CN104418860A

CN104418860A - 嘧啶并杂环类化合物及其药用组合物和应用

Info

Publication number: CN104418860A
Application number: CN201310365460.XA
Authority: CN
Inventors: 丁克; 徐石林; 徐田锋; 张连文; 丁芳; 涂正超; 陆小云; 丁健; 耿美玉
Original assignee: Guangzhou Institute of Biomedicine and Health of CAS
Current assignee: Guangzhou Institute of Biomedicine and Health of CAS
Priority date: 2013-08-20
Filing date: 2013-08-20
Publication date: 2015-03-18
Anticipated expiration: 2033-08-20
Also published as: CN104418860B

Abstract

本发明公开了一种具有式（Ⅰ）结构的嘧啶并杂环类化合物或者其药学上可接受的盐或立体异构体或其前药分子。该化合物可以有效抑制多种肿瘤细胞的生长，并对EGFR蛋白酶产生抑制作用，可用于制备抗肿瘤药物，并可以克服现有药物吉非替尼，厄洛替尼等诱发的耐药，对野生型非小细胞肺癌具有选择性，具有良好的药代动力学性质。

Description

嘧啶并杂环类化合物及其药用组合物和应用

技术领域

本发明属于化学医药领域，特别是涉及嘧啶并杂环类化合物及其药用组合物和应用。

背景技术

无论在世界范围内还是在中国，以恶性肿瘤（癌症）、心血管疾病以及糖尿病等为代表的慢性病（或者说非传染性疾病），都正在成为更主要的长期威胁。2008年5月19日，世界卫生组织在其最新公布的报告中就明确指出，非传染性疾病正在成为人类最为致命的“杀手”。其中，癌症位列首位。2004年，全球有740万人死于癌症，其中，中国的情况则更为严峻。2008年4月底公布的第三次全国死因回顾调查表明，中国城乡居民的癌症死亡率在过去30年中增长了八成以上；其中每四到五个死亡的中国人中就有一个人死于癌症。中国每年死于癌症的总人口，接近200万人。近年来，虽然各种各样的治疗途径以及药物的发现对癌症患者带来了希望，但是常规治疗的弊端，副作用大，治疗效果不佳，肿瘤预后复发，转移等现象迫切需要新的治疗技术来解决这类瓶颈作用。国际医学界将分子分型基础上的个体化化疗和靶向治疗看作是突破目前肺癌治疗瓶颈的希望所在。

肿瘤分子靶向治疗是基于对肿瘤生长密切相关的关键分子通过化学或生物学手段选择性杀伤肿瘤细胞的一种治疗方法。靶向治疗的特点为：特异性高，选择性强，毒副作用较轻；联合应用时，它可加强传统化疗、放疗的疗效，减少术后复发。以伊马替尼甲磺酸盐（STI571）（Novartis,2001），吉非替尼（ZD1839）（AstraZeneca,2003），厄罗替尼（OSI774）（Genentech and OSIP,2004），索拉菲尼对甲苯磺酸盐（Bay43-9006）（Bayer and Onyx,2005），舒尼替尼苹果酸盐（SU11248）（Pfizer,2006）以及达沙替尼（BMS-354825）（Bristol-Myers Squibb,2006）为代表的靶向药物为肿瘤化疗开创了一个新时代。肿瘤靶向治疗在短短几年内得到了迅速发展。肿瘤靶向治疗的出现已对传统给药观念和模式构成冲击，例如，因毒副作用小靶向药物在I期临床试验中往往无法达到剂量限制性毒性和最大耐受剂量；用靶向治疗药物时无需用最大耐受剂量即可达到满意疗效。肿瘤靶向治疗是肿瘤治疗的热点和发展趋势。

蛋白酪氨酸激酶（PTKs）是一类能够催化多种重要蛋白质的酪氨酸残基上的酚羟基发生磷酸化，进而激活功能蛋白的功能的蛋白质酶系。人体内的520多种蛋白激酶中大约有一半是酪氨酸激酶（PTKs）。它们在细胞内的信号传导通路中占据了十分重要的地位，调节着细胞体内生长、分化、死亡等一系列生理化过程。蛋白酪氨酸激酶功能失调会引发生物体内的一系列疾病。研究表明，半数以上的原癌基因和癌基因的激活都与蛋白酪氨酸激酶相关。蛋白酪氨酸激酶的异常表达可导致细胞增殖调节发生紊乱，进而导致肿瘤发生。此外，酪氨酸激酶的异常表达还与肿瘤的侵袭和转移，肿瘤新生血管的生成，肿瘤的化疗抗药性密切相关。以酪氨酸激酶为靶点进行抗肿瘤药物研发成为国际上的一个热点，也是各国药物开发机构研究投入的重点。

表皮生长因子受体（EGFR），一种受体酪氨酸蛋白激酶，调控了细胞的增殖，存活，粘连，迁移与分化。EGFR在多种肿瘤细胞中过度活化或持续活化，比如肺癌，乳腺癌，前列腺癌等。EGFR是一种跨膜蛋白，其家族有四种亚型：EGFR-1（后来被称为EGFR，Erb-B1或Her-1），HER-2（Erb-B2或neu），HER-3（Erb-B3）和HER-4（Erb-B4）。其中EGFR和Erb-B2的异常活化在肿瘤的转化与增长中起着关键性的作用。阻断EGFR和Erb-B2的活化已被临床验证为主导的方法来靶向治疗肿瘤细胞。以肺癌为例，EGFR在50%的NSCLC（非小型性细胞肺癌）病例中有表达，而且其表达与预后不佳相关。这两个因素使得EGFR及其家族成员成为开展靶向治疗的主要候选者。两种靶向EGFR的小分子抑制剂，吉非替尼和厄洛替尼，得到了美国FDA的快速批准用于治疗晚期NSCLC患者，这些患者对常规化疗已经失去了反应。

早期的临床数据表明，10%的NSCLC患者对吉非替尼和厄洛替尼有反应。这种显著的临床疗效可见于特定的患者群体，包括非吸烟的东亚地区女性和表现为支气管肺泡性病理类型的腺癌患者。分子水平的分析表明，在多数情况下，对药物有反应的患者在编码EGFR基因上带有特定的突变。第19外显子的第747～750位氨基酸的缺失占突变的45%，还有10%的突变在第18和第20外显子。EGFR激酶结构域的突变高度激活激酶，使得肿瘤细胞的生存对突变激酶具有依赖性。已有多项前瞻性临床研究证实，EGFR活化突变阳性的NSCLC患者对EGFR-TKI（EGFR-酪氨酸激酶抑制剂）的反应率显著高于EGFR野生型NSCLC患者，无进展生存（PFS）期和总生存（OS）期也显著延长。但尽管如此，大部分EGFR突变阳性患者的PFS不超过12～14个月，即对TKI发生了耐药。获得性耐药的机制及其临床应对策略成为靶向治疗领域的又一研究热点。

靶向EGFR抑制剂耐药机制可分为两类：耐药突变和旁路激活途径。耐药机制1：T790M突变是EGFR20外显子中的一个点突变，是目前较为认可的耐药机制之一。T790M导致TKI耐药的机制尚不完全清楚。最初的研究显示，T790M可能改变了激酶区腺苷三磷酸（ATP）结合口袋的晶体结构，封闭了TKI与激酶区的结合。最新研究显示，L858R合并T790M突变对ATP的亲和力比单纯L858R强，而TKI是ATP竞争性激酶抑制剂，故导致TKI与激酶区结合率降低。关于T790M的争议之一是，该突变是在TKI治疗后产生还是原本就存在、经TKI治疗选择后才被发现。最初，T790M只在TKI治疗失败的NSCLC患者标本中被发现，但随后在未经任何治疗的标本中也被发现，故目前认为，该突变也存在于未经TKI治疗的肿瘤组织中，但仅见于少数细胞克隆，由于这些细胞克隆对TKI的抵抗性而在治疗后被选择出来。与T790M相似的耐药突变还有D761Y、L747S和T854A等，这些突变统称为“非T790M继发突变”，其总发生率低于5%。耐药机制2：MET扩增是2007年发现的又一EGFR-TKI获得性耐药机制。MET是一种跨膜酪氨酸激酶受体。在对TKI获得性耐药的EGFR突变阳性NSCLC患者中，约20%有野生型MET基因扩增，且大部分在治疗前无MET扩增。MET联合ErbB家族成员，绕过EGFR活化下游AKT介导的信号通路，促进肿瘤细胞生长，抑制其凋亡。在体外实验中，通过RNA干扰技术抑制MET信号通路，可恢复耐药者对吉非替尼的敏感性。同时抑制EGFR和MET，可克服MET扩增介导的TKI耐药。其他还有些受体与MET作用类似。最近的体外TKI耐药模型显示，胰岛素样生长因子1受体（IGF-1R）也可绕过EGFR，激活其下游信号通路，但由于技术原因，很难在患者标本中进行IGF-1R活化检测。这些绕过EGFR、激活其下游信号通路的耐药机制统称为“旁路激活途径”。对TKI耐药的EGFR突变阳性患者，约30%～40%既无继发突变，也无MET扩增，这些患者的耐药机制还在探索中。

针对耐药性，临床上采用的策略是：策略1——继续使用EGFR-TKI，吉非替尼和厄洛替尼的交叉使用。总之，TKI进展后继续使用TKI有一定益处，但获益程度非常有限。策略2——开发新型EGFR-TKI。临床前研究显示，EGFR不可逆抑制剂可在体外抑制T790M，此后，很多EGFR不可逆抑制剂被研制出来，称为“二代EGFR-TKI”，目前已从临床前研究逐渐走向临床，研究较多的有neratinib、XL647、BIBW2992和PF-00299804。Neratinib是泛ErbB（EGFR、ErbB2和ErbB3）不可逆TKI。基于Ⅰ期研究结果，目前正在开展临床研究，探讨在吉非替尼或厄洛替尼治疗后进展的NSCLC患者中，neratinib（240mg/d）是否能克服T790M突变或MET扩增导致的TKI耐药。但一些临床前研究显示了不利结果，一种EGFR19外显子缺失的细胞株PC-9在暴露于neratinib时，产生了T790M突变；在鼠L858R-T790M肿瘤模型中，单用neratinib未使肿瘤缓解。故neratinib对T790M突变者是否有效尚不得知。XL647能不可逆抑制EGFR、HER2、血管内皮生长因子受体2（VEGFR-2）和EphB4，在L858R-T790M突变模型中，可抑制肿瘤生长。2008年，一项关于XL647的Ⅱ期临床研究初步显示，在34例吉非替尼或厄洛替尼治疗缓解超过3个月后发生疾病进展或伴有T790M突变的NSCLC患者中，用XL647（300mg/d）治疗后，仅1例部分缓解，该患者不吸烟，19外显子缺失，血浆中无T790M突变；而T790M突变阳性的患者无一缓解，大部分在2个月内进展。BIBW2992是EGFR和ErbB2的不可逆TKI。在Ⅱ期临床研究中，BIBW2992使有19外显子缺失，L858R、L861Q及G719S/S768I突变患者出现缓解。一项BIBW2992三线治疗化疗失败、吉非替尼或厄洛替尼获益后进展NSCLC的临床研究正在开展。BIBW2992对比安慰剂，三线治疗吉非替尼或厄洛替尼治疗失败NSCLC的随机Ⅱb/Ⅲ期临床研究也在进行中。这些研究将有助于确定BIBW2992能否给吉非替尼或厄洛替尼耐药患者带来益处。目前，BIBW2992被美国FDA批准上市用于治疗NSCLC，但仅作用于激活突变肺癌，例如L858R突变。PF-00299804是泛ErbBTKI抑制剂。在Ⅰ期临床研究中，1例T790M突变阳性者出现疾病缓解。PF-00299804（45mg/d）治疗KRAS野生型、化疗和厄洛替尼治疗失败NSCLC患者的Ⅱ期临床研究正在开展。策略3——针对其他靶点治疗。由于“旁路激活途径”在EGFR-TKI耐药中发挥重要作用，针对这些旁路的靶向药物不断涌现。MET-TKI可能在伴有MET扩增的患者中发挥作用。临床前研究显示，EGFR-TKI与MET-TKI联合，对EGFR突变阳性且伴有MET扩增的细胞株有效，但两者单独使用均无效。一个重要的问题是，约一半具有MET扩增的患者同时具有T790M突变，故MET-TKI可能需要与T790M抑制剂联合。XL184是一种新型TKI，对MET、VEGFR-2和RET有抑制作用。其他MET抑制剂，如ARQ197、PF-2341066、SGX523等，也有相关临床研究在进行。PF-2341066是一种选择性c-MET和ALK受体酪氨酸激酶抑制剂，在Ⅰ期临床研究中展示了较好的肿瘤控制效果，尤其是对ALK-EML4融合基因阳性患者。关于PF-2341066的Ⅱ/Ⅲ期临床研究正在开展，其已然成为靶向治疗领域的一个新热点。针对其他可能的旁路激活途径，一些药物，如IGF-1R抑制剂、热休克蛋白90抑制剂等的相关研究也在进行之中。

总之，目前的EGFR-TKI仍不能解决药物耐药性所引起的临床压力，而且现有的药物多是以喹唑啉或者喹啉胺类为基本母核的EGFR可逆或不可逆抑制剂，其对野生型细胞的选择性差带来的毒副作用也是不可避免的。因此，迫切需要新类型的，尤其是新颖骨架的化合物来解决耐药性，选择性差，药代性质差等问题。

发明内容

本发明的目的是提供一种新的嘧啶并杂环类化合物。

具体的技术方案如下：

具有式（Ⅰ）结构的嘧啶并杂环类化合物或者其药学上可接受的盐或立体异构体或其前药分子：

其中，X任选自N或C原子；

Y任选自H，CH₃，CF₃；

R₁任选自：

1）C₁～C₃烷基；

2）C₃～C₆环烷基；

3）其中，m任选自0,1,2；A₁,A₂,A₃,A₄,A₅任选自：

a)H；

b)F,Cl,Br；

c)C₁～C₃烷基

d)C₁～C₃烷氧基；

e)苯氧基；

4）其中，A₆,A₇,A₈,A₉,A₁₀任选自：H,F,Cl；

R₂任选自：

1）其中，B₁,B₂,B₃,B₄,B₅任选自：

a)H；

b)F,Cl；

c)C₁～C₂烷基；

d)含氟甲基；

e)C₁～C₄烷氧基；

f)N,N-二甲基氨基；

g)5～6元饱和杂环；

h)被B₆取代的4-7元饱和杂环，其中，B₆任选自：甲基，二甲基氨基，4-甲基哌嗪基，2-氟乙基；

i)C₁～C₂-4-甲基哌嗪基；

2）C₁～C₄-NB₇B₈，其中，B₇,B₈任选自甲基，乙基；

上述杂环中的杂原子选自N，O，S；

R₃任选自：

W任选自：

1）–(CH₂)_nNH–，其中n任选自1,2,3；

2）含N原子的5-6元饱和环。

在其中一些实施例中，所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅰ）结构：

其中，

当X为N原子时，Y选自H，虚线所在位置的化学键为单键；

当X为C原子时，Y任选自H，CH₃，CF₃，虚线所在位置的化学键为双键；

所述R₁选自：

1）甲基，乙基，正丙基，异丙基；

2）环戊基，环己基；

3）苯基，苄基，苯乙基；

4）卤代苯基，其中，卤素任选自F，Cl；

5）卤代苯氧基，其中，卤素任选自F，Cl；

6）甲基取代苯基，甲氧基取代苯基，苯氧基取代苯基；

所述R₂选自：

1）其中，B₁,B₂,B₃,B₄,B₅任选自：

a）H；

b）F,Cl；

c）甲基，三氟甲基；

d）甲氧基，乙氧基，异丙氧基；

e）吡咯基，哌啶基，吗啡啉基，硫啡啉基，N,N-二甲基氨基；

f）4-甲基哌嗪基，4-甲基哌啶基，2-（4-甲基哌嗪）乙基，4-（4-甲基哌嗪）哌啶基，4-（N,N-二甲基）哌啶基，4-甲基高哌嗪基，1-（2-氟乙基）氮杂环丁烷-3-氨基，4-（N,N-二乙基）丁基；

