.56(m,1H),3.84~3.86(m,1H),4.20~4.22(m,1H),6.95(d,J=8.22Hz,2H),7.05(d,J=7.47Hz,2H),7.21(t,J=5.55Hz,1H),7.39(t,J=7.14Hz,2H),7.59(d,J=5.97Hz,2H),8.21(s,1H),8.41(br s,1H).
(R)-[4-二甲胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(6d)的制备
参照9a的制备方法,由5d反应制得黄色固体,收率92.6%,mp 72-74℃。ESI-MS:418[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.66~1.68(m,3H),1.83~1.84(m,1H),2.02~2.04(m,1H),2.74(s,6H),3.07~3.09(m,2H),3.87~3.89(m,1H),4.27~4.29(m,1H),6.96(d,J=8.97Hz,2H),7.07~7.09(m,2H),7.20~7.21(m,1H),7.41(t,J=7.26Hz,2H),7.60(d,J=8.37Hz,2H),8.19(s,1H),8.50(d,J=7.26Hz,1H).
(R)-1-[-3-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-5)的制备
参照LX-1的制备方法,由6d与丙烯酰氯反应制得黄色固体,收率49.3%,mp 173-175℃。ESI-MS:472[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.23~1.52(m,4H),1.87~1.91(m,1H),2.64(s,6H),3.62~3.65(m,2H),3.89~3.91(m,1H),4.10~4.13(m,1H),5.60(d,J=10.68Hz,1H),5.96(d,J=16.59Hz,1H),6.60(dd,J1=6.12Hz,J2=7.92Hz,1H),7.01(d,J=8.01Hz,2H),7.11(d,J=7.20Hz,2H),7.19~7.21(m,1H),7.48(t,J=7.17Hz,2H),7.60(d,J=6.27Hz,2H),8.19(s,1H).
实施例6
(R)-3-[[5-(4-苯氧苯甲酰基)-6-哌啶基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5e)的制备
参照5a的制备方法,由4a和哌啶反应制得黄色固体,收率57.1%,mp 52-54℃。ESI-MS:558[M+H]+; 1H NMR(300MHz,CDCl3):δ(ppm):1.13~1.21(m,10H),1.37(s,9H),2.44~2.47(m,5H),3.53~3.56(m,4H),4.41~4.43(m,1H),6.98(d,J=7.87Hz,2H),7.05(d,J=8.55Hz,2H),7.18~7.20(m,1H),7.34(t,J=7.22Hz,2H),7.63(d,J=7.01Hz,2H),8.21(s,1H).
(R)-[4-哌啶基-6-(哌啶-3-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(6e)的制备
参照9a的制备方法,由5e反应制得黄色固体,收率95.2%,mp 89-90℃。ESI-MS:480[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.18~1.23(m,10H),2.52~2.55(m,5H),3.48~3.52(m,4H),4.41~4.42(m,1H),6.98(d,J=7.83Hz,2H),7.05(d,J=8.55Hz,2H),7.17~7.18(m,1H),7.39(t,J=7.29Hz,2H),7.61(d,J=7.05Hz,2H),8.16(s,1H),8.39(br s,1H).
(R)-1-[[3-[[5-(4-苯氧基苯甲酰基)-6-哌啶基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-6)的制备
参照LX-1的制备方法,由6e与丙烯酰氯反应制得黄色固体,收率49.1%,mp 53-55℃。ESI-MS:512[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.58~1.63(m,11H),3.23~3.26(m,3H),3.49~3.52(m,2H),4.34~4.39(m,4H),5.61(d,J=9.90Hz,1H),6.23(d,J=11.12Hz,1H),6.69(dd,J1=6.00Hz,J2=10.98Hz,1H),7.00(d,J=8.85Hz,2H),7.06(d,J=7.80Hz,2H),7.20~7.22(m,1H),7.39(q,J=7.80Hz,2H),7.59(d,J=8.31Hz,2H),8.23(s,1H),8.39(br s,1H).
实施例7
(4,6-二氯嘧啶-5-基)(4-乙氧苯基)甲酮(3b)的制备
参照3a的制备方法,由2和苯乙醚反应制得黄色固体,收率75.0%,mp 91-93℃。ESI-MS:319[M+Na]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.38(t,J=6.96Hz,3H),4.20(q,J=6.96Hz,2H),7.10(d,J=8.43Hz,2H),7.94(d,J=8.34Hz,2H),9.16(s,1H).
(4-氨基-6-氯嘧啶-5-基)(4-乙氧苯基)甲酮(7b)的制备
参照7a的制备方法,由3b和氨水反应制得白色固体,收率63.6%,mp 56-58℃。ESI-MS:276[M-H]-; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.35(t,J=6.96Hz,3H),4.14(q,J=6.96Hz,2H),7.07(d,J=8.94Hz,2H),7.32(br s,2H),7.84(d,J=9.00Hz,2H),8.32(s,1H).
(R)-3-[[6-氨基-5-(4-乙氧基苯甲酰基)嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8b)的制备
参照8a的制备方法,由7b和(R)-1-Boc-3-氨基哌啶反应制得黄色固体,收率60.3%,mp 89-91℃。ESI-MS:464[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.14~1.17(m,3H),1.17~1.19(m,2H),1.30(t,J=6.99Hz,3H),1.37(s,9H),1.47~1.49(m,1H),1.68~1.70(m,1H),2.14~2.16(m,1H),3.98~4.00(m,1H),4.05(q,J=7.02Hz,2H),6.72(s,2H),7.03(d,J=8.34Hz,2H),7.65(d,J=8.28Hz,2H),8.08(s,1H).
(R)-[4-氨基-6-(哌啶-3-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(9b)的制备
参照9a的制备方法,由8b反应制得黄色固体,收率93.1%,mp 89-91℃。ESI-MS:342[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.28~1.30(m,2H),1.70(t,J=7.44Hz,3H),1.81~1.82(m,1H),1.91(m,1H),2.65~2.67(m,1H),2.77~2.79(m,1H),3.05~3.06(m,1H),3.29(d,J=10.98Hz,1H),4.11(q,J=6.90Hz,2H),4.28~4.31(m,1H),5.49(s,2H),6.95(d,J=8.73Hz,2H),7.24(d,J=6.72Hz,1H),7.45(t,J=7.50Hz,2H),7.70(d,J=8.70Hz,2H),8.12(s,1H).
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-7)的制备
参照LX-1的制备方法,由9b与丙烯酰氯反应制得黄色固体,收率60.2%,mp 72-74℃。ESI-MS:418[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.50(t,J=6.84Hz,3H),1.52~1.61(m,4H),1.97~1.99(m,1H),3.39(br s,2H),3.79~3.82(m,2H),3.92~3.94(m,1H),4.12(q,J=7.32Hz,2H),4.27~4.30(m,1H),5.48(d,J=6.99,1H),5.68(d,J=9.96Hz,1H),6.28(d,J=14.28Hz,1H),6.58(dd,J1=5.37Hz,J2=10.71Hz,1H),6.96(d,J=8.04Hz,2H),7.67(d,J=7.83Hz,2H),8.17(s,1H).
实施例8
(R)-3-[[5-(4-乙氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(4b)的制备
参照4a的制备方法,由3b和(R)-1-Boc-3-氨基哌啶反应制得黄色固体,收率96.0%,mp 57-59℃。ESI-MS:483[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.28~1.30(m,2H),1.38(s,9H),1.70(t,J=6.96Hz,3H),1.81~1.83(m,1H),1.90~1.92(m,1H),2.64~2.66(m,1H),2.77~2.79(m,1H),3.04~3.06(m,1H),3.29(d,J=9.68Hz,1H),4.09(q,J=6.90Hz,2H),4.28(m,1H),6.95(d,J=6.73Hz,2H),7.34(t,J=8.50Hz,2H),7.69(d,J=8.56Hz,2H),8.39(s,1H).
(R)-3-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5f)的制备
参照5a的制备方法,由4b与甲胺盐酸盐反应制得黄色固体,收率57.9%,mp 61-63℃。ESI-MS:456[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.85(d,J=7.23Hz,1H),1.15~1.18(m,4H),].32(s,9H),1.43(t,J=6.96Hz,3H),1.64~1.66(m,1H),2.27~2.29(m,1H),2.83(d,J=5.21Hz,3H),3.48~3.50(m,1H),3.83~3.85(m,1H),4.05(q,J=6.96Hz,2H),7.12(d,J=7.68Hz,2H),7.58~7.60(m,1H),7.67(d,J=8.02Hz,2H),8.12(s,1H).
