CN109081828A - 聚（adp-核糖）聚合酶抑制剂、制备方法及用途 - Google Patents
聚（adp-核糖）聚合酶抑制剂、制备方法及用途 Download PDFInfo
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- CN109081828A CN109081828A CN201710454485.5A CN201710454485A CN109081828A CN 109081828 A CN109081828 A CN 109081828A CN 201710454485 A CN201710454485 A CN 201710454485A CN 109081828 A CN109081828 A CN 109081828A
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- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
本发明涉及一类如下通式I所示的化合物及其药学上可接受的盐、异构体、溶剂化物、多晶型物、稳定的同位素衍生物或前药、其制备方法及在药学上的应用，其中各基团的定义如说明书所述。本发明的化合物是聚(ADP‑核糖)聚合酶(poly(ADP‑ribose)polymerase，PARP)抑制剂，可用于治疗与PARP相关的疾病，如癌症、炎症疾病等。
Description
技术领域
本发明涉及一种具有聚(ADP-核糖)聚合酶(PARP)抑制活性的化合物、及其异构体、前药或药学可接受的盐、稳定的同位素衍生物、药物组合物、制备方法和治疗相关疾病的用途。
背景技术
聚腺苷二磷酸核糖聚合酶(poly(ADP-ribose)polymerase，PARP)是真核生物细胞中的一类核酶，涉及多种细胞过程，如与DNA损伤修复、基因组稳定性和程序性细胞死亡等密切相关，于1963年首次被报道，PARP家族至少含有18种亚型，它们具有不同的结构和细胞功能，包括PARP-1、PARP-2、PARP-4、Tankyrase-1和2和其它PARP-3～16。PARP由四个结构域组成，包括DNA结合域、半胱天冬酶切域、自身修饰域和催化域。其中PARP-1最先被发现，尽管PARP-1和PARP-2结构相似，但是DNA损伤修复的过程大部分是由PARP-1来完成，所以PARP抑制剂药物研究主要集中于PARP-1抑制剂上。
多种类型的癌症细胞比常规细胞更加依赖于PARP，使得PARP抑制剂药物成为癌症治疗中最为吸引力的靶标。PARP-1抑制剂可以作为增敏剂来提高抗癌药物的疗效，化疗或放疗药物是通过破坏肿瘤细胞的DNA的结构来抑制或杀死细胞，而肿瘤细胞可以通过PARP-1对受损的DNA细胞进行修复，从而对化疗药物产生耐药性，所以PARP-1抑制剂药物可以联合化疗药物来应对耐药性，从而可以降低药量和提高疗效的效果。另外研究表明单独使用PARP-1抑制剂可以杀死DNA修复缺陷型癌细胞，特别是BRCA-1/2缺失或者突变型癌细胞。
基于多年来对PARP抑制剂的研究，目前PARP-1抑制剂已经成为癌症药物研发的热点之一，而且已经证实该靶点的可靠和可行性。阿斯利康公司的奥拉帕利(Olaparib)，商品名Lynparza，于2014年先后被EMA和FDA批准，用于BRCA基因突变相关的晚期卵巢癌化疗后的单药治疗。随后辉瑞的Rucaparib和Tesaro的Niraparib相继被FDA批准上市用于化疗后的患者治疗，除此之外其它在研药物如Talazoparib、Veliparib等都处于临床实验阶段。近期这些研究结果也证实了PARP抑制剂用于BRCA基因缺失或者突变相关的癌症的治疗方面具有巨大优势。
发明内容
本发明的目的是提供一类PARP抑制活性的化合物，其制备方法和用途。
第一方面，本发明涉及一种如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药；
式中，
Ra选自氢、氘、氟、取代或未取代的C1-6烷基、取代或未取代的环烷基；
Rb选自氢、氘、取代或未取代的C1-6烷基、取代或未取代的环烷基；
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自氢、氘或氟，且当Ra为氢时，R1、R2、R3、R4、R5、R6、R7、R8和R9中至少有一个为氘或氟，其中且当R9为5位氟或者R7为氟时，R1、R2、R3、R4、R5、R6和R8中至少有一个为氘或氟；
m为R7的数目，且为0、1、2、3或4；
n为R9的数目，且为0、1、2或3。
在本发明的一个优选例中，Rb为氢或氘。
在本发明的一个优选例中，通式I具有以下结构式：
其中Ra选自氘、氟、取代或未取代的C1-6烷基，R7、R8、R9、m和n的定义如权利要求1中所定义。
在本发明的一个优选例中，通式I具有以下结构式：
其中R1、R2、R3、R4、R5和R6至少含有一个氘或氟，其它R7、R8、R9、m和n的定义如权利要求1中所定义。
在本发明的一个优选例中，通式I具有以下结构式：
其中Ra优先选自氘、氟、取代或未取代的C1-6烷基。
在本发明的一个优选例中，所述化合物具有如下结构：
第二方面，本发明还提供一种制备通式I所示的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药的方法，该方法包括：
a1)通式I-A与通式I-B化合物在碱性和金属催化剂条件下进行偶联反应得到中间体通式I-C化合物；和
b1)中间体I-C在酸性条件下脱去保护基得到式I化合物；
其中X为卤素，R0为胺基保护基，其它基团Ra、Rb、R1、R2、R3、R4、R5、R6、R7、R8、m和n的定义如权利要求1中所定义。
提供的碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、二异丙基氨基锂、正丁基锂、仲丁基锂、三乙胺、吡啶、2，6-二甲基吡啶、N，N-二异丙基乙基胺、叔丁醇钾、叔丁醇钠、叔丁醇锂、四丁基氟化铵或N-甲基吗啡啉等。所述的无机碱类包括但不限于碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、氟化铯、碳酸铯、碳酸锂、磷酸钾、氢化钠或氢化钾等。
金属催化剂包括但不限于碘化亚铜、溴化亚铜、氯化亚铜、铜粉、氧化亚铜、氧化铜、溴化铜、氯化铜、醋酸铜、醋酸亚铜、三氟醋酸铜、三氟磺酸铜、三氯化铁等。
提供的酸性条件的试剂包括有机酸和无机酸类，所述的有机酸类包括但不限于三氟乙酸、三氟甲磺酸、对甲苯磺酸、苯磺酸、三氯乙酸、甲酸、乙酸、草酸等。所述的无机酸类包括但不限于盐酸、硫酸、磺酸、磷酸、偏磷酸等。
金属催化剂包括但不限于碘化亚铜、溴化亚铜、氯化亚铜、铜粉、氧化亚铜、氧化铜、溴化铜、氯化铜、醋酸铜、醋酸亚铜、三氟醋酸铜、三氟磺酸铜、三氯化铁等。
第三方面，本发明涉及一种药物组合物，所述的药物组合物包括有效量的根据权利要求1所述的通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂；
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备用于预防、缓解和/或治疗可通过PARP抑制剂减轻疾病的药物中的应用。