所述R₃选自：

所述W选自：

在其中一些实施例中，所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅱ）结构：

其中，X，Y，R₃如权利要求2所述；

所述R₁选自：

1）甲基，异丙基；

2）环戊基，环己基；

3）苯基，苄基，苯乙基；

4）3-氯-4-氟苯基，2-氯苯基，3-氯苯基，4-氯苯基，4-氟苯基，3,5-二氯苯基；

5）苯氧基，2-氯苯氧基，2-氟苯氧基，2,4-二氟苯氧基；

6）2-甲基苯基，4-甲氧基苯基，4-苯氧基苯基；

所述R₂选自：

在其中一个实施例中，所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅲ）结构：

其中，R₂如权利要求3所述；

所述R₁选自：

1)甲基，异丙基；

2)环戊基，环己基；

3)苯基，苄基，苯乙基；

4)3-氯-4-氟苯基，2-氯苯基，3-氯苯基，4-氯苯基，4-氟苯基，3,5-二氯苯基；

5)2-甲基苯基，4-甲氧基苯基，4-苯氧基苯基。

本发明另一目的是提供一种治疗肿瘤的药用组合物。

具体的技术方案如下：

一种治疗肿瘤的药用组合物，其活性成分包括上述的嘧啶并杂环类化合物或其药学上可接受的盐或立体异构体或其前药分子。

本发明另一目的是提供一种上述化合物的应用。

具体技术方案如下：

上述嘧啶并杂环类化合物及其药学上可接受的盐或立体异构体或其前药分子在制备治疗肿瘤的药物中的应用。

在其中一些实施例中，所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌中的任一种。

本发明涉及具有通式（Ⅰ-Ⅲ）结构特征的嘧啶并杂环类化合物，可以抑制多种肿瘤细胞，尤其是能够选择性作用于EGFR^L858R/T790M以及EGFR^{Del E745_A750}肺癌细胞。对比野生型癌细胞，该类化合物的具有85-245倍的选择性。相比专利WO2012167415(A1)中嘧啶并嘧啶酮类化合物，该类化合物具有更优的药代动力学性质。该类化合物是一类新颖的能够克服现有EGFR酪氨酸激酶抑制剂耐药的并具有选择性和良好药代性质的蛋白激酶抑制剂。

本发明涉及的嘧啶并杂环类化合物及其药学上可接受的盐，可以有效抑制多种肿瘤细胞的生长，并对EGFR蛋白酶产生抑制作用，可用于制备抗肿瘤药物，并可以克服现有药物吉非替尼，厄洛替尼等诱发的耐药。如本领域技术人员所理解的，本申请所涉及的化合物及其药学可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病。

附图说明

图1为化合物XSL190162对EGFR激酶及其下游信号通路蛋白磷酸化影响测试结果；

图2-3为化合物XSL190162对小鼠移植瘤抑制的测试结果；

图4为化合物XSL190162对小鼠体重影响的测试结果。

具体实施方式

本发明所述化学物中，当任何变量（例如R₁、R等）在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。

本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C₁-C₅烷基”中“C₁-C₅”的定义包括以直链或支链排列的具有1、2、3、4、或5个碳原子的基团。例如，“C₁-C₅烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。

本文中所用术语“杂环”或“杂环基”是指含有1-4个选自O、N和S的杂原子的5元-6元芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括上面提及的杂芳基，也包括其二氢化及四氢化类似物。“杂环基”进一步的实施例包括但不限于：咪唑基、吲哚基、异噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、l,4－二噁烷基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基和四氢噻吩基，及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。

正如本领域技术人员所理解的，本文中所用“卤素”（“halo”）或“卤素”意指包括氟、氯、溴和碘。

除非另有定义，烷基、环烷基、芳基和杂环基取代基可为未被取代的或取代的。例如，(C₁-C₆)烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。

本发明包括式Ⅰ-Ⅲ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ-Ⅲ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。

可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。

因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。

如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐．得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。

Berg等，“Pharmaceutical Salts”J.Pharm.Sci.1977：66：1－19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。

由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。

除在文献中已知的或在实验程序中例证的标准方法外，可采用如下列方案中显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式Ⅰ-Ⅲ的定义下允许有多取代基的化合物上。

方案

如发明所述式Ⅰ-Ⅲ化合物，可以由4-氯-2-甲巯基嘧啶-5-碳酸乙酯为起始原料通过9步反应合成。

在一个实施方案中，本申请提供了一种利用具有式Ⅰ-Ⅲ的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。

在一个实施方案中，本申请所设计的化合物及其药学可接受的盐可以用于治疗或控制非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌等过渡增殖性疾病。

药物代谢物及前药

本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。

联合用药

式Ⅰ-Ⅲ化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用式Ⅰ-Ⅲ化合物。当式Ⅰ-Ⅲ化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式Ⅰ-Ⅲ化合物的药用组合物。药物联用也包括在重叠的时间段服用式Ⅰ-Ⅲ化合物与其它一种或几种已知药物。当式Ⅰ-Ⅲ化合物与其它一种或几种药物进行药物联用时，式Ⅰ-Ⅲ化合物或已知药物的剂量可能比它们单独用药时的剂量较低。

可以与式Ⅰ-Ⅲ化合物进行药物联用的药物或活性成分包括但不局限为：

雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂，Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。

在一个实施方案中，可以与式Ⅰ-Ⅲ化合物进行药物联用的药物或活性成分包括但不局限为：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-154、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。

以下实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1氢)-酮(XSL1710)

1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-d ihydropyrimido[4,5-d]pyrimidin-2(1H)-one

步骤1.4-(1-叔丁氧羰基哌啶基-4-氨基)-2-甲巯基嘧啶-5-碳酸乙酯(2)

（ethyl4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(methylthio)pyrimidine-5-carboxylate）

4-氯-2-甲巯基嘧啶-5-碳酸乙酯（5g,21.5mmol）4-氨基-1-叔丁氧羰基哌啶（4.53g, 22.6mmol），K₂CO₃（5.9g,43mmol）溶于50mL无水DMF中，氩气保护下，加热至80℃，搅拌过夜。冷却至室温，搅拌下加入200mL冰水，大量固体析出。减压过滤，真空干燥得白色油状物7.78g(91%)。

¹H NMR(400MHz,CDCl₃)δ8.63(s,1H),8.50(d,J=7.2Hz,1H),4.31(q,J=7.2Hz,2H),4.27-4.21(m,1H),4.00-3.97(m,2H),3.02(t,J=11.4Hz,2H),2.51(s,3H),2.03-1.99(m,2H),1.54-1.49(m,2H),1.46(s,9H),1.36(t,J=7.2Hz,3H).

MS(ESI)m/z397.1[M+H]⁺.

步骤2.叔丁基4-(5-(羟甲基)-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(3)

（tert-butyl4-(5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-ylamino)piperidine-1-carboxylate）

4-(1-叔丁氧羰基哌啶基-4-氨基)-2-甲巯基嘧啶-5-碳酸乙酯(2)（4g，10.08mmol）溶于100mL四氢呋喃中，冷却至-40℃，缓慢滴加四氢锂铝（766mg，20.16mmol）的四氢呋喃悬浊液，搅拌并缓慢升至10℃，点半检测反应。原料反应完后，降温至-40℃，先后缓慢滴加1mL的水，1mL的10%氢氧化钠溶液和3mL的水淬灭反应，随后加入干燥的MgSO₄粉末，抽滤，浓缩。再用二氯甲烷和水萃取，取有机相，无水Na₂SO₄干燥，然后过滤旋干，柱层析分离得白色油状物2.07g（58%）。

¹H NMR(400MHz,CDCl₃)δ7.63(s,1H),5.95(d,J=7.2Hz,1H),4.48(s,2H),4.21-4.14(m,1H),3.99-3.96(m,2H),2.95(t,J=11.4Hz,2H),2.47(s,3H),2.03-1.99(m,2H),1.45(s,9H),1.43-1.37(m,2H).

MS(ESI)m/z355.1[M+H]⁺.

步骤3.叔丁基4-(5-甲酰基-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(4)

（tert-butyl4-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)piperidine-1-carboxylate）

叔丁基4-(5-(羟甲基)-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(3)（2g，5.64mmol）溶于100mL无水二氯甲烷中，分批加入3当量的活性二氧化锰（1.5g，16.92mmol），原料反应完后，用硅藻土抽滤，除去固体，旋干得油状物1.89g（95%）。

¹H NMR(400MHz,CDCl₃)δ9.70(s,1H),8.59(d,J=6.8Hz,1H),8.31(s,1H),4.34-4.25(m,1H),4.03-4.01(m,1H),3.01(t,J=11.4Hz,2H),2.54(s,3H),2.04-2.00(m,2H),1.54-1.50(m,2H),1.47(s,9H).

MS(ESI)m/z353.0[M+H]⁺.

步骤4.叔丁基4-(5-(苄胺基甲基)-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(5)

tert-butyl4-(5-((benzylamino)methyl)-2-(methylthio)pyrimidin-4-ylamino)piperidine-1-carboxylate

叔丁基4-(5-甲酰基-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(4)（1.89g，5.36mmol）溶于100mL无水甲醇中，加入苄胺（1.5g，10.72mmol）和催化量的醋酸，室温搅拌，点半监测。待原料反应完后，冰浴下，分批加入硼氢化钠（407mg，10.72mmol）。加水淬灭反应，浓缩，加入10%NaHCO₃水溶液，二氯甲烷萃取两遍，合并有机相，用饱和食盐水洗涤一遍，无水Na₂SO₄干燥，过滤旋干，柱层析分离得固体2.24g（94%）。

¹H NMR(400MHz,CDCl₃)δ7.71(s,1H),7.44(d,J=7.2Hz,1H),7.35-7.31(m,2H),7.28-7.22(m,3H),4.18-4.10(m,1H),3.96-3.94(m,2H),3.69(s,2H),3.65(s,2H),3.00(t,J=11.2Hz,2H),2.48(s,3H),2.01-1.97(m,2H),1.75(s,1H),1.47(s,9H),1.42-1.38(m,2H).

MS(ESI)m/z444.1[M+H]⁺。

步骤5.叔丁基4-(3-苄基-7-(甲巯基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)嘧啶-1-碳酸酯(6)

（tert-butyl4-(3-benzyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate）

叔丁基4-(5-(苄胺基甲基)-2-甲巯基嘧啶-4-氨基)哌啶-1-碳酸酯(5)（2.15g，4.85mmol）溶于20mL无水二氯甲烷中，加入DIPEA（110μL，0.63mmol），冰浴下，滴加三光气（0.53g， 1.78mmol）的二氯甲烷溶液，搅拌并缓慢升至室温。反应完后，加入10%NaHCO₃水溶液，二氯甲烷萃取两遍，合并有机相，用饱和食盐水洗涤一遍，无水Na₂SO₄干燥，过滤旋干，柱层析分离得固体2g（88%）

¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.37-7.26(m,5H),4.92-4.86(m,1H),4.64(s,2H),4.31-4.22(m,2H),4.15(s,2H),2.83-2.71(m,4H),2.50(s,3H),1.69-1.66(m,2H),1.47(s,9H).

MS(ESI)m/z470.5[M+H]⁺。

步骤6.叔丁基4-(3-苄基-7-(甲砜基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)哌啶-1-碳酸酯(7)

（tert-butyl4-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate）

叔丁基4-(3-苄基-7-(甲巯基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2氢)-yl)嘧啶-1-碳酸酯(6)（2.45g，5.22mmol)溶于50mL无水二氯甲烷中，0℃冰浴下，缓慢加入间氯过氧苯甲酸（2.1g，10.44mmol），回至室温，搅拌4小时。加入二氯甲烷稀释反应液，用50%Na₂S₂O₃/NaHCO₃水溶液淬灭反应。有机相用饱和食盐水洗涤两遍，无水Na₂SO₄干燥，过滤旋干，用乙酸乙酯和石油醚混合液重结晶得固体1.7g（63%）。

¹H NMR(400MHz,CDCl₃)δ8.29(s,1H),7.40-7.29(m,5H),4.96-4.88(m,1H),4.66(s,2H),4.30(s,2H),4.26(s,2H),3.27(s,3H),2.82(s,2H),2.73-2.65(m,2H),1.72-1.69(m,2H),1.48(s,9H).

MS(ESI)m/z524.0[M+Na]⁺。

步骤7.叔丁基4-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)哌啶-1-碳酸酯(8)

（tert-butyl4-(3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate）

叔丁基4-(3-苄基-7-(甲砜基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2氢)-基)哌啶-1-碳酸酯(7)（1g，2mmol）加入装有10mL仲丁醇的封瓶中，依次加入2-甲氧基-4-(4-甲基哌嗪-1-取代)苯胺（531mg，2.4mmol）和TFA（180μL,2.4mmol）。加热到110℃，搅拌18小时。冷却至室温，倒入10%NaHCO₃水溶液中，二氯甲烷萃取两遍，合并有机相，饱和食盐水洗涤两遍，无水Na₂SO₄干燥，过滤旋干，柱层析分离的固体0.684g（53.3%）。

MS(ESI)m/z643.2[M+H]⁺.

步骤8.3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-1-(哌啶-4-基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(9)

（3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-1-(piperidin-4-yl)-3,4-dihydrop yrimido[4,5-d]pyrimidin-2(1H)-one）

叔丁基4-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2氢)-基)哌啶-1-碳酸酯(8)（620mg，0.96mmol）溶于5mL二氯甲烷中，加入TFA（0.143mL，1.92mmol），室温搅拌4h。反应用二氯甲烷稀释，用饱和NaHCO₃溶液调节PH至9，二氯甲烷萃取两遍，合并有机相，10%NaHCO₃水溶液洗涤两遍，饱和食盐水洗涤两遍，无水Na₂SO₄干燥，过滤旋干，柱层析分离的固体443mg（85%）。

¹H NMR(400MHz,CDCl₃)δ.8.12(d,J=9.6Hz,1H),7.85(s,1H),7.37-7.29(m,6H),6.56-6.53(m,2H),4.92-4.84(m,1H),4.63(s,2H),4.09(s,2H),3.88(s,3H),3.48(s,1H),3.25-3.22(m,2H),3.18(t,J=4.8Hz,4H),2.77-2.70(m,2H),2.67-2.63(m,2H),2.60(t,J=4.8Hz,4H),2.36(s,3H),1.75-1.72(m,2H).

MS(ESI)m/z543.0[M+H]⁺。

步骤9.1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1710)

（1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one）

3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-1-(哌啶-4-基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(9)（240mg，0.442mmol）溶于10mL无水二氯甲烷中，0℃冰浴下加入DIEA（230μL，1.326mmol），缓慢加入丙烯酰氯（72μL，0.884mmol）。回至室温搅拌4小时。反应完后，加入10%NaHCO₃水溶液，二氯甲烷萃取两遍，合并有机相，用饱和食盐水洗涤一遍，无水Na₂SO₄干燥，过滤旋干，柱层析分离，并用高效液相色谱仪进一步纯化得固体210mg（80%）

¹H NMR(400MHz,CDCl₃)δ8.08(d,J=8.8Hz,1H),7.87(s,1H),7.37-7.33(m,3H),7.31-7.28(m,3H),6.63(dd,J=10.8,16.8Hz,1H),6.54(d,J=2.4Hz,1H),6.49(dd,J=2.4,8.8Hz,1H),6.29(dd,J=2.0,16.8Hz,1H),5.69(dd,J=2.0,10.4Hz,1H),5.01-4.95(m,1H),4.89-4.87(m,1H),4.62(s,2H),4.16-4.12(m,1H),4.10(s,2H),3.88(s,3H),3.17(t,J=4.8Hz,4H),3.13-3.10(m,1H),2.86-2.71(m,3H),2.59(t,J=4.8Hz,4H),2.35(s,3H),1.85-1.79(m,2H).

¹³C NMR(125MHz,CDCl₃)δ165.48,159.11,157.41,153.87,153.41,149.18,147.39,136.29,128.78,128.10,127.78,127.39,121.81,119.83,107.88,102.22,100.27,55.64,55.16,52.98,51.43,49.94,46.24,46.12,43.77,42.49,29.28,28.47.

HRMS(ESI)for C₃₃H₄₀N₈O₃[M+H]⁺,Calcd:597.3296,Found:597.3297.

HPLC analysis:MeOH-H₂O(85:15),7.96min,97.18%.