(R)-[4-甲胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(6f)的制备
参照9a的制备方法,由5f反应制得黄色固体,收率92.1%,mp 58-60℃。ESI-MS:356[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.29~1.31(m,2H),1.46(t,J=7.02Hz,3H),1.78~1.80(m,1H),1.90~1.91(m,1H),2.63~2.65(m,1H),2.77~2.79(m,1H),3.03~3.05(m,1H),2.83(d,J=5.25Hz,3H),3.20~3.21(m,1H),4.10(q,J=6.96Hz,2H),4.29~4.31(m,1H),5.56~5.57(m,1H),6.99(d,J=8.53Hz,2H),7.20(d,J=6.72Hz,1H),7.70(d,J=8.26Hz,2H),8.34(s,1H).
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-8)的制备
参照LX-1的制备方法,由6f与丙烯酰氯反应制得黄色固体,收率62.2%,mp 49-51℃。ESI-MS:432[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.23~1.27(m,2H),1.47~1.54(m,5H),1.80~1.82(m,1H),2.95~3.01(m,4H),3.59~3.61(m,1H),3.74~3.77(m,1H),4.16~4.21(m,4H),5.65(d,J=8.49Hz,1H),6.28(d,J=10.38Hz,1H),6.54(dd,J1=5.86Hz,J2=10.39Hz,1H),6.96(d,J=7.44Hz,2H),7.61(d,J=7.23Hz,2H),8.45(s,1H).
实施例9
(R)-3-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯的(5g)的制备
参照5a的制备方法,由4b与乙胺盐酸盐反应制得黄色固体,收率58.1%,mp 57-59℃。ESI-MS:470[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.85(m,1H),1.01(t,J=7.00Hz,3H),1.21~1.24(m,4H),1.31(s,9H),1.34(t,J=6.96Hz,3H),1.43~1.45(m,1H),1.70~1.72(m,1H),2.25~2.27(m,1H),3.46~3.48(m,2H),3.96~3.98(m,1H),4.02(q,J=6.96Hz,2H),7.09(d,J=8.21Hz,2H),7.33~7.35(m,1H),7.65(d,J=8.24Hz,2H),8.16(s,1H).
(R)-[4-乙胺基-6-(哌啶-3-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(6g)的制备
参照9a的制备方法,由5g反应制得黄色固体,收率93.3%,mp 55-57℃。ESI-MS:370[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.15~1.17(m,2H),1.35(t,J=7.02Hz,3H),1.50(t,J=6.96Hz,3H),1.84~1.85(m,1H),2.01~2.03(m,1H),2.65~2.67(m,1H),2.69~2.70(m,1H),3.03~3.05(m,1H),3.24(d,J=9.75Hz,1H),3.46~3.48(m,2H),4.11(q,J=6.90Hz,2H),4.27~4.28(m,1H),6.00(s,2H),6.96(d,J=8.22Hz,2H),7.31(d,J=7.01Hz,1H),7.66(d,J=8.34Hz,2H),8.40(s,1H).
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-9)的制备
参照LX-1的制备方法,由6g与丙烯酰氯反应制得黄色固体,收率64.3%,mp 52-54℃。ESI-MS:446[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.05~1.10(m,2H),1.25(t,J=6.93Hz,3H),1.45(t,J=6.81Hz,3H),1.91~1.96(m,3H),3.40~3.44(m,3H),3.89~3.91(m,2H),4.06~4.12(m,4H),5.65(d,J=8.19Hz,1H),6.29(d,J=14.37Hz,1H),6.53(dd,J1=5.93Hz,1H),J2=11.71Hz,6.94(d,J=7.64Hz,2H),7.61(d,J=8.23Hz,2H),8.20(s,1H).
实施例10
4-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11a)的制备
参照8a的制备方法,由7a与1-Boc-4-氨基哌啶反应制得黄色固体,收率51.2%,mp 169-171℃。ESI-MS:512[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.32~1.35(m,1H),1.47(s,9H),1.70~1.73(m,1H),1.96(d,J=9.81Hz,2H),2.98(t,J=11.31Hz,2H),3.93~3.96(m,2H),4.22~4.24(m,1H),5.51(s,2H),7.03~7.09(m,5H),7.24(t,J=6.09Hz,1H),7.43(t,J=7.35Hz,2H),7.69(d,J=7.26Hz,2H),8.19(s,1H).
[4-氨基-6-(哌啶-4-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(12a)的制备
参照9a的制备方法,由11a反应制得黄色固体,收率95.2%,mp 97-99℃。ESI-MS:390[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.28~1.32(m,2H),1.78~1.82(m,2H),2.88~2.90(m,2H),3.07~3.10(m,2H),4.12~4.15(m,1H),6.57(s,2H),6.68(d,J=7.25Hz,1H),6.96~7.01(m,4H),7.19(t,J=8.24Hz,1H),7.29~7.31(m,1H),7.44(t,J=8.05Hz,2H),7.65(d,J=7.68Hz,2H),8.01(s,1H).
1-[4-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-10)的制备
参照LX-1的制备方法,由12a与丙烯酰氯反应制得黄色固体,收率61.2%,mp 169-170℃。ESI-MS:444[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.24~1.27(m,2H),1.80~1.84(m,2H),2.05~2.07(m,1H),3.00(t,J=10.44Hz,1H),3.30(t,J=10.23Hz,1H),3.92~3.94(m,1H),4.39~4.41(m,2H),5.48(s,2H),5.72(d,J=8.76Hz,1H),6.29(d,J=16.71Hz,1H),6.60(dd,J1=6.33Hz,J2=10.62Hz,1H),7.06(dd,J1=7.35Hz,J2=6.57Hz,4H),7.20~7.22(m,1H),7.43(t,J=7.56Hz,2H),7.69(d,J=8.43Hz,2H),8.15(s,1H).
实施例11
4-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(10a)的制备
参照4a的制备方法,以3a(6.00g,17.44mmol)和1-Boc-4-氨基哌啶(4.18g,20.88mmol)反应制得浅黄色固体8.81g,收率99.4%,mp 61-63℃。ESI-MS:507[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):1.21~1.25(m,2H),1.37(s,9H),1.87~1.90(m,2H),2.71~2.75(m,2H),3.87~3.90(m,2H),4.18~4.20(m,1H),7.06(d,J=8.61Hz,2H),7.16(d,J=7.98Hz,2H),7.27~7.30(m,2H),7.49(t,J=7.29Hz,2H),7.83(d,J=8.70Hz,2H),8.42(s,1H).
4-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶4-基]氨基]哌啶-1-甲酸叔丁酯(11b)的制备
参照5a的制备方法,由10a与甲胺盐酸盐反应制得黄色固体,收率62.3%,mp 151-153℃。ESI-MS:526[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.28~1.31(m,1H),1.43(s,9H),1.71~1.73(m,1H),1.72~1.75(m,2H),2.83(d,J=6.21Hz,3H),3.00~3.02(m,2H),3.77~3.79(m,2H),4.17~4.19(m,1H),5.91~5.93(m,1H),7.05~7.11(m,5H),7.23(t,J=6.87Hz,1H),7.45(t,J=7.26Hz,2H),7.65(d,J=8.02Hz,2H),8.23(s,1H).
[4-甲胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(12b)的制备
参照9a的制备方法,由11b反应制得黄色固体,收率93.6%,mp 72-74℃。ESI-MS:404[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.20~1.23(m,2H),1.80~1.84(m,2H),2.89(d,J=8.68Hz,3H),2.94~3.00(m,2H),3.10~3.14(m,2H),4.17~4.19(m,1H),6.79(d,J=7.02Hz,1H),7.02(dd,J1=4.09Hz,J2=7.53Hz,4H),7.21(t,J=7.23Hz,1H),7.34~7.37(m,1H),7.44(t,J=8.07Hz,2H),7.63(d,J=8.55Hz,2H),8.12(s,1H).1-[4.[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-11)的制备
参照LX-1的制备方法,由12b与丙烯酰氯反应制得黄色固体,收率57.4%,mp 151-153℃。ESI-MS:480[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):0.97~1.02(m,2H),1.74~1.77(m,2H),1.98~2.02(m,1H),2.96(d,J=5.02Hz,3H),3.21~3.24(m,1H),3.82~3.85(m,1H),4.27~4.31(m,2H),5.70(d,J=7.89Hz,1H),6.30(d, J=14.28Hz,1H),6.63(dd,J1=6.21Hz,J2=11.28Hz,1H),7.00~7.03(m,4H),7.18~7.21(m,1H),7.43(t,J=7.90Hz,2H),7.63(d,J=8.40Hz,2H),8.24(s,1H).
实施例12
4-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11c)的制备
参照5a的制备方法,由10a与乙胺盐酸盐反应制得黄色固体,收率57.4%,mp 143-145℃。ESI-MS:540[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.05(t,J=7.11Hz,3H),1.13~1.16(m,2H),1.38(s,9H),1.64~1.66(m,2H),2.83~2.86(m,2H),3.36(q,J=6.90Hz,2H),3.72(d,J=12.51Hz,2H),4.09~4.11(m,1H),6.78(d,J=7.59Hz,1H),7.02(dd,J1=3.69Hz,J2=7.92Hz,4H),7.20(t,J=7.41Hz,1H),7.42~7.46(m,3H),7.61(d,J=8.64Hz,2H),8.10(s,1H).