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药可用于制备用于预防、缓解和/或治疗癌症、炎症性疾病、血管疾病、中风、肾衰竭、糖尿病、帕金森氏病、感染性休克、神经毒性、缺血性休克或损伤、移植排斥、再灌注损伤、视网膜损伤、UV-诱导的皮肤损伤、病毒感染或多发性硬化症的药物。
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药可用于制备癌症治疗中的辅助药物或者用于强化放疗和/或化疗对癌症的治疗药物。
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备治疗癌症中的药物用途，其中所述的癌症包括乳腺癌、卵巢癌、前列腺癌、黑色素癌、脑瘤(例如神经胶质瘤)、鼻咽癌、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如小细胞肺癌、非小细胞肺癌、鳞形细胞癌、末分化癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨癌、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫瘤(例如子宫颈癌、子宫内膜癌等)、头颈肿瘤(例如喉癌、咽癌、舌癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、篱淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如成神经细胞瘤、胚胎睾丸癌、视网膜母细胞瘤等)。
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备治疗癌症中的药物用途，其中所述的癌症可选自实体瘤、急性或慢性白血病、淋巴瘤、中枢神经系统癌症、脑癌、血源性癌症、腹膜癌、胃癌、肺癌、缺乏同源重组依赖性DNA双链断裂修复活性的癌症、BRCA-1或BRCA2上缺陷性或突变表型的癌症(如乳腺癌、卵巢癌、前列腺癌和胰腺癌)。
本发明进一步涉及通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药可以与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂类药物、拓扑异构酶抑制剂、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗、PD-L1单抗等。
本发明进一步涉及通式(I)或(II)的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备治疗癌症中的药物用途，其中所述的药物可以与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂(环磷酰胺、盐酸氮芥、二溴甘露醇、卡莫司汀、达卡巴嗪、美法仑等)、铂类药物(例如顺铂、卡铂、环硫铂、奈达铂、奥沙利铂、洛铂等)、拓扑异构酶抑制剂(拓扑替康、伊力替康、卢比替康、伊沙替康、勒托替康、吉马替康、二氟替康)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、卡培他滨、培美曲塞等)、生物碱(例如多西他赛、紫杉醇、长春碱等)、抗体药物(曲妥单抗、帕曲妥单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、度他雄胺、地塞米松等)、蛋白酶体抑制剂(硼砂佐米、艾莎佐米、来那度胺等)、CDK激酶抑制剂(palbociclib、ribociclib等)、VEGFR或EGFR抑制剂(阿法替尼、伊马替尼、吉非替尼、厄洛替尼等)、m-TOR抑制剂(依维莫司、西罗莫司等)、PI3K激酶抑制剂(艾拉利司等)、B-Raf抑制剂(索拉菲尼、维罗菲尼、瑞伐菲尼等)、其它PARP抑制剂(olaparib、niraparib等)、HDAC抑制剂(西达苯胺、帕比司他、伏立诺他等)c-Met激酶抑制剂(克唑替尼)、ALK激酶抑制剂(色瑞替尼、阿来替尼等)、AKT抑制剂(哌立福新等)、ABL抑制剂、FLT3抑制剂、PD-1单抗(Opdivo、Keytruda等)、PD-L1单抗(Atezolizumab)等。
发明详述
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义：
术语“烷基”是指饱和的脂肪族烃基团，包括1～20个碳原子的直链或支链基团。优选1～10个碳原子的烷基，更优选1～8个碳原子，非限制实施例包括但不限于：甲基、乙基、正丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、2-甲基丁基、3-甲基丁基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、正己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、3，3-二甲基丁基、1，1，2-三甲基丙基、1-乙基-2-甲基丙基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，2-二甲基戊基、2，3-二甲基戊基、2，4-二甲基戊基、3，3-二甲基戊基、3，4-二甲基戊基、2-乙基戊基、3-乙基戊基、幸基、壬基、癸基、十一烷基、十二烷基，以及它们的各种异构体等。烷基可以是取代的或未取代的，当被取代时可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。当“烷基”和其前缀在此处使用，都包含直链和支链的饱和碳键。
术语“环烷基”是指饱和或部分不饱和单环或多环环状取代基，包括3～20个碳原子，优选3～12个碳原子，更优选3～10个碳原子，最优选包括3～6个碳原子，单环环烷基的非限制实施例包括但不限于：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基等。多环环烷基的非限制实施例包括但不限于螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。
术语“卤素”是指氟、氯、溴或碘，优选溴或碘。
“取代的”是指基团中的一个或多个氢或氘原子，优选为1～5个氢或氘原子彼此独立地被相应数目的取代基所取代。
“药学上可接受的盐”是指能够保留游离碱的生物有效性而无其它毒副作用的，它可以是酸性基团、碱性基团或两性基团，非限制实施例包括但不限于：酸性盐包括盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、(D，L)-酒石酸、柠檬酸盐、马来-酸盐、(D，L-)苹果酸盐、富马酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、谷氨酸盐、天冬氨酸盐、三氟甲磺酸盐、扁桃体酸盐、抗败血酸盐、水杨酸盐等。当本发明化合物含有酸性基团是，其药学上可接受的盐还可以包括：碱金属盐(例如钠盐或钾盐)、碱士金属盐(例如钙盐或镁盐)、有机碱盐(例如烷基芳香基氨类、氨基酸等)。