实施例2

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1720)

1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃)δ7.89(s,1H),7.52(d,J=8.0Hz,2H),7.37-7.30(m,7H),7.12(s,1H),7.04(t,J=7.6Hz,1H),6.61(dd,J=10.4,16.8Hz,1H),6.29(dd,J=1.6,16.8Hz,1H),5.69(dd,J=1.6,10.4Hz,1H),4.99-4.92(m,1H),4.88-4.86(m,1H),4.63(s,2H),4.13(s,2H),4.11-4.09(m,1H),3.13(t,J=9.6Hz,1H),2.80-2.69(m,3H),1.78-1.72(m,2H).

¹³C NMR(125MHz,CDCl₃)δ165.48,159.05,157.48,153.73,153.27,139.09,136.19,128.90,128.80,128.12,128.06,127.84,127.42,123.07,119.87,103.08,53.10,51.49,46.17,43.73,42.45,29.29,28.43.

MS(ESI)m/z469.1[M+H]⁺.

HPLC analysis:MeOH-H₂O(78:22),8.69min,97.61%.

实施例3

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(4-氟苯胺基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1714)

1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(4-fluorophenylamino)-3,4-dihydropyrimido[4,5-d]pyrimid in-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃)δ7.88(s,1H),7.47-7.44(m,2H),7.37-7.34(m,2H),7.32-7.29(m,3H),7.03-6.99(m,3H),6.61(dd,J=10.4,16.8Hz,1H),6.31(dd,J=1.6,16.8Hz,1H),5.70(dd,J=1.6,10.4Hz,1H),4.95-4.85(m,2H),4.63(s,2H),4.12(s,2H),4.09-4.08(m,1H),3.12(t,J=12.0Hz,1H),2.81-2.67(m,3H),1.81-1.75(m,2H).

¹³C NMR(125MHz,CDCl₃)δ165.44,159.75,159.12,157.82,157.51,153.77,153.31,136.17,135.07,128.81,128.13,127.85,127.65,121.88,121.82,115.63,115.45,103.21,53.08,51.55,46.15,43.72,42.44,29.33,28.41.

HPLC analysis:MeOH-H₂O(78:22),8.91min,98.65%.

实施例4

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1752)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.95(d,J=8.8Hz,1H),7.90(s,0.6H)and7.89(s,0.4H),7.38-7.23(m,6H),6.58-6.44(m,3H),6.40-6.38(m,1H),5.72-5.55(m,2H),4.72-4.56(m,2H),4.31-4.26(m),4.10-3.89(m)and3.85-3.80(m)together(3H),4.13(s)and4.12(s)together(2H),3.87(s)and3.86(s)together(3H),3.67-3.51(m,1H),3.20-3.15(m,4H),2.99-2.85(m,1H),2.62-2.58(m,4H),2.37(s,3H),2.28-2.08(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.61,164.28,159.19,159.14,157.12,157.01,153.72,153.64,153.55,153.50,149.72,149.45,147.65,136.06,136.00,128.77,128.28,128.08,128.04,127.84,127.78,127.34,127.31,121.54,121.32,120.67,120.29,107.83,107.73,102.18,102.15,100.35,100.11,55.57,55.11,52.36,51.54,51.42,50.74,49.92,49.70,46.88,46.65,46.07,45.66,44.37,43.65,28.21,25.78.

HRMS(ESI)for C₃₂H₃₈N₈O₃[M+H]⁺,Calcd:583.3140,Found:583.3135.

HPLC analysis:MeOH-H₂O(78:22),11.31min,97.8%.-1.105(c0.181,CHCl₃).

实施例5

(R)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1754)

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.95(d,J=8.4Hz,1H),7.90(s,0.6H)and7.89(s,0.4H),7.38-7.23(m,6H),6.58-6.38(m,4H),5.72-5.55(m,2H),4.72-4.56(m,2H),4.31-4.27(m),4.10-3.89(m)and3.85-3.80(m)together(3H),4.13(s)and4.12(s)together(2H),3.87(s)and3.86(s)together(3H),3.67-3.51(m,1H),3.20-3.15(m,4H),2.99-2.85(m,1H),2.62-2.59(m,4H),2.37(s,3H),2.28-2.08(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.62,164.30,159.21,159.16,157.14,157.03,153.74,153.66,153.57,153.52,149.73,149.45,147.66,136.08,136.01,128.79,128.30,128.10,128.06,127.86,127.80,127.36,127.32,121.56,121.34,120.67,120.28,107.85,107.75,102.20,102.16,100.37,100.12,55.59,55.13,52.38,51.56,51.44,50.76,49.95,49.73,46.90,46.67,46.09,45.68,44.39,43.67,28.23,25.81.

HRMS(ESI)for C₃₂H₃₈N₈O₃[M+H]⁺,Calcd:583.3140,Found:583.3138.

HPLC analysis:MeOH-H₂O(78:22),11.28min,98.5%.+1.075(c0.186,CHCl₃).

实施例6

(R)-1-(1-丙烯酰基哌啶-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1756)

(R)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.99(d,J=8.4Hz,1H),7.89(s,0.6H)and7.86(s,0.4H),7.37-7.25(m,6H),6.67-6.60(m,1H),6.53-6.46(m,2H),6.30(t,J=16.0Hz,1H),5.72-5.61(m,1H),4.82-4.76(m,1H),4.72-4.64(m,2H),4.62-4.55(m,1H),4.15-4.13(m),4.00-3.97(m)and3.82-3.77(m)together(2H),4.11(s,2H),3.87(s,3H),3.18-3.14(m,4H),3.09-2.63(m,2H),2.60-2.58(m,4H),2.35(s,3H),1.98-1.86(m,2H),1.63-1.55(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.62,165.14,159.35,157.30,153.75,153.48,149.78,149.58,147.74,147.60,136.24,136.14,128.78,128.01,127.80,127.72,127.34,121.86,121.49,121.10,120.64,107.96,102.17,102.03,100.57,100.26,55.57,55.14,52.54,51.31,50.10,49.89,48.20,46.09,44.41,43.80,43.74,42.33,27.49,27.34,26.52,25.37.

HRMS(ESI)for C₃₃H₄₀N₈O₃[M+H]⁺,Calcd:597.3296,Found:597.3292.

HPLC analysis:MeOH-H₂O(78:22),12.63min,97.39%.+123.337(c0.154,CHCl₃).

实施例7

(S)-1-(1-丙烯酰基哌啶-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1758)

(S)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.00(d,J=8.8Hz,1H),7.89(s,0.6H)and7.86(s,0.4H),7.37-7.29(m,6H),6.67-6.60(m,1H),6.53-6.47(m,2H),6.30(t,J=16.4Hz,1H),5.72-5.61(m,1H),4.83-4.77(m,1H),4.72-4.55(m,3H),4.18-4.15(m),4.00-3.97(m)and3.83-3.77(m)together(2H),4.11(s,2H),3.87(s,3H),3.18-3.16(m,4H),3.10-2.67(m,2H),2.62-2.60(m,4H),2.37(s,3H),1.98-1.86(m,2H),1.63-1.60(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.61,165.13,159.33,157.28,153.74,153.47,149.77,149.57,147.73,147.58,136.24,136.13,128.76,127.99,127.78,127.71,127.33,121.85,121.48,121.13,120.65,107.95,102.15,102.03,100.56,100.25,55.56,55.11,52.52,51.30,50.07,49.87,48.18, 46.06,44.39,43.73,42.32,27.48,27.32,26.51,25.36.

HRMS(ESI)for C₃₃H₄₀N₈O₃[M+H]⁺,Calcd:597.3296,Found:597.3291.

HPLC analysis:MeOH-H₂O(78:22),12.63min,98.5%.-124.090(c0.137,CHCl₃).

实施例8

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-甲基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1787)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,amixture of rotamers)δ7.96(s,0.6H)and7.95(s,0.4H),7.93(d,J=8.8Hz,1H),7.31(s)and7.22(s)together(1H),6.55-6.42(m,3H),6.38-6.35(m,1H),5.71-5.51(m,2H),4.28-4.21(m),4.04-3.91(m)and3.78-3.74(m)together(3H),4.24(s,2H),3.86(s)and3.85(s)together(3H),3.64-3.48(m,1H),3.18-3.14(m,4H),3.03(s)and3.02(s)together(3H),2.93-2.79(m,1H),2.60-2.58(m,4H),2.35(s,3H),2.22-2.02(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.62,164.28,159.21,159.17,157.23,157.13,153.67,153.59,153.55,153.44,149.75,149.47,147.64,128.78,128.31,127.34,121.61,121.40,120.70,120.30,107.89,107.81,102.12,102.06,100.40,100.17,55.61,55.11,52.09,50.50,49.93,49.71,46.87,46.61,46.39,46.37,46.06,46.04,45.68,44.40,35.69,35.63,28.17,25.78.

MS(ESI)m/z507.4[M+H]⁺.

HRMS(ESI)for C₂₆H₃₄N₈O₃[M+H]⁺,Calcd:507.2827,Found:507.2822.

HPLC analysis:MeOH-H₂O(78:22),6.66min,97.09%.-4.000(c0.100,CHCl₃).

实施例9

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-异丙基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1788)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-isopropyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamin o)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.00(s,0.6H)and7.99(s,0.4H),7.98-7.94(m,1H),7.32(s)and7.23(s)together(1H),6.57-6.36(m,4H),5.71-5.61(m,1H),5.55-5.43(m,1H),4.75-4.67(m,1H),4.28-4.23(m),4.05-3.89(m)and3.83-3.78(m)together(3H),4.10(s)and4.09(s)together(2H),3.87(s)and3.86(s)together(3H),3.65-3.49(m,1H),3.21-3.16(m,4H),2.97-2.83(m,1H),2.65-2.61(m,4H),2.39(s)and2.38(s)together(3H),2.26-2.05(m,1H),1.22-1.18(m,6H).

¹³C NMR(125MHz,CDCl₃)δ164.63,164.26,159.24,159.20,157.41,157.31,153.42,153.33,153.25,153.19,149.69,149.42,147.55,128.81,128.32,127.32,127.29,121.72,121.48,120.60,120.25,107.89,107.80,102.76,102.73,100.41,100.15,55.60,55.11,52.51,50.90,49.94,49.70,46.95,46.66,46.05,46.04,46.01,45.86,45.70,44.37,37.34,28.20,25.73,19.23,19.19.

HRMS(ESI)for C₂₈H₃₈N₈O₃[M+H]⁺,Calcd:535.3140,Found:535.3138.

HPLC analysis:MeOH-H₂O(78:22),8.34min,98.42%.+9.589(c0.146,CHCl₃).

实施例10

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1789)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.02-7.99(m,2H),7.44-7.39(m,3H),7.32-7.28(m,3H),6.54-6.37(m,4H),5.70-5.61(m,1H),5.59-5.51(m,1H),4.68-4.58(m,2H),4.31-4.27(m),4.07-3.91(m)and3.86-3.80(m)together(3H),3.89(s)and3.88(s)together(3H),3.66-3.52(m,1H),3.22-3.18(m,4H),2.98-2.82(m,1H),2.65-2.61(m,4H),2.39(s,3H),2.33-2.12(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.59,164.24,159.38,159.34,157.34,157.24,153.52,153.37,153.32,153.15,149.72,149.47,147.68,142.00,141.92,129.15,129.13,128.76,128.30,127.33,127.31,126.75,126.65,125.25,125.20,121.52,121.32,120.66,120.28,107.88,107.77,102.84,102.81,100.37,100.14,55.61,55.10,52.68,51.04,49.90,49.69,47.16,47.06,47.04,46.72,46.05,45.69,44.35,28.35,25.82.

HRMS(ESI)for C₃₁H₃₆N₈O₃[M+H]⁺,Calcd:569.2983,Found:569.2980.

HPLC analysis:MeOH-H₂O(78:22),8.79min,96.98%.-8.421(c0.095,CHCl₃).

实施例11

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-(4-苯氧基苯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1790)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-(4-phen oxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.03-7.98(m,2H),7.39-7.26(m,5H),7.14-7.11(m,1H),7.04-7.03(m,4H),6.53-6.49(m,2H),6.41-6.37(m,2H),5.70-5.57(m,2H),4.66-4.57(m,2H),4.30-4.26(m),4.06-3.93(m)and3.85-3.83(m)together(3H),3.89(s,3H),3.65-3.51(m,1H),3.26-3.22(m,4H),2.95-2.87(m,1H),2.72-2.69(m,4H),2.44(s)and2.43(s)together(3H),2.30-2.14(m,1H).

¹³C NMR(125MHz,CDCl₃)δ157.37,157.25,156.83,156.81,155.94,155.85,153.58,153.46,153.42,153.28,149.75,149.54,147.66,137.05,136.96,129.82,129.80,128.76,128.30,127.40,126.90,126.87,123.64,123.60,121.61,121.39,120.68,120.36,119.22,119.20,119.12,107.98,107.89,102.78,102.74,100.44,100.20,55.65,55.09,55.06,52.68,51.05,49.87,49.64,47.42,47.40,47.19,46.73,46.01,45.97,45.72,44.38,28.38,25.85.

MS(ESI)m/z661.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),9.81min,95.13%.

实施例12

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯乙基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL1791)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-pheneth yl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.98-7.94(m,1H),7.86(s)and7.83(s)together(1H),7.31-7.26(m,3H),7.24-7.21(m,3H),6.53-6.37(m,4H),5.73-5.62(m,1H),5.54-5.47(m,1H),4.24-4.20(m),4.02-3.94(m)and3.80-3.76(m)together(3H),4.13-4.05(m,2H),3.87(s,3H),3.67-3.61(m,2H),3.59-3.48(m,1H),3.25-3.22(m,4H),2.94-2.90(m,2H),2.88-2.92(m,1H),2.72-2.69(m,4H),2.45(s)and2.43(s)together(3H),2.22-2.06(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.65,164.32,159.19,159.16,157.36,157.25,153.42,153.30,153.25,153.14,149.69,149.46,147.55,138.71,138.63,128.81,128.62,128.32,127.38,127.34,126.58,121.74,121.50,120.60,120.27,107.97,107.90,102.37,102.30,100.46,100.21,55.62,55.10,55.07,52.33,50.72,50.47,49.91,49.66,46.88,46.65,46.01,45.98,45.68,45.15,45.08,44.39,33.76,28.18,25.78.

MS(ESI)m/z597.3[M+H]⁺.

HPLC analysis:MeOH-H₂O(78:22),12.01min,98.44%.

实施例13

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(1-甲基哌啶-4-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190023)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(1-methylpiperidin-4-yl)phenylamino)-3,4-dihydro pyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.91(s,0.6H)and7.90(s,0.4H),7.46-7.40(m,2H),7.36-7.29(m,5H),7.17-7.15(m)and6.95(s)together(3H),6.57-6.34(m,2H),5.74-5.53(m,2H),4.71-4.57(m,2H),4.21-4.16(m),4.12-4.05(m)and3.98-3.82(m)together(3H),4.15(s)and4.13(s)together(2H),3.66-3.46(m,1H),3.06-3.04(m,2H),2.90-2.73(m,1H),2.50-2.44(m,1H),2.39(s)and2.38(s)together(3H),2.30-2.22(m,1H),2.17-2.13(m,2H),1.99-1.86(m,4H).

¹³C NMR(125MHz,CDCl₃)δ165.06,164.38,159.08,158.99,157.23,156.81,153.76,153.56,153.47,140.86,137.15,137.12,136.01,135.95,128.83,128.20,128.14,128.09,127.92,127.87,127.61,127.55,127.24,127.21,120.15,119.95,102.82,56.26,56.21,52.59,51.69,51.49,50.92,47.74,46.86,46.27,46.20,45.71,44.75,43.66,43.63,41.22,41.08,33.36,33.28,33.20,28.40,26.35.

MS(ESI)m/z552.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),11.68min,99.18%.

实施例14

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-苯氨基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190024)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.92(s,0.6H)and7.90(s,0.4H),7.54-7.47(m,2H),7.39-7.28(m,8H),7.06-7.02(m,1H),6.56-6.38(m,2H),5.74-5.54(m,2H),4.72-4.58(m,2H),4.20-4.18(m),4.12-4.07(m)and3.97-3.83(m)together(3H),4.15(s)and4.14(s)together(2H),3.64-3.46(m,1H),2.89-2.73(m,1H),2.28-2.13(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.117,164.43,159.00,158.90,157.25,156.84,153.74,153.46,153.32,139.10,139.02,135.98,135.93,128.92,128.88,128.83,128.19,128.15,129.10,127.94,127.88,127.58,123.09,123.05,120.13,119.67,103.06,103.01,52.65,51.71,51.51,50.97,47.74,46.80,45.66,44.74,43.64,63.61,28.33,26.34.

