CN102711475A - 新颖化合物及其用于抑制蛋白激酶的治疗用途 - Google Patents
新颖化合物及其用于抑制蛋白激酶的治疗用途 Download PDFInfo
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- CN102711475A CN102711475A CN2010800420578A CN201080042057A CN102711475A CN 102711475 A CN102711475 A CN 102711475A CN 2010800420578 A CN2010800420578 A CN 2010800420578A CN 201080042057 A CN201080042057 A CN 201080042057A CN 102711475 A CN102711475 A CN 102711475A
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- thiophene
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Abstract
具有如下结构的新颖化合物：
Description
技术领域
本发明涉及调节检测点激酶1(CHK1)和检测点激酶2(CHK2)、受体酪氨酸激酶和非受体酪氨酸激酶的活性的方法和组合物。更具体地，本发明涉及上述酶抑制剂的制备和应用。
背景技术
癌症的病因学非常复杂，仍然知之甚少。已知的是癌症与环境因素和人体的内部因素密切相关。约四分之三的癌症可归因于外部环境因素。癌症持续对人类构成极大的威胁，世界范围内每年有至少五百万人死于癌症。目前可采用的治疗方法，例如外科手术、放射线疗法、化学疗法都具有局限性。
在可采用的癌症治疗和预防方法中，化学制剂最为有效。
一类癌症化疗制剂是受体酪氨酸激酶和非受体酪氨酸激酶的抑制剂或拮抗剂。具体靶向包括血管内皮生长因子受体(VEGFR)、表皮生长因子受体(EGFR)、HER2(人表皮生长因子受体2)、SRC、JAK(Janus激酶)和TEK。
已经发现某些噻吩-哒嗪化合物具有抗肿瘤活性。例如，WO2005105808公开了一种这样的化合物作为IKK抑制剂：
另外，WO2007124181公开p38蛋白酶抑制剂化合物，p38蛋白酶为一类酪氨酸激酶：
此外，WO 03029241、WO 03028731和WO2005066163公开了类似的化合物作为CHK1抑制剂。
然而，需要更多作为酪氨酸激酶，尤其是CHK1/CHK2抑制剂的抗癌症化合物。
发明内容
本发明提供某类蛋白激酶，尤其是细胞检测点激酶(CHK1和CHK2)，和受体酪氨酸激酶和非受体酪氨酸激酶，例如VEGFR(血管内皮生长因子受体)、EGFR(表皮生长因子受体)、HER2(人表皮生长因子受体2)、SRC激酶、JAK激酶和TEK激酶；和丝氨酸/苏氨酸激酶例如MEK、JNK、c-MET、AKT、PIM、TIE和PLK的新颖抑制剂。
检测点激酶1是一种进化上高度保守的蛋白激酶，并具有控制S和G2/M检测点细胞周期进展的功能。DNA的损伤激活Chk1、终止细胞周期并引起损伤的DNA的修复。如果待修复的DNA损伤过于广泛，则细胞死亡以维持基因组的完整性和稳定性。癌症细胞的Chk1缺乏或缺陷显示为细胞周期控制中的许多缺陷，包括细胞分裂速度降低、缺乏对细胞周期检测点的反应、和DNA损伤的敏感性增加。由于在损伤修复方面的功能，Chk1在癌症存在、癌症细胞死亡、和癌症耐药中起着重要作用。
对细胞周期调节检测点的研究显示抑制CHK1的表达可扭转肿瘤细胞的耐药性或耐受性，从而增加癌症细胞对DNA损伤治疗的敏感性、并大幅增加抗癌制剂的活性和效力。大多数癌症具有p53基因突变，这特定地消除G1/S检测点，也可作为特定抗癌制剂筛选的基础。Chk1激酶抑制剂可为特效抗癌制剂或增强其它抗癌药物活性的良好候选物，因为Chk1激酶也调节G2/M检测点。即使Chk1抑制剂本身不具有强抗癌活性，它们仍然可在联合使用时增强其它药物的抗癌活性。
本发明提供新颖的具有抗癌活性的蛋白激酶抑制剂化合物或其药学上可接受的盐或衍生物。本发明的化合物是癌症相关蛋白激酶如CHK1和CHK2的抑制剂，并可增强其它抗癌制剂的活性。本发明也提供制备该化合物、含该化合物的药物组合物的方法，和在制备用于抑制温血动物如人类的细胞繁殖或细胞增殖的药物组合物时使用该化合物的方法。
可用本发明化合物或含该化合物的药物组合物治疗的细胞周期停止相关或细胞增殖相关疾病包括癌症(包括实体瘤和白血病)、纤维化及相关疾病、银屑癣、风湿性关节炎、卡波西肉瘤、急性和慢性肾脏疾病、动脉粥样化、动脉硬化、动脉狭窄、自身免疫性疾病、急性或慢性炎症、骨疾病、和由视网膜血管新生引起的眼部疾病。
本发明的新颖化合物通常具有如下所述的结构式I。
其中
Y＝NH、O、或S，
R1＝选自以下基团：
其中X＝CH2、NH、S、或O，
R8＝-H、-NH2、-OH、-N(R4R5)、-C(R4R5)1-7NR6R7、-C(R4R5)1-7OR6、或-N(R4)NR5R6，
其中R4、R5、R6、R7＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、和N的环烷基(C3-C8)、芳基(未取代或取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，
R9、R10、R11、R12、和R13＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S或N的环烷基(C3-C8)；芳基(未取代和取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，
R2选自H、OH、NH2、OR14、NR14R15、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、和炔基，
其中R14、R15＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、N的环烷基(C3-C8)、芳基(未取代或取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，和
R3选自H、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、和炔基。特别地，R3选自以下基团：
其中R16、R17、和R18选自以下基团：H；杂原子如F、Cl、Br、I；烷基(C1-C8)；未取代或取代的环烷基(C3-C8)，其中取代基选自烷基(C1-C8)、环烷基(C3-C8)、芳基、杂芳基；-OR19；-SR19；-NR19R20；-S(O)R19；-S(O)2R19；-S(O)2NR19R20；-C(O)NR19R20；-N(R19)C(O)R20；-N(R19)S(O)2R20；-N(R19)C(O)N(R20R21)；N(R19)C(O)OR20；取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的芳基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基；取代或未取代的烯基、和取代或未取代的炔基；
其中R19、R20、和R21独立地选自H、烷基(C1-C8)、环烷基(C3-C8)、取代或未取代的芳基、取代或未取代的烷基芳基、取代或未取代的杂芳基，
或R16、R17、和R21可为含0-3个选自N、O、和S的杂原子的稠环的一部分。
上述化合物可如以下通用方案制备：
方案1：
方案2：
方案3：
在优选的实施方案中，本发明的新颖化合物具有结构式II：
其中，
R1选自以下基团：
其中X＝CH2、NH、S、或O；
R8＝-H、-NH2、-OH、-N(R4R5)、-C(R4R5)1-7NR6R7、-C(R4R5)1-7OR6、-N(R4)NR5R6
R4、R5、R6、R7＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、N的环烷基(C3-C8)、芳基(选自未取代和取代的芳香物)、或杂芳基(选自未取代和取代的杂芳物)R9、R10、R11、R12、R13＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、N的环烷基(C3-C8)、芳基(选自未取代和取代的芳香物)杂芳基(选自未取代和取代的杂芳物)，
R2选自H、OH、NH2、OR14、NR14R15、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、炔基，其中R14和R15为H、烷基(C1-C6)；不具有或具有含杂原子如O、S、和N的取代基的环烷基(C3-C8)；或取代或未取代的芳香环，
R3选自H、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、和炔基；优选地，R3选自以下基团：
其中R16、R17和R18选自以下基团：H；杂原子如F、Cl、Br、I；烷基(C1-C8)；未取代或取代的环烷基(C3-C8)：取代基选自烷基(C1-C8)、环烷基(C3-C8)、芳基、和杂芳基；-OR19；-SR19；-NR19R20、-S(O)R19；-S(O)2R19；-S(O)2NR19R20；-C(O)NR19R20；-N(R19)C(O)R20；-N(R19)S(O)2R20；-N(R19)C(O)N(R20R21)；-N(R19)C(O)OR20；取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的芳基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的烯基、取代或未取代的炔基；
其中R19、R20和R21选自H、烷基(C1-C8)、环烷基(C3-C8)、取代或未取代的芳基、取代或未取代的烷基芳基、和取代或未取代的杂芳基；
或R16、R17和R18可为含0-3个选自N、O、和S的杂原子的稠环的一部分。
上述化合物可如以下通用方案制备：
