CN106749042B - 磺酰胺基嘧啶类化合物，组合物及用途 - Google Patents
磺酰胺基嘧啶类化合物，组合物及用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- Organic Chemistry (AREA)
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Abstract
本发明涉及磺酰胺基嘧啶类化合物，组合物及用途，所述磺酰胺基嘧啶类化合物具体为通式(I)所示的化合物，通式(I)的各取代基如说明书中的定义。本发明还涉及所述通式(I)所示的化合物或其药学上可接受的盐，或含其的药物组合物通过抑制布鲁顿氏酪氨酸激酶，进而治疗肿瘤疾病，特别是用于治疗伯基特氏淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病的用途；
Description
技术领域
本发明涉及磺酰胺基嘧啶类化合物，组合物及用途，属于医药技术领域。
背景技术
蛋白酪氨酸激酶(protein tyrosine kinase,PTKs)通过控制细胞的信号传导通路调节细胞的生长、分化、凋亡等一系列生理生化过程。受体型酪氨酸激酶是一类横跨细胞膜相对较大的激酶，其具有配体结合的胞外结构域、跨膜结构域和起激酶作用—在磷酸化特定酪氨酸残基并且由此影响细胞增殖的胞内结构域。在一般人类癌症中(如肺癌、乳腺癌、胃癌、卵巢癌、淋巴瘤)已发现所述激酶的异常表达。蛋白酪氨酸激酶已成为抗肿瘤药物研究开发的重要靶点之一。
BTK是一种胞浆蛋白，属于非受体酪氨酸激酶Tec家族，其表达于多数的造血细胞中，如B细胞、肥大细胞、巨核细胞等，但在T细胞、NK细胞及浆细胞中不表达。布鲁顿氏酪氨酸激酶的表达贯穿于整个B细胞的发育阶段(除浆细胞外)，调控B细胞参与的信号通路，并在过敏反应与炎症反应中发挥重要作用。近年来研究显示，BTK信号通路是目前非霍奇金淋巴瘤(NHL)，特别是慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤及自身免疫疾病临床治疗研究中的新热点。目前报道的布鲁顿氏酪氨酸激酶抑制剂根据与激酶作用方式不同可分为两种：一是与BTK中特有的氨基酸残基Cys481形成共价键而开发的不可逆抑制剂，另一种是进入BTK中所特有的口袋中(该口袋被称为“H3”口袋)，与非活化状态的构象结合，而开发的可逆抑制剂。代表药物有：Ibrutinib(依鲁替尼)是一种口服的布鲁顿酪氨酸激酶抑制剂，由美国加州的Pharmacyclics公司开发(US 7514444,CN101610676A)，已被美国FDA批准上市，用于治疗套细胞淋巴瘤(MCL)和慢性淋巴细胞白血病(CLL)。其他多个化合物，如Spebrutinib(AVL-292、CC-292)(US8563568,WO2014100748A1)是一个通过共价结合的，可以口服的高选择性BTK抑制剂，其IC50小于0.5nmol/L，展示了比其他被测激酶至少1400倍的选择性，目前正进行Phase I研究(Evans,E.K.,et al.J.Pharmacol Exp.Ther.,2013,346,219-228)；又如ONO-4059(Yasuhiro,T.,et al.Blood,2013,122,5151-5151.)是依鲁替尼类似物，高度选择性抑制BTK，IC50为23.9nmol/L，进入Phase I研究。此外CNX-774(Akinleye,A.,et al.J.Hematol Oncol.,2013,6,59.)也是一种口服有效的高选择性BTK抑制剂，IC50小于1nmol/L。Phase 3的Acalabrutinib，用于治疗复发性CLL，整体效果约有95％的缓解，是Acerta Pharma研制的“第二代”BTK抑制剂，具有比Ibrutinib更高的选择性(更低的副作用)目前约有24个与之相关的临床试验在进行。
另外与本发明密切相关的专利如：WO2010141406 A2、US20140256759 A1、CN102083800 A、WO 2014130693 A1、WO 2015006754 A2、WO 2015048689 A8、WO2012161812A1。
鉴于治疗癌症的迫切需要，本领域有必要开发新的效果更加良好的药物。
发明内容
本发明的目的之一在于提供一种磺酰胺基嘧啶类化合物或其药学上可接受的盐，该类化合物具有良好的抗肿瘤活性。
本发明的另一目的在于提供含所述磺酰胺基嘧啶类化合物或其药学上可接受的盐的药物组合物。
本发明的再一目的在于提供所述磺酰胺基嘧啶类化合物或其药学上可接受的盐，或所述组合物的用途。
一方面，本发明提供一种通式(I)所示的化合物或其药学上可接受的盐，所述通式(I)所示的化合物具有如下结构：
R1选自氯、氟、硝基或三氟甲基；
R2选自氢、甲基、甲氧基或氯；
X选自NH或O；
R3选自甲基、甲氧基或氟。
作为本发明的一种具体实施方式，本发明所述通式(I)所示的化合物具有I-1～I-34所示的结构：
优选地，所述通式(I)所示的化合物为I-21。
如上所示结构化合物为磺酰胺基嘧啶类化合物，抗肿瘤活性筛选显示本发明中的化合物大部分都具有较强的抑制B淋巴细胞瘤细胞(Ramos细胞和Raji细胞)增殖能力，部分化合物显示出比参照药物Spebrutinib预料不到的更加优良的抗BTK激酶活性。作为一类结构新颖的分子，本发明中的化合物具有开发成新型高效BTK抑制剂的潜力，对治疗相关的肿瘤疾病尤其是弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病有较大的应用价值。
前述I-1～I-34所示的结构分别具有如下名称：
(I-1)N-[3-[[5-氯-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺；
(I-2)N-[3-[[5-氟-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺；
(I-3)N-[3-[[5-氯-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氧基]苯基]-2-丙烯酰胺；
(I-4)N-[3-[[5-硝基-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺；
(I-5)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-6)N-[3-[[5-氟-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-7)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-8)N-[3-[[5-硝基-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-9)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-10)N-[3-[[5-氟-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-11)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-12)N-[3-[[5-硝基-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-13)N-[3-[[5-氯-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-14)N-[3-[[5-氟-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-15)N-[3-[[5-氯-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-16)N-[3-[[5-硝基-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-17)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-18)N-[3-[[5-氟-