MS(ESI)m/z455.1[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),5.59min,98.38%.

实施例15

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(2-(4-甲基哌嗪-1-基)乙基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190031)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.91(s,0.6H)and7.90(s,0.4H),7.44-7.31(m)and7.14-7.12(m)together(10H),6.57-6.34(m,2H),5.74-5.55(m,2H),4.72-4.57(m,2H),4.15(s)and4.13(s)together(2H),4.11-4.05(m,1H),3.98-3.88(m,1H),3.86-3.81(m,1H),3.66-3.46(m,1H),2.88-2.85(m,1H),2.80-2.74(m,4H),2.72-2.62(m,8H),2.41(s)and2.39(s)together(3H)，2.28-2.13(m，1H).

¹³C NMR(125MHz,CDCl₃)δ165.07,164.39,158.99,157.23,156.81,153.77,153.59,153.50,137.22,137.17,136.01,135.95,129.12,129.09,128.84,128.53,128.21,128.16,128.11,127.95,127.89,127.64,127.55,120.16,119.98,102.95,102.88,60.13,59.98,54.72,54.62,52.63,52.55,52.42,51.72,51.52,50.95,47.74,46.87,45.72,45.62,45.54,44.76,43.66,32.70,32.56,28.40,26.36.

MS(ESI)m/z581.3[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),7.00min,100%.

实施例16

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(二乙氨基)丁氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190033)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(diethylamino)butylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.79(s,0.6H)and7.77(s,0.4H),7.35-7.28(m,5H),6.56-6.33(m,2H),5.70-5.42(m,3H),4.70-4.55(m,2H),4.22-4.16(m),4.05-3.89(m)and3.83-3.78(m)together(3H),4.09(s)and4.07(s)together(2H),3.66-3.47(m,1H),3.34-3.31(m,2H),2.89-2.82(m,1H),2.60-2.54(m,4H),2.50-2.45(m,2H),2.30-2.10(m,1H),1.60-1.54(m,4H),1.07-1.02(m,6H).

¹³C NMR(125MHz,CDCl₃)δ164.36,161.42,161.34,157.12,156.88,153.89,153.71,136.21,136.15,128.79,128.47,128.22,128.10,128.07,127.84,127.78,127.42,100.66,52.55,52.17,51.57,51.44,50.54,47.02,46.69,45.77,44.66,43.70,41.48,28.49,27.69,26.30,24.45.

MS(ESI)m/z506.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(90:10),13.28min,95.04%.

实施例17

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(1-甲基哌啶-4-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190048)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(4-(1-methylpiperidin-4-yl)phenylamino)-3-phenyl-3,4-dihydro pyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.04(s,0.65H)and8.03(s,0.35H),7.50-7.40(m,4H),7.32-7.29(m,3H),7.21-7.18(m)and7.02(s)together(3H),6.55-5.37(m,2H),5.72-5.63(m,1H),5.61-5.51(m,1H),4.69-4.60(m,2H),4.23-4.19(m)and4.11-3.99(m)together(2H),3.95-3.85(m,1H),3.66-3.60(m)and3.54-3.46(m)together(1H),3.14-3.10(m,2H),2.89-2.74(m,1H),2.55-2.50(m,1H),2.45(s)and2.43(s)together(3H),2.33-2.29(m,1H),2.26-2.17(m,2H),2.02-1.92(m,4H).

¹³C NMR(125MHz,CDCl₃)δ164.98,164.33,159.28,159.20,157.41,157.02,153.41,153.35,153.30,153.06,141.89,141.13,141.03,137.04,129.17,129.15,128.75,128.16,127.56,127.23,127.20,126.83,126.73,125.26,125.22,120.19,120.01,103.45,103.41,56.27,56.23,52.81,51.16,47.63,47.10,47.02,46.33,46.29,45.69,44.64,41.27,41.16,33.44,33.37,33.33,28.44,26.24.

HRMS(ESI)for C₃₁H₃₅N₇O₂[M+H]⁺,Calcd:538.2925,Found:538.2921.

HPLC analysis:MeOH-H₂O(85:15),10.26min,99.75%.-28.000(c0.100,CHCl₃).

实施例18

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苯基-7-苯氨基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190049)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-phenyl-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05(s,0.62H)and8.03(s,0.38H),7.57-7.51(m,2H),7.48-7.41(m,3H),7.34-7.28(m,5H),7.08-7.05(m,1H),6.52-6.38(m,2H),5.72-5.63(m,1H),5.61-5.49(m,1H),4.70-4.62(m,2H),4.22-4.18(m)and4.09-3.99(m)together(2H),3.90-3.84(m,1H),3.63-3.58(m)and3.54-3.48(m)together(1H),2.86-2.75(m,1H),2.32-2.17(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.05,164.36,159.06,157.49,157.08,153.32,153.23,153.02,141.89,139.04,138.93,129.21,129.19,128.93,128.90,128.78,128.18,127.58,127.54,126.88,126.79,125.27,125.24,123.19,123.14,120.17,119.73,103.66,52.91,51.24,47.72,47.06,47.02,45.66,44.67,28.41,26.32.

HRMS(ESI)for C₂₅H₂₄N₆O₂[M+H]⁺,Calcd:441.2034,Found:441.2030.

HPLC analysis:MeOH-H₂O(85:15),4.73min,99.24%.-2.564(c0.078,CHCl₃).

实施例19

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(2-(4-甲基哌嗪-1-基)乙基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190051)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.04(s,0.6H)and8.02(s,0.4H),7.48-7.40(m,4H),7.32-7.27(m,3H),7.23(s)and7.03(s)together(1H),7.15(d,J=8.0Hz,2H),6.54-6.37(m,2H),5.72-5.62(m,1H),5.60-5.49(m,1H),4.69-4.59(m,2H),4.22-4.18(m)and4.11-3.99(m)together(2H),3.93-3.85(m,1H),3.65-3.59(m)and3.54-3.47(m)together(1H),2.88-2.83(m,1H),2.81-2.77(m,2H),2.73-2.66(m,2H),2.64-2.47(m,8H),2.35(s,3H),2.31-2.16(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.92,164.27,159.25,159.19,157.36,157.01,153.36,153.29, 153.05,141.88,141.86,137.07,137.03,135.07,134.97,129.14,129.12,129.06,129.03,128.74,128.14,127.49,126.80,126.70,125.22,125.19,120.20,119.96,103.40,60.34,60.26,54.97,52.99,52.95,52.81,51.14,47.63,47.06,46.99,45.89,45.65,44.62,32.79,32.74,28.39,26.27.

HRMS(ESI)for C₃₂H₃₈N₈O₂[M+H]⁺,Calcd:567.3191,Found:567.3185.

HPLC analysis:MeOH-H₂O(85:15),6.29min,99.55%.-5.455(c0.110,CHCl₃).

实施例20

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(二乙基氨基)丁基氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190061)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(4-(diethylamino)butylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.92(s)and7.90(s)together(1H),7.43-7.39(m,2H),7.31-7.28(m,3H),6.54-6.33(m,2H),5.69-5.64(m,1H),5.60-5.47(m,2H),4.64-4.53(m,2H),4.24-4.16(m),4.05-3.95(m)and3.87-3.83(m)together(3H),3.66-3.61(m)and3.53-3.47(m)together(1H),3.41-3.39(m,2H),3.03-2.90(m,1H),2.89-2.80(m,4H),2.74-2.68(m,2H),2.33-2.15(m,1H),1.82-1.70(m,4H),1.25-1.21(m,6H).

¹³C NMR(125MHz,CDCl₃)δ164.49,164.17,161.49,161.42,157.20,156.98,153.35,153.17,141.98,141.93,129.00,128.98,128.62,128.10,127.28,127.25,126.55,126.45,125.12,125.11,101.12,52.40,52.28,50.68,47.15,46.92,46.52,45.65,44.46,41.39,28.43,27.55,27.52,26.13,24.36,24.33,11.12,11.10.

HRMS(ESI)for C₂₇H₃₇N₇O₂[M+H]⁺,Calcd:492.3082,Found:492.3081.

HPLC analysis:MeOH-H₂O(90:10),11.15min,98.53%.-21.239(c0.113,CHCl₃).

实施例21

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190064)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydro pyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.01(s,0.64H)and8.00(s,0.36H),7.44-7.36(m,4H),7.32-7.27(m,3H),7.09(s)and6.92-6.88(m)together(3H),6.52-6.33(m,2H),5.70-5.63(m,1H),5.57-5.47(m,1H),4.67-4.58(m,2H),4.23-4.20(m),4.09-3.98(m)and3.87-3.83(m)together(3H),3.62-3.46(m,1H),3.24-3.20(m,4H),2.85-2.77(m,1H),2.69-2.65(m,4H),2.42(s)and2.41(s)together(3H),2.29-2.14(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.73,164.18,159.59,159.49,157.25,156.98,153.39,153.35,153.30,153.12,147.48,141.89,141.85,131.29,129.08,129.06,128.68,128.17,127.44,127.39,126.71,126.61,125.16,125.13,122.05,121.63,116.51,116.47,102.83,54.95,54.93,52.67,51.01,49.37,49.23,47.19,46.93,45.95,45.90,45.55,44.46,28.15,25.95.

HRMS(ESI)for C₃₀H₃₄N₈O₂[M+H]⁺,Calcd:539.2878,Found:539.2872.

HPLC analysis:MeOH-H₂O(81:19),5.74min,98.71%.+1.770(c0.113,CHCl₃).

实施例22

N-(4-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)环己基)丙烯酰胺(XSL190069)

N-(4-(3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-2-oxo-3,4-dihydropyrimido [4,5-d]pyrimidin-1(2H)-yl)cyclohexyl)acrylamide

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃)δ8.07(d,J=8.5Hz,1H),7.84(s,1H),7.36-7.29(m,5H),7.24(s,1H),6.70(d,J=8.5Hz,1H),5.57(s,1H),6.29(d,J=17.0Hz,1H),6.08(dd,J=10.0,17.0Hz,1H),5.64(d,J=10.0Hz,1H),5.42(d,J=7.5Hz,1H),4.71(t,J=12.0Hz,1H),4.63(s,2H),4.08(s,2H),4.04-3.97(m,1H),3.89(s,3H),3.21(s,4H),2.78(q,J=12.0Hz,2H),2.61(s,4H),2.37(s,3H),2.16(d,J=12.0Hz,2H),1.78(s,2H),1.34(q,J=12.0Hz,2H).

¹³C NMR(125MHz,CDCl₃)δ164.55,159.36,157.65,154.23,153.12,149.70,147.61,136.42,131.17,128.74,128.07,127.70,126.11,121.82,120.87,108.30,102.46,100.38,55.63,55.15,54.16,51.49,49.90,47.97,46.04,43.77,32.97,27.58.

HRMS(ESI)for C₃₄H₄₂N₈O₃[M+H]⁺,Calcd:611.3453,Found:611.3440.

HPLC analysis:MeOH-H₂O(85:15),7.68min,99.58%.

实施例23

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190074)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-fluorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.09(s)and8.28(s)together(1H),8.04-7.96(m,1H),7.40-7.32(m,2H),7.20-7.15(m,2H),6.53-6.48(m,2H),6.44-6.34(m,2H),5.71-5.63(m,1H),5.57-5.52(m,1H),4.63-4.55(m,2H),4.27-4.24(m),4.05-3.91(m)and3.85-3.80(m)together(3H),3.89(s,3H),3.66-3.51(m,1H),3.26-3.24(m,4H),2.92-2.81(m,1H)),2.73-2.70(m,4H),2.46(s)and2.44(s)together(3H),2.30-2.12(m,1H).

¹³C NMR(125MHz,CDCl₃)δ159.33,157.39,157.35,157.03,156.93,155.40,155.36,153.67,153.52,153.19,153.02,149.74,149.51,147.74,138.40,138.38,138.33,128.64,128.17,127.68,127.40,125.35,125.29,125.23,121.38,121.32,121.28,121.23,121.17,121.08,120.69,120.34, 116.84,116.66,107.78,107.69,102.30,100.27,100.06,55.57,55.02,52.69,51.08,49.78,49.57,47.09,47.04,46.63,45.97,45.59,44.29,28.25,25.77.

MS(ESI)m/z621.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),7.68min,99.71%.

实施例24

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-环戊基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190078)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-cyclopentyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylami no)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.00(s)and7.98(s)together(1H),7.97-7.94(m,1H),7.32(s)and7.24(s)together(1H),6.56-6.33(m,4H),5.71-5.61(m,1H),5.52-5.43(m,1H),4.85-4.79(m,1H),4.27-4.20(m),4.06-3.89(m)and3.82-3.77(m)together(3H),4.11(s)and4.10(s)together(2H),3.87(s,3H),3.65-3.48(m,1H),3.25-3.22(m,4H),2.95-2.83(m,1H),2.72-2.69(m,4H),2.45(s)and2.43(s)together(3H),2.26-2.06(m,1H),1.91-1.85(m,2H),1.76-1.72(m,2H),1.66-1.55(m,4H).

¹³C NMR(125MHz,CDCl₃)δ164.54,164.16,159.18,159.13,157.40,157.30,153.70,153.53,153.18,153.03,149.61,149.34,147.46,147.44,128.75,128.28,127.21,127.19,121.65,121.42,120.53,120.16,107.81,107.73,102.83,102.80,100.33,100.07,55.96,55.83,55.53,55.03,55.01,52.54,50.93,49.84,49.59,46.93,46.62,45.97,45.94,45.63,44.30,38.62,38.57,28.15,27.91,27.83,27.80,25.68,24.08,24.06,24.04.

MS(ESI)m/z561.2[M+H]⁺.

实施例25

N-(2-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)乙基)丙烯酰胺(XSL190089)

N-(2-(3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)ethyl)acrylamide

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃)8.09(d,J=8.5Hz,1H),7.90(s,1H),7.38-7.28(m,7H),7.02(s,1H),6.59-6.56(m,2H),6.21-6.17(m,2H),5.98(dd,J=10.5,17.0Hz,1H),5.56(d,J=10.5Hz,1H),4.68(s,2H),4.37-4.35(m,2H),4.24(s,2H),3.90(s,3H),3.72-3.71(m,2H),3.27(s,4H),2.75(s,4H),2.47(s,3H).

¹³C NMR(125MHz,CDCl₃)δ165.84,159.12,156.32,154.47,153.60,149.32,147.41,135.82,131.11,128.76,127.95,127.81,125.49,121.66,120.21,108.11,100.89,100.40,55.57,55.03,51.59,49.85,45.95,44.01,40.28.

HRMS(ESI)for C₃₀H₄₀N₈O₃[M+H]⁺,Calcd:561.3296,Found:561.3290.

HPLC analysis:MeOH-H₂O(85:15),7.21min,99.51%.+6.667(c0.120,CHCl₃).

实施例26

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-环己基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190105)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-cyclohexyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylami no)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.02-7.95(m,2H),7.32(s)and7.26(s) together(1H),6.55-6.47(m,2H),6.42-6.33(m,2H),5.72-5.61(m,1H),5.54-5.45(m,1H),4.30-4.27(m,1H),4.25-4.22(m),4.02-3.94(m)and3.83-3.77(m)together(3H),4.13(s,2H),3.87(s,3H),3.67-3.49(m,1H),3.25-3.22(m,4H),2.96-2.81(m,1H),2.73-2.70(m,4H),2.46(s)and2.44(s)together(3H),2.24-2.05(m,1H),1.86-1.68(m,5H),1.52-1.36(m,4H),1.15-1.07(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.60,164.22,159.19,159.15,157.44,157.33,153.47,153.29,153.24,153.08,149.59,149.34,147.39,128.79,128.32,127.27,121.79,121.56,120.47,120.14,107.92,107.85,102.93,102.88,100.42,100.14,55.58,55.06,55.03,54.28,54.11,52.52,50.89,49.88,49.62,47.04,46.70,45.98,45.94,45.70,44.36,38.56,29.66,29.65,28.27,25.76,25.61,25.45.

HRMS(ESI)for C₃₁H₄₂N₈O₃[M+H]⁺,Calcd:575.3453,Found:575.3446.

HPLC analysis:MeOH-H₂O(82:18),10.51min,98.94%.+5.085(c0.118,CHCl₃).