[4-乙胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(12c)的制备
参照9a的制备方法,由11c反应制得黄色固体,收率94.3%,mp 70-72℃。ESI-MS:418[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.05(t,J=4.89Hz,3H),1.36~1.39(m,2H),1.81~1.84(m,2H),2.84~2.87(m,2H),3.08~3.11(m,2H),3.36(q,J=4.71Hz,2H),4.14~6.17(m,1H),6.97~7.02(m,3H),7.07(d,J=7.95Hz,2H),7.22(t,J=7.20Hz,1H),7.42~7.46(m,3H),7.63(d,J=6.48Hz,2H),8.12(s,1H).
1-[4-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-12)的制备
参照LX-1的制备方法,由12c与丙烯酰氯反应制得黄色固体,收率60.0%,mp 143-145℃。ESI-MS:494[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.02(t,J=7.08Hz,3H),1.20~1.24(m,3H),1.71~1.74(m,2H),2.23(d,J=14.67Hz,1H),2.83(t,J=11.55Hz,1H),3.16(t,J=11.28Hz,1H),3.83~3.86(m,1H),4.14~4.18(m,2H),5.65(d,J=10.32Hz,1H),6.08(d,J=16.62Hz,1H),6.77(dd,J1=5.85Hz,J2=7.11Hz,1H),6.82~6.85(m,1H),7.02(dd,J1=7.92Hz,J2=3.54Hz,4H),7.20(t,J=7.14Hz,1H),7.44(t,J=7.47Hz,3H),7.62(d,J=8.64Hz,2H),8.11(s,1H).
实施例13
4-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11d)的制备
参照5a的制备方法,由10a与异丙胺反应制得黄色固体,收率55.4%,mp 64-66℃。ESI-MS:554[M+Na]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.11(d,J=6.48Hz,6H),1.23~1.27(m,2H),1.47(s,9H),1.88~1.92(m,2H),2.96(t,J=11.70Hz,2H),3.89~3.92(m,2H),4.16~4.18(m,1H),4.31~4.33(m,1H),6.36(d,J=7.44Hz,1H),6.73(d,J=7.50Hz,1H),7.03~7.06(m,4H),7.22(t,J=7.41Hz,1H),7.44(t,J=7.53Hz,2H),7.65(d,J=8.73Hz,2H),8.21(s,1H).
[4-异丙胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-苯氧苯基)甲酮(12d)的制备
参照9a的制备方法,由11d反应制得黄色固体,收率95.1%,mp 59-61℃。ESI-MS:432[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.08(d,J=6.45Hz,6H),1.25~1.29(m,2H),1.69(q,J=11.73Hz,2H),2.14(d,J =11.43Hz,2H),2.98(t,J=13.50Hz,2H),3.36(d,J=12.75Hz,2H),4.29~4.32(m,2H),6.01(d,J=7.35Hz,1H),7.03(d,J=8.76Hz,2H),7.06(d,J=8.49Hz,2H),7.19(t,J=7.22Hz,1H),7.42(t,J=7.89Hz,2H),7.65(d,J=8.70Hz,2H),8.19(s,1H).
1-[4-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-13)的制备
参照LX-1的制备方法,由12d与丙烯酰氯反应制得黄色固体,收率58.6%,mp 64-66℃。ESI-MS:508[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.05(d,J=6.27Hz,6H),1.16~1.19(m,2H),1.72~1.75(m,2H),2.84(t,J=14.74Hz,1H),3.19(t,J=7.17Hz,1H),3.85~3.87(m,1H),4.15~4.27(m,3H),5.66(d,J=10.11Hz,1H),6.08(d,J=16.17Hz,1H),6.80(dd,J1=5.88Hz,J2=10.74Hz,1H),6.94(d,J=7.26Hz,1H),7.02(t,J=7.62Hz,4H),7.20(t,J=7.32Hz,1H),7.29(d,J=7.65Hz,1H),7.43(t,J=7.44Hz,2H),7.60(d,J=8.22Hz,2H),8.11(s,1H).
实施例14
4-[[5-(4-乙氧基苯甲酰基)-6-氯嘧啶4-基]氨基]哌啶-1-甲酸叔丁酯(10b)的制备
参照4a的制备方法,由3b与1-Boc-4-氨基哌啶反应制得黄色固体,收率96.5%,mp 74-76℃。ESI-MS:483[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.04(t,J=6.93Hz,3H),1.16~1.19(m,2H),1.37(s,9H),1.76~1.80(m,2H),2.73~2.75(m,2H),3.88~3.91(m,2H),4.04(q,J=6.86Hz,2H),4.18~4.20(m,1H),7.04(d,J=8.62Hz,2H),7.69(d,J=8.57Hz,2H),8.38(s,1H).
4-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯的(11e)的制备
参照5a的制备方法,由10b与甲胺盐酸盐反应制得黄色固体,收率65.1%,mp 59-61℃。ESI-MS:478[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.25~1.31(m,3H),1.45(s,9H),1.48(t,J=6.90Hz,3H),2.63~2.67(m,2H),2.91~2.95(m,3H),2.97~3.02(m,3H),4.13(q,J=6.69Hz,2H),6.08~6.10(m,1H),6.95(t,J=6.45Hz,1H),7.46(t,J=7.41Hz,1H),7.65(d,J=8.70Hz,1H),8.21(s,1H),8.31(br s,1H).
[4-甲胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(12e)的制备
参照9a的制备方法,由11e反应制得黄色固体,收率92.3%,mp 79-81℃。ESI-MS:356[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.25~1.31(m,3H),1.48(t,J=6.90Hz,3H),1.90~1.92(m,1H),2.64~2.67(m,2H),2.95~2.99(m,3H),3.01~3.07(m,3H),4.18(q,J=6.60Hz,2H),6.06~6.11(m,1H),6.95(t,J=6.45Hz,1H),7.46(t,J=7.41Hz,1H),7.65(d,J=7.08Hz,1H),8.22(s,1H),8.55(br s,1H).
1-[4-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-14)的制备
参照LX-1的制备方法,由12e与丙烯酰氯反应制得黄色固体,收率63.0%,mp 59-61℃。ESI-MS:432[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.23(m,3H),1.46(t,J=6.99Hz,3H),1.89~1.91(m,2H),2.89~2.91(m,1H),2.94(d,J=4.86Hz,3H),2.96~2.99(m,1H),3.21~3.23(m,1H),3.45~3.49(m,2H),3.80~3.83(m,1H),4.10(q,J=6.99Hz,2H),4.23~4.26(m,2H),5.67(d,J=8.82Hz,1H),6.28(d,J=10.42Hz,1H),6.57(dd,J1=5.72Hz,J2=10.56Hz,1H),6.94~6.97(m,2H),7.06(t,J=7.41Hz,1H),7.45(t,J=7.29Hz,1H),7.63(d,J=8.73Hz,2H),8.24(s,1H).
实施例15
4-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11f)的制备
参照5a的制备方法,由10b与乙胺盐酸盐反应制得黄色固体,收率56.2%,mp 46-48℃。ESI-MS:492[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.09(d,J=6.60Hz,3H),1.46(t,J=6.96Hz,3H),1.48(s,9H),2.01~2.03(m,1H),2.63~2.66(m,2H),2.88~2.91(m,3H),3.22~3.25(m,2H),4.12~4.15(m,2H),4.32~4.35(m,1H),6.31~6.33(m,1H),6.60~6.63(m,1H),6.94(d,J=8.24Hz,2H),7.65(d,J=8.49Hz,2H),8.22(s,1H),8.36(br s,1H).
[4-乙胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(12f)的制备
参照9a的制备方法,由11f反应制得黄色固体,收率95.2%,mp 56-58℃。ESI-MS:370[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.10(d,J=6.24Hz,3H),1.46(t,J=6.93Hz,3H),2.03~2.05(m,1H),2.64~2.67(m,2H),2.85~2.91(m,3H),3.16~3.20(m,2H),4.12~4.14(m,2H),4.32~4.34(m,1H),6.35~6.37(m,1H),6.60~6.63(m,1H),6.94(d,J=8.67Hz,2H),7.65(d,J=8.49Hz,2H),8.10(s,1H),8.21(br s,1H).