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-19)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-20)N-[3-[[5-硝基-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-21)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-22)N-[3-[[5-氟-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-23)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-24)N-[3-[[5-硝基-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-25)N-[3-[[5-氯-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-26)N-[3-[[5-氟-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-27)N-[3-[[5-氯-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-28)N-[3-[[5-硝基-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-29)N-[3-[[5-氯-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-30)N-[3-[[5-氟-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-31)N-[3-[[5-氯-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺；
(I-32)N-[3-[[5-硝基-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
(I-33)N-[3-[[5-三氟甲基-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺；
(I-34)N-[3-[[5-三氟甲基-2-[4-[3-(4-甲基苯磺酰胺)氯基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺；
另一方面，本发明提供一种药物组合物，其含有有效剂量的本发明所述通式(I)所示的化合物或其药学上可接受的盐，及药用载体。
本发明所述化合物由于它们在药物中的可能用途，式(I)化合物的盐优选药物可接受的盐。本发明的化合物为碱，其中所需盐形式可以通过本领域已知的合适方法制备，包括用无机酸处理游离碱，所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或用有机酸处理游离碱、所述有机酸例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟基乙酸、水杨酸、吡喃糖苷酸(pyranosidy1acid)，例如葡糖醛酸或半乳糖醛酸，α-羟基酸，例如柠檬酸或酒石酸，氨基酸，例如天冬氨酸或谷氨酸，芳香酸，例如苯甲酸或肉桂酸，磺酸，例如p-甲苯磺酸、甲磺酸、乙磺酸等。药学上可接受的盐的实施例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙酸盐(propiolates)、草酸盐、丙二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐(phenylbutrates)、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、羟基乙酸盐、酒石酸盐、苦杏仁酸盐和磺酸盐、例如二甲苯磺酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐和萘-2-磺酸盐。
本发明的药物组合物通常含有一种本发明化合物。然而，在一些实施方案中，本发明的药物组合物含有超过一种本发明的化合物。另外，本发明的药物组合物还可任选包括一种或多种其它药学活性化合物。
本发明还提供所述磺酰胺基嘧啶类化合物或其药学上可接受的载体，所述药物组合物通过抑制布鲁顿氏酪氨酸激酶，进而抑制肿瘤增殖的用途。具体地，该用途主要为制备用于治疗伯基特氏淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病的药物中的用途。
本发明提供所示的化合物或其药学上可接受的盐，或本发明所述的药物组合物在制备布鲁顿氏酪氨酸激酶抑制剂中的应用。
本发明提供所述通式(I)所示的化合物或其药学上可接受的盐，或本发明所述的药物组合物在制备治疗肿瘤的药物中的用途。优选地，所述肿瘤选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病中的一种或多种，进一步优选慢性淋巴细胞白血病。更优选地，所述用途主要通过抑制布鲁顿氏酪氨酸激酶实现的。
附图说明
图1为化合物I-21的Ramos细胞活性实验结果图。
图2为化合物I-21对PBMC细胞毒性实验结果图。
具体实施方式
以下结合具体实施例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1目标分子的制备
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胺板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
本发明使用的原料主要购自可购买自国药集团化学试剂有限公司，北京偶合科技有限公司、阿拉丁化学试剂有限公司、达瑞化学品等公司。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
本发明采用的技术方案如下：
化合物I-k的合成路线、试剂及条件:(g)三乙胺,二氧六环,100℃,12h,72％；(h)Fe-NH4Cl,MeOH-H2O,2h,70℃,72％。
I-j的合成
取I-h(2mmol)和I-i(2mmol)于20mL二氧六环中，慢慢加入三乙胺(1.5mmol)，100℃反应12h后，反应完毕，抽干溶剂，加入400mL水，析出固体，抽滤，烘干，得固体I-j，未纯化直接下一步反应。
I-k的合成
取I-j(2mmol)和NH4Cl(4mmol)于50ml MeOH-H2O(1:1)中，搅拌下慢慢加入铁粉(8mmol)，升温60℃，反应2小时后，反应完毕，趁热抽滤，加入400mL水，析出固体，抽滤，烘干，得固体I-k。
化合物(I)的合成路线、试剂及条件:(a)丙烯酰氯,NaHCO3,CH3CN,rt,0.5h,95％；(b)Fe-NH4Cl,MeOH-H2O,2h,70℃,72％；(c)ArNH2,DIPEA,1,4-二氧六环,60℃,2h,91％；(d)丙烯酰氯,NaHCO3,CH3CN,rt,0.5h,95％；(e)K2CO3,DMF,60℃,12h；(f)三氟乙酸,2-BuOH,100℃,4h,10-15％。
I-b的合成
取I-a(7.24mmol,1.00g)和NaHCO3(10.86mmol,0.91g)于50mL乙腈中，慢慢加入丙烯酰氯(10.86mmol,0.99g)，冰浴，反应半小时后，反应完毕，加入400mL水，析出白色固体，抽滤，烘干，得白色固体I-b，未纯化直接下一步反应。
I-c的合成
取I-b(7.24mmol,1.39g)和NH4Cl(14.48mmol,0.77g)于50ml MeOH-H2O(1:1)中，搅拌下慢慢加入铁粉(28.96mmol,1.62g)，升温60℃，反应2小时后，反应完毕，趁热抽滤，水相用乙酸乙酯萃取(100mL×3)，合并乙酸乙酯层，饱和食盐水洗一次，无水硫酸钠干燥，减压蒸干得黄色半固体I-c。
I-d的合成
取2,4,5-三氯嘧啶、2,4-二氯-5-氟嘧啶或2,4-二氯-5-三氟甲基嘧啶(7.24mmol)、I-c(7.24mmol)和DIPEA(10.86mmol)于反应瓶，加入1,4-二氧六环，60℃反应2小时，反应液减压蒸干，加水析出固体，抽滤，烘干，得固体I-d。