实施例27

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190106)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-chlorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phen ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.08-7.97(m,2H),7.39-7.33(m,3H),7.25-7.22(m,2H),6.53-6.48(m,2H),6.44-6.33(m,2H),5.71-5.52(m,2H),4.71-4.55(m,2H),4.29-4.25(m),4.05-3.93(m)and3.85-3.79(m)together(3H),3.88(s,3H),3.66-3.50(m,1H),3.27-3.24(m,4H),2.94-2.82(m,1H),2.74-2.71(m,4H),2.46(s)and2.44(s)together(3H),2.30-2.11(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.50,164.18,159.31,159.28,157.09,156.98,153.57,153.42,153.14,152.97,149.67,149.46,147.65,140.39,140.32,132.06,131.96,129.13,129.11,128.63,128.17,127.37,127.35,126.42,126.37,121.35,121.14,120.61,120.30,107.77,107.68,102.47, 100.26,100.05,55.55,55.01,54.99,52.64,51.02,49.76,49.55,47.08,46.84,46.62,45.96,45.94,45.60,44.28,28.26,25.74.

MS(ESI)m/z603.1[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),8.57min,98.33%.

实施例28

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190108)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chlorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phen ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.11-7.99(m,2H),7.42-7.35(m,3H),7.25-7.23(m,2H),6.55-6.51(m,2H),6.44-6.39(m,2H),5.74-5.65(m,1H),5.61-5.55(m,1H),4.68-4.59(m,2H),4.32-4.27(m),4.08-3.94(m)and3.88-3.82(m)together(3H),3.91(s,3H),3.69-3.50(m,1H),3.29-3.26(m,4H),2.99-2.86(m,1H),2.77-2.73(m,4H),2.49(s)and2.47(s)together(3H),2.32-2.14(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.53,164.22,159.35,159.32,157.09,156.99,153.62,153.46,153.11,152.94,149.69,149.48,147.63,142.98,142.90,134.52,134.48,129.95,129.92,128.66,128.19,127.40,127.38,126.74,126.63,125.34,123.37,123.31,121.40,121.20,120.63,120.32,107.84,107.76,102.53,102.50,100.31,100.09,55.58,55.01,54.98,52.71,51.09,49.75,49.53,47.06,46.80,46.63,45.94,45.90,45.61,44.30,28.26,25.76.

MS(ESI)m/z603.1[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),8.92min,99.51%.

实施例29

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(2-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190119)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(2-chlorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phen ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.07-7.99(m,2H),7.52-7.49(m,1H),7.38-7.31(m,4H),6.54-6.49(m,2H),6.48-6.33(m,2H),5.69-5.58(m,2H),4.66-4.60(m,2H),4.30-4.23(m),4.11-3.92(m)and3.87-3.80(m)together(3H),3.89(s,3H),3.66-3.51(m,1H),3.29-3.27(m,4H),2.94-2.86(m,1H),2.79-2.76(m,4H),2.50(s)and2.48(s)together(3H),2.36-2.13(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.58,164.24,159.28,157.46,157.28,153.72,153.55,152.64,149.49,147.52,139.00,132.62,130.60,129.61,129.43,129.34,128.77,128.33,128.14,127.34,121.45,120.65,120.49,120.35,107.94,102.59,100.44,100.19,55.63,55.03,54.99,52.47,50.82,49.80,49.54,47.55,47.17,46.96,46.75,45.92,45.87,44.37,28.73,28.45,25.87.

MS(ESI)m/z603.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(75:25),11.41min,99.17%.

实施例30

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-氟苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190123)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-fluorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phen ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.03-7.97(m,2H),7.39-7.27(m,3H),7.13-7.08(m,2H),6.54-6.48(m,2H),6.41-6.36(m,2H),5.71-5.63(m,1H),5.59-5.51(m,1H),4.64-4.55(m,2H),4.29-4.25(m),4.05-3.91(m)and3.85-3.80(m)together(3H),3.89(s,3H),3.66-3.51(m,1H),3.27-3.24(m,4H),2.96-2.81(m,1H),2.74-2.71(m,4H),2.46(s)and2.45(s)together(3H),2.32-2.12(m,1H).

¹³C NMR(125MHz,CDCl₃)δ161.90,159.98,159.94,159.31,159.29,157.27,157.10,153.62,153.41,153.19,149.62,149.58,147.13,147.09,137.93,137.90,137.88,137.85,128.70,128.23,127.42,127.24,127.20,127.17,127.13,121.97,121.66,120.47,116.14,116.10,115.96,115.92,108.27,108.24,102.73,102.68,100.61,100.27,55.63,54.67,54.57,52.63,51.03,49.37,49.02,47.31,47.17,46.59,45.67,45.36,45.23,44.32,28.34,25.72.

MS(ESI)m/z587.1[M+H]⁺.

HPLC analysis:MeOH-H₂O(75:25),9.98min,97.40%.

实施例31

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-(4-甲氧基苯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190125)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-(4-meth oxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.06-7.98(m,2H),7.38(s)and7.33(s)together(1H),7;23-7.21(m,2H),6.95-6.92(m,2h),6.53-6.48(m,2H),6.40-6.33(m,2H),5.70-5.62(m,1H),5.60-5.54(m,1H),4.63-4.54(m,2H),4.30-4.26(m),4.08-3.92(m)and3.86-3.84(m)together(3H),3.88(s,3H),3.82(s)and8.31(s)together(3H),3.65-3.50(m,1H),3.27-3.25(m,4H),2.95-2.83(m,1H),2.76-2.74(m,4H),2.29-2.21(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.55,164.21,159.24,158.20,158.14,157.35,157.22,153.46, 153.28,149.68,149.50,147.53,134.86,134.78,128.71,128.25,127.34,127.30,126.75,126.69,121.59,121.36,120.60,120.36,114.45,107.91,107.83,102.78,100.38,100.14,55.58,55.46,54.99,54.95,52.52,50.90,49.75,49.51,47.46,47.17,46.64,45.89,45.85,45.68,44.32,28.33,25.74.

MS(ESI)m/z599.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(75:25),10.30min,97.78%.

实施例32

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190128)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.04(s)and8.02(s)together(1H),7.44-7.40(m,2H),7.32-7.28(m,3H),7.22-6.89(m,4H),6.53-6.35(m,2H),5.72-5.51(m,2H),4.69-4.60(m,2H),4.18-4.15(m),4.10-3.99(m)and3.94-3.89(m)together(3H),3.87(s)and3.86(s)together(3H),3.64-3.59(m)and3.51-3.46(m)together(1H),3.19(s,4H),2.87-2.77(m,4H),2.75-2.69(m,1H),2.50(s,3H),2.32-2.18(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.99,164.27,159.34,159.17,157.38,156.95,153.36,153.30,153.25,152.97,152.46,141.86,136.95,136.81,134.66,134.52,129.16,129.14,128.74,128.12,127.60,127.53,126.82,126.72,125.22,118.40,112.56,112.10,104.75,104.32,103.23,55.46,55.43,55.20,52.74,51.02,50.57,50.51,47.97,47.10,47.00,45.89,45.65,44.74,28.46,26.48.

HRMS(ESI)for C₃₁H₃₆N₈O₃[M+H]⁺,Calcd:569.2983,Found:569.2975.

HPLC analysis:MeOH-H₂O(75:25),8.83min,99.39%.-25.263(c0.095,CHCl₃).

实施例33

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氟-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并 [4,5-d]嘧啶-2(1H)-酮(XSL190134)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.04(s)and8.03(s)together(1H),7.56-7.49(m,1H),7.44-7.40(m,2H),7.32-7.28(m,4H),7.16-7.08(m,1H),6.93-6.89(m,1H),6.53-6.33(m,2H),5.71-5.48(m,2H),4.69-4.61(m,2H),4.18-4.08(m)and4.01-3.87(m)together(3H),3.66-3.61(m)and3.53-3.47(m)together(1H),3.18-3.17(m,4H),2.88-2.82(m,1H),2.78-2.67(m,4H),2.47(s)and2.46(s)together(3H),2.36-2.21(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.10,164.36,158.89,157.47,157.01,156.43,154.49,153.25,152.97,141.85,135.16,134.41,129.18,128.81,128.18,127.55,127.46,126.85,126.76,125.22,119.15,115.51,115.43,108.69,108.57,108.36,103.70,55.04,52.94,51.30,50.49,50.39,48.07,46.99,45.85,45.65,44.75,28.51,26.56.

HRMS(ESI)for C₃₀H₃₃FN₈O₂[M+H]⁺,Calcd:557.2783,Found:557.2775.

HPLC analysis:MeOH-H₂O(75:25),10.74min,99.9%.-1.538(c0.130,CHCl₃).

实施例34

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190138)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydro pyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05(s)and8.04(s)together(1H),7.44-7.40(m,2H),7.32-7.25(m,4H),7.23-7.04(m,3H),6.65-6.63(m,1H),6.52-6.34(m,2H),5.71-5.53(m,2H),4.70-4.60(m,2H),4.19-4.16(m),4.12-4.03(m)and3.94-3.84(m)together(3H),3.65-3.60(m)and3.53-3.47(m)together(1H),3.30-3.29(m,4H),2.83-2.74(m,1H),2.75-2.65(m,4H),2.45(s)and2.43(s)together(3H),2.34-2.18(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.98,164.24,159.25,159.15,157.36,156.95,153.35,153.29,153.24,152.91,151.86,141.86,139.98,139.88,129.46,129.41,129.16,128.78,128.20,127.54,127.43,126.81,126.72,125.22,111.60,111.21,110.94,110.88,107.78,107.38,103.42,54.94,54.91,52.79,51.03,48.83,47.86,47.21,46.99,45.94,45.89,45.68,44.70,28.56,26.44.

HRMS(ESI)for C₃₀H₃₄N₈O₂[M+H]⁺,Calcd:539.2878,Found:539.2872.

HPLC analysis:MeOH-H₂O(75:25),9.27min,99.87%.-5.825(c0.103,CHCl₃).

实施例35

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(4-甲基哌请-1-基)-3-(三氟甲基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190148)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.08-7.99(m,2H),7.74-7.60(m,2H),7.46-7.42(m,3H),7.32-7.29(m,3H),6.56-6.37(m,2H),5.75-5.52(m,2H),4.79-4.64(m,2H),4.20-3.88(m,3H),3.69-3.62(m,1H),3.52-3.44(m,4H),3.07(s,4H),2.84(s,3H),2.68-2.60(m,1H),2.36-2.26(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.23,164.36,158.84,158.76,157.61,157.08,153.35,153.14,152.77,146.56,141.80,136.53,136.43,129.25,129.22,128.83,128.16,127.98,127.74,127.61,126.94,126.85,125.29,125.26,124.96,124.91,123.39,122.69,118.06,118.01,117.97,104.19,55.28,53.01,52.84,51.36,48.52,47.19,47.02,45.70,44.89,28.64,26.86.

HRMS(ESI)for C₃₁H₃₃F₃N₈O₂[M+H]⁺,Calcd:607.2751,Found:607.2750.

HPLC analysis:MeOH-H₂O(85:15),8.56min,99.62%.-36.190(c0.105,CHCl₃).

实施例36

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氯-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190160)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-chloro-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05(s)and8.04(s)together(1H),7.87(s)and7.79(s)together(1H),7.44-7.40(m,2H),7.36-7.28(m,5H),7.07-7.02(m,1H),6.53-6.33(m,2H),5.71-5.50(m,2H),4.77-4.62(m,2H),4.18-3.89(m,3H),3.68-3.63(m)and3.54-3.48(m)together(1H),3.18(s,4H),2.86-2.82(m,4H),2.75-2.71(m,1H),2.53(s)and2.51(s)together(3H),2.38-2.22(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.97,164.30,158.97,158.90,157.46,157.07,153.34,153.25,153.13,152.86,144.35,141.79,141.77,135.06,129.14,129.12,128.86,128.84,128.76,128.11,127.51,126.81,126.72,125.22,125.18,122.06,121.91,120.47,120.44,118.96,118.83,103.68,103.65,55.15,52.91,51.30,51.21,51.13,47.87,47.04,46.94,45.92,45.90,45.65,44.69,28.49, 26.47.

HRMS(ESI)for C₃₀H₃₃ClN₈O₂[M+H]⁺,Calcd:573.2488,Found:573.2483.

HPLC analysis:MeOH-H₂O(85:15),7.52min,98.38%.-23.704(c0.135,CHCl₃).

实施例37

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-甲基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190162)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-methyl-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ8.03(s)and8.02(s)together(1H),7.42-7.40(m,3H),7.35-7.29(m,4H),7.14-6.96(m,2H),6.54-6.33(m,2H),5.73-5.51(m,2H),4.68-4.59(m,2H),4.19-3.85(m,3H),3.67-3.61(m)and3.52-3.47(m)together(1H),3.13(s,4H),2.96(s,4H),2.87-2.77(m,1H),2.62(s,3H),2.28(s,3H),2.24-2.19(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.92,164.32,159.38,159.33,157.46,157.10,153.47,153.36,153.29,153.04,146.83,141.89,134.48,133.37,129.19,128.77,128.17,127.56,126.83,126.73,125.26,125.23,123.01,122.95,119.69,118.52,118.43,103.22,55.43,55.39,52.83,51.40,51.29,51.18,47.73,47.16,47.04,45.72,45.67,44.65,28.53,26.37,17.93,17.88.

HRMS(ESI)for C₃₁H₃₆N₈O₂[M+H]⁺,Calcd:553.3034,Found:553.3032.

HPLC analysis:MeOH-H₂O(85:15),7.09min,99.95%.-42.478(c0.113,CHCl₃).

实施例38

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190169)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-fluorophenyl)-7-(3-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05(s)and8.04(s)together(1H),7.40-7.38(m,1H),7.20-7.00(m,5H),6.94-6.87(m,1H),6.53-6.37(m,2H),5.73-5.64(m,1H),5.61-5.49(m,1H),4.65-4.56(m,2H),4.14-3.88(m,4H),3.87(s)and3.86(s)together(3H),3.64-3.59(m)and3.51-3.45(m)together(1H),3.23(s,4H),2.90(s,4H),2.83-2.67(m,1H),2.55(s,3H),2.32-2.21(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.03,164.32,159.41,159.24,157.48,157.13,156.67,155.49,153.56,153.51,153.20,152.91,152.46,138.31,137.10,136.97,134.48,134.35,128.67,128.04,127.75,127.67,125.35,125.29,121.45,121.31,118.38,116.91,116.73,112.66,112.23,104.85,104.43,102.75,55.45,55.20,52.84,51.11,50.58,50.51,47.99,47.12,47.04,45.93,45.61,44.75,28.42,26.48.

MS(ESI)m/z621.3[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),7.52min,99.28%.

实施例39

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-氟-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190170)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-fluorophenyl)-7-(3-fluoro-4-(4-methylpiperazin-1-y l)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.06(s)and8.05(s)together(1H),7.57-7.51(m,1H),7.40-7.35(m,2H),7.20-7.08(m,3H),6.94-6.90(m,1H),6.54-6.33(m,2H),5.72-5.64(m,1H),5.58-5.49(m,1H),4.65-4.57(m,2H),4.14-3.86(m,3H),3.67-3.62(m)and3.51-3.46(m)together(1H),3.27(s,4H),2.92(s,4H),2.84-2.64(m,1H),2.58(s)and2.55(s)together(3H),2.34-2.23(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.16,164.40,159.04,158.95,157.51,157.20,156.71,156.42,155.52,154.47,153.51,153.46,153.21,152.92,138.29,138.27,135.38,135.34,134.24,134.15,128.74,128.10,127.78,127.70,127.61,125.41,125.35,125.29,121.49,121.45,121.34,121.29,119.13,116.94,116.76,115.58,115.49,108.75,108.61,108.54,108.41,103.25,103.21,55.05,53.04,51.38,50.54,50.46,48.15,47.11,46.96,45.93,45.89,45.61,44.78,28.48,26.60.

MS(ESI)m/z609.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),8.70min,99.81%.