依据以上方案合成该新颖化合物可通过使用本领域技术人员已知的方法实现，例如U.S.专利公开号US2009-0275585A1和WO2005105808所公开的，其在此作为参考全文引入。
本发明的新颖化合物为蛋白激酶包括CHK1和CHK2的抑制剂，并可预防来自G2/M检测点细胞周期停止的DNA损伤修复机制。因此这些化合物具有抗增生(例如抗癌)活性，并也可与其它抗癌制剂联用，以增强它们的抗癌效果。因此该化合物用作人类和动物的癌症治疗剂。本发明进一步包括制备该新颖化合物、含该化合物的药物组合物的方法，该化合物或其盐或前体用于生产药物组合物的用途，以及使用该药物组合物治病的方法。
在另一个实施方案中，本发明提供一种含前述化合物和药学上可接受的助剂或赋形剂的药物组合物，和通过向患者施用有效量的该药物组合物而治疗癌症的方法。施用“有效量”或“治疗有效量”本发明化合物是指在实现理想结果所必要的剂量和时间下的有用量。依照本发明化合物的治疗有效量可根据众多因素而不同，例如患病阶段、年龄、性别、以及受体体重。可调整病人的摄入剂量以提供最佳治疗反应。例如，可每天施用多个分开的剂量或当显示治疗情况紧急时可按比例缩小剂量。在本发明的上下文中，“药学上可接受的盐”指由药学上可接受的非毒性酸制备的盐。
依照本发明的药物组合物可以液态、半固态或固态药物的形式存在和施用，例如注射溶液、滴剂、汁液、糖浆、悬浮液、喷雾、颗粒、片剂、丸剂、胶布、胶囊、膏药、栓剂、软膏、乳膏、洗剂、凝胶、乳剂或气雾剂形式，并包含本发明化合物、和依照盖伦制剂(galenical form)形式的药物辅助物质，例如载体材料、装填物、溶剂、稀释剂、表面活性物质、染料、防腐剂、崩解剂、抗摩擦剂、润滑剂、调味剂和/或粘合剂。这些辅助物质可为，例如：水、乙醇、2-丙醇、甘油、乙二醇、丙二醇、聚乙二醇、聚丙二醇、葡萄糖、果糖、乳糖、蔗糖、右旋糖、糖蜜、淀粉、改性淀粉、胶质、山梨醇、纤维醇、甘露醇、微晶纤维素、甲基纤维素、羧甲基纤维素、醋酸纤维素、虫漆、鲸蜡醇、聚乙烯吡咯烷酮、石蜡、蜡、自然生成和合成树胶、阿拉伯树胶、藻酸盐、右旋糖苷、饱和和不饱和脂肪酸、硬脂酸、硬脂酸镁、硬脂酸锌、硬脂酸甘油酯、十二烷基硫酸钠、食用油、香油、椰子油、花生油、大豆油、卵磷脂、乳酸钠、聚氧乙烯和丙烯脂肪酸酯、山梨糖醇干脂肪酸酯、山梨酸、安息香酸、柠檬酸、抗坏血酸、单宁酸、氯化钠、氯化钾、氯化镁、氯化钙、氧化镁、氧化锌、二氧化硅、氧化钛、二氧化钛、硫酸镁、硫酸锌、硫酸钙、苛性钾、磷酸钙、磷酸二钙、溴化钾、碘化钾、滑石、高岭土、果胶、交联聚维酮、琼脂和膨润土。辅助物质及其用量的选择取决于药剂是被口服、经口、皮下、肠外、静脉、腹膜内、皮层内、肌肉、鼻内、口腔、直肠还是局部给药，例如接种于皮肤、黏膜和眼部。片剂、包衣片剂、胶囊、颗粒、滴剂、汁液和糖浆形式的配方尤其适于口服给药，而溶液、悬浮液、可轻易干燥配方和喷雾适于肠外、局部和吸入给药。以溶解的形式在储存处中或胶布中的本发明化合物，任选地带有促皮肤渗透剂，为适于经皮给药的配方。可口服或经皮给药的配方形式可以延时或控制方式释放本发明化合物。
依照本发明的药物和药物组合物可借助于药物配方领域所熟知的试剂、设备、方法和过程而制备，例如Remington′s Pharmaceutical Sciences，18th ed.，MackPublishing Co.，Easton，Pa.(1990)，尤其是第8部分第76-93节中所描述的。
因此，对于固态配方，例如片剂，药物的活性化合物可与药学载体，例如传统的片剂成分，如玉米淀粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸镁、磷酸二钙或树胶，和药学稀释剂，如水相混合，以形成包含均匀分布的本发明化合物或其药学上可接受盐的固态粗成品。此处的均匀分布理解为意指活性化合物均匀分布于整个粗成品中，以使其可容易的分成相同活性的单元制剂，例如片剂、药丸或胶囊。该固态粗成品随后被分成单元制剂形式。依照本发明的药物或依照本发明的组合物的片剂或药丸也可被包衣，或以其它方式混合以提供延时释放药剂形式。适合的包衣成分为，尤其是，聚合酸和聚合酸与材料如虫漆、鲸蜡醇和/或醋酸纤维素的混合物。
施用于病人的活性化合物的量依赖于病人的体重、年龄和疾病史而变化，也依赖于给药方式、症状和疾病严重程度。通常施用的剂量范围为，例如0.1-5,000mg本发明化合物/kg体重，特别是1-500mg本发明化合物/kg体重，优选2-250mg本发明化合物/kg体重。
本发明的药物组合物可肠内(如口服或通过直肠给药)、外用、或肠外例如注射给药。适合的配方包括片剂(如传统片剂、含片、舌下含片、口腔胶布、咀嚼片、泡腾片、阴道片、阴道泡腾片、缓释片、控释片、肠衣片、口腔速释片)、胶囊(硬胶囊、软胶囊、缓释胶囊、控释胶囊、肠衣胶囊等)、药丸(滴丸、糖衣丸、颗粒)、口服液(口服溶液、口服悬浮液、口服乳液等)、颗粒(悬浮颗粒、冲剂、泡腾冲剂、肠溶颗粒、缓释颗粒、控释颗粒等)、注射剂(注射溶液、注射乳液、注射悬浮液)、静脉输液、注射用粉末、注射用浓缩液、植入物等，和其它药物形式如栓剂、气雾剂、气雾剂粉末、喷雾、凝胶、药膜、胶布等。
本发明化合物可与可生物降解聚合物结合，聚合物可缓释该化合物，聚合物被植入给药位置的周边，例如，在肿瘤处或植入以缓慢释放该化合物。可生物降解聚合物和它们的应用描述于，例如Brem et al.，J.Neurosurg.74：441-446(1991)。渗透微型泵也可用于提供控制输送。
该化合物的毒性和疗效可通过细胞培养或实验动物的标准药物程序测定，例如测定LD50(种群的50％致死量)和ED50(种群的50％治疗有效量)。中毒和疗效之间的剂量率为治疗指数，其可表示为比值LD50/ED50。优选治疗指数大的化合物。由细胞培养实验和动物研究获得的数据可用于设计供人类使用的剂量范围。该化合物的剂量优选处于包括具有很小或无毒性的ED50循环浓度的范围之内。剂量可在该范围内变化，取决于所用的制剂形式和给药路线。
本发明的药物组合物适用于治疗癌症和相关疾病，并可单独或与其它抗癌药物联合使用。本领域的普通技术人员可决定治疗的适合剂量，取决于待治疗的疾病类型、配方和病人状况。
本发明化合物可用于预防或治疗非正常细胞增生，尤其是那些发现于肿瘤或癌症中的细胞增生，例如肺癌、肝癌、白血病、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌癌、软组织癌、尿道癌、前列腺癌、皮肤淋巴细胞瘤、膀胱癌、肾癌、脊柱肿瘤、大脑神经胶质肿瘤、和垂体腺瘤。
本发明的药物组合物也可用于预防或治疗自身免疫疾病、炎症、神经系统疾病、和心血管疾病。特别地，本发明的药物组合物可用于治疗细胞周期相关或细胞增殖相关疾病。
实施例
实施例1化合物(S)-2-(3-氟苯基)-4-(哌啶-3-yl氨基)噻吩[2，3-d]哒嗪-7-甲酰胺的合成
依照以下方案3，合成化合物(S)-2-(3-氟苯基)-4-(哌啶-3-yl氨基)噻吩[2，3-d]哒嗪-7-甲酰胺：
步骤1
在-78℃下，向噻吩(5.34g，20mmol)和草酸二乙酯的THF溶液(100mL)中滴加LDA(20mmol)。滴加完毕后，使所得混合物升温至0℃，0℃搅拌30min。加入HCl(1N)猝灭反应，EtOAc萃取。Na2SO4干燥有机物，浓缩。色谱柱纯化剩余物，得到黄色固态产物(7.07g)。HPLC-MS tR＝2.39min(UV254nm)；结构式C17H15FO5S的计算质量为350.0，测定LCMS m/z 351.0(M+H)。
步骤2
将步骤1得到的酮(7.07g，19.2mmol)溶于乙醇(50mL)，加入肼(1mL)。将混合物加热至60℃，搅拌10min。然后，冷却混合物至室温，再次搅拌30min。过滤收集固体，少量冷乙醇洗涤。空气干燥固体，得到白色固态纯产物(6.17g)。HPLC-MS tR＝1.88min(UV254nm)；结构式C15H11FN2O3S的计算质量为318.0，测定LCMS m/z 319.0(M+H)。
步骤3
将步骤2得到的杂环化合物(2.8g，8.8mmol)加入P(O)Cl3(20mL)，并将混合物加热至90℃，该温度下搅拌3小时。减压移除溶剂，EtOAc溶解剩余物。过滤固体，浓缩有机物，柱色谱(硅胶)纯化，得黄色固态产物(2.31g)。HPLC-MS tR＝2.40min(UV254nm)；结构式C15H10ClFN2O2S的计算质量为336.0，测定LCMS m/z 337.0(M+H)。
步骤4
将得到的氯-化合物(336mg，1.0mmol)溶于NMP(5mL)，加入K2CO3(272mg，2.0mmol)和3-氨基哌啶-1-甲酸(S)-叔丁基酯(200mg，1.0mmol)。将混合物加热至80℃，搅拌3小时。冷却至室温后，EtOAc稀释混合物，水、盐水洗涤，Na2SO4干燥。浓缩后，柱色谱纯化粗产物，得产物(357mg)。HPLC-MS tR＝2.09min(UV254nm)；结构式C25H29FN4O4S的计算质量为500.2，测定LCMS m/z501.1(M+H)。
步骤5
室温下，使4-(1-(叔丁氧基羰基)哌啶-3-基氨基)-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸(S)-乙基酯(50mg，0.1mmol)与氨水(4mL)混合于密封管中。将混合物加热至80℃，搅拌过夜。然后浓缩移除溶剂。粗产物3-(7-氨基甲酰基-2-(3-氟苯基)噻吩[2，3-d]哒嗪-4-基氨基)哌啶-1-甲酸(S)-叔丁基酯无需进一步纯化，直接用于下一步骤。HPLC-MS tR＝1.75min(UV254nm)；结构式C23H26FN5O3S的计算质量为471.2，测定LCMS m/z 472.2(M+H)。
步骤6
室温下，用HCl(4N的环氧乙烷溶液，3mL)处理步骤5得到的粗产物3-(7-氨基甲酰基-2-(3-氟苯基)噻吩[2，3-d]哒嗪-4-基氨基)哌啶-1-甲酸(S)-叔丁基酯30min。然后减压移除溶剂，HPLC纯化剩余物，获得最终化合物(S)-2-(3-氟苯基)-4-(哌啶-3-基氨基)噻吩[2，3-d]哒嗪-7-甲酰胺。HPLC-MS tR＝1.27min(UV254nm)；结构式C18H18FN5OS的计算质量为371.1，测定LCMS m/z 372.1(M+H)。
实施例2