I-f的合成
取I-e(9.16mmol,1.0g)和NaHCO3(13.74mol,1.15g)于50mL乙腈中，慢慢加入丙烯酰氯(13.74mmol,1.24g)，冰浴，反应半小时后，反应完毕，加入400mL水，析出白色固体，抽滤，烘干，得白色固体I-f，未纯化直接下一步反应。
I-g的合成
取I-f(9.16mmol)、2,4,5-三氯嘧啶(9.16mmol,1.68g)和K2CO3(1.5mmol,1.90g)于反应瓶，加入N,N-二甲基甲酰胺，60℃反应12小时，反应液减压蒸干，加水析出固体，抽滤，烘干，得固体I-d。
目标物(I)的合成
取I-d或I-g(1.0mmol)与取代芳胺I-k(1.0mmol)分别反应，溶于10mL 2-BuOH中，慢慢滴加三氟乙酸(1.5mmol)，升温100℃反应4小时，反应完毕后抽干溶剂，加MeOH 10mL，再加饱和碳酸氢钠析出固体，薄层层析分离纯化得目标化合物(I)。
根据以上方法合成了目标分子，所合成目标分子的理化数据如下：
(I-1)N-[3-[[5-氯-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.32(s,3H),5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7；155.5,156.9,158.3,164.0；HRMS(ESI)，C26H23ClN6O3S,[M+H]+理论计算:535.1314,实测:535.1274。
(I-2)N-[3-[[5-氟-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.35(s,3H),5.78-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7；155.5,156.9,158.3,164.0；HRMS(ESI)，C26H23FN6O3S,[M+H]+理论计算:518.1536,实测:518.1516。
(I-3)N-[3-[[5-氯-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.33(s,3H),5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7；155.5,156.9,158.3,164.0；HRMS(ESI)，C26H22ClN6O4S,[M+H]+理论计算:535.1081,实测:535.1069。
(I-4)N-[3-[[5-硝基-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.31(s,3H),5.77-5.80(m,1H),6.28(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7,155.5,156.9,158.3,164.0；HRMS(ESI)，C26H23N7O5S,[M+H]+理论计算:545.1481,实测:545.1468。
(I-5)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),2.37(s,3H),5.77-5.80(m,1H),6.26(d,J＝16.0Hz,1H),6.44(dd,J＝12.0Hz,16.0Hz,1H),6.63(d,J＝8.0Hz,1H),6.98-7.05(m,2H),7.18(s,1H),7.33(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,1H),7.70(s,1H),8.10(s,1H),8.47(s,1H),9.25(s,1H),9.74(s,1H),10.39(s,1H)；13C(400MHz,DMSO-d6):δ18.15,21.46,105.1,112.9,116.9,117.4,120.5,127.1(2C),127.6,127.9,128.8,129.9,130.4(2C),132.1,135.3,138.3(2C),138.5,140.9,143.3,152.7,157.9,158.6,163.8,164.3,165.8；HRMS(ESI)，C27H25ClN6O3S,[M+H]+理论计算:548.1397,实测:548.1377。
(I-6)N-[3-[[5-氟-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),2.37(s,3H),5.77-5.80(m,1H),6.26(d,J＝16.0Hz,1H),6.44(dd,J＝12.0Hz,16.0Hz,1H),6.63(d,J＝8.0Hz,1H),6.98-7.05(m,2H),7.18(s,1H),7.33(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,1H),7.70(s,1H),8.10(s,1H),8.47(s,1H),9.25(s,1H),9.74(s,1H),10.39(s,1H)；13C(400MHz,DMSO-d6):δ18.15,21.46,105.1,112.9,116.9,117.4,120.5,127.1(2C),127.6,127.9,128.8,129.9,130.4(2C),132.1,135.3,138.3(2C),138.5,140.9,143.3,152.7,157.9,158.6,163.8,164.3,165.8；HRMS(ESI)，C27H25FN6O3S,[M+H]+理论计算:532.1693,实测:532.1687。
(I-7)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),2.37(s,3H),5.77-5.80(m,1H),6.26(d,J＝16.0Hz,1H),6.44(dd,J＝12.0Hz,16.0Hz,1H),6.63(d,J＝8.0Hz,1H),6.98-7.05(m,2H),7.18(s,1H),7.33(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,1H),7.70(s,1H),8.47(s,1H),9.25(s,1H),9.74(s,1H),10.39(s,1H)；13C(400MHz,DMSO-d6):δ18.15,21.46,105.1,112.9,116.9,117.4,120.5,12 7.1(2C),127.6,127.9,128.8,129.9,130.4(2C),132.1,135.3,138.3(2C),138.5,140.9,143.3,152.7,157.9,158.6,163.8,164.3；HRMS(ESI)，C27H24ClN5O4S[M+H]+理论计算:550.1310,实测:550.1343。
(I-8)N-[3-[[5-硝基-2-[4-[3-(4-甲基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.74(s,3H),5.78(dd,J＝4.0Hz,8.0Hz,2H),6.26(d,J＝16.0Hz,1H),6.45(dd,J＝8.0Hz,16Hz,1H),6.73(d,J＝8.0Hz,1H),7.31(m,3H),7.35(d,J＝8.0Hz,4H),7.50-7.58(m,4H),7.77(d,J＝16.0Hz,1H),9.09(s,1H),9.37(s,1H),10.30(s,1H),10.35(s,1H),10.40(s,1H)；13C NMR(400MHz,DMSO-d6):δ18.14,21.41,113.9,116.6,118.3,121.2,127.1(2C),127.3,127.6,129.3,130.0(2C),130.5,132.2,135.2,137.2,137.8,138.2,139.9,140.1,143.3,143.8,155.2,158.15,159.6,163.7；HRMS(ESI)，C27H25N7O5S,[M+H]+理论计算:560.1711,实测:560.1651。