1-[4-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-15)的制备
参照LX-1的制备方法,由12f与丙烯酰氯反应制得黄色固体,收率60.8%,mp 46-48℃。ESI-MS:446[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.09~1.15(m,3H),1.29(t,J=6.56Hz,2H),1.47(t,J=7.02Hz,3H),1.89~1.92(m,2H),2.94~2.97(m,1H),3.22~3.25(m,1H),3.45~3.49(m,2H),3.83~3.85(m,1H),4.11(q,J=6.93Hz,2H),4.28~4.33(m,2H),5.68(d,J=10.65Hz,1H),6.26(d,J=12.42Hz,1H),6.60(dd,J1=9.72Hz,J2=11.76Hz,1H),6.95~6.98(m,2H),7.07(t,J=7.29Hz,1H),7.46(t,J=7.89Hz,1H),7.65(d,J= 8.52Hz,2H),8.23(s,1H).
实施例16
4-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11g)的制备
参照5a的制备方法,由10b与异丙胺反应制得黄色固体,收率56.2%,mp 67-69℃。ESJ-MS:506[M+Na]+;ESI-MS:384[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.29(d,J=6.90Hz,6H),1.42(t,J=6.69Hz,3H),1.47(s,9H),1.90~1.92(m,1H),2.64~2.68(m,2H),2.95~2.99(m,2H),3.00~3.04(m,2H),3.83~3.85(m,1H),4.02~4.04(m,2H),4.14(q,J=6.24Hz,2H),6.32(d,J=7.02Hz,1H),6.94~4.97(m,2H),7.46(t,J=7.29Hz,1H),7.66(d,J=8.70Hz,2H),8.34(s,1H).
[4-异丙胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(12g)的制备
参照9a的制备方法,由11g反应制得黄色固体,收率95.2%,mp 60-62℃。ESI-MS:384[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.24~1.31(m,6H),1.46(t,J=6.93Hz,3H),1.90~1.93(m,1H),2.64~2.67(m,2H),2.95~2.99(m,3H),3.00~3.05(m,3H),4.03~4.05(m,1H),4.13(q,J=6.69Hz,2H),6.32(d,J=7.21Hz,1H),6.92~6.95(m,3H),7.07(t,J=7.32Hz,1H),7.46(t,J=7.41Hz,1H),7.65(d,J=8.73Hz,2H),8.19(s,1H).
1-[4-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-16)的制备
参照LX-1的制备方法,由12g与丙烯酰氯反应制得黄色固体,收率63.1%,mp 67-69℃。ESI-MS:460[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.00(d,J=5.88Hz,6H),1.18~1.21(m,2H),1.30(t,J=6.24Hz,3H),1.70~1.76(m,2H),2.79(t,J=10.29Hz,1H),3.12(t,J=11.54Hz,1H),3.82~3.85(m,1H),4.05(t,J=6.69Hz,2H),4.13~4.18(m,3H),5.61(d,J=9.75Hz,1H),6.03(d,J=16.26Hz,1H),6.60(dd,.J1=5.73Hz,J2=10.86Hz,1H),6.84(d,J=7.05Hz,1H),6.91(d,J=8.04Hz,2H),7.04(d,J=7.14Hz,1H),7.53(d,J=8.04Hz,2H),8.08(s,1H).
实施例17
4-[[5-(4-乙氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(11h)的制备
参照5a的制备方法,由10b与二甲胺盐酸盐反应制得黄色固体,收率50.1%,mp 63-65℃。ESI-MS:492[M+Na]+;1H NMR(300MHz,CDCl3):δ(ppm):1.47(s,9H),1.45(t,J=6.90Hz,3H),1.70~1.75(m,2H),1.95~1.99(m,2H),2.65~2.67(m,1H),3.15(s,6H),3.55~3.61(m,4H),4.13(q,J=6.99Hz,2H),7.01(d,J=8.45Hz,2H),7.46(d,J=6.41Hz,1H),7.69(d,J=8.70Hz,1H),8.25(s,1H).
[4-二甲胺基-6-(哌啶-4-氨基)嘧啶-5-基](4-乙氧苯基)甲酮(12h)的制备
参照9a的制备方法,由11h反应制得黄色固体,收率94.1%,mp 55-57℃。ESI-MS:370[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.38(t,J=6.96Hz,3H),1.88~1.90(m,1H),2.51~2.54(m,2H),2.88~2.91(m,3H),3.06~3.11(m,2H),3.15(s,6H),4.01~4.04(m,1H),4.14(q,J=6.96Hz,2H),7.01(d,J=8.26Hz,2H),7.52(d,J=6.92Hz,1H),7.63(d,J=8.65Hz,2H),8.22(s,1H).
1-[4-[[5-(4-乙氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(LX-17)的制备
参照LX-1的制备方法,由12h与丙烯酰氯反应制得黄色固体,收率56.9%,mp 63-65℃。ESI-MS:446[M+H]+;1H NMR(300MHz,CDCl3):δ(ppm):1.23~1.29(m,2H),1.44(t,J=6.90Hz,3H),1.65~1.70(m,2H),2.70(s,6H),3.10~3.14(m,1H),3.30(t,J=10.23Hz,1H),3.95~3.97(m,1H),4.09(q,J=7.11Hz,2H),4.43~4.46(m,2H),5.69(d,J=10.68Hz,1H),6.28(d,J=16.59Hz,1H),6.59(dd,J1=6.12Hz,J2=8.55Hz,1H),6.87(d,J=8.73Hz,2H),7.60(d,J=7.97Hz,2H),8.22(s,1H).
实施例18
[4-氨基-6-(哌嗪-1-基)嘧啶-5-基](4-苯氧苯基)甲酮(14a)的制备
7a(101mg,0.31mmol)和无水哌嗪(80mg,0.93mmol),加入15mL乙醇,回流反应2h。抽滤,减压浓缩,得黄色固体83.9mg,收率69.6%,mp 101-103℃。ESI-MS:376[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.23~2.30(m,4H),2.70~2.76(m,4H),7.05~7.09(m,4H),7.23(t,J=5.07Hz,1H),7.27(br s,2H),7.44(t,J=4.98Hz,2H),7.58(d,J=5.19Hz,2H),8.06(s,1H).
1-[4-[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-18)的制备
参照LX-1的制备方法,由14a与丙烯酰氯反应制得黄色固体,收率52.3%,mp 158-159℃。ESI-MS:430[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):3.12~3.20(m,7H),3.57~3.59(m,1H),5.66(d,J=10.26Hz,1H),6.08(d,J=15.99Hz,1H),6.70(dd,J1=5.88Hz,J2=10.95Hz,1H),7.02~7.07(m,4H),7.23(t,J=6.99Hz,1H),7.33(s,2H),7.41(t,J=6.96Hz,2H),7.63(d,J=7.47Hz,2H),8.11(s,1H).
实施例19
(4-氯-6-甲胺基嘧啶-5-基)(4-苯氧苯基)甲酮(13b)的制备
3a(248mg,0.72mmol)溶于15mL异丙醇中,加入甲胺水溶液(10.8mmol),冰浴下反应1h。抽滤,得白色固体149mg,收率60.9%,mp 179-180℃。ESI-MS:338[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):2.79(d,J=4.44Hz,3H),7.07(d,J=8.82Hz,2H),7.16(d,J=7.74Hz,2H),7.28(t,J=7.38Hz,1H),7.39(br s,1H),7.49(t,J=8.01Hz,2H),7.85(d,J=8.76Hz,2H),8.43(s,1H).
[4-甲胺基-6-(哌嗪-1-基)嘧啶-5-基](4-苯氧苯基)甲酮(14b)的制备
参照14a的制备方法,由13b和无水哌嗪发应制得黄色固体,收率58.3%,mp 87-89℃。ESI-MS:390[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.75~2.79(m,4H),3.00~3.04(m,4H),5.94~5.96(m,1H),7.01~7.07(m,4H),7.21(t,J=7.02Hz,1H),7.41(t,J=7.23Hz,2H),7.60(d,J=8.26Hz,2H),8.19(s,1H).
1-[4-[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-19)的制备
参照LX-1的制备方法,由14b与丙烯酰氯反应制得黄色固体,收率50.9%,mp 83-85℃。ESI-MS:466[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.91(d,J=5.96Hz,3H),3.12~3.17(m,7H),3.62~3.66(m,1H),5.74(d,J=12.03Hz,1H),6.08(d,J=16.41Hz,1H),6.69(dd,J1=4.69Hz,J2=11.65Hz,1H),7.01~7.06(m,4H),7.21(t,J=6.96Hz,1H),7.41(t,J=7.02Hz,2H),7.62(d,J=7.86Hz,2H),8.03~8.05(m,1H),8.21(s,1H).
实施例20
(4-氯-6-乙胺基嘧啶-5-基)(4-苯氧苯基)甲酮(13c)的制备
参照13b的制备方法,由3a与乙胺水溶液反应制得白色固体,收率53.6%,mp 149-150℃。ESI-MS:354[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):1.13(t,J=5.28Hz,3H),7.03(d,J=7.47Hz,2H),7.13(d,J=7.86Hz,2H),7.27(t,J=7.68Hz,1H),7.37(br s,1H),7.46(t,J=8.21Hz,2H),7.83(d,J=8.37Hz,2H),8.38(s,1H).