化合物2-(3-氟苯基)-4-(哌啶-3-基氧基)噻吩[2，3-d]哒嗪-7-甲酰胺的合成
实施例1步骤3制备4-氯-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸乙酯。
步骤1
3-羟基哌啶-1-甲酸叔丁基酯(100mg，0.5mmol)溶解于干燥NMP(5mL)，小心加入NaH(20mg，60％的油溶液，0.5mmol)。室温下搅拌混合物10min。然后，加入4-氯-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸乙酯(130mg，0.5mmol)。将混合物加热至80℃，搅拌30min。冷却至室温后，加入EtOAc稀释反应，水、盐水洗涤。Na2SO4干燥有机物，过滤，浓缩。柱色谱(硅胶)纯化粗产物，得产物4-(1-(叔丁氧基羰基)哌啶-3-基氧基)-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸乙酯(151mg)。HPLC-MS tR＝2.17min(UV254nm)；结构式C25H28FN3O5S的计算质量为501.2，测定LCMS m/z 502.2(M+H)。
步骤2
使用与实施例1步骤5相同的条件制备化合物3-(7-氨基甲酰基-2-(3-氟苯基)噻吩[2，3-d]哒嗪-4-基氧基)哌啶-1-甲酸叔丁基酯。HPLC-MS tR＝1.88min(UV254 nm)；结构式C23H25FN4O4S的计算质量为472.2，测定LCMS m/z 473.1(M+H)。
步骤3
使用与实施例1步骤6相同的条件制备化合物2-(3-氟苯基)-4-(哌啶-3-基氧基)噻吩[2，3-d]哒嗪-7-甲酰胺。HPLC-MS tR＝1.33min(UV254nm)；结构式C18H17FN4O2S的计算质量为372.1，测定LCMS m/z 373.1(M+H)。
实施例3
化合物2-(3-氟苯基)-4-(哌啶-3-基硫代氧基)噻吩[2，3-d]哒嗪-7-甲酰胺的合成
依照实施例2所述的相同过程制备以下化合物2-(3-氟苯基)-4-(哌啶-3-基硫代氧基)噻吩[2，3-d]哒嗪-7-甲酰胺。HPLC-MS tR＝1.35min(UV254nm)；结构式C18H17FN4OS2的计算质量为388.1，测定LCMS m/z 389.0(M+H)。
实施例4化合物2-(3-氟苯基)-4-(哌啶-3-基甲基)噻吩[2，3-d]哒嗪-7-甲酰胺的合成
步骤1
氩气条件下，将化合物3-亚甲基哌啶-1-甲酸叔丁基酯(600mg，3.0mmol)溶于干燥THF(15mmol)，滴加9-BBN(3.0mmol)。室温搅拌所得混合物2小时。氩气条件下，将所得溶液加入氯-化合物4-氯-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸乙酯(260mg，1.0mmol)与Pd(dppf)Cl2(40mg，0.05mmol)、K3PO4(636mg，3.0mmol)的环氧乙烷溶液(10mL，含1ml水)的混合物中。将所得混合物加热至90℃，搅拌过夜。冷却至室温后，EtOAc(60mL)稀释混合物，硅藻土过滤。浓缩后，柱色谱(硅胶，0～30％ EtOAc/己烷)纯化粗产物，得产物4-((1-(叔丁氧基羰基)哌啶-3-基)甲基)-2-(3-氟苯基)噻吩[2，3-d]哒嗪-7-甲酸乙酯(266mg)。HPLC-MS tR＝2.38min(UV254nm)；结构式C26H30FN3O4S的计算质量为499.2，测定LCMS m/z 500.3(M+H)。
步骤2
使用与实施例1步骤5相同的条件制备化合物3-((7-氨基甲酰基-2-(3-氟苯基)噻吩[2，3-d]哒嗪-4-基)甲基)哌啶-1-甲酸叔丁基酯。HPLC-MS tR＝1.95min(UV254 nm)；结构式C24H27FN4O3S的计算质量为470.2，测定LCMS m/z 471.2(M+H)。
步骤3
使用与实施例1步骤6相同的条件制备化合物2-(3-氟苯基)-4-(哌啶-3-基甲基)噻吩[2，3-d]哒嗪-7-甲酰胺。HPLC-MS tR＝1.39min(UV254nm)；结构式C19H19FN4OS的计算质量为370.1，测定LCMS m/z 371.1(M+H)。
实施例4
类似地，依照上述方案3，合成以下化合物。
实施例5式II化合物的合成：
依照下述方法合成本发明化合物：碱的存在下，用草酸二烷基酯处理式A化合物，得式B化合物：
用肼处理化合物B，得式C化合物：
用三氯磷酸(POCl3)处理化合物C，得式D化合物：
然后用胺NH2R1处理化合物D，得式E化合物，
然后化合物E与另外的胺NH2R2反应，随后移除R1上的保护基团，碱处理，得到式1化合物、或其药学上可接受的盐。
在上述合成方案中，R、R1、R2和R3如前述定义。优选地，R为C1-4烷基；R1为饱和或不饱和的含N、S、或O的5-或6-元环、或其立体异构体，R2独立地为H、或C1-4烷基；和R1为单或双卤取代的苄基，其中取代可发生于任何位置。
依照上述方法，合成以下化合物：
1.2-(4-氟苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2.2-(4-氯苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
3.2-(4-溴苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
4.2-(4-氟苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
5.2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
6.2-(4-溴苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
7.2-(4-氟苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
8.2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
9.2-(4-溴苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
10.2-(4-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
11.2-(4-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
12.2-(4-氯苯基)-4-(S-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
13.2-(4-氯苯基)-4-(R-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
14.2-(4-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
15.2-(4-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
16.2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
17.2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
18.2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
19.2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
20.2-(4-氟苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
21.2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
22.2-(4-溴苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
23.2-(4-氟苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
24.2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
25.2-(4-溴苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
26.2-(4-氟苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
27.2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
28.2-(4-溴苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
29.2-(4-氯苯基)-4-(2-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
30.2-(4-氯苯基)-4-(S-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
31.2-(4-氯苯基)-4-(R-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
32.2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
33.2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
34.2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
35.2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
36.2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