(I-9)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.39(s,3H),3.19(s,3H)5.81(d,J＝8.0Hz,1H),6.30(dd,J＝4.0Hz,16.0Hz,1H),6.50(m,1H),6.96(s,1H),7.06(s,1H),7.8-7.41(m,6H),7.58(d,J＝8.0Hz,4H),7.84(s,1H),9.12(s,1H),9.30(s,1H),10.37(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,143.1,152.9,155.1,158.2,159.7,163.8；HRMS(ESI)，C27H25ClN6O4S,[M+H]+理论计算:564.1347.1660,实测:564.1325。
(I-10)N-[3-[[5-氟-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.39(s,3H),3.19(s,3H)5.81(d,J＝8.0Hz,1H),6.30(dd,J＝4.0Hz,16.0Hz,1H),6.50(m,1H),6.96(s,1H),7.06(s,1H),7.8-7.41(m,6H),7.58(d,J＝8.0Hz,4H),7.84(s,1H),9.12(s,1H),9.30(s,1H),10.37(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,143.1,152.9,155.1,158.2,159.7,163.8；HRMS(ESI)，C27H25FN6O4S,[M+H]+理论计算:548.1642,实测:548.1632。
(I-11)N-[3-[[5-氯-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.39(s,3H),3.19(s,3H)5.81(d,J＝8.0Hz,1H),6.30(dd,J＝4.0Hz,16.0Hz,1H),6.50(m,1H),6.96(s,1H),7.06(s,1H),7.8-7.41(m,6H),7.58(d,J＝8.0Hz,4H),9.12(s,1H),9.30(s,1H),10.37(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,143.1,152.9,155.1,158.2,159.7,163.8；HRMS(ESI)，C27H24ClN5O5S,[M+H]+理论计算:565.1187,实测:565.1168。
(I-12)N-[3-[[5-硝基-2-[4-[3-(4-甲基苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.39(s,3H),3.19(s,3H)5.81(d,J＝8.0Hz,1H),6.30(dd,J＝4.0Hz,16.0Hz,1H),6.50(m,1H),6.96(s,1H),7.06(s,1H),7.8-7.41(m,6H),7.58(d,J＝8.0Hz,4H),7.84(s,1H),9.12(s,1H),9.30(s,1H),10.37(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,143.1,152.9,155.1,158.2,159.7,163.8；HRMS(ESI)，C27H25N7O6S,[M+H]+理论计算:575.1587,实测:575.1561。
(I-13)N-[3-[[5-氯-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,152.9,155.1,158.2,163.8；HRMS(ESI)，C25H20ClFN6O3S,[M+H]+理论计算:538.0990,实测:538.0987。
(I-14)N-[3-[[5-氟-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,152.9,155.1,158.2,163.8；HRMS(ESI)，C25H20F2N6O3S,[M+H]+理论计算:522.1286,实测:522.1267。
(I-15)N-[3-[[5-氯-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,,152.9,155.1,158.2,163.8；HRMS(ESI)，C25H19ClFN5O4S,[M+H]+理论计算:539.0830,实测:539.0827。
(I-16)N-[3-[[5-硝基-2-[4-(4-氟苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.44,55.55,104.6,112.8,116.5,117.1,121.2,125.9,127.2(2C),127.4,127.6,129.3,129.6(2C),129.9,132.2,137.4,137.8,138.2,140.1,152.9,155.1,158.2,163.8；HRMS(ESI)，C25H20FN7O5S,[M+H]+理论计算:549.1231,实测:539.1211。
(I-17)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.92(s,3H),5.75(dd,J＝4.0Hz,12.0Hz,1H),6.25(d,J＝12.0Hz,1H),6.48-6.55(m,2H),6.66(d,J＝8.0Hz,1H),7.07(t,J＝8.0,1H),7.22(t,J＝8.0Hz,1H),7.28-7.50(m,4H),7.66(dd,J＝8.0Hz,1H),7.95-8.02(m,2H),8.14(s,1H),8.71-8.77(m,1H),8.92(s,1H),9.40(s,1H),10.36(s,1H)；13C NMR(400MHz,DMSO-d6):δ29.65,55.62,116.9,120.1,122.9,125.5,126.4,127.2,127.7,128.5,129.8(2C),132.6,134.1,135.5,136.4,137.5,139.3,139.7,140.3,154.4,156.5,158.0,158.8,160.0,163.4；HRMS(ESI)，C26H22ClFN6O3S,[M+H]+理论计算:553.1219,实测:553.1177。
(I-18)N-[3-[[5-氟-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.92(s,3H),5.75(dd,J＝4.0Hz,12.0Hz,1H),6.25(d,J＝12.0Hz,1H),6.48-6.55(m,2H),6.66(d,J＝8.0Hz,1H),7.07(t,J＝8.0,1H),7.22(t,J＝8.0Hz,1H),7.28-7.50(m,4H),7.66(dd,J＝8.0Hz,1H),7.95-8.02(m,2H),8.14(s,1H),8.71-8.77(m,1H),8.92(s,1H),9.40(s,1H),10.36(s,1H)；13C NMR(400MHz,DMSO-d6):δ29.65,55.62,116.9,120.1,122.9,125.5,126.4,127.2,127.7,128.5,129.8(2C),132.6,134.1,135.5,136.4,137.5,139.3,139.7,140.3,154.4,156.5,158.0,158.8,160.0,163.4；HRMS(ESI)，C26H22F2N6O3S,[M+H]+理论计算:536.1442,实测:536.1412。
(I-19)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.92(s,3H),5.75(dd,J＝4.0Hz,12.0Hz,1H),6.25(d,J＝12.0Hz,1H),6.48-6.55(m,2H),6.66(d,J＝8.0Hz,1H),7.07(t,J＝8.0,1H),7.22(t,J＝8.0Hz,1H),7.28-7.50(m,4H),7.66(dd,J＝8.0Hz,1H),7.95-8.02(m,2H),8.14(s,1H),8.71-8.77(m,1H),8.92(s,1H),9.40(s,1H),10.36(s,1H)；13C NMR(400MHz,DMSO-d6):δ29.65,55.62,116.9,120.1,122.9,125.5,126.4,127.2,127.7,128.5,129.8(2C),132.6,134.1,135.5,136.4,137.5,139.3,139.7,140.3,154.4,156.5,158.0,158.8,160.0,163.4；HRMS(ESI)，C26H21ClFN5O4S,[M+H]+理论计算:553.0987,实测:553.0965。