实施例40

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-甲基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190177)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-fluorophenyl)-7-(3-methyl-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.04(s)and8.03(s)together(1H),7.40-7.30(m,3H),7.22-7.16(m)and7.03-6.96(m,4H),6.53-6.34(m,2H),5.73-5.64(m,1H),5.58-5.48(m,1H),4.64-4.56(m,2H),4.16-3.85(m,3H),3.65-3.46(m,1H),3.04(s,4H),2.86-2.73(m,4H),2.71-2.69(m,1H),2.51(s,3H),2.29(s)and2.28(s)together(3H),2.24-2.17(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.83,164.25,159.43,159.36,157.40,157.12,156.79,155.41, 155.37,153.59,153.50,153.15,152.92,147.22,147.19,138.29,134.09,133.29,128.64,128.02,127.70,127.59,125.35,125.30,125.24,123.11,122.94,121.38,121.33,121.23,121.18,119.43,118.56,118.36,116.85,116.68,102.61,102.58,55.52,52.84,51.75,51.68,51.18,47.59,47.07,47.00,46.02,46.00,45.59,44.56,28.38,26.28,17.90,17.86.

MS(ESI)m/z605.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),11.03min,99.85%.

实施例41

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氯-4-(4-甲基哌嗪-1-基)苯氨基)-3-(3-氯-4-氟苯)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL190179)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(3-chloro-4-(4-methylpiperazin-1-yl)phenylamino)-3-(3-chloro-4-fluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.06(s)and8.05(s)together(1H),7.86-7.78(m,1H),7.40-7.39(m,1H),7.34-7.28(m)and7.20-7.09(m)together(4H),7.03(d,J=6.8Hz,1H),6.53-6.34(m,2H),5.72-5.63(m,1H),5.59-5.48(m,1H),4.65-4.58(m,2H),4.14-3.88(m,3H),3.68-3.62(m)and3.53-3.47(m)together(1H),3.18(s,4H),2.85-2.77(m,4H),2.72-2.67(m,1H),2.53(s)and2.52(s)together(3H),2.35-2.24(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.00,164.34,159.02,158.95,157.41,157.22,156.80,155.46,153.53,153.46,153.08,152.79,144.43,138.20,134.93,128.83,128.69,128.03,127.73,127.65,125.33,125.27,122.11,121.97,121.43,121.28,121.23,120.45,119.03,118.92,116.88,116.70,103.19,55.13,53.00,51.39,51.17,51.09,47.88,47.06,46.97,45.87,45.61,44.69,28.44,26.46.

MS(ESI)m/z625.0[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),11.97min,99.68%.

实施例42

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-邻甲苯-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL198406)

(S)-1-(1-acryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3-o-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05-7.98(m,2H),7.39-7.22(m,5H),6.54-6.33(m,4H),5.69-5.57(m,2H),4.67-4.61(m,1H),4.33-3.92(m)and3.87-3.80(m)together(2H),3.89(s,3H),3.65-3.52(m,1H),3.23-3.20(m,4H),2.96-2.78(m,1H),2.67-2.65(m,4H),2.41(s)and2.40(s)together(3H),2.32-2.28(m)and2.17-2.13(m)together(1H),2.22(s)and2.20(s)together(3H).

¹³C NMR(125MHz,CDCl₃)δ164.55,154.24,159.28,157.38,153.52,153.36,152.59,149.66,149.49,147.64,147.60,140.62,140.56,135.37,131.21,128.73,128.27,128.07,128.02,127.99,127.25,127.18,126.80,126.71,126.56,126.53,121.54,121.30,120.62,120.58,120.36,107.90,107.87,107.77,102.63,100.34,100.12,55.58,55.05,55.03,52.42,52.38,50.71,49.84,49.62,47.44,47.34,47.21,46.76,45.98,45.96,45.73,44.34,28.54,25.93,25.84,17.70,17.67,17.65.

MS(ESI)m/z583.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),7.00min,97.50%.

实施例43

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二氯苯基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(XSL198412)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3,5-dichlorophenyl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)p henylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.05(s)and8.04(s)together(1H),7.99-7.95(m,1H),7.40(s)and7.33(s)together(1H),7.27-7.25(m,3H),6.53-6.49(m,2H),6.42-6.37(m,2H),5.72-5.64(m,1H),5.56-5.49(m,1H),4.64-4.56(m,2H),4.28-4.24(m),4.07-3.91(m)and3.86-3.79(m)together(3H),3.89(s,3H),3.66-3.52(m,1H),3.24-3.20(m,4H),2.94-2.81(m,1H),2.67-2.65(m,4H),2.42(s)and2.41(s)together(3H),2.32-2.26(m)and2.18-2.12(m)together(2H).

¹³C NMR(125MHz,CDCl₃)δ164.54,164.25,159.38,156.89,156.79,253.71,153.56,152.91,152.73,149.77,149.57,147.81,143.56,143.49,135.05,135.00,128.60,128.13,127.46,126.54,126.44,123.58,121.19,120.98,120.75,120.45,107.75,107.66,102.21,100.24,100.05,55.57,55.02,52.80,51.20,49.77,49.57,46.97,46.61,45.98,45.57,44.29,28.21,25.74.

MS(ESI)m/z637.0[M+H]⁺.

HPLC analysis:MeOH-H₂O(80:20),16.56min,97.76%.

实施例44

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139842)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydro pyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.87(s,0.6H)and7.85(s,0.4H),7.36-7.28(m,7H),7.17(s)and7.02(s)together(1H),6.87(d,J=9.2Hz,2H),6.55-6.33(m,2H),5.72-5.49(m,2H),4.70-4.56(m,2H),4.22-4.14(m),4.08-3.91(m)and3.86-3.78(m)together(3H),4.12(s)and4.10(s)together(2H),3.61-3.44(m,1H),3.17-3.13(m,4H),2.89-2.74(m,1H),2.58-2.55(m,4H),2.23-2.09(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.88,164.31,159.49,159.34,157.13,156.83,153.81,153.59,153.53,147.65,147.60,136.03,135.97,131.30,128.80,128.79,128.24,128.10,128.05,127.87,127.81,127.47,122.15,121.61,116.56,116.52,102.31,102.28,58.27,55.08,52.51,51.65,51.48,50.83,49.53,49.42,47.35,46.72,46.07,45.61,44.61,43.64,43.62,28.14,26.10,18.39.

MS(ESI)m/z553.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),6.14min,98.30%.

实施例45

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(哌啶-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139843)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(piperidin-1-yl)phenylamino)-3,4-dihyd ropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.93-7.87(m,2H),7.37-7.28(m)and7.23(s)together(6H),6.57-6.33(m,4H),5.72-5.54(m,2H),4.71-4.55(m,2H),4.30-4.28(m),4.09-3.90(m),3.82-3.80(m)together(3H),4.12(s)and4.11(s)together(2H),3.67-3.51(m,1H),3.10-3.06(m,4H),2.98-2.84(m,1H),2.27-2.08(m,1H),1.74-1.69(m,4H),1.58-1.53(m,2H).

¹³C NMR(125MHz,CDCl₃)δ164.62,164.30,159.24,159.17,157.11,157.03,153.73,153.64,153.58,153.51,149.72,149.40,148.83,136.08,136.01,128.80,128.78,128.26,128.08,128.04,127.84,127.78,127.35,127.28,121.14,121.04,120.67,120.17,108.28,108.16,102.06,100.99,100.95,58.29,55.55,52.35,51.57,51.52,51.47,51.42,50.74,46.86,46.69,45.66,44.38,43.65, 28.18,25.94,25.81,24.19,18.37.

MS(ESI)m/z568.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),9.08min,99.16%.

实施例46

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-吗啡啉基苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139848)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-morpholinophenylamino)-3,4-dihydrop yrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.94-7.22(m,1H),7.90(s)and7.87(s)together(1H),7.49(s,1H),7.37-7.29(m,5H),6.61-6.35(m,4H),5.72-5.55(m,2H),4.71-4.57(m,2H),4.30-4.26(m),4.06-3.96(m)and3.83-3.80(m)together(3H),4.14(s)and4.13(s)together(2H),3.90-3.88(m,4H),3.87(s,3H),3.65-3.48(m,1H),3.15-3.12(m,4H),2.98-2.82(m,1H),2.26-2.08(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.63,164.28,158.94,158.89,157.32,157.10,153.72,153.45,153.29,152.82,149.94,149.60,147.47,136.00,135.95,128.82,128.28,128.12,128.08,127.91,127.86,127.42,127.36,121.79,121.67,120.87,120.42,107.62,107.53,102.36,102.30,100.11,99.93,66.84,55.63,52.43,51.63,51.48,50.82,50.31,50.13,46.87,46.58,45.65,44.37,43.64,43.60,28.20,25.72.

MS(ESI)m/z570.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(81:19),6.78min,98.57%.

实施例47

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139850)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.95-7.87(m,2H),7.35-7.26(m,6H),6.52-6.38(m,4H),5.71-5.61(m,2H),4.71-4.58(m,2H),4.32-4.26(m),4.07-3.92(m)and3.82-3.75(m)together(3H),4.16-4.10(m,2H),3.86(s,3H),3.68-3.61(m,2H),3.57-3.38(m,1H),2.98-2.86(m,1H),2.83-2.61(m,10H),2.51-2.45(m,1H),2.44(s,3H),2.30-2.08(m,1H),2.03-1.91(m,2H),1.78-1.66(m,2H).

¹³C NMR(125MHz,CDCl₃)δ164.64,164.31,159.23,159.19,157.16,157.05,153.78,153.69,153.60,153.54,149.68,149.45,147.89,147.85,136.10,136.03,128.86,128.81,128.31,128.13,128.08,127.89,127.82,127.37,127.30,121.42,121.25,120.60,120.24,108.29,108.14,102.18,102.15,100.89,61.73,55.61,55.30,52.40,51.59,51.46,50.78,50.25,50.22,50.12,50.06,48.85,46.92,46.67,45.86,45.70,44.40,43.69,28.25,28.20,25.80.

MS(ESI)m/z666.4[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),9.91min,99.79%.

实施例48

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(4-二甲氨基哌啶-1-基)-2-甲氧基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139854)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxypheny lamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.97-7.89(m,2H),7.36-7.30(m,6H),6.60-6.34(m,4H),5.72-5.57(m,2H),4.71-4.57(m,2H),4.31-4.28(m),4.07-3.95(m)and3.82-3.77(m)together(3H),4.14(s)and4.12(s)together(2H),3.86(s,3H),3.68-3.64(m,2H),3.56-3.43(m,1H),2.99-2.81(m,1H),2.74-2.69(m,2H),2.49(s)and2.46(s)together(6H),2.29-2.11(m,1H),2.09-2.04(m,2H),1.79-1.72(m,2H).

¹³C NMR(125MHz,CDCl₃)δ164.59,164.27,159.19,159.15,157.11,156.99,153.74,153.65,153.55,153.50,149.64,149.41,147.92,147.88,136.07,136.00,128.83,128.77,128.28,128.08,128.04,127.84,127.78,127.32,127.24,121.42,121.26,120.56,120.21,108.30,108.15,102.15,102.12,100.95,62.08,55.56,52.36,51.55,51.41,50.73,50.13,50.09,50.02,49.95,46.88,46.62,45.66,44.36,43.65,41.59,28.31,28.21,25.75.

MS(ESI)m/z611.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(90:10),11.65min,99.14%.

实施例49

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139857)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methyl-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.86(s)and7.84(s)together(1H),7.38-7.30(m,6H),6.76-6.70(m,2H),6.56-6.34(m,3H),5.70-5.63(m,1H),5.53-5.46(m,1H),4.71-4.55(m,2H),4.12(s,2H),4.10-4.08(m),3.99-3.86(m)and3.74-3.64(m)together(3H),3.28-3.20(m,4H),2.81-2.76(m,1H),2.75-2.64(m,4H),2.47(s)and2.41(s)together(3H),2.22(s,3H),2.16-2.00(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.43,164.24,160.44,157.20,156.97,153.84,153.73,153.65, 148.56,148.48,136.08,136.00,133.25,133.22,129.33,129.17,128.89,128.80,128.36,128.14,128.09,127.89,127.82,127.26,127.21,126.05,118.10,118.05,114.22,114.19,102.04,101.97,54.89,54.57,52.33,51.72,51.55,50.71,48.93,48.35,46.75,46.54,45.75,45.43,45.32,44.33,43.67,43.65,27.90,25.65,18.46.

MS(ESI)m/z567.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),7.44min,99.61%.

实施例50

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-乙氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139861)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-ethoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.00-7.89(m,2H),7.35-7.30(m,6H),6.57-6.34(m,4H),5.72-5.62(m,2H),4.72-4.57(m,2H),4.33-4.29(m),4.03-3.92(m)and3.84-3.80(m)together(3H),4.14(s)and4.12(s)together(2H),4.10-4.06(m,2H),3.68-3.52(m,1H),3.26-3.22(m,4H),2.98-2.89(m,1H),2.74-2.71(m,4H),2.46-(s,3H),2.27-2.08(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.62,164.29,159.06,157.10,156.99,153.74,153.64,153.51,148.77,148.64,147.45,147.37,136.03,135.96,128.75,128.22,128.06,128.02,127.83,127.77,127.41,127.36,121.79,121.49,120.26,120.10,107.89,107.79,102.07,101.38,101.12,64.15,55.02,52.36,51.54,51.40,50.73,49.87,49.61,46.92,46.57,45.95,45.67,44.34,43.63,28.21,25.70,14.86.

MS(ESI)m/z597.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),10.12min,98.03%.

实施例51

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(吡咯烷-1-基)苯胺)-3,4-二氢嘧啶并 [4,5-d]嘧啶-2(1H)-酮(DF139862)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(pyrrolidin-1-yl)phenylamino)-3,4-dihy dropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.85(s)and7.82(s)together(1H),7.69-7.62(m,1H),7.36-7.30(m,6H),6.49-6.34(m,2H),6.21-6.09(m,2H),5.68-5.51(m,2H),4.71-4.57(m,2H),4.21-4.12(m),3.99-3.90(m)and3.78-3.73(m)together(3H),4.12(s,2H),3.85(s,3H),3.56-3.48(m,1H),3.29(s,4H),2.91-2.83(m,1H),2.19-2.16(m,1H),2.02(s,4H).

¹³C NMR(125MHz,CDCl₃)δ164.46,164.19,159.66,159.57,157.14,157.04,153.82,153.63,153.32,152.99,151.42,151.12,145.54,136.08,136.04,128.92,128.26,128.07,128.04,127.82,127.77,127.13,127.00,123.27,122.93,116.92,116.74,103.19,101.58,95.29,95.15,60.32,55.46,52.35,51.56,51.46,50.73,47.96,47.90,46.56,46.43,45.52,44.25,43.65,43.62,27.93,25.55,25.38,20.98,14.14.

MS(ESI)m/z554.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),10.18min,96.19%.

实施例52

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-硫啡啉基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139866)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-thiomorpholinophenylamino)-3,4-dihyd ropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.00-7.88(m,2H),7.56(s,1H),7.36-7.31(m,6H),6.57-6.38(m,3H),5.74-5.55(m,2H),4.72-4.57(m,2H),4.31-4.27(m),4.04-3.95(m)and3.85-3.81(m,3H),4.15(s,2H),3.89(s,3H),3.51-3.49(m,4H),3.17-2.96(m,1H),2.94-2.84(m,4H),2.26-2.11(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.60,164.27,158.85,157.29,157.08,153.69,153.42,153.36,152.94,149.69,149.42,135.98,135.94,128.82,128.23,128.13,128.09,127.92,127.86,127.49,127.41,120.47,120.05,109.40,109.25,102.42,101.94,101.80,55.69,53.31,52.40,51.62,51.47,50.81,46.88,46.59,45.66,44.38,43.63,28.22,27.14,27.05,25.74.

MS(ESI)m/z586.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),9.22min,99.45%.

实施例53

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139877)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(3-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.91(s)and7.89(s)together(1H),7.36-7.31(m,5H),7.14-6.87(m,4H),6.57-6.38(m,2H),5.74-5.57(m,2H),4.71-4.57(m,2H),4.14(s,2H),4.11-4.08(m)and3.97-3.88(m)together(3H),3.85(s,3H),3.65-3.45(m,1H),3.16(s,4H),2.79(s,4H),2.74-2.69(m,1H),2.47(s,3H),2.26-2.17(m,1H).

¹³C NMR(125MHz,CDCl₃)δ165.08,164.37,159.16,158.99,157.20,156.74,153.67,153.52,153.49,153.38,152.46,136.85,136.71,135.99,135.94,134.75,134.62,128.81,128.12,128.07,127.90,127.85,127.64,118.44,118.41,112.53,112.11,104.71,104.29,102.64,55.44,55.20,52.50,51.63,51.43,50.76,50.55,50.46,48.08,46.89,45.90,45.87,45.69,44.86,43.63,43.61,28.42, 26.56.