37.2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
38.2-(4-氟苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
39.2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
40.2-(4-溴苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
41.2-(4-氟苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
42.2-(4-氯苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
43.2-(4-溴苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
44.2-(4-氟苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
45.2-(4-氯苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
46.2-(4-溴苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
47.2-(4-氯苯基)-4-(2-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
48.2-(4-氯苯基)-4-(4-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
49.2-(4-氯苯基)-4-(S-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
50.2-(4-氯苯基)-4-(R-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
51.2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
52.2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
53.2-(4-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
54.2-(4-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
55.2-(4-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
56.2-(4-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
57.2-(4-氟苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
58.2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
59.2-(4-溴苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
60.2-(4-氟苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
61.2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
62.2-(4-溴苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
63.2-(4-氟苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
64.2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
65.2-(4-溴苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
66.2-(4-氯苯基)-4-(2-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
67.2-(4-氯苯基)-4-(S-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
68.2-(4-氯苯基)-4-(R-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
69.2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
70.2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
71.2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
72.2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
73.2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
74.2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
75.2-(3-氟苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
76.2-(3-氯苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
77.2-(3-溴苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
78.2-(3-氟苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
79.2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
80.2-(3-溴苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
81.2-(3-氟苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
82.2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
83.2-(3-溴苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
84.2-(3-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
85.2-(3-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
86.2-(3-氯苯基)-4-(S-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
87.2-(3-氯苯基)-4-(R-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
88.2-(3-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
89.2-(3-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
90.2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
91.2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
92.2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
93.2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
94.2-(3-氟苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
95.2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
96.2-(3-溴苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
97.2-(3-氟苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
98.2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
99.2-(3-溴苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
100.2-(3-氟苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
101.2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
102.2-(3-溴苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
103.2-(3-氯苯基)-4-(2-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
104.2-(3-氯苯基)-4-(S-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
105.2-(3-氯苯基)-4-(R-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
106.2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