(I-20)N-[3-[[5-硝基-2-[4-[3-(4-氟苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.9(s,3H),4.74(s,1H),5.78(s,2H),6.28(d,J＝12.0Hz,1H),6.43-6.50(m,2H),7.10(dd,J＝4.0Hz,8Hz,1H),7.23(s,2H),7.33(t,J＝8.0Hz 2H),7.45(d,J＝12.0Hz,2H),7.61(d,J＝8.0Hz,1H),7.77(s,1H),9.05(s,1H),10.21(s,1H),10.31(s,1H),10.38(s,1H)；13C NMR(400MHz,DMSO-d6):δ55.40,114.0,114.1,115.8,116.9,120.1,121.4,120.4,123.1,123.2,127.6,127.9,129.4,130.1,130.2,132.2,132.4,137.9,138.0,140.0,143.8,155.0,155.1,157.9,159.3,163.7；HRMS(ESI)，C26H22FN7O5S,[M+H]+理论计算:563.1387,实测:563.1365。
(I-21)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.14(s,3H),5.74-5.77(m,1H),6.26(d,J＝16.0Hz,1H),6.48(dd,J＝8.0Hz,16.0Hz,1H),6.93(d,J＝8.0Hz,1H),7.17-7.25(m,3H),7.31-7.37(m,3H),7.48(d,J＝8.0Hz,1H),7.65-7.68(m,2H),7.90(s,1H),8.15(s,1H),8.95(s,1H),9.3(s,1H),9.34(s,1H),10.25(s,1H)；13C NMR(400MHz,DMSO-d6):δ55.20,102.7,104.8,110,9,115.2,115.7,116.1,116.3,118.0,119.5,127.4,128.0,129.0,130.2,132.4,137.6,139.3,139.7,140.6,153.9,155.1,156.5,157.9,163.3,163.6,165.7；HRMS(ESI)，C26H22ClFN6O4S,[M+H]+理论计算:569.1169,实测:569.1197。
(I-22)N-[3-[[5-氟-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.14(s,3H),5.74-5.77(m,1H),6.26(d,J＝16.0Hz,1H),6.48(dd,J＝8.0Hz,16.0Hz,1H),6.93(d,J＝8.0Hz,1H),7.17-7.25(m,3H),7.31-7.37(m,3H),7.48(d,J＝8.0Hz,1H),7.65-7.68(m,2H),7.90(s,1H),8.15(s,1H),8.95(s,1H),9.3(s,1H),9.34(s,1H),10.25(s,1H)；13C NMR(400MHz,DMSO-d6):δ55.20,102.7,104.8,110,9,115.2,115.7,116.1,116.3,118.0,119.5,127.4,128.0,129.0,130.2,132.4,137.6,139.3,139.7,140.6,153.9,155.1,156.5,157.9,163.3,163.6,165.7；HRMS(ESI)，C26H22ClFN6O4S,[M+H]+理论计算:552.1391,实测:552.1371。
(I-23)N-[3-[[5-氯-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.14(s,3H),5.74-5.77(m,1H),6.26(d,J＝16.0Hz,1H),6.48(dd,J＝8.0Hz,16.0Hz,1H),6.93(d,J＝8.0Hz,1H),7.17-7.25(m,3H),7.31-7.37(m,3H),7.48(d,J＝8.0Hz,1H),7.65-7.68(m,2H),7.90(s,1H),8.15(s,1H),8.95(s,1H),9.34(s,1H),10.25(s,1H)；13C NMR(400MHz,DMSO-d6):δ55.20,102.7,104.8,110,9,115.2,115.7,116.1,116.3,118.0,119.5,127.4,128.0,129.0,130.2,132.4,137.6,139.3,139.7,140.6,153.9,155.1,156.5,157.9,163.3,163.6,165.7；HRMS(ESI)，C26H21ClFN5O5S,[M+H]+理论计算:569.0936,实测:569.0922。
(I-24)N-[3-[[5-硝基-2-[4-[3-(4-氟苯磺酰胺)甲氧基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.14(s,3H),5.74-5.77(m,1H),6.26(d,J＝16.0Hz,1H),6.48(dd,J＝8.0Hz,16.0Hz,1H),6.93(d,J＝8.0Hz,1H),7.17-7.25(m,3H),7.31-7.37(m,3H),7.48(d,J＝8.0Hz,1H),7.65-7.68(m,2H),7.90(s,1H),8.15(s,1H),8.95(s,1H),9.3(s,1H),9.34(s,1H),10.25(s,1H)；13C NMR(400MHz,DMSO-d6):δ55.20,102.7,104.8,110,9,115.2,115.7,116.1,116.3,118.0,119.5,127.4,128.0,129.0,130.2,132.4,137.6,139.3,139.7,140.6,153.9,155.1,156.5,157.9,163.3,163.6,165.7；HRMS(ESI)，C26H22FN7O6S,[M+H]+理论计算:579.1336,实测:579.1321。
(I-25)N-[3-[[5-氯-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.78(s,3H),5.75-5.78(m,1H),6.27(dd,J＝4.0Hz,16.0Hz,1H),6.43-6.53(m,1H),6.83(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.21-7.31(m,2H),7.43(d,J＝12.0Hz,2H),7.51(d,J＝8.0Hz,1H),7.60-7.63(m,2H),7.90(s,1H),8.10(s,1H),8.92(s,1H),9.27(s,1H),9.79(br,1H),10.25(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.03,104.2,114.7(2C),115.3,115.6,119.7,119.9(2C),121.9(2C),127.3,128.9,129.4(2C),131.5,131.7,132.4,137.6,139.3,139.7,155.2,156.6,157.9,162.7,163.7；HRMS(ESI)，C26H23ClN6O4S,,[M+H]+理论计算:551.1263,实测:551.1292。