MS(ESI)m/z583.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(82:18),7.56min,99.70%.

实施例54

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基-1,4-高哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139882)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methyl-1,4-diazepan-1-yl)phenylami no)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(400MHz,CDCl₃,a mixture of rotamers)δ7.95-7.68(m,2H),7.36-7.32(m,5H),7.06-7.04(m,1H),6.56-6.28(m,2H),6.24-6.19(m,2H),5.71-5.55(m,2H),4.72-4.56(m,2H),4.29-4.24(m),4.09-3.96(m)and3.76-3.66(m)together(3H),4.16-4.11(m,2H),3.88-3.83(m,4H),3.63-3.57(m,1H),3.46(s,3H),3.06-2.96(m,1H),2.93-2.88(m,2H),2.81-2.70(m,2H),2.58(s)and2.47(s)together(3H),2.26-2.17(m,2H),2.11-2.03(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.53,164.21,159.58,159.51,157.06,156.94,153.85,153.69,153.55,150.88,150.62,146.50,146.45,136.10,136.03,128.85,128.20,128.07,128.03,127.82,127.75,127.30,127.17,122.43,122.06,117.70,117.53,103.28,101.65,95.41,95.28,58.15,58.08,57.06,57.02,55.50,52.31,51.56,51.42,50.68,48.79,48.55,48.51,48.38,46.74,46.57,46.51,46.44,45.61,44.32,43.67,28.07,27.69,27.58,25.60.

MS(ESI)m/z597.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),13.93min,96.32%.

实施例55

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-二甲氨基-2-甲氧基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139883)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(4-(dimethylamino)-2-methoxyphenylamino)-3,4-dihy dropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.89-7.87(m,2H),7.36-7.30(m,6H),6.55-6.34(m,4H),5.72-5.55(m,2H),4.72-4.57(m,2H),4.29-4.26(m),4.07-3.93(m)and3.82-3.78(m)together(3H),4.13(s,2H),3.88(s,3H),3.64-3.49(m,1H),2.99-2.86(m,6H),2.25-2.06(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.54,164.23,159.46,157.10,157.00,153.81,153.62,153.59,153.38,150.58,150.32,147.59,136.08,136.02,128.86,128.77,128.22,128.08,128.04,127.84,127.77,127.29,127.18,122.02,121.68,118.84,118.63,104.67,101.85,96.95,96.85,55.51,52.35,51.56,51.44,50.73,46.71,46.52,45.59,44.31,43.66,41.26,41.19,28.05,25.64.

MS(ESI)m/z528.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),6.19min,97.26%.

实施例56

(S,E)-3-苄基-1-(1-丁基-2-烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139886)

(S,E)-3-benzyl-1-(1-but-2-enoylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylam ino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ7.98-7.94(m,1H),7.90(s)and7.88(s)together(1H),7.36-7.29(m,6H),7.00-6.88(m,1H),6.52-6.42(m,2H),6.25-6.07(m,1H), 5.63-5.55(m,1H),4.72-4.56(m,2H),4.28-4.19(m),4.09-3.93(m)and3.82-3.77(m)together(3H),4.13(s)and4.12(s)together(2H),3.87(s,3H),3.64-3.47(m,1H),3.36-3.23(m,4H),2.98-2.88(m,1H),2.77-2.61(m,4H),2.48(s)and2.45(s)together(3H),2.24-2.19(m)and2.10-2.05(m)together(1H),1.93-1.83(m,3H).

¹³C NMR(125MHz,CDCl₃)δ165.03,164.69,159.12,157.14,157.05,153.77,153.61,153.49,149.58,149.38,147.45,140.91,140.75,136.08,136.02,128.78,128.09,128.05,127.84,127.78,123.20,122.56,121.71,121.46,120.50,120.23,107.93,102.20,100.38,100.11,55.58,55.08,55.02,52.41,51.53,51.44,50.84,49.86,49.59,46.66,46.59,45.98,45.92,45.54,44.23,43.64,28.09,25.77,18.12,18.04.

MS(ESI)m/z597.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),8.03min,96.68%.

实施例57

(S,E)-3-苄基-1-(1-甲基丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139887)

(S)-3-benzyl-1-(1-methacryloylpyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylami no)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.07-7.96(m,1H),7.89(s,1H),7.37-7.28(m,6H),6.54-6.47(m,2H),5.63-5.51(m,1H),5.28-5.08(m,2H),4.71-4.57(m,2H),4.22-4.19(m),4.01-3.90(m)and3.81-3.74(m)together(3H),4.15-4.09(m,2H),3.87(s,3H),3.63-3.56(m,1H),3.31-3.23(m,4H),2.97-2.93(m,1H),2.74-2.63(m,4H),2.43(s,3H),2.23-2.11(m,1H),2.01(s)and1.93(s)together(3H).

¹³C NMR(125MHz,CDCl₃)δ170.73,170.32,159.04,157.21,156.93,153.73,153.59,153.38,149.42,149.36,147.54,147.37,141.56,141.19,136.06,135.97,128.74,128.04,127.99,127.80,127.75,121.79,121.40,120.20,116.16,107.96,107.72,102.29,102.14,100.42,100.16,55.56, 55.01,52.20,51.52,51.25,50.73,49.90,49.64,48.60,47.66,46.65,45.96,44.15,43.61,28.81,25.85,20.06,19.87.

MS(ESI)m/z597.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),8.66min,96.20%.

实施例58

(S)-3-苄基-1-(1-(2-氯乙酰)吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139888)

(S)-3-benzyl-1-(1-(2-chloroacetyl)pyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

MS(ESI)m/z605.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),6.63min,97.70%.

实施例59

(S,E)-3-苄基-1-(1-(4-(二甲氨基)丁基-2-烯酰基)吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139892)

(S,E)-3-benzyl-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-7-(2-methoxy-4-(4-methylpipe razin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.01-7.94(m,1H),7.90(s)and7.89(s)together(1H),7.38-7.28(m,6H),6.97-6.87(m,1H),6.53-6.27(m,3H),5.63-5.55(m,1H),4.72-4.55(m,2H),4.32-4.28(m),4.09-3.94(m)and3.85-3.81(m)together(3H),4.16-6.12(m,2H),3.87(s,3H),3.69-3.50(m,1H),3.23-3.20(m,4H),3.12-3.10(m,2H),2.98-2.84(m,1H),2.69-2.64(m,4H),2.42(s)and2.41(s)together(3H),2.34(s)and2.27(s)together(6H),2.13-2.08(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.50,164.23,159.12,159.06,157.19,157.00,153.71,153.61,153.45,153.42,149.48,149.31,147.49,147.46,141.57,136.06,135.98,128.76,128.06,128.02,127.82,127.76,123.69,123.12,121.70,121.36,120.36,120.13,107.91,107.78,102.20,102.13,100.39,100.05,60.60,60.56,55.56,55.08,55.05,52.32,51.50,51.32,50.70,49.91,49.64,46.97,46.66,46.01,45.99,45.71,45.32,44.34,43.62,28.33,27.65,25.78,19.09.

MS(ESI)m/z640.2[M+H]⁺.

实施例60

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-异丙氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(DF139898)

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-benzyl-7-(2-isopropoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

合成方法如实施例1。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.03-7.97(m,1H),7.91(s)and7.90(s)together(1H),7.39-7.31(m,6H),6.58-6.34(m,4H),5.73-5.60(m,2H),4.72-4.65(m,2H),4.59-4.55(m,1H),4.34-4.21(m),4.03-3.97(m)and3.84-3.81(m)together(3H),4.17-4.08(m,2H),3.67-3.54(m,1H),3.34-3.22(m,4H),3.00-2.91(m,1H),2.76-2.63(m,4H),2.48(s)and2.46(s)together(3H),2.27-2.12(m,1H),1.36-1.24(m,6H).

¹³C NMR(125MHz,CDCl₃)δ164.59,164.25,158.95,157.09,156.98,153.73,153.66,153.53, 147.42,147.29,147.22,147.17,136.02,135.96,128.76,128.72,128.22,128.07,128.03,127.83,127.77,127.42,127.36,122.94,122.63,120.08,119.87,108.33,108.20,103.32,102.98,102.07,102.03,71.43,55.02,54.99,52.36,51.53,51.39,50.71,49.88,49.58,46.93,46.53,45.96,45.93,45.67,44.32,43.63,28.23,25.68,22.20,22.16.

MS(ESI)m/z611.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(85:15),8.48min,98.69%.

实施例61

(S)-8-(1-丙烯酰基吡咯烷-3-基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-6-苯氧基吡啶[2,3-d]嘧啶-7(8H)-酮(XSL198430)

(S)-8-(1-acryloylpyrrolidin-3-yl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-phenox ypyrido[2,3-d]pyrimidin-7(8H)-one

起始原料1合成中间体2的合成方法，以及中间体3合成终产物XSL198430的合成方法如实施例1.

其中，中间体3的合成步骤如下：

将中间体2（1.5g，4.43mmol）和2-苯氧基乙酸甲酯（1.1g，6.65mmol）先后溶于N-甲基吡咯烷酮中，再加入碳酸钾（0.9g，6.65mmol），氩气保护下，加热至120度，搅拌过夜。反应完后，加水猝灭，用乙酸乙酯萃取，干燥，过滤，过柱（石油醚：乙酸乙酯=3：1）得产物1.6g（80%）。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.40(s)and8.39(s)together(1H),7.99-7.94(m,1H),7.58(s)and7.53(s)together(1H),7.41-7.38(m,2H),7.21-7.17(m,1H),7.09-7.07(m, 2H),6.91-6.89(m,1H),6.58-6.35(m,4H),6.34-6.26(m,1H),5.74-5.64(m,1H),4.48-4.45(m),4.17-4.03(m)and3.84-3.80(m)together(3H),3.92(s)and3.89(s)together(3H),3.74-3.58(m,1H),3.30(s)and3.25(s)together(4H),3.09-2.97(m,1H),2.76(s)and2.71(s)together(4H),2.48(s)and2.45(s)together(3H),2.31-2.13(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.58,164.24,159.52,159.41,158.06,157.95,157.63,157.55,155.60,152.86,152.80,150.14,149.82,148.21,143.77,143.70,129.92,128.57,128.22,127.56,127.53,124.34,124.26,120.97,120.55,120.33,118.78,117.11,117.03,107.64,105.37,105.32,100.09,99.85,55.59,54.99,51.56,50.17,49.59,49.36,46.64,45.98,45.96,45.88,44.59,27.74,25.27.

MS(ESI)m/z582.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(80:20),8.50min,98.22%.

实施例62

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-氯苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮(XSL198448)

(S)-8-(1-acryloylpyrrolidin-3-yl)-6-(2-chlorophenoxy)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phe nylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

合成方法如实施例61。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.40(s)and8.39(s)together(1H),7.96-7.91(m,1H),7.57-7.48(m,2H),7.31-7.27(m,1H),7.20-7.15(m,1H),7.09-7.06(m,1H),6.78(s)and6.77(s)together(1H),6.58-6.41(m,3H),6.37-6.35(m,1H),6.32-6.27(m,1H),5.75-5.64(m,1H),4.49-4.46(m),4.18-3.98(m)and3.84-3.81(m)together(3H),3.88(s,3H),3.31-3.29(m)and3.26-3.24(m)together(4H),3.10-2.99(m,1H),2.76(s)and2.70(s)together(4H),2.48(s)and2.44(s)together(3H),2.33-2.26(m)and2.18-2.12(m)together(1H).

¹³C NMR(125MHz,CDCl₃)δ164.61,164.27,158.95,158.85,158.13,158.02,157.71,157.64, 152.95,152.87,151.11,151.04,150.22,149.94,148.29,142.98,142.92,130.99,130.95,128.58,128.22,128.10,127.58,125.69,125.58,125.50,121.08,120.73,120.48,120.42,120.25,116.37,107.66,105.18,105.12,100.10,99.86,55.60,54.98,54.97,51.59,50.22,49.56,49.31,46.59,45.96,45.93,45.87,44.57,27.70,25.27.

MS(ESI)m/z616.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(80:20),9.51min,96.41%.

实施例63

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-氟苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮(XSL198451)

(S)-8-(1-acryloylpyrrolidin-3-yl)-6-(2-fluorophenoxy)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phe nylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

合成方法如实施例61。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.40(s)and8.39(s)together(1H),7.97-7.93(m,1H),7.57(s)and7.51(s)together(1H),7.22-7.16(m,4H),6.82-6.81(m,1H),6.58-6.36(m,4H),6.33-6.25(m,1H),5.74-5.64(m,1H),4.48-4.45(m),4.18-4.03(m)and3.84-3.81(m)together(3H),3.92(s)and3.88(s)together(3H),3.74-3.69(m)and3.64-3.58(m)together(1H),3.30(s)and3.25(s)together(4H),3.10-2.98(m,1H),2.77(s)and2.71(s)together(4H),2.48(s)amd2.45(s)together(3H),2.31-2.15(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.67,164.32,159.05,158.94,158.16,158.04,157.68,157.62,154.85,154.81,152.93,152.84,150.22,149.91,148.27,148.21,143.67,143.63,142.50,142.43,142.34,128.66,128.31,127.60,125.97,125.91,125.85,125.79,124.96,124.94,121.84,121.73,121.05,120.66,120.46,117.40,117.37,117.25,117.22,115.30,107.82,105.25,105.19,100.22,55.66,55.04,55.00,51.67,50.30,49.62,49.34,46.68,45.98,45.92,44.65,27.81,25.35.

MS(ESI)m/z600.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(80:20),8.22min,95.85%.

实施例64

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2,4-二氟苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮(XSL198453)

(S)-8-(1-acryloylpyrrolidin-3-yl)-6-(2,4-difluorophenoxy)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

合成方法如实施例61。

¹H NMR(500MHz,CDCl₃,a mixture of rotamers)δ8.41(s)and8.40(s)together(1H),7.95-7.92(m,1H),7.58(s)and7.51(s)together(1H),7.18-7.12(m,1H),7.00-6.90(m,2H),6.80(s)and6.79(s)together(1H),6.58-6.26(m,5H),5.74-5.64(m,1H),4.47-4.44(m),4.18-4.00(m)and3.84-3.80(m)together(3H),3.92(s)and3.88(s)together(3H),3.73-3.69(m)and3.63-3.58(m)together(1H),3.28(s)and3.23(s)together(4H),3.06-2.99(m,1H),2.73(s)and2.68(s)together(4H),2.45(s)and2.43(s)together(3H),2.31-2.14(m,1H).

¹³C NMR(125MHz,CDCl₃)δ164.67,164.35,160.28,158.97,158.86,158.40,158.32,158.20,158.11,157.75,157.67,154.81,154.71,152.92,152.84,152.75,150.28,150.02,148.35,143.66,143.59,138.75,128.60,128.24,127.68,122.55,122.47,122.39,121.13,120.82,120.54,120.31,115.28,115.22,111.75,111.57,107.77,105.89,105.69,105.51,105.09,105.03,100.18,99.94,55.65,55.02,54.99,51.65,50.30,49.59,49.33,46.65,45.97,45.92,44.63,27.78,25.32.

MS(ESI)m/z618.2[M+H]⁺.

HPLC analysis:MeOH-H₂O(80:20),8.33min,97.28%.

实施例65

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-5-甲基吡啶[2,3-d]嘧啶-7(8H)-酮(XTF81093)

(S)-8-(1-acryloylpyrrolidin-3-yl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5-methylp yrido[2,3-d]pyrimidin-7(8H)-one

合成方法如实施例61。

¹H NMR(400MHz,DMSO)δ8.68-8.73(m,2H),7.33(s,1H),6.39-6.55(m,3H),6.12-6.18(m,2H),5.88(br,1H),5.62-5.72(m,1H),3.80-4.11(m,1H),3.75(s,3H),3.51-3.67(m,3H),3.12-3.15(m,4H),2.67-2.80(m,1H),2.36(s,3H),2.26-2.28(m,3H),1.85-1.96(m,1H).

MS(ESI)m/z504.2[M+H]⁺.

实施例66

(S)-8-(1-丙烯酰基吡咯烷-3-基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-5-(三氟甲基)吡啶[2,3-d]嘧啶-7(8H)-酮(XSL198488)

(S)-8-(1-acryloylpyrrolidin-3-yl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5-(trifluor omethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

合成方法如实施例61。

MS(ESI)m/z558.1[M+H]⁺.