[4-乙胺基-6-(哌嗪-1-基)嘧啶-5-基](4-苯氧苯基)甲酮(14c)的制备
参照14a的制备方法,由13c和无水哌嗪发应制得黄色固体,收率63.1%,mp 75-77℃。ESI-MS:404[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.12(t,J=6.69Hz,3H),3.04~3.12(m,7H),3.24~3.28(m,2H),3.59~3.61(m,1H),6.00~6.02(m,1H),7.03~7.06(m,4H),7.21(t,J=6.56Hz,1H),7.39(t,J=6.62Hz,2H),7.65(d,J=7.38Hz,2H),8.25(s,1H).
1-[4-[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-20)的制备
参照LX-1的制备方法,由14c与丙烯酰氯反应制得黄色固体,收率50.4%,mp 71-73℃。ESI-MS:430[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.13(t,J=6.27Hz,3H),3.12~3.18(m,7H),3.42~3.45(m,2H),3.62~3.64(m,1H),5.67(d,J=10.26Hz,1H),6.08(d,J=16.29Hz,1H),6.70(dd,J1=5.49Hz,J2=10.62Hz,1H),7.00~7.05(m,4H),7.21(t,J=6.45Hz,1H),7.39(t,J=5.85Hz,2H),7.61(d,J=6.75Hz,2H),8.20(s,1H).
实施例21
(4-氯-6-异丙胺基嘧啶-5-基)(4-苯氧苯基)甲酮(13d)的制备
参照13b的制备方法,由3a与异丙胺反应制得白色固体,收率40.8%,mp 127-128℃。ESI-MS:366[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):1.07(d,J=3.21Hz,6H),4.32(m,J=3.34Hz,1H),7.07(d,J =7.09Hz,2H),7.11~7.14(m,3H),7.27(t,J=6.98Hz,1H),7.49(t,J=8.21Hz,2H),7.82(d,J=8.17Hz,2H),8.40(s,1H).
[4-异丙胺基-6-(哌嗪-1-基)嘧啶-5-基](4-苯氧苯基)甲酮(14d)的制备
参照14a的制备方法,由13d和无水哌嗪发应制得黄色固体,收率62.8%,mp 49-51℃。ESI-MS:418[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.20(d,J=6.60Hz,6H),3.05~3.11(m,7H),3.40~3.45(m,1H),4.27~4.29(m,1H),7.00~7.05(m,4H),7.20(t,J=8.02Hz,1H),7.38(t,J=7.42Hz,2H),7.60(d,J=8.35Hz,2H),8.20(s,1H).
1-[4-[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-21)的制备
参照LX-1的制备方法,由14d与丙烯酰氯反应制得黄色固体,收率54.1%,mp 67-69℃。ESI-MS:494[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.19(d,J=6.21Hz,6H),3.09~3.12(m,7H),3.62~3.65(m,1H),4.28~4.31(m,1H),5.67(d,J=10.26Hz,1H),6.07(d,J=16.62Hz,1H),6.70(dd,J1=6.24Hz,J2=10.41Hz,1H),6.99~7.03(m,4H),7.20(t,J=7.14Hz,1H),7.40(t,J=7.44Hz,2H),7.59(d,J=8.31Hz,2H),8.11(d,J=7.83Hz,1H),8.20(s,1H).
实施例22
[4-氨基-6-(哌嗪-1-基)嘧啶-5-基](4-乙氧苯基)甲酮(14e)的制备
参照14a的制备方法,由7b与无水哌嗪反应制得黄色固体,收率52.3%,mp 82-93℃。ESI-MS:328[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.30(t,J=6.96Hz,3H),3.09~3.13(m,4H),3.26~3.31(m,4H),4.02(q,J=6.96Hz,2H),7.07(d,J=8.20Hz,2H),7.20(s,2H),7.56(d,J=7.92Hz,2H),8.11(s,1H).1-[4-[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-22)的制备
参照LX-1的制备方法,由14e与丙烯酰氯反应制得黄色固体,收率49.2%,mp 191-193℃。ESI-MS:404[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.32(t,J=6.90Hz,3H),3.11~3.19(m,8H),4.09(q,J=6.96Hz,2H),5.63(d,J=10.44Hz,1H),6.04(d,J=16.71Hz,1H),6.67(dd,J1=6.15Hz,J2=10.44Hz,1H),7.01(d,J=8.70Hz,2H),7.20(s,2H),7.56(d,J=8.52Hz,2H),8.11(s,1H).
实施例23
(4-氯-6-甲胺基嘧啶-5-基)(4-乙氧苯基)甲酮(13f)的制备
参照13b的制备方法,由3b与甲胺水溶液反应制得白色固体,收率45.8%,mp 188-189℃。ESI-MS: 290[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):1.35(t,J=6.90Hz,3H),2.78(d,J=4.47Hz,3H),4.14(q,J=6.99Hz,2H),7.07(d,J=8.88Hz,2H),7.35(q,J=4.47Hz,1H),7.78(d,J=8.85Hz,2H),8.42(s,1H).[4-甲胺基-6-(哌嗪-1-基)嘧啶-5-基](4-乙氧苯基)甲酮(14f)的制备
参照14a的制备方法,由13f与无水哌嗪反应制得黄色固体,收率61.3%,mp 66-68℃。ESI-MS:342[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.32(t,J=6.90Hz,3H),2.89(d,J=6.74Hz,3H),3.17~3.23(m,7H),3.37~3.42(m,2H),3.47~3.49(m,1H),4.08(q,J=6.90Hz,2H),7.07(d,J=8.05Hz,2H),7.48(d,J=7.03Hz,1H),7.68(q,J=7.97Hz,1H),8.21(s,1H).
1-[4-[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-23)的制备
参照LX-1的制备方法,由14f与丙烯酰氯反应制得黄色固体,收率53.5%,mp 72-74℃。ESI-MS:418[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.32(t,J=6.90Hz,3H),2.89(d,J=4.74Hz,3H),3.16(m,7H),3.57~3.60(m,1H),4.08(q,J=6.87Hz,2H),5.63(d,J=8.10Hz,1H),6.05(d,J=14.34Hz,1H),6.67(dd,J1=6.24Hz,J2=10.44Hz,1H),7.07(d,J=8.97Hz,2H),7.55(d,J=8.46Hz,2H),7.88(q,J=4.71Hz,1H),8.21(s,1H).
实施例24
(4-氯-6-乙胺基嘧啶-5-基)(4-乙氧苯基)甲酮(13g)的制备
参照13b的制备方法,由3b与乙胺水溶液反应制得白色固体,收率26.1%,mp 158-159℃。ESI-MS:304[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):1.04(t,J=7.08Hz,3H),1.35(t,J=6.96Hz,3H),3.31(q,J=7.02Hz,2H),4.14(q,J=6.99Hz,2H),7.07(d,J=8.94Hz,2H),7.42(t,J=5.43Hz,1H),7.76(d,J=8.88Hz,2H),8.40(s,1H).
[4-乙胺基-6-(哌嗪-1-基)嘧啶-5-基](4-乙氧苯基)甲酮(14g)的制备
参照14a的制备方法,由13g与无水哌嗪反应制得黄色固体,收率67.9%,mp 57-59℃。ESI-MS:356[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.13(t,J=6.90Hz,3H),1.34(t,J=6.69Hz,3H),2.12~2.19(m,4H),3.16~3.20(m,4H),3.44~3.47(m,2H),4.04(q,J=6.69Hz,2H),6.98(d,J=8.40Hz,2H),7.58(d,J=8.01Hz,2H),8.25(s,1H).
1-[4-[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-24)的制备
参照LX-1的制备方法,由14g与丙烯酰氯反应制得黄色固体,收率49.7%,mp 61-63℃。ESI-MS:432[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.12(t,J=7.08Hz,3H),1.22~1.24(m,1H),1.32(t,J=6.57Hz,3H),3.15~3.19(m,7H),3.44(q,J=6.24Hz,2H),4.06(q,J=6.66Hz,2H),5.63(d,J=10.2Hz,1H),6.05 (d,J=15.69Hz,1H),6.66(dd,J1=5.97Hz,J2=10.35Hz,1H),6.99(d,J=8.40Hz,2H),7.54(d,J=7.95Hz,2H),8.01(t,J=4.77Hz,1H),8.20(s,1H).