(I-26)N-[3-[[5-氟-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ3.37(s,3H),5.76(d,J＝12.0Hz,1H),6.24-6.29(m,1H),6.55(dd,J＝12.0H,16.0Hz,1H),6.88(d,J＝8.0Hz,2H),7.04(d,J＝12.0Hz,2H),7.20(t,J＝8.0Hz,1H),7.46-7.54(m,4H),7.62(d,J＝12.0Hz,2H),8.06(d,J＝4.0Hz,2H),.9.22(s,1H),9.42(s,1H),9.81(br,1H),10.35(s,1H)；13C NMR(400MHz,DMSO-d6):δ56.03,113.3,114.7(2C),114.9,117.5,119.5(2C),122.2(2C),127.2,128.9,129.4(2C),131.2(2C),131.7,132.5,138.2,139.7,140.9,142.2,150.2,155.8,155.8,162.7；HRMS(ESI)，C26H23FN6O4S,[M+H]+理论计算:535.1558,实测:535.1598。
(I-27)N-[3-[[5-氯-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):1H NMR(400MHz,DMSO-d6):δ3.79(s,3H),5.78-5.81(m,1H),6.28(d,J＝16.0Hz,1H),6.47(dd,J＝12.0Hz,16.0Hz,1H),6.77(d,J＝8.0Hz,2H),7.01-7.04(m,3H),7.23(d,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.60-7.71(m,4H),8.44(s,1H),9.69(s,1H),9.85(br,1H),10.41(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.05,113.0,114.7(2C),114.8,116.9,117.5,119.9,120.9,121.5,121.9,127.9,129.3(2C),129.4,130.3,131.6,132.1,136.6,140.9,152.7,157.9,158.5,162.7,163,9,164.2；HRMS(ESI)，C26H22ClN5O5S,[M+H]+理论计算:552.1103,实测:552.1137。
(I-28)N-[3-[[5-硝基-2-[4-(4-甲氧基苯磺酰胺)苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ1.22(s,3H),5.78(d,J＝12.0Hz,1H),6.24-6.29(m,1H),6.50(dd,J＝12.0Hz,16.0Hz,1H),6.83(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,3H),7.24(s,2H),7.37(d,J＝8.0Hz,3H),7.63(d,J＝8.0Hz,4H),7.82(s,1H),9.05(s,1H),10.32(s,1H)；13C NMR(400MHz,DMSO-d6):δ56.06,114.7(2C),116.7,117.1,120.9,121.5,127.5,128.3,129.2,129.4(2C),126.6,131.6,132.3,133.8,135.1,137.8,140.1(2C),145.9,155.2,158.2,159.5,162.8(2C),163.8；HRMS(ESI)，C26H23N7O6S,[M+H]+理论计算:562.1503,实测:562.1533。
(I-29)N-[3-[[5-氯-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),3.79(s,3H),5.78-5.81(m,1H),6.28(d,J＝16.0Hz,1H),6.47(dd,J＝12.0Hz,16.0Hz,1H),6.77(d,J＝8.0Hz,2H),7.01-7.04(m,3H),7.23(d,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.60-7.71(m,4H),8.44(s,1H),9.69(s,1H),9.85(br,1H),10.41(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.05,113.0,114.7(2C),114.8,116.9,117.5,119.9,120.9,121.5,121.9,127.9,129.3(2C),129.4,130.3,131.6,132.1,136.6,140.9,145.9,152.7,157.9,158.5,162.7,163,9,164.2；HRMS(ESI)，C27H25ClN6O4S,[M+H]+理论计算:564.1347,实测:564.1324。
(I-30)N-[3-[[5-氟-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),3.79(s,3H),5.78-5.81(m,1H),6.28(d,J＝16.0Hz,1H),6.47(dd,J＝12.0Hz,16.0Hz,1H),6.77(d,J＝8.0Hz,2H),7.01-7.04(m,3H),7.23(d,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.60-7.71(m,4H),8.44(s,1H),9.69(s,1H),9.85(br,1H),10.41(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.05,113.0,114.7(2C),114.8,116.9,117.5,119.9,120.9,121.5,121.9,127.9,129.3(2C),129.4,130.3,131.6,132.1,136.6,140.9,145.9,152.7,157.9,158.5,162.7,163,9,164.2；HRMS(ESI)，C27H25FN6O4S,[M+H]+理论计算:548.1642,实测:548.1631。
(I-31)N-[3-[[5-氯-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氧基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),3.79(s,3H),5.78-5.81(m,1H),6.28(d,J＝16.0Hz,1H),6.47(dd,J＝12.0Hz,16.0Hz,1H),6.77(d,J＝8.0Hz,2H),7.01-7.04(m,3H),7.23(d,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.60-7.71(m,4H),9.69(s,1H),9.85(br,1H),10.41(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.05,113.0,114.7(2C),114.8,116.9,117.5,119.9,120.9,121.5,121.9,127.9,129.3(2C),129.4,130.3,131.6,132.1,136.6,140.9,145.9,152.7,157.9,158.5,162.7,163,9,164.2；HRMS(ESI)，C27H24ClN5O5S,[M+H]+理论计算:565.1187,实测:565.1165。
(I-32)N-[3-[[5-硝基-2-[4-[3-(4-甲氧基苯磺酰胺)甲基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):1H NMR(400MHz,DMSO-d6):δ1.69(s,3H),3.79(s,3H),5.78-5.81(m,1H),6.28(d,J＝16.0Hz,1H),6.47(dd,J＝12.0Hz,16.0Hz,1H),6.77(d,J＝8.0Hz,2H),7.01-7.04(m,3H),7.23(d,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.60-7.71(m,4H),8.44(s,1H),9.69(s,1H),9.85(br,1H),10.41(s,1H)；13C NMR(4.9000MHz,DMSO-d6):δ56.05,113.0,114.7(2C),114.8,116.9,117.5,119.9,120.9,121.5,121.9,127.9,129.3(2C),129.4,130.3,131.6,132.1,136.6,140.9,145.9,152.7,157.9,158.5,162.7,163,9,164.2；HRMS(ESI)，C27H25N7O6S,[M+H]+理论计算:575.1587,实测:575.1565。