107.2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
108.2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
109.2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
110.2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
111.2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
112.2-(3-氟苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
113.2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
114.2-(3-溴苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
115.2-(3-氟苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
116.2-(3-氯苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
117.2-(3-溴苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
118.2-(3-氟苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
119.2-(3-氯苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
120.2-(3-溴苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
121.2-(3-氯苯基)-4-(2-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
122.2-(3-氯苯基)-4-(4-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
123.2-(3-氯苯基)-4-(S-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
124.2-(3-氯苯基)-4-(R-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
125.2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
126.2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
127.2-(3-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
128.2-(3-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
129.2-(3-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
130.2-(3-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
131.2-(3-氟苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
132.2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
133.2-(3-溴苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
134.2-(3-氟苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
135.2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
136.2-(3-溴苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
137.2-(3-氟苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
138.2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
139.2-(3-溴苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
140.2-(3-氯苯基)-4-(2-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
141.2-(3-氯苯基)-4-(S-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
142.2-(3-氯苯基)-4-(R-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
143.2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
144.2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
145.2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
146.2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
147.2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺，和
148.2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺。
实施例6配方
通过多种途径输送的药物制备按照以下方式进行。以下所用“活性成分”或“活性化合物”意指一种或多种式I化合物。
1.肠外注射。配方：活性成分，50g；氯化钠，2250g；注射用水加至250,000ml，以制成1,000瓶。
制备：将活性成分溶解于部分注射用水中；然后搅拌加入足够量的氯化钠以使溶液等渗。调节pH至4.0-5.0。加入活性炭(250g)30min，然后使用滤棒移除之。然后用钛棒过滤直至溶液澄清，后将混合物装入250ml瓶中，随后115℃水浴灭菌30min。
2.丸剂。配方：活性成分，50g；淀粉，160g；羟丙基纤维素，39g；聚维酮K30，q.s.；羧甲基淀粉钠，10.4g；硬脂酸镁，1.3g；以制成1000颗。[0073]制备：将活性成分、淀粉和羟丙基纤维素置于流化床造粒机的料斗里，加热至38-60℃。喷洒聚维酮K30水溶液以使混合物成颗粒状。随后55-60℃干燥混合物10min，与羧甲基淀粉钠和硬脂酸镁混合压片。
3.胶囊。配方：活性成分，50g；乳糖，194.4g；羧甲基淀粉钠，7.8g；二氧化硅，5.2g；硬脂酸镁，2.6g。
制备：混合器中混合活性成分、乳糖、羧甲基淀粉钠和二氧化硅1h，随后加入硬脂酸镁，继续混合10min后填入明胶塑料壳中。
实施例7毒性，体外和体内有效性测试
使用SRB和MTT方法对一些前述化合物进行体外或体内抗癌或抗肿瘤活性测试，以及细胞毒性测试。人类癌症HT-29和鼠类肺癌细胞3LL的体外抗癌效果总结于表1，对移植至裸鼠的人类直肠癌HT-99的治疗效果总结于表2。
表1 体外抗癌细胞活性IC50(μM)
表2：移植于裸鼠的人类直肠癌HT-99的效果
注释：ip＝腹腔注射
iv：静脉注射；
GCT＝吉西他滨
以上数据显示本发明化合物具有抗癌效果，并也能够增强其它化合物如GCT、CPT-11、ADR的抗癌效果。
实施例5XC608的体外抗癌效果
材料和方法
细胞株：人类低分化胃癌BGC-823、人类肝癌QGY-7701、鼠类肺癌3LL。
DMEM细胞培养介质(GIBCO BRL)，辅以10％牛胎儿血清、L-谷氨酰胺、和抗生素
0.25％胰蛋白酶溶液(Invitrogen)
MTT溶液：使用磷酸缓冲液制成5mg/ml。
分散液：SDS 10g、异丁醇5ml、和浓硫酸0.12ml，加入至100ml二次蒸馏水。
测试化合物和制备方法用于该测试的化合物为XC608，其为白色粉末，并具有以下结构：
对照：XC302，另一种正处于临床试验的抗癌化合物。
实验细节：使用MTT方法测量XC608的细胞毒性。具体地：(1)细胞培养：(i)从液氮中移出冷冻细胞，37℃水浴快速解冻；无菌条件下加入到置于10ml离心管中的6ml DMEM培养介质中，1000rpm离心5min，移除上清液。向沉淀物中加入5-6ml DMEM介质，再次悬浮并于37℃过夜培养。(ii)离心细胞，PBS洗涤两次，37℃下3-4滴胰蛋白酶溶液处理约3分钟，显微镜下监控以确保全部细胞由培养管壁分离，再次悬浮于额外的DMEM介质中。将细胞分离至额外的培养皿中，重复上述过程以确保附着于壁上的细胞不变得过于密集且悬浮细胞保持对数增长状态。(2)测试化合物制备：XC608和XC302溶解于PBS并连续稀释至1000、100、10、1、0.1和0.01μg/ml。(3)将所制备的测试化合物溶液加入至96孔培养盘的孔中，10μl/孔，每个浓度点具有两孔，10μl PBS作对照。(4)制备对数期细胞的DMEM介质悬浮液，含10％新生牛血清，细胞浓度为2x105/ml。(5)将90μl细胞悬浮液加入至每个含测试化合物或对照物的孔中。(6)37℃下5％CO2中培养细胞48小时。(7)加入20μl的5mg/ml MTT溶液，继续培养3-4小时。(8)加入20μl分散液，过夜培养。这确保甲臜结晶完全溶解。(9)测量OD570。(10)用公式：相对细胞存活率＝(治疗组OD-背景OD)/(PBS对照组OD-背景OD)x 100％计算相对细胞存活率。
结果：结果示于下表3：
表3.X608对癌症细胞繁殖的抑制效果