实施例25
(4-氯-6-异丙胺基嘧啶-5-基)(4-乙氧苯基)甲酮(13h)的制备
参照13b的制备方法,由3b与异丙胺反应制得白色固体,收率39.2%,mp 122-123℃。ESI-MS:318[M-H]-;1H NMR(300MHz,CDCl3):δ(ppm):1.21(d,J=6.96Hz,6H),1.46(t,J=6.90Hz,3H),4.12(q,J=6.30Hz,2H),4.34(m,1H),7.03(d,J=10.53Hz,2H),7.92(d,J=10.56Hz,2H),8.48(s,1H).
[4-异丙胺基-6-(哌嗪-1-基)嘧啶-5-基](4-乙氧苯基)甲酮(14h)的制备
参照14a的制备方法,由13h与无水哌嗪反应制得黄色固体,收率64.7%,mp 54-56℃。ESI-MS:370[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.16(d,J=6.90Hz,6H),1.20~1.24(m,1H),1.31(t,J=6.69Hz,3H),3.02~3.13(m,7H),4.07(d,J=6.60Hz,2H),4.17~4.21(m,1H),6.98(d,J=7.72Hz,2H),7.57(d,J=7.67Hz,2H),7.75(m,1H),8.20(s,1H).
1-[4-[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮(LX-25)的制备
参照LX-1的制备方法,由14h与丙烯酰氯反应制得黄色固体,收率54.2%,mp 165-166℃。ESI-MS:446[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.16(d,J=5.49Hz,6H),1.19~1.22(m,1H),1.31(t,J=6.69Hz,3H),2.98~3.02(m,7H),4.07(d,J=6.54Hz,2H),4.25~4.29(m,1H),5.63(d,J=10.32Hz,1H),6.04(d,J=16.35Hz,1H),6.66(dd,J1=5.07Hz,J2=11.10Hz,1H),6.98(d,J=7.74Hz,2H),7.52(d,J=7.17Hz,2H),7.95(d,J=7.35Hz,1H),8.18(s,1H).
实施例26
1-(2-硝基苯基)哌嗪(15)的制备
邻溴硝基苯(4.04g,20.00mmol)和无水哌嗪(6.88g,80.00mmol),100℃反应1h。反应液用乙酸乙酯溶解,过滤,减压浓缩,制得红色油状液体,直接进行下一步。
4-(2-硝基苯基)哌嗪基-1-甲酸叔丁酯(16)的制备
15溶于20mL CH2Cl2,加入Et3N(3.80mL,28.01mmol),室温下缓慢滴加(Boc)2O(5.08g,24.00mmol)的CH2Cl2溶液,滴毕,继续反应30min。减压浓缩,制得黄色油状液体,直接进行下一步。
4-(2-氨基苯基)哌嗪-1-甲酸叔丁酯(17)的制备
16溶于50mL乙醇和50mL水的混合溶剂中,升温回流,加入保险粉(13.92g,80.00mmol),反应30min,抽滤,得白色固体2.10g,三步总收率为37.9%(以邻溴硝基苯计),mp 122-123℃。ESI-MS:278[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.37(s,9H),2.45~2.49(m,4H),3.23~3.26(m,4H),5.01(s,2H),6.67~6.69(m,1H),6.92~6.99(m,2H),7.03~7.05(m,1H).
4-[2-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(18a)的制备
3a(2.0g,5.82mmol)和17(1.61g,5.82mmol)加入DIPEA(1.02mL,5.82mmol)和25mL DMSO,120℃反应3h,倒入水中,抽滤,柱层析纯化[P∶E=5∶1(V∶V)],得黄色固体1.40g,收率41.2%,mp 183-185℃。ESI-MS:608[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.42(s,9H),2.46~2.51(m,4H),3.18~3.22(m,4H),7.09(d,J=8.73Hz,3H),7.21~7.24(m,4H),7.31(d,J=7.20Hz,1H),7.49(t,J=7.38Hz,2H),7.98(d,J=8.94Hz,2H),8.26(d,J=7.38Hz,1H),8.67(s,1H),8.89(s,1H).
[4-氯-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-苯氧苯基)甲酮(21)的制备
参照9a的制备方法,由18a反应制得黄色固体,收率92.1%,mp 163-165℃。ESI-MS:486[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.94~2.99(m,4H),3.12~3.17(m,4H),7.10(d,J=8.82Hz,2H),7.11~7.20(m,5H),7.30(t,J=7.35Hz,1H),7.50(t,J=7.44Hz,2H),7.95(d,J=8.94Hz,2H),8.62(s,1H),8.78(br s,1H),8.96(s,1H).
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-26)的制备
参照LX-1的制备方法,以21与丙烯酰氯反应制得黄色固体,收率62.3%,mp 158-159℃。ESI-MS:562[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.63~2.69(m,4H),3.57~3.62(m,4H),5.69(d,J=10.71Hz,1H),6.13(d,J=16.74Hz,1H),6.80(dd,J1=5.73Hz,J2=10.77Hz,1H),7.00~7.10(m,6H),7.21~7,25(m,2H),7.47(t,J=7.68Hz,2H),7.96(d,J=8.31Hz,2H),8.22(d,J=7.35Hz,1H),8.65(s,1H),8.98(s,1H).
实施例27
4-[2-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19a)的制备
18a(0.40g,0.69mmol)、甲胺盐酸盐(1.38mmol)和DIPEA(0.13mL,0.76mmol)溶于25mL乙醇中,回流反应6h,乙酸乙酯溶解,抽滤,柱层析纯化[P∶E=2∶1(V∶V)],得黄色固体0.24g,收率60.0%,mp 63-65℃。ESI-MS:581[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.42(s,9H),2.62~2.68(m,4H),2.73~2.77(m,4H),6.79(dd,J=4.29Hz,1H),7.00(d,J=8.82Hz,3H),7.07~7.11(m,4H),7.24(t,J=7.32Hz,1H),7.45(t,J=7.44Hz,2H),7.75(d,J=8.88Hz,2H),8.31(s,1H),8.39(d,J=8.34Hz,1H),9.52(s,1H).
[4-甲胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-苯氧苯基)甲酮(20a)的制备
参照9a的制备方法,由19a反应制得黄色固体,收率94.8%,mp 87-88℃。ESI-MS:481[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.62~2.66(m,4H),2.76(d,J=4.29Hz,3H),2.86~2.89(m,4H),6.64(dd,J=4.72Hz,1H),7.05~7.10(m,7H),7.22(t,J=6.86Hz,1H),7.45(t,J=7.56Hz,2H),7.75(d,J=8.69Hz,2H),8.30(s,1H),8.33(d,J=10.29Hz,1H),9.37(s,1H).
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-27)的制备
参照LX-1的制备方法,以20a与丙烯酰氯反应制得黄色固体,收率58.1%,mp 83-85℃。ESI-MS:535[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.73~2.79(m,4H),2.92(s,3H),3.65~3.71(m,4H),5.76(d,J=9.66Hz,1H),6.14(d,J=16.23Hz,1H),6.63~6.65(m,1H),6.80(dd,J1=6.86Hz,J2=13.43Hz,1H),7.02~7.08(m,6H),7.23~7.27(m,3H),7.44(t,J=6.27Hz,1H),7.75(d,J=7.83Hz,2H),8.31(s,1H),8.41(d,J=5.70Hz,1H),9.62(s,1H).
实施例28
4-[2-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19b)的制备
参照19a的制备方法,以18a与乙胺盐酸盐反应制得黄色固体,收率56.1%,mp 72-74℃。ESI-MS:595[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.94(t,J=7.17Hz,3H),1.42(s,9H),2.65~2.71(m,4H),3.32(q,J=6.45Hz,2H),3.45~3.51(m,4H),6.79(dd,J=5.73Hz,1H),7.00(d,J=8.01Hz,3H),7.08(d,J=7.83Hz,3H),7.15(d,J=7.77Hz,1H),7.23(t,J=6.78Hz,1H),7.45(t,J=7.77Hz,2H),7.74(d,J=8.55Hz,2H),8.29(s,1H),8.40(d,J=8.28Hz,1H),9.75(s,1H).
[4-乙胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-苯氧苯基)甲酮(20b)的制备
参照9a的制备方法,由19b反应制得黄色固体,收率95.3%,mp 90-91℃。ESI-MS:493[M-H]-;1H NMR(300MHz,DMSO-d6):δ(ppm):0.95(t,J=6.45Hz,3H),2.64~2.68(m,4H),2.87~2.91(m,4H),6.82(dd,J=5.77Hz,1H),7.00(d,J=8.49Hz,3H),7.04~7.12(m,4H),7.23(t,J=6.33Hz,1H),7.43(t,J=7.56Hz,2H),7.74(d,J=8.28Hz,2H),8.28(s,1H),8.38(d,J=7.92Hz,1H),9.60(s,1H).