“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的聚集体(或缔合物)。形成的溶剂化物的溶剂包括，但不限于：水、二甲亚砜、甲醇、乙醇、异丙醇、乙酸等。
“多晶型物”是指本发明的化合物在固态状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相，它可以存在单一晶型或多晶型混合物。
“稳定的同位素衍生物”是指本发明的化合物任意的氢原子被1～5氘原子取代所得到的同位素取代衍生物、或任意的碳原子被1～3个C14原子取代所得到的同位素取代衍生物、或任意的氧原子被1～3个O18原子取代所得到的同位素衍生物。
“前药”表示可在生理学条件下(例如体内)或通过溶剂分解而被转化成本发明的生物活性化合物的化合物，可以理解为药学上可接受的代谢前体。前药可以为非活性物质或者比活性母体化合物活性小，但是可以在体内迅速转化产生本发明的母体化合物，可以改善其在动物体内的溶解度以及某些代谢特性，前药包括例如氨基保护基、羧基保护基、磷脂类等。
“药物组合物”是指含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其它化学组分的混合物，以及其它组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收而发挥生物活性。
“异构体”是指立体异构体，包括：对映异构体和非对映异构体，顺反异构体是非对映异构体的一种。本分明的化合物中的异构体可以是其对映异构体、非对映异构体以及它们的任意混合物，包括游离或成盐的形成存在。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参考IUPAC-IUBC Commission on BiochemicalNomenclature(参见Biochem.1972，11，942-944)。
具体实施方式
下面通过实施例进一步描述本说明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规方法和条件，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。
本发明所有化合物的结构可通过核磁共振(NMR)或质谱(MS)来确定。NMR位移(δ)以10-6(ppm)的单位记录。NMR的测定仪器是Bruker AVANCE-400光谱仪进行。测试的氘代溶剂为氘代氯仿(CDCl3)、氘代甲醇(MeOD)、氘代二甲基亚砜(DMSO-D6)，内标为四甲基硅烷(TMS)。
低分辨率质谱(MS)是由Agilent 6120quadruple LCMS质谱仪测定。
HPLC纯度的测定是由安捷伦高效液相色谱仪Agilent 1260/1220色谱仪(AgilentZorbax Bonus RP 3.5μm×4.6mm×150mm或Boston pHlex ODS 4.6mm×150mm×3μm)。
本发明化合物及其中间体的纯化可以使用常规的制备级HPLC、硅胶板、柱色谱或使用快速分离仪进行分离纯化。
薄层层析硅胶板使用烟台黄海、烟台新诺化工的HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是2.5x 5cm，0.2mm～0.25mm，薄层层析分离法(pre-TLC)纯化产品采用的的规格是1mm或者0.4mm～0.5mm，20x 20cm。
柱色谱(硅胶柱层析)一般使用的规格是100～200目或200～300目或300～400目。
快速分离仪使用的仪器型号是Agela Technologies MP200，色谱柱规格一般为Flash column silica-CS(12g～330g)。
制备级HPLC(Pre-HPLC)使用的仪器是Gilson GX-281，柱子型号：Welch ultimateXB-C18 21.2mm X 250mm X 10μm。
手性测试柱的型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 4.6mm X250mm X 5μm，制备柱型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 10mm X250mm X 5μm，
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或从供应商sigma-Aldrich、ACROS、Alaf、TCI、百灵威、安耐吉化学、韶远化学、麦克林、思言化学等公司购买所得。
无水溶剂例如无水四氢呋喃、无水二氯甲烷、无水N，N-二甲基乙酰胺等都购自上述化学公司。
实施例中无特殊说明，反应一般是在氮气或氩气氛围中进行，氮气或氩气氛围是指反应瓶连接一个约1L容积大小的氮气或者氩气的气球并进行三次抽气置换。
实施例中无特殊说明，反应的温度为室温，温度为15～25℃。
实施例中的反应一般采用LCMS或者TLC进行监测，其中LCMS仪器见上所述，TLC所使用的展开剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或37％的氨水等)或酸(例如醋酸等)进行调节。
纯化化合物采用的prep-TLC、柱层析或者Agela制备体系，洗脱溶剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或37％的氨水等)或酸(例如醋酸等)进行调节。
实施例1：
2-(4-(3-氘哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
第一步：乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯
室温下，将2-(4-溴苯基)乙酸乙酯(24.3g，0.1mol)溶于DMSO(60mL)中，分批加入60％NaH(4.3g，0.107mol)，加料完毕，搅拌20分钟，滴加(3-溴丙基)氨基甲酸叔丁酯(21.4g，0.09mol)的DMSO(60mL)溶液，滴加完毕，加热至40～45℃，并搅拌反应2小时，TLC显示有新物质生成，仍有少量原料(TLC条件：EA∶PE＝1∶10)向反应体系中加入100mL氯化铵溶液，对其进行淬灭，乙酸乙酯萃取(300mL+100mL)，有机相干燥浓缩得粗品37.0g，将上述粗品混合100～200目硅胶进行柱层析(洗脱条件：石油醚梯度洗脱至乙酸乙酯∶石油醚1∶4)，得中间体乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯为油状物18.0g，收率45％。
MS(ESI)，m/z，300.0[M-100]+
1H NMR(400MHz，CDCl3)δ(ppm)7.48-7.43(m，2H)，7.22-7.17(m，2H)，4.52(s，1H)，4.13(dd，J＝13.6，7.1Hz，2H)，3.52(s，1H)，3.13(s，2H)，2.07(s，1H)，1.87-1.73(m，1H)，1.47-1.37(m，4H)，1.22(t，J＝7.1Hz，3H).