(I-33)N-[3-[[5-三氟甲基-2-[4-(4-甲基苯磺酰胺)苯胺]-4-嘧啶]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.32(s,3H),5.77-5.80(m,1H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,59.73,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7；155.5,156.9,158.3,164.0；HRMS(ESI)，C27H23F3N6O3S,[M+H]+理论计算:568.1504,实测:568.1523。
(I-34)N-[3-[[5-三氟甲基-2-[4-[3-(4-甲基苯磺酰胺)氯基]苯胺]-4-嘧啶基]氨基]苯基]-2-丙烯酰胺
1H NMR(400MHz,DMSO-d6):δ2.32(s,3H),6.27(dd,J＝4.0Hz,8.0Hz,1H),6.45-6.52(m,1H),6.83(d,J＝8.0Hz,2H),7.21-7.32(m,4H),7.42(d,J＝12.0Hz,2H),7.51(s,1H),7.57(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,1H),8.10(s,1H),8.93(s,1H),9.26(s,1H),9.87(br,1H),10.24(s,1H)；13C NMR(400MHz,DMSO-d6):δ21.72,59.73,104.5,115.6,116.0,130.1,120.3(2C),122.2(2C),127.5(2C),127.6,129.2,130.3(2C),131.7,132.7,137.5,137.9,139.6,140.0,143.7；155.5,156.9,158.3,164.0；HRMS(ESI)，C27H22ClF3N6O3S,[M+H]+理论计算:602.1115,实测:602.1110。
目标分子成盐的方法
无机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加无机酸(1mmol)的5mL无水甲醇溶液，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除甲醇，即得目标分子的无机酸盐。
有机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加有机酸(1mmol)的5mL干燥乙醚，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除溶剂，即得目标分子的有机酸盐。
两个目标分子混合物的制备
取等摩尔量(1mmol)的上述两个目标分子于无水甲醇中(5mL)，室温搅拌10分钟，常温蒸除溶剂，即得目标分子的混合物。
实施例2目标分子生物活性评价
1、体外对受体酪氨酸激酶抑制活性测试方法
(1)制备激酶检测缓冲液
①在室温融解激酶检测缓冲液(Kinase Detection Buffer)，观察是否有沉淀。
②如果出现沉淀，就在37℃孵育(Kinase Detection Buffer)15分钟并经常摇动，溶解沉淀。或者，小心吸走上清，去除沉淀。
(2)制备激酶检测试剂
①使用前在室温平衡激酶检测缓冲液(Kinase Detection Buffe)和激酶检测底物(Kinase Detection Substrate)。
②将激酶检测缓冲液(Kinase Detection Buffer)全部倒进装有激酶检测底物(Kinase Detection Substrate)的棕色瓶中，使冻干粉底物溶解，这样就制成了激酶检测试剂。
③轻轻震荡、涡旋或颠倒混匀，成为均质溶液，底物应在1分钟内溶解。
④激酶检测试剂配好后应立即使用，或分装存于-20℃，我们认为配好的试剂经过几次冻融后循环信号活性都没有损失。
(3)制作ATP转化成ADP的标准曲线
①用1×激酶反应缓冲液(kinase reaction buffer)稀释试剂盒提供的UltraPure ATP和ADP，制成900μL 50μM ATP和500μL 50μM ADP。
②将上一步配好的50μM ATP和50μM ADP溶液按表1所示在384孔板A1-A12中混合，模拟每个转化百分比的ATP和ADP的浓度，混合好。
表1.制备50μM系列ATP+ADP标准品
③每孔加入5μL的ADP-GloTM试剂来终止激酶反应。在室温孵育40分钟。
④每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。
⑤在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥绘制ATP转化成ADP的标准曲线。
(4)确定激酶抑制物的IC50值
①按照promega试剂盒说明书配制1×激酶反应缓冲液(kinase reactionbuffer)，2.5×50ng/μL激酶和2.5×0.5μg/μL底物和125μM ATP。
②在无酶对照孔中加入3μL 1×激酶反应缓冲液(kinase reaction buffer)，2μL2.5×0.5μg/μL底物和125μM ATP。在阴性对照孔中加入1μL 1×激酶反应缓冲液(kinasereaction buffer)，2μL 2.5×50ng/μL激酶，2μL 2.5×0.5μg/μL底物和125μM ATP。在测试孔中加入1μL 5×待测药物，2μL 2.5×50ng/μL激酶，2μL 2.5×0.5μg/μL底物和125μMATP。
③混合好平板，孵育60分钟。
④每孔加入5μL的ADP-GloTM试剂来终止激酶反应。在室温孵育40分钟。
⑤每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥结果分析，结果如表2所示。
2、抑制BTK高表达细胞生长实验(CCK-8检测法)
(1)细胞类型及选择：Ramos细胞(人Burkitt's淋巴瘤细胞，BTK激酶高表达)、Raji细胞(人Burkitt's淋巴瘤细胞，BTK激酶高表达)。
(2)细胞接种：收集对数生长期细胞，调整细胞悬液浓度，以每孔4×103个细胞，每孔体积100μL接种到96孔板，每组设3个复孔(边缘孔用无菌PBS填充)；
(3)细胞培养：细胞接种后，对照组用10％FBS RPMI-1640培养，实验组分别用10μL不同浓度梯度的Spebrutinib(1.25-40μmol/L)、各不同药物(1.25-40μmol/L)干预，37℃，5％CO2培养箱中继续培养(按实验要求分别培养不同时间)；
(4)呈色：两组细胞分别于培养48h后加入10μL CCK-8溶液(5mg/ml)，4h后终止培养，于摇床上低速振荡10min，使结晶充分溶解；
(5)比色：在酶联免疫检测仪上测定各孔光度值(OD值)，选择450nm波长，以无细胞的即RPMl-1640培养液空白孔调零，测各孔的吸光度值。实验重复三次；
(6)记录结果：细胞生长抑制率＝(对照组吸光度值一实验组吸光度值)/对照组吸光度值×100％，细胞增殖率＝(实验组吸光度值/对照组吸光度值)×100；
(7)绘制细胞生长曲线：以时间为横坐标，抑制率/增殖率为纵坐标绘制细胞生长曲线。在GraphPad软件中的GraphPad Prism作图软件中针对抑制剂浓度做图，以便由log[抑制剂]相对于反应，可变斜率模型估算出IC50。
测试结果如表2所示，表2显示所获得的化合物在抑制BTK激酶和抗肿瘤细胞增殖中的活性效果。
表2
a:IC50：半数有效抑制浓度.b:Ramos,Raji为典型B-淋巴细胞白血病细胞，BTK激酶高度表达.