实施例6.与吉西他滨结合的XC608更有效地抑制裸鼠中的人卵巢癌
目标：使用裸鼠的人类卵巢癌模型(BALB/c-nu)测定癌症治疗中与吉西他滨结合的XC608、XC608-Cl、AZD7762的效果。
实验细节
1.测试化合物和制备方法用于测试的化合物为如前所述的XC608，而XC608-Cl是XC608的氯化物盐，090208-1，同样为白色粉末。AZD7762为黄色粉末。
将上述全部物质溶于5％葡糖糖注射溶液中，稀释至适宜浓度。对照：将获自江苏Haosen Pharmaceuticals Co.，Ltd.的吉西他滨溶于适宜浓度的盐溶液中。
动物和癌症细胞株：测试动物：30只裸鼠BALB/c-nu，雌性，重18-20g，由中国上海B&K Universal Group Limited提供。癌症细胞株：商购人类卵巢细胞株，移入裸鼠，裸鼠由上海医药工业研究院供养。
测试方法：将裸鼠卵巢癌中的肿瘤分离，切成1-mm3小块，然后移至测试裸鼠的皮下。十天后，肿瘤的尺寸长至约0.1cm3。将测试小鼠随机分成每组6只的五组。
治疗组：吉西他滨25mg/kg+XC608-F 50mg/kg、吉西他滨25mg/kg+AZD776210mg/kg、和对照。
由肿瘤移植后的11天开始，对动物施用测试药物i.v.。每两天称重动物一次，并测量肿瘤体积。施用测试药物的24天后，杀死动物，取出肿瘤并称重。
测量肿瘤体积(TV)并计算。
相对肿瘤体积(RTV)为Vt/V0，其中Vt为测量时的肿瘤体积，V0为给药开始时的肿瘤体积。
以RTV生长速率T/C(％)衡量化合物的抗癌活性，其计算式为：T/C＝治疗RTC/对照组RTC x 100％。
如果TC(％)大于60，则认为治疗无效。只有当TC小于60时，且差异为统计学显著时才认为治疗有效。
另一个量度为肿瘤抑制率，其为IR(％)＝(对照组肿瘤重量-治疗组肿瘤重量)/对照组肿瘤重量x 100％。
结果：结果总结于以下两表：
表4-1.与吉西他滨结合的XC608，and XC608-Cl(i.v.)在治疗移入裸鼠的人类卵巢癌中的效果(体重)
表4-2.与吉西他滨结合的XC608，and XC608-Cl(i.v.)在治疗移入裸鼠的人类卵巢癌中的效果(肿瘤体积和重量)
注释：*p＜0.05；**p＜0.01；i.v.＝静脉注射
以上结果的图形描述示于图1。
实施例7：XC608的抗癌效果及其机制
I.概述
以下实验检验了XC608对细胞毒性抗癌药物的作用机制和敏化效果，以及其与5-氟尿嘧啶(5-Fu)和阿霉素(ADR)结合时对移入人类直肠癌和乳腺癌的裸鼠的治疗效果。
XC608的作用机制
XC608显著地抑制Chk1和Chk2的活性，但对c-met、HER2、或EGFR没有明显效果；它消除了由拓扑异构酶I引起的cdc2磷酸化、驱使具有DNA损伤的细胞进入细胞周期；并显著增加细胞对引起DNA损伤的药物的反应。这些结果综合体现了XC608为一种特定Chk1抑制剂，并通过抑制DNA修复过程而敏化其它抗癌药物。
2.XC608在细胞水平上敏化细胞毒性抗癌药物的效果
通过细胞培养评价XC608和AZD7762在一系列细胞毒性抗癌药物中的效果。对包括顺铂(DDP)、紫杉醇、培美曲塞、5-氟尿嘧啶(5-Fu)、长春瑞滨、奥沙利铂、和吉西他滨的细胞毒性抗癌药物进行研究。结果显示XC608对吉西他滨、DDP、5-Fu和培美曲塞具有强敏化效果，其中对吉西他滨的效果最强，达到大于20倍。
3.显示XC608敏化细胞毒性抗癌药物效果的动物测试
使用单独的XC608和与ADR和5-Fu结合的XC608测试移植了人类直肠癌HT-29和SW-620和乳腺癌MDA-MB-231的裸鼠。结果显示XC608在ADR和5-Fu对HT-29和SW-620的治疗效果中具有显著的敏化效果。
4.结论
XC608是一种特定Chk1抑制剂；它通过抑制DNA损伤修复而敏化癌症细胞以增强其它细胞毒性抗癌药物的效果。XC608的这种敏化效果与细胞毒性抗癌药物的种类和癌症细胞株的种类具有很强的关联性。
II.XC608的作用机制
1.概述对XC608在蛋白激酶Chk1、Chk2和c-met活性方面的效果，和在药物导致的DNA损伤后细胞进入细胞周期和细胞对DNA损伤的反应方面的效果进行研究。XC608显著抑制Chk-1和Chk-2的活性、减少由拓扑异构酶I带来的cdc-2磷酸化、并驱动细胞持续进入细胞周期。同时，XC608显著地增加细胞对DNA损伤的敏感性。这些结果显示XC608抑制了DNA损伤修复。
2.材料和方法
XC608和AZD-7762为白色粉末，批号分别为090309-2和081107。将它们溶解于DMSO，制成10mM原液。
K-LISATM Chk-1/Chk2活性盒由Calibiochem(Cat.No.CBA020)提供。Chk1和Chk2来自Upstate Biotechnology，Inc.，C-Met、HER2、EGFR来自Sigma。Chk肽(KKKVSRSGLYRSPSMPENLNRPR)(SEQ ID NO：1)来自Cell Signaling，Inc.，(Beverly，MA，USA)，并储存于-70℃。
细胞株HT29购自ATCC，37℃下用5％CO2培养于Mycoy’s 5A介质(GIBCO，Grand Island，NY，USA)中，其含10％牛血清、L-谷氨酰胺、青霉素(100IU/ml)和链霉素(100μg/ml)。
激酶活性测量：将酶、样品、Chk肽、5μm ATP、和反应缓冲液加入生物素化反应板的孔中。待用停止缓冲液将反应终止后，将内容物丢弃，用100μl/孔的丝氨酸激酶抗体替换，以探测磷酸化，加入HRP-标记的羊抗兔IgG，室温培育1小时。进行TMB反应以用适当的对照物测定物质的磷酸化。使用VERSAmax(Sunnyvale，CA，USA)测量OD450。抑制速率按下式计算：抑制速率(I)＝(反应孔OD值-无酶对照OD值)/(阴性对照OD值-无酶对照OD值)x 100％。
4.结果
4.1 XC608对蛋白激酶的效果
结果示于表5，其显示XC608对蛋白激酶具有显著的抑制效果。
表5 XC608对蛋白激酶活性的效果
III.XC608在敏化癌症细胞对细胞毒性抗癌药物反应方面的效果
1.概述
评价XC608 and AZD7762在众多细胞毒性抗癌药物上的效果。对包括顺铂(DDP)、紫杉醇、培美曲塞、5-氟尿嘧啶(5-Fu)、长春瑞滨、奥沙利铂、和吉西他滨的细胞毒性抗癌药物进行研究。结果显示XC608对吉西他滨、DDP、5-Fu和培美曲塞具有强敏化效果，其中对吉西他滨的效果最强，达到大于20倍。
2.目标
评价XC608敏化细胞对众多细胞毒性抗癌药物的反应效果，并与已知的敏化剂AZD7762作对比。
3.材料和方法
3.1测试化合物：XC608和AZD-7762为白色粉末，批号分别为090309-2和081107。
3.2细胞株：HT-29细胞株(来自ATCC)。
3.3设备/装置：McCoy’s 5a，来自Gibco BRL；牛胎儿血清，来自JRH；McCoy′s 5a，来自Gibco BRL；牛胎儿血清，来自JRH Biosciences，澳大利亚，SPECTRA MAX 190微孔板分光光度计，来自Molecular Device；SRB来自Sigma。
4.测试方案：使用黄酰罗丹明B(SRB)测量化合物对癌症细胞繁殖的效果。具体地，将对数期细胞接种至96-孔培养盘的孔中，37℃、5％CO2下利用壁粘附过程使其生长。加入9种不同浓度的测试化合物，每种浓度两份，带有适量盐水和无细胞对照。进一步培养细胞72小时，用TCA固定，加入SRB着色，洗涤，空气干燥。加入氨基丁三醇溶液之后，用Spectra Max 190在510nm处测定OD值。依照下述公式计算抑制速率：抑制速率＝(OD对照-OD药物)/OD对照x 100％。
基于上述速率计算IC50。
5.结果XCCS650(S)和AZD7762的敏化效果示于表6。与之前结果一致，XC608对吉西他滨、DDP、5-Fu和培美曲塞具有强敏化效果，其中对吉西他滨的效果最强，达到大于20倍。
表6 XC608在细胞毒性抗癌药物上的敏化效果
结论：XC-608为细胞毒性抗癌药物DDP、5-Fu、奥沙利铂、和吉西他滨而有效敏化癌症细胞。
实施例8：XC620的抗癌效果及其机制
合成一种除式I中Y＝O以外与XC608相同的化合物，并命名为XC620。依照前述过程，测试XC620在细胞毒性抗肿瘤药物上的作用机制和敏化效果、和当与5-氟尿嘧啶(5-Fu)和阿霉素(ADR)结合时对植有人类直肠癌和乳腺癌的裸鼠的治疗效果。结果显示XC620也显著地抑制Chk1和Chk2的活性，是一种特定Chk1抑制剂，并通过抑制DNA修复过程而敏化其它抗癌药物。
XC620在细胞水平上敏化细胞毒性抗癌药物的效果与XC608相类似。它具有相似的效果，虽然不是一样有效，对为包括顺铂(DDP)、紫杉醇、培美曲塞、5-氟尿嘧啶(5-Fu)、长春瑞滨、奥沙利铂、和吉西他滨的细胞毒性抗肿瘤药物而敏化肿瘤细胞株进行研究。
因此，XC620也是一种特定Chk1抑制剂；它通过抑制DNA损伤修复而敏化癌症细胞以增强其它细胞毒性抗癌药物的效果。
实施例9：XC655的抗癌效果及其机制
合成一种除式I中Y＝S以外与XC608相同的化合物，并命名为XC620。依照前述过程，测试XC655在细胞毒性抗肿瘤药物上的作用机制和敏化效果、和当与5-氟尿嘧啶(5-Fu)和阿霉素(ADR)结合时对植有人类直肠癌和乳腺癌的裸鼠的治疗效果。结果显示XC655也显著地抑制Chk1和Chk2的活性，是一种特定Chk1抑制剂，并通过抑制DNA修复过程而敏化其它抗癌药物。
XC655在细胞水平上敏化细胞毒性抗癌药物的效果与XC608相类似。它具有相似的效果，虽然不是一样有效，对为包括顺铂(DDP)、紫杉醇、培美曲塞、5-氟尿嘧啶(5-Fu)、长春瑞滨、奥沙利铂、和吉西他滨的细胞毒性抗肿瘤药物而敏化肿瘤细胞株进行研究。
因此，XC650也是一种特定Chk1抑制剂；它通过抑制DNA损伤修复而敏化癌症细胞以增强其它细胞毒性抗癌药物的效果。
前述描述和实施例仅是为了阐明本发明，而并不意图限制本发明。既然本领域技术人员可结合本发明的精神和主旨而对所公开的实施方案进行修改，本发明应当被宽泛的解释为包括全部落入后述权利要求书及其等价物范围之内的变形。本文前述和/或下述的全部参考文献在此明确作为参考引入。