第二步：3-(4-溴苯基)哌啶-2-酮
向乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯(45.0g，0.11mol)的200mL乙醇中滴加2M的盐酸乙醇溶液(200mL)，滴加完毕，搅拌反应30分钟，LC-MS显示原料消失，浓缩，将获得残留物混合碳酸钾(23.0g，0.15mol)，于乙醇(500mL)中加热回流18h，LC-MS显示原料消失，浓缩掉大部分乙醇，残留物混合200mL水，用6N的盐酸调节pH至1～2，用乙酸乙酯萃取(500mL×2)，干燥，浓缩，残留物用石油醚打浆得白色固体，真空干燥得3-(4-溴苯基)哌啶-2-酮，23.7g，收率：83％。
MS(ESI)，m/z，254.0[M+H]+
1H NMR(400MHz，MeOD)δ(ppm)7.53-7.42(m，2H)，7.23-7.13(m，2H)，3.64(dd，J＝8.2，6.2Hz，1H)，3.49-3.35(m，2H)，2.19(tdd，J＝8.7，6.1，2.6Hz，1H)，1.96-1.75(m，3H).
第三步：3-(4-溴苯基)-3-氘代哌啶-2-酮
将3-(4-溴苯基)哌啶-2-酮(7.6g，30mmol)混于氘代甲醇(100g)中，氮气保护下，加热至40～45℃，加入甲醇钠(3.2g，60mmol)，并在40～45℃下反应16h，LCMS检测显示氘代率90％，将反应液冷却至20～25℃，加入100mL氯化铵溶液淬灭，用乙酸乙酯(100mL×2)萃取，干燥，浓缩得粗品，用石油醚打浆过滤得白色固体为3-(4-溴苯基)-3-氘代哌啶-2-酮7.0g，收率92％，LCMS分析氘代率92％，核磁显示氘代率94％。
MS(ESI)，m/z，255.0[M+H]+
1H NMR(400MHz，MeOD)δ(pp)7.46(d，J＝8.4Hz，2H)，7.15(d，J＝8.4Hz，2H)，3.65-3.57(m，0H)，3.38(dd，J＝12.6，7.0Hz，2H)，2.15(d，J＝3.6Hz，1H)，1.97-1.70(m，3H).
第四步：3-(4-溴苯基)-3-氘代哌啶
将3-(4-溴苯基)-3-氘代哌啶-2-酮(7.0g，27.5mmol)溶于四氢呋喃(140mL)中，冷却至0～5℃，分批加入硼氢化钠(3.15g，82.9mmol)，并搅拌反应30分钟，加入乙醇，并搅拌反应30分钟，滴加三氟化硼乙醚(11.7g，82.9mmol)，滴加完毕，自然升温至20～25℃，并搅拌反应18h，LCMS显示大部分原料消失，将反应液用100mL水淬灭，乙酸乙酯(200mL×2)萃取，有机相浓缩干，残留物混合30mL浓盐酸和60mL甲醇，40～45℃下反应30分钟，反应液加水稀释，再用2N NaOH水溶液中和至pH至8～9，乙酸乙酯萃取，干燥浓缩得粗品3-(4-溴苯基)-3-氘代哌啶，6.0g，收率90％。
MS(ESI)，m/z，241.0[M+H]+
第五步：3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯
20～25℃，将3-(4-溴苯基)-3-氘代哌啶(1.1g，3.3mmol)、1N NaOH(10mL)的MTBE(20mL)溶液中，加入Boc2O(0.73g，3.3mmol)，加料完毕搅拌1h，加入50mL MTBE，收集有机相，干燥，浓缩得粗品3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯1.22g，收率95％。
MS(ESI)，m/z，241.0[M+H]+
第六步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯
20～25℃，将3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯(1.0g，3mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(0.65g，3mmol)、碳酸钾(1.2g，9mmol)、溴化亚铜(0.1g，0.7mmol)和8-羟基喹啉(0.1g，0.68mmol)混于DMAc(30mL)中，置换氮气保护，110～120℃搅拌反应18h，LCMS显示有部分的原料剩余，有产物生成，反应液冷却至室温，加入50mL水淬灭，MTBE(200mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯，1.6g，直接用于下一步。
第七步：2-(4-(3-氘代哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯混于甲苯(3mL)中，室温加入甲烷磺酸(6mL)，加料完毕，升温至40～45℃，搅拌反应30分钟，LCMS显示原料消失，有产物生成，加水稀释，用2N NaOH水溶液中和pH至8～9，乙酸乙酯(100mL×2)萃取，干燥浓缩得粗品1.1g，上述粗品通过HPLC分离获得制备液，制备分离液约400mL，用1N NaOH中和pH至8～9，再用乙酸乙酯(400ml×2)萃取，干燥浓缩得粗品2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺114mg。上述粗品可与64mg对甲苯磺酸在乙醇中加热至完全溶解，浓缩掉乙醇，残留物用四氢呋喃打浆，过滤，干燥得对甲苯磺酸盐产品110mg。
MS(ESI)，m/z，322.2[M+H]+
1H NMR(400MHz，MeOD)δ(ppm)9.00(s，1H)，8.18(dd，J＝7.0，0.8Hz，1H)，8.05(t，J＝9.1Hz，3H)，7.74(d，J＝8.2Hz，2H)，7.53(d，J＝8.6Hz，2H)，7.34-7.17(m，3H)，3.48(d，J＝12.3Hz，2H)，3.22-3.01(m，2H)，2.37(s，3H)，2.09(d，J＝10.1Hz，2H)，1.99-1.80(m，2H).