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-28)的制备
参照LX-1的制备方法,以20b与丙烯酰氯反应制得黄色固体,收率53.5%,mp 86-88℃。ESI-MS:571[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.94(t,J=6.90Hz,3H),2.69~2.72(m,4H),3.70~3.76(m,4H),5.71(d,J=11,06Hz,1H),6.15(d,J=15.99Hz,1H),6.60(d,J=7.83Hz,1H),6.81(dd,J1=6.36Hz,J2=12.13Hz,1H),7.06~7.12(m,8H),7.20(dd,J=8.88Hz,2H),7.44(t,J=7.65Hz,1H),7.74(d,J=7.34Hz,2H),8.30(s,1H),8.42(d,J=7.56Hz,1H),9.85(s,1H).
实施例29
4-[2-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19c)的制备
参照19a的制备方法,以18a与异丙胺反应制得黄色固体,收率57.3%,mp 57-59℃。ESI-MS:609[M+H]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):0.95(d,J=6.48Hz,6H),1.42(s,9H),2.67~2.72(m,4H),3.48~3.52(m,4H),4.25~4.28(m,J=6.30Hz,1H),6.53(d,J=7.47Hz,1H),7.00(d,J=8.67Hz,3H),7.07(d,J=11.49Hz,3H),7.16(d,J=7.71Hz,1H),7.23(t,J=7.47Hz,1H),7.49(t,J=6.96Hz,2H),7.70(d,J=8.61Hz,2H),8.28(s,1H),8.41(d,J=8.04Hz,1H),10.01(s,1H).
[4-异丙胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-苯氧苯基)甲酮(20c)的制备
参照9a的制备方法,由19c反应制得黄色固体,收率95.0%,mp 125-126℃。ESI-MS:509[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.95(d,J=6.36Hz,6H),2.90~3.01(m,8H),4.25~4.28(m,J=6.78Hz,1H),6.54(d,J=7.65Hz,1H),7.03(t,J=8.67Hz,3H),7.14~7.19(m,5H),7.44(t,J=7.44Hz,2H),7.70(d,J=8.58Hz,2H),8.30(s,1H),8.48(d,J=7.77Hz,1H),10.16(s,1H).
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-29)的制备
参照LX-1的制备方法,以20c与丙烯酰氯反应制得黄色固体,收率61.2%,mp 175-177℃。ESI-MS:585[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.96(d,J=6.54Hz,6H),1.19~1.25(m,1H),2.72~2.76(m,4H),3.74~3.78(m,4H),4.25~4.28(m,1H),5.71(d,J=10.08Hz,1H),6.16(d,J=16.32Hz,1H),6.55(d,J=7.77Hz,1H),6.86(dd,J1=6.33Hz,J2=10.23Hz,1H),7.02~7.09(m,5H),7.20(dd,J=8.88Hz,2H),7.44(t,J=7.62Hz,1H),7.72(d,J=8.43Hz,2H),8.30(s,1H),8.45(d,J=8.49Hz,1H),10.11(s,1H).
实施例30
4-[2-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19d)的制备
参照19a的制备方法,以18a与二甲胺盐酸盐反应制得黄色固体,收率51.2%,mp 164-166℃。ESI-MS:617[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.42(s,9H),2.64~2.72(m,10H),3.71~3.77(m,4H),7.03(d,J=7.23Hz,3H),7.12(d,J=7.68Hz,3H),7.22(dd,J=7.35Hz,2H),7.45(t,J=6.18Hz,2H),7.66(d,J=6.72Hz,2H),8.30(s,1H),8.59(d,J=6.06Hz,1H),10.41(s,1H).
[4-二甲胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-苯氧苯基)甲酮(20d)的制备
参照9a的制备方法,由19d反应制得黄色固体,收率92.3%,mp 90-91℃。ESI-MS:495[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.73(s,6H),2.76~2.82(m,4H),3.08~3.11(m,4H),7.05(d,J=8.42Hz,3H),7.10(d,J=9.27Hz,3H),7.22(dd,J=7.23Hz,2H),7.46(t,J=7.59Hz,2H),7.66(d,J=8.19Hz,2H),8.31(s,1H),8.59(d,J=7.32Hz,1H),10.40(s,1H).
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-30)的制备
参照LX-1的制备方法,以20d与丙烯酰氯反应制得黄色固体,收率51.2%,mp 178-180℃。ESI-MS:571[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):2.74(s,6H),2.75~2.81(m,4H),3.82~3.89(m,4H),5.71(d,J=9.66Hz,1H),6.16(d,J=18.15Hz,1H),6.86(dd,J1=6.72Hz,J2=10.35H z,1H),7.01~7.12(m,6H),7.23(dd,J=7.02Hz,3H),7.46(t,J=7.98Hz,1H),7.68(d,J=8.31Hz,2H),8.33(s,1H),8.65(d,J=7.95Hz,1H),10.54(s,1H).
实施例31
4-[2-[[5-(4-乙氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(18b)的制备
参照18a的制备方法,由3b与17反应制得黄色固体,收率54.6%,mp 134-136℃。ESI-MS:560[M+Na]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.38(t,J=6.96Hz,3H),1.43(s,9H),2.59~2.62(m,4H),3.16~3.20(m,4H),4.16(q,J=6.99Hz,2H),7.19(m,5H),7.93(d,J=8.88Hz,2H),8.32~8.34(m,1H),8.67(s,1H),8.81(s,1H).
4-[2-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19e)的制备
参照19a的制备方法,以18b与甲胺盐酸盐反应制得黄色固体,收率51.7%,mp 83-85℃。ESI-MS:433[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.40(t,J=6.96Hz,3H),1.42(s,9H),2.49(s,3H),2.58~2.62(m,4H),2.72~2.75(m,4H),4.09(q,J=6.99Hz,2H),6.63~6.65(m,1H),7.06~7.11(m,5H),7.72(d,J=4.80Hz,2H),8.27~8.29(m,1H),8.30(s,1H),8.42(s,1H),9.34(s,1H).
[4-甲胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-乙氧苯基)甲酮(20e)的制备
参照9a的制备方法,由19e反应制得黄色固体,收率92.5%,mp 70-71℃。ESI-MS:433[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):,2.66~2.72(m,4H),2.89~2.93(m,4H),3.21~3.25(m,2H),4.04(q,J=6.62Hz,2H),6.69~6.71(m,1H),6.99(t,J=7.52Hz,3H),7.08~7.12(m,3H),7.67(d,J=7.68Hz,2H),8.30(s,1H),8.45(s,1H),9.47(s,1H).
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-31)的制备
参照LX-1的制备方法,以20e与丙烯酰氯反应制得黄色固体,收率50.2%,mp 81-83℃。ESI-MS:509[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.33(t,J=6.96Hz,3H),2.70~2.78(m,4H),3.64~3.69(m,4H),3.80(d,J=6.93Hz,3H),4.09(q,J=6.60Hz,2H),5.71(d,J=9.54Hz,1H),6.16(d,J=11.01Hz,1H),6.79(dd,J1=7.32Hz,J2=9.99Hz,1H),6.96(d,J=8.82Hz,2H),7.09~7.12(m,3H),7.72(d,J=7.77Hz,2H),8.32(s,1H),8.45(d,J=8.49Hz,1H),9.49(s,1H).
实施例32
4-[2-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19f)的制备
参照19a的制备方法,以18b与乙胺盐酸盐反应制得黄色固体,收率50.5%,mp 62-64℃。ESI-MS:569[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.98(t,J=5,23Hz,3H),1.34(t,J=6.84Hz,3H),1.43(s,9H),2.62~2.67(m,4H),3.28(q,J=5.10Hz,2H),3.42~3.47(m,4H),4.09(q,J=7.02Hz,2H),6.66~6.68(m,1H),7.00(t,J=6.18Hz,3H),7.07~7.12(m,3H),7.71(d,J=6.54Hz,2H),8.29(s,1H),8.41(s,1H),9.53(s,1H).
[4-乙胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-乙氧苯基)甲酮(20f)的制备
参照9a的制备方法,由19f反应制得黄色固体,收率91.4%,mp 69-71℃。ESI-MS:447[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.05(t,J=5.49Hz,3H),1.33(t,J=4.89Hz,3H),2.63~2.69(m,4H),2.89~2.93(m,4H),3.28(q,J=4.91Hz,2H),4.09(q,J=5.07Hz,2H),6.70~6.72(m,1H),6.98(t,J=6.60Hz,3H),7.06~7.11(m,3H),7.71(d,J=6.87Hz,2H),8.29(s,1H),8.43(s,1H),9.43(s,1H).