实施例67

嘧啶类化合物对EGFR野生型和EGFR-T790M突变型激酶IC₅₀测试

激酶活性检测：应用Z′-LYTE^TM技术（采用荧光进行检测、酶偶联形式，以磷酸化和非磷酸化多肽对蛋白水解切割的敏感性差异为基础），采用荧光共振能量转移(FRET)原理，使用Z′-LYTE^TMFRET肽类底物，二级反应检测化合物对激酶活性。（Invitrogen,Z′-LYTE^TMKINASE ASSAY KIT–TYR2PEPTIDE,PV3191）将EGFR-T790M激酶（invitrogen,PV4803）逐级稀释后加入FRET肽，ATP，再加入不同浓度化合物，反应1h后，加入位点特异性蛋白酶，识别并切割非磷酸化的FRET肽，反应1h，使用400nm激发波长，检测445nm及520nm吸收。得出抑制率与药物浓度成正相关，做出激酶活性与浓度关系曲线，计算IC₅₀值，结果见表1。

E_{\cdot}^{\cdot} mission Ratio = \frac{Coumarin Emission (445 nm)}{Fluorescein Emission (520 nm)} % Phosphorylation = 1 - \frac{(Emissiom Ratio \times F 100 %) - C 100 %}{(C 0 % - C 100 %) + [Emission Ratio \times (F 100 % - F 0 %)]}

表1化合物编号以及对应激酶活性结果。

嘧啶类化合物与ATP的竞争实验中，部分化合物（例如XSL1752，XSL190023，XSL190031，XSL190074，XSL190119，XSL190128，XSL190162，XSL190177等）对EGFR激酶（包括T790M突变型）表现出强烈的抑制活性。对通式（Ⅰ-Ⅲ）中W取代基的改造，发现当W为五元吡咯环时，活性最好，且为S构型时，活性更好；当R₁取代基为芳香环时，活性更好；当R₂取代基为取代苯胺时，活性较好，且活性能容忍苯胺上取代基的较大改造。

实施例68

嘧啶类化合物对EGFR高表达的癌细胞IC₅₀测试

MTT检测化合物对细胞增殖的影响：1500个/每孔，H1975（肺癌细胞，EGFR^L858R/T790M），HCC827（肺癌细胞，EGFR^{Del E746-A750}），H460（肺癌细胞，EGFR高表达），95D（肺癌细胞，EGFR高表达），H1299（肺癌细胞，EGFR高表达），H358（肺癌细胞，EGFR高表达），HL7702（正常人肝细胞），铺96孔板，24h后，用DMSO配制的不同浓度化合物处理（DMSO终浓度1‰，平行对照3-5个），72h后加入MTT（噻唑蓝，5mg/ml,10ul/孔），37度孵育4h。吸去上清，加入DMSO150ul，充分振荡后，检测OD570，使用GraphPadPrism4Demo软件处理。

表2MTT检测化合物对细胞增殖的影响

结果发现（见表2），经过嘧啶类化合物处理可明显降低H1975和HCC827癌细胞对MTT的吸收，说明嘧啶类化合物可显著抑制上述癌细胞的增殖，抑制率与药物浓度成正相关。根据嘧啶类化合物对这些细胞的生长抑制作用，我们计算出其半数抑制浓度IC₅₀值如表2所描述。（所用化合物在表2中用实施例标号表示）。

表3代表化合物XSL190162对肺癌细胞和正常细胞的影响

结果发现（见表3），经过代表化合物XSL190162对其它野生型EGFR高表达的肺癌处理，野生型肺癌细胞H460，95D，H1299和H358被抑制作用较弱，与H1975相比，具有85-245倍的选择性。同时，对正常人肝细胞IC₅₀值>10μM。这些数据也说明，我们的化合物毒副作用较小。

实施例69

嘧啶类化合物的溶解度测试

样品饱和溶液准备：化合物样品加入到大约1mL的磷酸缓冲液（PBS，PH6.8），配制成饱和溶液，摇床震荡24h，离心，去上清液，滤膜过滤样品待测。

标准溶液曲线准备：称量标准样品（约1mg），准确定容至100μg/mL浓度，逐级稀释至80μg/mL，60μg/mL，40μg/mL，20μg/mL，1μg/mL。以待测物浓度(x)为横坐标，待测物峰面积(y)为纵坐标，用最小二乘法进行回归运算，求得直线回归方程，即为标准曲线。

计算溶解度：以待测样品的峰面积响应值，对标曲进行插值计算，即得溶解度。

表4化合物的水溶解度

结果显示，相比之前WO2012167415(A1)中代表化合物N-(3-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)苯基)丙烯酰胺（C-EGF29）（溶解度为4.1μg/mLPH6.8），我们的化合物的水溶解度得到不同程度的提高。

实施例70

嘧啶类化合物的体内药代性质测试

给药与样品采集

1.大鼠静脉给药：SD大鼠4只，雌雄各半，体重180～220g。给药前禁食12h，试验期间少量进食，饮水自由。按5mg/kg的剂量静脉注射给予化合物。给药后2min，10min，30min，1.0h，2.0h，3.0h，4.0h，6.0h，8.0h，12.0h，21h，24.0h，30h，36h，48h，60h，72h，经眼眶取血约0.3mL，置肝素化试管中，6000rpm离心10min，分离血浆，4℃保存待测。

2.大鼠口服给药：SD大鼠4只，雌雄各半，体重180～220g。给药前禁食12h，试验期间少量进食，自由饮水。分别按25mg/kg的剂量口服给予化合物。给药后5min，10min，30min，1.0h，2.0h，3.0h，4.0h，6.0h，8.0h，12.0h，21h，24.0h，30h，36h，48h，60h，72h经眼眶取血约0.3mL置肝素化试管中，6000rpm离心10min，分离血浆，4℃保存待测。

血浆样品测定

1.血浆样品处理

向50μL大鼠血浆样品中加入150μL内标溶液（5μg/mL，乙腈溶液），混匀；涡流混合2min，离心30min（13000rpm，4℃），取上清于另一离心管中，取20μL进行LC/MS/MS分析。

2.标准曲线的配制

取大鼠空白血浆50μL，依次加入化合物标准系列溶液10μL，配制相当于血浆浓度为20，50，100，500，1000，2000，4000，6000，12000，40000ng/mL的化合物血浆样品，按“血浆样品处理”项下操作，建立标准曲线。以待测物浓度(x)为横坐标，待测物与内标物的峰面积比值(y)为纵坐标，用加权（W=1/x2）最小二乘法进行回归运算，求得直线回归方程，即为标准曲线。

3.数据处理和分析

采用DAS2.0软件计算大鼠给药后的药代动力学参数。

表5化合物在SD大鼠体内的药代动力学性质参数

结果显示，相比之前WO2012167415(A1)中代表化合物N-(3-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶[4,5-d]嘧啶-1(2H)-基)苯基)丙烯酰胺（C-EGF29，口服给药时，大鼠体内血液中检测不到化合物），我们的化合物的口服药代动力学性质得到不同程度提高。

实施例71

嘧啶类化合物对H1975细胞EGFR激酶磷酸化的影响

使用常规Western Blot(免疫印迹法)，其包括四个步骤：样品制备；电泳分离；蛋白的膜转移；免疫杂交与显色(蛋白检测)。

样品制备

1．培养细胞或药物处理；

2．弃培养基，用1XPBS漂洗细胞2次，去尽残留培养基；

3．加入1X SDS样品缓冲液(6-well plate,100μl/w或75cm² plate,500-1000μl/瓶)，刮落细胞，转移到Ep管；

4．超声10～15秒剪切DNA以减低样品粘性；

5．煮沸样品5minutes；

6．离心12000g,5min，取上清；

7．电泳分离：上样15μl～20μl至SDS-PAGE胶(10cm×10cm)电泳。(参照SDS-PAGE电泳方法）

转膜

1．将胶浸于转移缓冲液中平衡10min；

2．依据胶的大小剪取膜和滤纸6片，放入转移缓冲液中平衡10min。PVDF膜需用纯甲醇浸泡饱和3-5秒钟；

3．装配转移三明治：海绵→3层滤纸→胶→膜→3层滤纸→海绵，每层放好后，用试管赶去气泡；

4．将转移槽置于冰浴中，放入三明治（黑色面对黑色面），加转移缓冲液，插上电极，100V，1h（电流约为0.3A）。转膜结束后，切断电源，取出杂交膜。

免疫杂交与显色

1．用25mlTBS洗膜5min，室温，摇动；

2．置膜于25ml封闭缓冲液中1h，室温，摇动；

3．15mlTBS/T洗6次（5min/T）；

4．加入合适稀释度的一抗，室温孵育1-2h或4℃过夜；

5．15mlTBS/T洗6次（5min/T）；

6．加入合适稀释度的碱性磷酸酶（AP）或辣根过氧化酶（HRP）标记的二抗，室温孵育1h，缓慢摇动；

7．15ml TBS/T洗3次（5min/T）；

8．15ml TBS洗1次；

9．用ECL进行蛋白压片；

10．显影。

通过图1可以发现，嘧啶类化合物中，XSL190162能显著引起EGFR及其下游信号通路蛋白磷酸化的阻滞。

实施例72

嘧啶类化合物对小鼠移植瘤生长抑制的影响

该实验遵照广州生物医药与健康研究院动物实验中心规则下完成。在六周大的免疫缺陷小鼠右侧皮下接种H1975非小细胞肺癌细胞（2×10⁶/小鼠）。当肿瘤体积达到200-300mm³（10-12天），小鼠被随机分成治疗组（每组5只）。小鼠试验组分成空白组和给药组，给药剂量分别为10或者30mg/kg/day，连续口服给药14天。给药溶媒组成为1%的DMSO，5%的乙醇，15%的蓖麻油和79%的水，给药剂量为0.1mL/20g。每隔一天测量肿瘤的长度（L）和宽度（W），肿瘤体积计算公式为：TV=W²(L/2)，肿瘤抑制（TGI）计算公式为：TGI=[1-(T-T₀)/(C-C₀)]×100，其中，T和T₀分别为测量当天和第一天时的肿瘤体积，C和C₀为空白对照组的肿瘤体积。

实验结果见图2-4，嘧啶类化合物XSL190162能够有效抑制小鼠体内肿瘤的生长，而且不显著影响小鼠体重的改变。

以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims

1.具有式（Ⅰ）结构的嘧啶并杂环类化合物或者其药学上可接受的盐或立体异构体或其前药分子：

其中，X任选自N或C原子；

Y任选自H，CH₃，CF₃；

R₁任选自：

1)C₁～C₃烷基；

2)C₃～C₆环烷基；

3)其中，m任选自0,1,2；A₁,A₂,A₃,A₄,A₅任选自：

a)H；

b)F,Cl,Br；

c)C₁～C₃烷基

d)C₁～C₃烷氧基；

e)苯氧基；

4)其中，A₆,A₇,A₈,A₉,A₁₀任选自：H,F,Cl；

R₂任选自：

1)其中，B₁,B₂,B₃,B₄,B₅任选自：

a)H；

b)F,Cl；

c)C₁～C₂烷基；

d)含氟甲基；

e)C₁～C₄烷氧基；

f)N,N-二甲基氨基；

g)5～6元饱和杂环；

i)C₁～C₂-4-甲基哌嗪基；

2)C₁～C₄-NB₇B₈，其中，B₇,B₈任选自甲基，乙基；

上述杂环中的杂原子选自N，O，S；

R₃任选自：

W任选自：

1)–(CH₂)_nNH–，其中n任选自1,2,3；

2)含N原子的5-6元饱和环。

2.根据权利要求1所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅰ）结构：

其中，

当X为N原子时，Y选自H，虚线所在位置的化学键为单键；

所述R₁选自：

1)甲基，乙基，正丙基，异丙基；

2)环戊基，环己基；

3)苯基，苄基，苯乙基；

4)卤代苯基，其中，卤素任选自F，Cl；

5)卤代苯氧基，其中，卤素任选自F，Cl；

6)甲基取代苯基，甲氧基取代苯基，苯氧基取代苯基；

所述R₂选自：

1)其中，B₁,B₂,B₃,B₄,B₅任选自：

a)H；

b)F,Cl；

c)甲基，三氟甲基；

d)甲氧基，乙氧基，异丙氧基；

e)吡咯基，哌啶基，吗啡啉基，硫啡啉基，N,N-二甲基氨基；

f)4-甲基哌嗪基，4-甲基哌啶基，2-（4-甲基哌嗪）乙基，4-（4-甲基哌嗪）哌啶基，4-（N,N-二甲基）哌啶基，4-甲基高哌嗪基，1-（2-氟乙基）氮杂环丁烷-3-氨基，4-（N,N-二乙基）丁基；

所述R₃选自：

所述W选自：

3.根据权利要求2所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅱ）结构：

其中，X，Y，R₃如权利要求2所述；

所述R₁选自：

1)甲基，异丙基；

2)环戊基，环己基；

3)苯基，苄基，苯乙基；

5)苯氧基，2-氯苯氧基，2-氟苯氧基，2,4-二氟苯氧基；

6)2-甲基苯基，4-甲氧基苯基，4-苯氧基苯基；

所述R₂选自：

4.根据权利要求3所述的嘧啶并杂环类化合物或者其药学上可接受的盐或其前药分子，其具有式（Ⅲ）结构：

其中，R₂如权利要求3所述；

所述R₁选自：

1)甲基，异丙基；

2)环戊基，环己基；

3)苯基，苄基，苯乙基；

5)2-甲基苯基，4-甲氧基苯基，4-苯氧基苯基。

5.根据权利要求1所述的嘧啶并杂环类化合物或者其药学上可接受的盐或立体异构体或其前药分子，其特征是，所述化合物选自：

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1氢)-酮；

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

1-(1-丙烯酰基哌啶-4-基)-3-苄基-7-(4-氟苯胺基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(R)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(R)-1-(1-丙烯酰基哌啶-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基哌啶-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-甲基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-异丙基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-(4-苯氧基苯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯乙基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(1-甲基哌啶-4-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-苯氨基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(2-(4-甲基哌嗪-1-基)乙基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(二乙氨基)丁氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(1-甲基哌啶-4-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苯基-7-苯氨基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(2-(4-甲基哌嗪-1-基)乙基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(二乙基氨基)丁基氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

N-(4-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)环己基)丙烯酰胺；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-环戊基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

N-(2-(3-苄基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶-1(2H)-基)乙基)丙烯酰胺；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-环己基-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(2-氯苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-氟苯)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-(4-甲氧基苯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氟-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(4-(4-甲基哌请-1-基)-3-(三氟甲基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氯-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-甲基-4-(4-甲基哌嗪-1-基)苯氨基)-3-苯基-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-氟-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3-氯-4-氟苯)-7-(3-甲基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(3-氯-4-(4-甲基哌嗪-1-基)苯氨基)-3-(3-氯-4-氟苯)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3-邻甲苯-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二氯苯基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(哌啶-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-吗啡啉基苯氨基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-(4-二甲氨基哌啶-1-基)-2-甲氧基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-乙氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(吡咯烷-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-硫啡啉基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-甲氧基-4-(4-甲基-1,4-高哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(4-二甲氨基-2-甲氧基苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S,E)-3-苄基-1-(1-丁基-2-烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S,E)-3-苄基-1-(1-甲基丙烯酰基吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-3-苄基-1-(1-(2-氯乙酰)吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S,E)-3-苄基-1-(1-(4-(二甲氨基)丁基-2-烯酰基)吡咯烷-3-基)-7-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-苄基-7-(2-异丙氧基-4-(4-甲基哌嗪-1-基)苯胺)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-6-苯氧基吡啶[2,3-d]嘧啶-7(8H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-氯苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-氟苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2,4-二氟苯氧基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)吡啶[2,3-d]嘧啶-7(8H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-6-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-5-甲基吡啶[2,3-d]嘧啶-7(8H)-酮；

(S)-8-(1-丙烯酰基吡咯烷-3-基)-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)-5-(三氟甲基)吡啶[2,3-d]嘧啶-7(8H)-酮。

6.一种治疗肿瘤的药用组合物，其活性成分包括权利要求1-5任一项所述的嘧啶并杂环类化合物或其药学上可接受的盐或立体异构体或其前药分子。

7.权利要求1-5任一项所述嘧啶并杂环类化合物及其药学上可接受的盐或立体异构体或其前药分子在制备治疗肿瘤的药物中的应用。

8.根据权利要求7所述的应用，其特征是：所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌中的任一种。