实施例2和3：
(R或S)-2-(4-(3-氘代哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
将上述消旋体化合物用手性柱CHIRALPAK AS-H(10mm x 250mm，5μm)进行拆分分离，得到第一个单一构型化合物(实施例2，RT 5.8min，ee＞99％)和第二个单一构型化合物(实施例3，RT 7.7min，ee＞99％)
实施例4-21：
按照实施例1～3的合成方法并采用相应的起始原料，制备得到实施例4～21的化合物如下表格：
实施例22：
2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
第一步：3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯
20～25℃条件下将1-溴-4-碘苯(29.0g，0.10mol)溶于无水四氢呋喃(500mL)中，氮气保护下冷却至-78℃，向反应体系中滴加2.5M正丁基锂溶液(45mL)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌15分钟，继续向反应体系中滴加3-氧代哌啶-1-甲酸叔丁酯的四氢呋喃溶液(19.5g，50mL THF)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌30分钟，TLC显示原料1-溴-4-碘苯基本消失(EA∶PE＝1∶4，254nm)，向反应体系中加入100mLaq.NH4Cl淬灭，乙酸乙酯萃取(300mL×2)，有机相水洗干燥浓缩得粗品35g，柱层析得3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯，19.0g产品，yield，51.9％(柱分离条件：石油醚洗脱至EA∶PE＝1∶4)。
MS(ESI)，m/z，283.0[M-72]+
第二步：3-(4-溴苯基)-3-氟哌啶-1-甲酸叔丁酯
20～25℃条件下将3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯(26.0g，0.074mol)溶于无水二氯甲烷(500mL)中，氮气保护下冷却至-78℃，向反应体系中滴加DAST(57.0g，0.353mol)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌2小时，LC-MS显示原料消失，向反应体系中加入100mL水淬灭，用2M aq.NaOH调节pH至7～8，收集有机相，水相再用二氯甲烷(300mL)萃取，合并有机相，有机相水洗干燥浓缩得粗品21.5g，柱层析得产品3-(4-溴苯基)-3-氟哌啶-1-甲酸叔丁酯，12.5g，yield，47.8％(柱分离条件：石油醚洗脱至EA∶PE＝1∶10)。
MS(ESI)，m/z，283.0[M-74]+
1H NMR(400MHz，CDCl3)δ(ppm)7.52(t，J＝10.4Hz，2H)，7.32-7.24(m，2H)，4.17(dd，J＝23.5，16.4Hz，2H)，3.35-2.69(m，2H)，2.27-1.86(m，3H)，1.57-1.33(m，9H).
第三步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯
20～25℃条件下将3-(4-溴苯基)-3-氟哌啶-2-酮(2.45g，6.8mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(1.5g，6.8mmol)、碳酸钾(2.95g，20.5mmol)、溴化亚铜(0.2g，1.5mmol)和8-羟基喹啉(0.2g，1.36mmol)混于DMAc(60mL)中，置换氮气保护，加热至110～120℃搅拌反应18h，LCMS显示有部分的原料剩余，将反应液冷却至室温，加入50mL水淬灭，MTBE(500mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3.5g，上述粗品柱层析(PE至EA/PE＝3∶2)得产品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯，1.56g。
MS(ESI)，m/z，283.0[M-43]+
1H NMR(400MHz，CDCl3)δ(ppm)9.31(s，1H)，8.57(s，1H)，8.29(d，J＝7.0Hz，1H)，7.90(dd，J＝34.5，8.3Hz，3H)，7.64(d，J＝8.5Hz，2H)，7.38-7.12(m，2H)，4.34(d，J＝58.7Hz，2H)，3.46-2.69(m，2H)，2.33-1.95(m，4H)，1.84-1.37(m，21H).
第四步：2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
20～25℃条件下将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯(0.68g，1.4mmol)混于甲苯(1.5mL)中，慢慢加入甲烷磺酸(3mL)，加料完毕，升温至30～35℃，搅拌反应30分钟，将反应液加水稀释，用2N NaOH水溶液中和pH至8～9，乙酸乙酯(200mL×2)萃取，干燥浓缩得粗品2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺，600mg，Pre-HPLC制备分离得产品的三氟醋酸盐，370mg。
MS(ESI)，m/z，339.2[M+H]+
1H-NMR(400MHz，MeOD)δ(ppm)9.02(s，1H)，8.21-8.12(m，3H)，8.02(dd，J＝8.4，0.9Hz，1H)，7.72(d，J＝8.8Hz，2H)，7.27(dd，J＝8.4，7.1Hz，1H)，3.75-3.39(m，3H)，3.22(td，J＝12.5，2.6Hz，1H)，2.26(s，4H).