Claims (7)
1.式I化合物：
其中
Y＝NH、O、或S，
R1＝选自以下基团：
其中X＝CH2、NH、S、或O，
R8＝-H、-NH2、-OH、-N(R4R5)、-C(R4R5)1-7NR6R7、-C(R4R5)1-7OR6、或-N(R4)NR5R6，
其中R4、R5、R6、R7＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、和N的环烷基(C3-C8)、芳基(未取代或取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，
R9、R10、R11、R12、和R13＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S或N的环烷基(C3-C8)；芳基(未取代或取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，
R2选自H、OH、NH2、OR14、NR14R15、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、和炔基，
其中R14、R15＝H、烷基(C1-C6)、具有或不具有核心杂原子如O、S、N的环烷基(C3-C8)、芳基(未取代或取代的芳香物)、或杂芳基(未取代或取代的杂芳物)，和
R3选自H、烷基、芳基、杂芳基、环烷基、芳基烷基、杂环基、杂环基烷基、烯基、和炔基。优选地，R3选自以下基团：
其中R16、R17、和R18选自以下基团：H；杂原子如F、Cl、Br、I；烷基(C1-C8)；未取代或取代的环烷基(C3-C8)，其中取代基选自烷基(C1-C8)、环烷基(C3-C8)、芳基、杂芳基；-OR19；-SR19；-NR19R20；-S(O)R19；-S(O)2R19；-S(O)2NR19R20；-C(O)NR19R20；-N(R19)C(O)R20；-N(R19)S(O)2R20；-N(R19)C(O)N(R20R21)；N(R19)C(O)OR20；取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的芳基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基；取代或未取代的烯基、和取代或未取代的炔基；
其中R19、R20、和R21独立地选自H、烷基(C1-C8)、环烷基(C3-C8)、取代或未取代的芳基、取代或未取代的烷基芳基、取代或未取代的杂芳基，
或R16、R17、和R21可为含0-3个选自N、O、和S的杂原子的稠环的一部分。
2.权利要求1的化合物，其中Y＝N。
3.权利要求1的化合物，其中Y＝S。
4.权利要求1的化合物，其中Y＝O。
5.权利要求1的化合物，选自：
2-(4-氟苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(S-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(R-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氟苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(2-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(S-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(R-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氟苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(2-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(4-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(S-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(R-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氟苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氟苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-溴苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(2-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(S-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(R-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(4-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氟苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-哌啶氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(2-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(S-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(R-3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-哌啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氟苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(2-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(S-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(R-3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-四氢呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氟苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-α-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-α-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(2-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(4-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(S-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(R-3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-吡啶-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-噻喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-吡喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氟苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氟苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-溴苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(2-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(S-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(R-3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-羧酸酰胺
2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-吡咯-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-噻吩-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺
2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N-甲基-羧酸酰胺，和
2-(3-氯苯基)-4-(3-呋喃-氨基)-噻吩[2，3-d]哒嗪-7-N，N-二甲基-羧酸酰胺。
6.一种药物组合物，包含治疗有效量的权利要求1化合物和药学上可接受的赋形剂。
7.一种治疗癌症的方法，包括向有需要的患者施用治疗有效量的权利要求5的药物组合物。
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| PCT/US2010/049199 WO2011035077A1 (en) | 2009-09-18 | 2010-09-17 | Novel compounds and therapeutic use thereof for protein kinase inhibition |