同时，本实验发现化合物I-21的Ramos细胞活性与时间和浓度有着很大的关系，如图1所示，随着浓度的增大，细胞存活率减小，尤其72h后的Ramos细胞在药物浓度达10μmol/L时，几乎不能存活，明显高于48h，由此可证明本药物属于浓度和时间依赖性药物。
3、活性药物毒性试验
外周血单个核细胞(Peripheral blood mononuclear cell,PBMC)包含淋巴细胞、单核细胞(monocyte)、树突状细胞和其它少量细胞(造血干细胞等)。对其进行毒性试验可以证明本发明的药物是否对正常免疫细胞具有杀伤力。目前国内外分离PBMC的常用方法是葡聚糖-泛影葡胺密度梯度离心法，实验步骤如下：
(1)采血并稀释：静脉取血2ml，加入含ACD抗凝溶液的试管中，混匀，使血液抗凝。用PBS溶液将抗凝血稀释1倍；
(2)加样：吸取2ml淋巴细胞分层液(天津TBD)置于刻度离心管中，然后将离心管倾斜45°角，用毛细滴管将稀释的全血沿管壁缓慢加至分离液上面，应注意保持两者界面清晰；
(3)离心：在18℃～20℃下，用水平离心机以2000r/min离心20min。离心后从管底至液面分四层，依次为红细胞和粒细胞层、分层液层、单个核细胞层、血浆层；
(4)回收：用毛细吸管轻轻插到混浊带，沿管壁轻轻吸出此层细胞，移入另一支离心管中。即要吸取所有单个核细胞，又要避免吸取过多的分层液或血浆，以免混入其他细胞成分；
(5)洗涤：用PBS液洗涤细胞3次。第一次2000r/min，10min；第2～3次1500r/min，10min，可去掉大部分混杂的血小板；
(6)将沉淀细胞悬于培养基中备用；
(7)计数铺板：调整细胞悬液浓度，以每孔2.5×105个细胞，每孔体积500μL接种到24孔板，每组设2个复孔；
(8)细胞培养：细胞接种后，对照组用10％FBS RPMI-1640培养，实验组分别用50μL不同浓度梯度的Ibrutinib(5-20μmol/L)、活性药物(5-20μmol/L)干预，37℃，5％CO2培养箱中继续培养(按实验要求分别培养不同时间)；
(9)染色：培养24h后加入20μL 1μg/μl AO(吖啶橙)，20μL 1μg/μl PI(碘化丙啶)染色5min，倒置荧光显微镜下观察并拍照。
(10)测试结果如图2所示，图2是化合物I-21对PBMC细胞毒性数据。
由表2的生物活性结果表明，本发明中的部分分子对BTK激酶有较强的抑制效果，大部分化合物达到纳摩尔水平的活性级别，且有2个化合物的有效抑制浓度IC50值小于1nM。抗细胞增殖活性结果揭示，大部分化合物对B淋巴肿瘤细胞Ramos有非常有效的抑制作用，其中化合物I-7、I-17、和I-21还显示出了优于Spebrutinib的活性。大部分化合物对Raji细胞也有很大抑制作用，优于Spebrutinib，其中I-1、I-7、I-8、I-17、I-21、I-25、I-28显示出了预料不到的优于Ibrutinib的活性。同时图2显示,化合物I-21的细胞毒性也比Ibrutinib显著减小，在保持药物活性的同时减轻药物的毒性，具有潜在的药用价值。综上所述，本发明的化合物对治疗布鲁顿氏酪氨酸激酶引起的疾病具有很深刻的潜在意义，特别是用于治疗弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病。预示此类分子具有开发成新型高效布鲁顿氏酪氨酸激酶抑制剂的潜力。
以上所述仅是本发明的优先实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.一种式(I-21)所示的化合物或其药学上可接受的盐，所述式(I-21)所示的化合物具有如下结构：
2.一种药物组合物，其含有有效剂量的权利要求1所述式(I-21)所示的化合物或其药学上可接受的盐，及药用载体。
3.权利要求1所述式(I-21)所示的化合物或其药学上可接受的盐，或权利要求2所述的药物组合物在制备布鲁顿氏酪氨酸激酶抑制剂中的应用。
4.权利要求1所述式(I-21)所示的化合物或其药学上可接受的盐，或权利要求2所述的药物组合物在制备治疗肿瘤的药物中的用途。
5.根据权利要求4所述的用途，其中，所述肿瘤选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病中的一种或多种。
6.根据权利要求5所述的用途，其中，所述肿瘤为慢性淋巴细胞白血病。
7.根据权利要求4～6中任一项所述的用途，其中，所述用途主要通过抑制布鲁顿氏酪氨酸激酶实现的。
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