实施例23和24：
(R或S)-2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
将上述消旋体化合物用手性柱CHIRALCEL OD-H(10mm x 250mm，5μm)进行拆分分离，得到第一个单一构型化合物(实施例23，RT 13.5min，ee＞99％)和第二个单一构型化合物(实施例24，RT 12.7min，ee＞99％)
实施例25-42：
按照实施例22～24的合成方法并采用相应的起始原料，制备得到实施例25-42的化合物如下表格：
实施例43：
2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
第一步：3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯
20～25℃条件下，将3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯(15.0g，42.3mmol)溶于DMSO(180mL)中，分别加入60％NaH(2.2g，55.0mmol)，加料完毕升温至40～45℃并搅拌30分钟，继续向反应体系中滴加碘甲烷(6.3g，44.4mmol)的DMSO(20mL)溶液，滴加完毕，40～45℃继续搅拌30分钟，LCMS显示原料消失，向反应体系中加入aq.NH4Cl(150mL)淬灭，乙酸乙酯萃取(200mL×2)，有机相水洗(100mL×2)，干燥浓缩得粗品3-(4-溴苯基)-3-甲基哌啶-2-酮，16.0g，收率99％。
MS(ESI)，m/z，314.0[M-55]+
1H NMR(400MHz，CDCl3)δ(ppm)7.51-7.44(m，2H)，7.24-7.18(m，2H)，3.71(ddd，J＝12.9，8.5，5.7Hz，1H)，3.49-3.40(m，1H)，2.39(ddd，J＝14.1，4.8，4.1Hz，1H)，1.96(ddd，J＝14.1，11.0，5.1Hz，1H)，1.88-1.68(m，2H)，1.56(s，9H)，1.50(s，3H).
第二步：3-(4-溴苯基)-3-甲基哌啶-2-酮
20～25℃条件下将3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯(16.0g，0.044mol)混于乙醇(200mL)中，慢慢滴加盐酸乙醇(200mL)，加料完毕，搅拌反应30分钟，将反应体系浓缩干，浓缩残留物用aq.NaHCO3游离，乙酸乙酯(500mL×2)萃取，有机相干燥浓缩得产品3-(4-溴苯基)-3-甲基哌啶-2-酮11.0g，收率95％。MS(ESI)，m/z，268.0[M+H]+
第三步：3-(4-溴苯基)-3-甲基哌啶
20～25℃将3-(4-溴苯基)-3-甲基哌啶-2-酮(11.5g，43mmol)溶于四氢呋喃(250mL)中，冷却至0～5℃，分批加入硼氢化钠(4.9g，130mmol)，并搅拌反应30分钟，加入乙醇(6.0g，130mmol)，并搅拌反应30分钟，滴加三氟化硼乙醚(19.0g，130mmol)，滴加完毕，自然升温至20～25℃，并搅拌反应18h，，向反应液中加入60mL浓盐酸，并搅拌30分钟，LCMS显示反应完成，向反应液中加入50mL水，加入2M NaOH溶液条件pH至8～9；用乙酸乙酯(500mL×2)，有机相水洗，干燥浓缩得粗品3-(4-溴苯基)-3-甲基哌啶，10.0g，91.7％。
MS(ESI)，m/z，254.0[M+H]+
第四步：3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯
20～25℃条件下，将3-(4-溴苯基)-3-甲基哌啶(3.0g，11.8mmol)、1N NaOH(18mL)和MTBE(100mL)混合，搅拌均匀，加入Boc2O(2.6g，11.9mmol)，加料完毕搅拌1h，反应液加入100mL MTBE，收集有机相，干燥，浓缩得粗品3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯，3.6g，收率86.1％。
MS(ESI)，m/z，298.0[M-55]+
第五步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯
20～25℃，将3-(4-溴苯基)-3-氘代哌啶(2.56g，7.2mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(1.56g，7.2mmol)、碳酸钾(3.0g，21.7mmol)、溴化亚铜(0.2g，1.48mmol)和8-羟基喹啉(0.2g，1.36mmol)混于DMAc(60mL)中，氮气置换保护保护并加热至110～120℃搅拌反应18h，LCMS显示有部分的原料剩余，有产物生成，将反应液冷却至升温，加入50mL水淬灭，MTBE(200mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3.5g，上述粗品柱层析分离纯化(石油醚洗脱至EA/PE＝3∶2)得产品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯，1.8g，收率47％。
MS(ESI)，m/z，435.0[M-100]+
第六步：2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
20～25℃条件下将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯(1.0g，2mmol)混于甲苯(2mL)中，慢慢加入甲烷磺酸(4mL)，加料完毕，升温至30～35℃，搅拌反应30分钟，LCMS显示原料消失，有产物生成，将反应液加水稀释，用aq.NaOH中和pH至8～9，乙酸乙酯(100mL×2)萃取，干燥浓缩得粗品750mg，HPLC制备分离得产品2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺的三氟醋酸盐，470mg。
MS(ESI)，m/z，335.2[M+H]+
1H-NMR(400MHz，MeOD)δ(ppm)8.94(s，1H)，8.21-7.96(m，4H)，7.69(d，J＝8.8Hz，2H)，7.27(dd，J＝8.3，7.1Hz，1H)，3.74(d，J＝13.1Hz，1H)，3.53-3.29(m，2H)，2.41(t，J＝13.0Hz，1H)，1.94(d，J＝12.1Hz，3H)，1.42(s，3H).