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-32)的制备
参照LX-1的制备方法,以20f与丙烯酰氯反应制得黄色固体,收率51.9%,mp 121-123℃。ESI-MS:523[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):0.96(d,J=6.78Hz,3H),1.33(t,J=6.90Hz,3H),2.66~2.72(m,4H),3.68~3.73(m,4H),3.83(q,J=7.05Hz,2H),4.10(q,J=6.78Hz,2H),5.72(d,J=12.66Hz,1H),6.16(d,J=16.59Hz,1H),6.41(m,1H),6.84(dd,J1=6.75Hz,J2=10.77Hz,1H),6.99(d,J=8.58Hz,2H),7.13(t,J=7.71Hz,2H),7.48~7.50(m,1H),7.72(d,J=8.76Hz,2H),8.30(s,1H),8.46(d,J=7.02Hz,1H),10.31(s,1H).
实施例33
4-[2-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-甲酸叔丁酯(19g)的制备
参照19a的制备方法,以18b与异丙胺反应制得黄色固体,收率46.6%,mp 69-71℃。ESI-MS:583[M+Na]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.06~1.14(m,6H),1.32(t,J=6.90Hz,3H),1.38(s,9H),2.63~2.67(m,4H),3.27~3.30(m,1H),3.43~3.48(m,4H),4.06(q,J=6.99Hz,2H),6.67~6.69(m,1H),7.00(t,J=6.82Hz,3H),7.10~7.14(m,3H),7.70(d,J=6.88Hz,2H),8.28(s,1H),8.39(s,1H),9.44(s,1H).
[4-异丙胺基-6-[[2-(哌嗪-1-基)苯基]氨基]嘧啶-5-基](4-乙氧苯基)甲酮(20g)的制备
参照9a的制备方法,由19g反应制得黄色固体,收率94.5%,mp 84-86℃。ESI-MS:461[M+H]+;1H NMR(300MHz,DMSO-d6):δ(ppm):1.02(d,J=6.72Hz,6H),1.33(t,J=6.81Hz,3H),2.76~2.81(m,4H),3.04~3.10(m,4H),3.82~3.85(m,1H),4.09(q,J=6.84Hz,2H),6.42(d,J=7.56Hz,1H),6.96(t,J=8.85Hz,3H),7.08~7.12(m,3H),7.68(d,J=8.37Hz,2H),8.28(s,1H),8.44(s,1H),9.79(s,1H).
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮(LX-33)的制备
参照LX-1的制备方法,以20g与丙烯酰氯反应制得,收率54.8%,mp 89-91℃。ESI-MS:537[M+Na]+; 1H NMR(300MHz,DMSO-d6):δ(ppm):1.01(d,J=6.99Hz,6H),1.33(t,J=6.87Hz,3H),2.69~2.74(m,4H),3.71~3.76(m,4H),4.09(q,J=6.96Hz,2H),4.24~4.26(m,1H),5.71(d,J=10.53Hz,1H),6.15(d,J=16.53Hz,1H),6.41(d,J=7.92Hz,1H),6.84(dd,J1=6.57Hz,J2=10.08Hz,1H),6.97(d,J=8.67Hz,2H),7.13(t,J=7.35Hz,2H),7.49~7.52(m,1H),7.68(d,J=8.70Hz,2H),8.29(s,1H),8.49(d,J=5.85Hz,1H),9.87(s,1H)。
Claims (9)
1.通式(I)所示的嘧啶类化合物或其药学上可接受的盐:
其中:
X为CH2、O、S或NH;
R1为氢、卤素或NR4R5;
R2为(C1-C8)烷基、(C3-C6)环烷基、(C1-C8)烷氧基(C1-C8)烷基、(C6-C10)芳基或(C5-C10)芳杂环基,其中所述的芳基和芳杂环基可任选地用一个至五个以下基团取代:卤素、硝基、氰基、羟基、氨基、(C1-C8)烷基、(C1-C8)烷氧基或(C3-C6)环烷基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、(C1-C6)烷基、(C3-C6)环烷基、或R4和R5与跟它们连接的氮原子一起形成5-7元杂环基团,其中所述的杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子。
2.根据权利要求1所述的嘧啶类化合物或其药学上可接受的盐,其特征在于:
X为CH2、O或NH;
R1为卤素或NR4R5;
R2为(C1-C8)烷基、(C6-C10)芳基或(C5-C10)芳杂环基,其中所述的芳基和芳杂环基可任选地用一个至五个以下基团取代:卤素、硝基、氰基、羟基、氨基、(C1-C8)烷基、(C1-C8)烷氧基或(C3-C6)环烷基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、(C1-C6)烷基、或R4和R5与跟它们连接的氮原子一起形成5-7元杂环基团,其中所述的杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子。
3.根据权利要求2所述的嘧啶类化合物或其药学上可接受的盐,其特征在于:
X为O;
R1为氯、氨基、甲胺基、乙胺基、异丙胺基、二甲胺基或哌啶基;
R2为乙基或苯基;
R3任选自:
R4和R5可以相同或不同,任选自:氢、甲基、乙基、异丙基、或R4和R5与跟它们连接的氮原子一起形成6元哌啶环。
4.根据权利要求1所述的嘧啶类化合物或其药学上可接受的盐,其特征在于所述化合物优先选自:
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-哌啶基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
(R)-1-[3-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[[5-(4-乙氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-乙氧基苯甲酰基)-6-氨基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-氯嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基)哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-苯氧基苯甲酰基)-6-二甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-甲胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-乙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮;
1-[4-[2-[[5-(4-乙氧基苯甲酰基)-6-异丙胺基嘧啶-4-基]氨基]苯基]哌嗪-1-基]-2-丙烯-1-酮。
5.根据权利要求1所述的嘧啶类化合物的制备方法,其特征在于:
a)当R3为时,通式(1)所示化合物的制备方法为:以4,6-二羟基嘧啶为原料,经Vilsmeier-Haack反应和氯代反应一锅法制得4,6-二氯-5-嘧啶甲醛1,1经次氯酸钠氧化制得4,6-二氯-5-嘧啶羧酸2,2与草酰氯反应制得酰氯中间体后分别与二苯醚和苯乙醚进行Friedel-Crafts酰基化反应制得(4,6-二氯嘧啶-5-基)(4-苯氧苯基)甲酮3a和(4,6-二氯嘧啶-5-基)(4-乙氧苯基)甲酮3b,3a-b与(R)-1-Boc-3-氨基哌啶反应制得4a-b,4a-b与胺类化合物反应制得5a-g,5a-g经脱Boc保护基制得6a-g,6a-g与丙烯酰氯反应制得LX-2-LX-6、LX-8和LX-9;其合成路线如下:
其中,R4和R5的定义如权利要求1所述,其中,R4和R5同时为H的化合物除外;
b)当R1为NH2,R3为时,通式(I)所示化合物的制备方法为:中间体3a-b与氨水反应制得7a-b,7a-b与(R)-1-Boc-3-氨基哌啶反应制得8a-b,8a-b脱Boc保护得到9a-b,9a-b与丙烯酰氯反应最后得到LX-1和LX-7;其合成路线如下:
c)当R3为时,通式(1)所示化合物的制备方法为:7a在缚酸剂DIPEA的作用下与1-Boc-4-氨基哌啶反应制得11a;3a-b与1-Boc-4-氨基哌啶反应制得10a-b,10a-b与胺类化合物在乙醇中回流反应制得11b-h,11a-h脱Boc保护基制得12a-h,12a-h与丙烯酰氯反应制得LX-10-LX-17;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
d)当R3为时,通式(I)所示化合物的制备方法为:中间体3a-b与胺反应制得13b-d和13f-h,13b-d或13f-h与无水哌嗪反应制得14a-h,14a-h与丙烯酰氯反应制得LX-18-LX-25;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
e)当R3为时,通式(I)所示化合物的制备方法为:以邻溴硝基苯为起始原料,与无水哌嗪反应制得15,15经Boc保护制得化合物16,16经过还原得到芳胺17,17与中间体3a-b发生反应制得化合物18a-b,18a-b与胺类化合物反应得到化合物19a-g,19a-g脱Boc保护基制得化合物20a-g,20a-g与丙烯酰氯反应制得LX-27-LX-33;此外,18a直接脱Boc得到另一中间体21,21与丙烯酰氯反应制得LX-26;其合成路线如下:
其中,R4和R5的定义如权利要求1所述;
制备18a-b所示化合物的特征在于,所用溶剂为二甲基亚砜或N,N-二甲基甲酰胺,温度为100-120℃,反应时间为3-6小时。
6.一种治疗肿瘤的药物组合物,其由治疗上有效量的权利要求1-4中任一项所述的嘧啶类化合物或其药学上可接受的盐和药学上可接受的载体或辅料组成。
7.权利要求1-5任一项所述的化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备治疗肿瘤或炎症的药物中的应用。
8.根据权利要求7所述的应用,其中所述的肿瘤为B细胞淋巴瘤。
9.根据权利要求8所述的应用,其中所述的B细胞淋巴瘤为慢性淋巴性白血病、套细胞淋巴瘤、小淋巴细胞性肿瘤、弥漫性大B细胞淋巴瘤或多发性骨髓瘤。
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