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| CN201410809035.XA Pending CN104628741A (zh) | 2009-09-18 | 2010-09-17 | 新颖化合物及其用于抑制蛋白激酶的治疗用途 |
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| ES (2) | ES2587509T3 (zh) |
| HK (1) | HK1170908A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115605484A (zh) * | 2020-04-17 | 2023-01-13 | 浙江医药股份有限公司新昌制药厂（Cn） | 一种噻吩并哒嗪类化合物的晶型及其制备方法和应用 |
| WO2023116763A1 (zh) * | 2021-12-23 | 2023-06-29 | 上海优理惠生医药有限公司 | 一种哒嗪类化合物、其药物组合物及应用 |
| WO2023241414A1 (zh) * | 2022-06-13 | 2023-12-21 | 上海优理惠生医药有限公司 | 一种哒嗪类化合物、其药物组合物及应用 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2587509T3 (es) * | 2009-09-18 | 2016-10-25 | Zhanggui Wu | Derivados de tieno[2,3-d]piridazina y uso terapéutico de los mismos para la inhibición de proteína cinasa |
| WO2015013579A1 (en) | 2013-07-26 | 2015-01-29 | Update Pharma Inc. | Compositions to improve the therapeutic benefit of bisantrene |
| AU2021206201A1 (en) * | 2020-01-07 | 2022-08-18 | Shanghai Huayu Biotechnology Co., Ltd. | Combination cancer therapy using CHK inhibitor |
| WO2021177728A1 (ko) * | 2020-03-04 | 2021-09-10 | (주)파로스아이바이오 | 2,3,5-치환된 싸이오펜 화합물의 난소암 예방, 개선 또는 치료 용도 |
| CN117003736B (zh) * | 2023-10-07 | 2023-12-15 | 天津匠新致成科技有限公司 | 3-氨基吡嗪-2-甲酰胺类靶向蛋白水解嵌合体及其制备方法、药物组合物和应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189243A (zh) * | 2005-04-06 | 2008-05-28 | 阿斯利康(瑞典)有限公司 | 取代的杂环及其作为chk1、pdk1和pak抑制剂的应用 |
| CN101481380A (zh) * | 2008-01-08 | 2009-07-15 | 浙江医药股份有限公司新昌制药厂 | 噻吩并哒嗪类化合物及其制备方法、药物组合物及其用途 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003029241A1 (en) | 2001-10-04 | 2003-04-10 | Smithkline Beecham Corporation | Chk1 kinase inhibitors |
| WO2003028731A1 (en) | 2001-10-04 | 2003-04-10 | Smithkline Beecham Corporation | Chk1 kinase inhibitors |
| CA2502429A1 (en) * | 2002-10-31 | 2004-05-21 | Amgen Inc. | Antiinflammation agents |
| CN100584840C (zh) * | 2004-01-05 | 2010-01-27 | 阿斯利康(瑞典)有限公司 | 取代杂环化合物及其应用 |
| JP2007536303A (ja) * | 2004-05-04 | 2007-12-13 | エフ．ホフマン−ラ ロシュ アーゲー | Ｉｋｋ阻害剤としてのチエノピリジン |
| CA2563990A1 (en) | 2004-05-04 | 2005-11-10 | Sharada Shenvi Labadie | Thienopyridazines as ikk inhibitors |
| KR20080009200A (ko) * | 2005-04-06 | 2008-01-25 | 아스트라제네카 아베 | 치환된 헤테로사이클 및 이것의 ｃｈｋ1, ｐｄｋ1 및ｐａｋ 억제제로서의 용도 |
| EP2038289A2 (en) * | 2006-04-21 | 2009-03-25 | Amgen Inc. | Thieno-[2,3-d]pyrimidine and thieno-pyridazine compounds and methods of use |
| KR20090027754A (ko) | 2006-07-03 | 2009-03-17 | 코닌클리케 필립스 일렉트로닉스 엔.브이. | 신선도 표시기를 갖는 음료 분배장치 |
| ES2587509T3 (es) * | 2009-09-18 | 2016-10-25 | Zhanggui Wu | Derivados de tieno[2,3-d]piridazina y uso terapéutico de los mismos para la inhibición de proteína cinasa |
-
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-
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- 2016-07-12 AU AU2016204867A patent/AU2016204867B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189243A (zh) * | 2005-04-06 | 2008-05-28 | 阿斯利康(瑞典)有限公司 | 取代的杂环及其作为chk1、pdk1和pak抑制剂的应用 |
| CN101481380A (zh) * | 2008-01-08 | 2009-07-15 | 浙江医药股份有限公司新昌制药厂 | 噻吩并哒嗪类化合物及其制备方法、药物组合物及其用途 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115605484A (zh) * | 2020-04-17 | 2023-01-13 | 浙江医药股份有限公司新昌制药厂（Cn） | 一种噻吩并哒嗪类化合物的晶型及其制备方法和应用 |
| WO2023116763A1 (zh) * | 2021-12-23 | 2023-06-29 | 上海优理惠生医药有限公司 | 一种哒嗪类化合物、其药物组合物及应用 |
| WO2023241414A1 (zh) * | 2022-06-13 | 2023-12-21 | 上海优理惠生医药有限公司 | 一种哒嗪类化合物、其药物组合物及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102711475B (zh) | 2015-01-28 |
| CA2774367C (en) | 2018-07-10 |
| AU2010295492B2 (en) | 2016-05-05 |
| JP6155026B2 (ja) | 2017-06-28 |
| MX2012003286A (es) | 2012-06-19 |
| EP2477496A4 (en) | 2013-02-27 |
| JP2013505254A (ja) | 2013-02-14 |
| AU2016204867B2 (en) | 2017-02-16 |
| US9487539B2 (en) | 2016-11-08 |
| US20150072987A1 (en) | 2015-03-12 |
| AU2016204867A1 (en) | 2016-07-28 |
| NZ599453A (en) | 2014-03-28 |
| US8815863B2 (en) | 2014-08-26 |
| IN2012DN03127A (zh) | 2015-09-18 |
| EP2477496A1 (en) | 2012-07-25 |
| AU2010295492A1 (en) | 2012-05-03 |
| EP2826780A1 (en) | 2015-01-21 |
| BR112012006062A2 (pt) | 2015-09-08 |
| RU2012109220A (ru) | 2013-10-27 |
| ES2587509T3 (es) | 2016-10-25 |
| HK1170908A1 (zh) | 2013-03-15 |
| US20120232082A1 (en) | 2012-09-13 |
| EP2826780B1 (en) | 2016-06-01 |
| CA2774367A1 (en) | 2011-03-24 |
| EP2477496B1 (en) | 2014-04-16 |
| WO2011035077A1 (en) | 2011-03-24 |
| ES2481791T3 (es) | 2014-07-31 |
| CN104628741A (zh) | 2015-05-20 |
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