实施例44和45：
(R或S)-2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
将上述消旋体化合物用手性柱进行拆分分离，得到单一构型的R构型产物(实施例44)和S构型产物(实施例45)。
实施例46-63：
按照实施例43～45的合成方法并采用相应的起始原料，制备得到实施例46～63的化合物如下表格：
生物测试实施例：
实验例1 PARP激酶活性的测定
PARP1激酶活性通过以下的方法进行测试：
本实验中使用的材料和仪器：
多功能酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
PARP1 Colorimetric Assay Kit(BPS，Cat#80580)
PBS(Life Technologies，Cat#003000)
Tween-20(Sigma，Cat#P9416-100mL)
H2SO4(国药，Cat#10021618)
实验方法和步骤
1.PARP1Colorimetric Assay
1.1PARP1 Colorimetric Assay Kit包含：
PARP1 5μg
5x histone mixture 1mL
10x assay mixture containing biotinylated substrate 300μl
10x PARP assay buffer 1mL
Blocking buffer 25mL
Activated DNA 500μl
Streptavidin-HRP 100μl
Colorimetric HRP substrate 10mL
96孔板一块
1.2试剂配制：
1x PBS：取一包PBS粉末加入1L去离子水充分溶解；
PBST：1x PBS中加入Tween-20；
2M H2SO4：用去离子水稀释H2SO4至2M；
1x PARP assay buffer：用去离子水按照1∶10的比例稀释10x PARP assaybuffer得到1x PARP assay buffer。
1.3化合物稀释
化合物用DMSO溶解、稀释至100μM备用。
测试时，用1x PARP assay buffer稀释100μM化合物储液至10μM，然后用含有10％DMSO的1x PARP assay buffer依次3倍梯度稀释化合物，得到一系列浓度的化合物备用。每反应孔加入5μl稀释好的化合物(总体积50μl)，这样化合物终浓度为1μM起始3倍稀释的一系列浓度。
1.4反应步骤
1.4.1包被
1)用1x PBS按照1∶5的比例稀释5x histone mixture得到1x的包被液；
2)每孔加入50ul稀释好的包被液4℃包被过夜；
3)弃去包被液，每孔200μl PBST buffer洗涤3次；
4)每孔加入200μl Blocking buffer，室温孵育90min；
5)弃去blocking buffer，用PBST洗涤3次；
1.4.2PARP1反应实验
1)按照每孔2.5μl 10x PARP buffer+2.5μl 10x PARP Assaymixture+5μlActivated DNA+15μl去离子水的比例制备反应液，每孔加入反应液25μl(参见表1)。
2)向样品测试孔中加入5μl稀释好的化合物.全活对照孔和空白孔中加入等体积的含10％DMSO的1x PARP buffer。
| 全活对照孔 | 样品测试孔 | 空白孔 | |
| 10x PARP buffer | 2.5μl | 2.5μl | 2.5μl |
| 10x Assay mixture | 2.5μl | 2.5μl | 2.5μl |
| Activated DNA | 5μl | 5μl | 5μl |
| 去离子水 | 15μl | 15μl | 15μl |
| 稀释好的待测化合物 | - | 5μl | - |
| 含10％DMSO的1x PARP buffer | 5μl | - | 5μl |
| 1x PARP buffer | - | - | 20μl |
| PARP1(2.5ng/ul) | 20ul | 20μl | - |
| 总体积 | 50μl | 50μl | 50μl |
3)向空白孔中加入20μl的1x PARP buffer。
4)冰上解冻PARP1，用1x PARP buffer稀释至2.5ng/ul，向出空白孔外的所有反应孔中加入20μl稀释好的PARP1，混匀，室温反应1h。
5)弃去反应液，用PBST洗涤3次。
1.4.3检测
1)用Blocking buffer按照1∶50的比例稀释Streptavidin-HRP，向所有孔中加入50μl稀释好的Streptavidin-HRP，室温孵育30min。
3)弃去HRP，用PBST洗涤3次。
4)每孔加入100μl的colorimetric HRP substrate，室温反应20min。
5)每孔加入100μl的2M H2SO4.在酶标仪上读取OD 450nm。
2.计算抑制率及IC50
抑制率用以下公式计算：
抑制率＝(ODsample-OD0％)/(OD100％-OD0％)×100％
ODsample：样品测试孔的OD值；
OD0％：空白孔的OD值；
OD100％：全活对照孔的OD值。
本发明化合物的PARP-1激酶抑制活性通过以上的实验方法进行测定，测得化合物体外酶学抑制活性(IC50)见下表：+表示10-100μm，++表示1-10μm，+++表示0.5-1μm，++++表示0.1-0.5μm，+++++表示＜0.1μm。
| 化合物编号 | PARP1 | 化合物编号 | PARP1 | 化合物编号 | PARP1 |
| 1 | +++++ | 21 | +++++ | 41 | ++++ |
| 2 | +++++ | 22 | +++++ | 42 | ++++ |
| 3 | +++++ | 23 | +++++ | 43 | ++++ |
| 4 | +++++ | 24 | +++++ | 44 | ++++ |
| 5 | +++++ | 25 | +++++ | 45 | ++++ |
| 6 | +++++ | 26 | +++++ | 46 | ++++ |
| 7 | +++++ | 27 | +++++ | 47 | ++++ |
| 8 | +++++ | 28 | +++++ | 48 | ++++ |
| 9 | +++++ | 29 | +++++ | 49 | ++++ |
| 10 | ++++ | 30 | +++++ | 50 | ++++ |
| 11 | ++++ | 31 | ++++ | 51 | ++++ |
| 12 | ++++ | 32 | ++++ | 52 | +++ |
| 13 | ++++ | 33 | ++++ | 53 | +++ |
| 14 | ++++ | 34 | ++++ | 54 | +++ |
| 15 | ++++ | 35 | ++++ | 55 | ++++ |
| 16 | +++++ | 36 | ++++ | 56 | ++++ |
| 17 | +++++ | 37 | ++++ | 57 | ++++ |
| 18 | +++++ | 38 | ++++ | 58 | ++++ |
| 19 | ++++++ | 39 | ++++ | 59 | ++++ |
| 20 | +++++ | 40 | ++++ | 60 | ++++ |
实验例2 实施例2、23和24化合物的大鼠药代动力学测定
1.实验摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定大鼠静注和灌胃给予实施例化合物后不同时刻血浆中的药物浓度，以研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1供试药品：
本发明实施例3、23、24和阳性对照niraparib化合物
2.2供试动物
健康成年雄性SD(Sprague-Dawley)大鼠，每个供试化合物各3只，6-9周龄，体重250±50g，购自上海斯莱克实验动物有限责任公司。
2.3供试药物配制
称取适量样品，加入0.5％Methocel/2％tween 80至终体积，配制2mg/mL用于灌胃给药。
2.4供试药品给药
雄性SD大鼠每个供试化合物各三只，禁食一夜后给予灌胃给药，剂量为10mg/kg。
3.实验操作
在给药前和后0.083-24h不同时间点与大鼠经颈静脉穿刺取血，K2-EDTA抗凝，离心，取血浆，-70℃冷冻保存直至LC/MS/MS分析。
4.药代动力学数据结果
结果表明，实施例3化合物和实施例24化合物的暴露量明显高于阳性化合物(niraparib)，实施例23化合物的T1/2显著大于阳性化合物(niraparib)。
Claims (13)
1.一种如通式I所示的化合物或其药学上可接受的盐、异构体、溶剂化物、多晶型物、稳定的同位素衍生物或前药：
式中，
Ra选自氢、氘、氟、取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基；
Rb选自氢、氘、取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基；
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自氢、氘或氟，且当Ra为氢时，R1、R2、R3、R4、R5、R6、R7、R8和R9中至少有一个为氘或氟，其中且当R9为5位氟或者R7为氟时，R1、R2、R3、R4、R5、R6和R8中至少有一个为氘或氟；
m为R7的数目，且为0、1、2、3或4；
n为R9的数目，且为0、1、2或3。
2.根据权利要求1所述的通式I所示的化合物或其药学上可接受的盐、异构体或、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，Rb为氢或氘。
3.根据权利要求1所述的通式I所示的化合物或其药学上可接受的盐、异构体或、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：
其中Ra选自氘、氟、取代或未取代的C1-6烷基，R7、R8、R9、m和n的定义如权利要求1中所定义。
4.根据权利要求1所述的通式I所示的化合物或其药学上可接受的盐、异构体、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：
其中R1、R2、R3、R4、R5和R6至少含有一个氘或氟，其它R7、R8、R9、m和n的定义如权利要求1中所定义。
5.根据权利要求1所述的通式I所示的化合物或其药学上可接受的盐、异构体、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：
其中Ra优先选自氘、氟、取代或未取代的C1-6烷基。
6.根据权利要求1所述的通式I所示的化合物或其药学上可接受的盐、异构体、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，所述的化合物具有如下结构：
7.一种制备根据权利要求1中通式I所述的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药的方法，其特征在于，所述方法包括步骤：
a1)通式I-A与通式I-B化合物在碱性和金属催化剂条件下进行偶联反应得到中间体通式I-C化合物；和
b1)中间体I-C在酸性条件下脱去保护基得到式I化合物；
其中X为卤素，R0为胺基保护基，其它基团Ra、Rb、R1、R2、R3、R4、R5、R6、R7、R8、m和n的定义如权利要求1中所定义。
8.一种药物组合物，所述的药物组合物包括有效量的根据权利要求1所述的通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂。
9.根据权利要求1所述的通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备用于预防、缓解和/或治疗可通过PARP抑制剂减轻疾病的药物中的应用。
10.根据权利要求9所述的应用，其特征在于所述的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药用于制备预防、缓解和/或治疗癌症、炎症性疾病、血管疾病、中风、肾衰竭、糖尿病、帕金森氏病、感染性休克、神经毒性、缺血性休克或损伤、移植排斥、再灌注损伤、视网膜损伤、UV-诱导的皮肤损伤、病毒感染或多发性硬化症的药物。
11.根据权利要求9所述的应用，其特征在于所述的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药用于制备癌症治疗中的辅助药物或者用于强化放疗和/或化疗对癌症的治疗药物。
12.根据权利要求1所述的通式I的化合物或其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备治疗癌症中的药物用途，其中所述的癌症选自实体瘤、急性或慢性白血病、淋巴瘤、中枢神经系统癌症、脑癌、血源性癌症、腹膜癌、胃癌、肺癌、缺乏同源重组依赖性DNA双链断裂修复活性的癌症、BRCA-1或BRCA2上缺陷性或突变表型的癌症(如乳腺癌、卵巢癌、前列腺癌和胰腺癌)。
13.根据权利要求12所述的用途，其中所述的药物与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂类药物、拓扑异构酶抑制剂、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗、PD-L1单抗等。
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| CN113637002A (zh) * | 2021-08-02 | 2021-11-12 | 天津太平洋化学制药有限公司 | 一种尼拉帕尼的制备方法 |
| CN114790198A (zh) * | 2022-06-24 | 2022-07-26 | 北京科翔中升医药科技有限公司 | 一种三嗪类化合物及其制备方法和应用 |
| WO2024240108A1 (zh) * | 2023-05-19 | 2024-11-28 | 上海海和药物研究开发股份有限公司 | 一种芳基脲类parp1抑制剂、其制备方法及用途 |
| WO2025140363A1 (zh) * | 2023-12-27 | 2025-07-03 | 海思科医药集团股份有限公司 | 一种苯基哌啶衍生物的制备方法 |
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| CN113637002A (zh) * | 2021-08-02 | 2021-11-12 | 天津太平洋化学制药有限公司 | 一种尼拉帕尼的制备方法 |
| CN114790198A (zh) * | 2022-06-24 | 2022-07-26 | 北京科翔中升医药科技有限公司 | 一种三嗪类化合物及其制备方法和应用 |
| WO2024240108A1 (zh) * | 2023-05-19 | 2024-11-28 | 上海海和药物研究开发股份有限公司 | 一种芳基脲类parp1抑制剂、其制备方法及用途 |
| WO2025140363A1 (zh) * | 2023-12-27 | 2025-07-03 | 海思科医药集团股份有限公司 | 一种苯基哌啶衍生物的制备方法 |
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| US20200207736A1 (en) | 2020-07-02 |
| EP3640245A4 (en) | 2020-04-22 |
| EP3640245A1 (en) | 2020-04-22 |
| US11072596B2 (en) | 2021-07-27 |
| CN109081828B (zh) | 2021-03-26 |
| JP2020523361A (ja) | 2020-08-06 |
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