CN113512042A - 取代喹唑啉-4-酮类化合物及其制备方法和用途 - Google Patents
取代喹唑啉-4-酮类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及取代喹唑啉‑4‑酮类化合物及其制备方法和用途，属于化学医药领域。本发明提供了式Ⅰ所示的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物。本发明还提供了上述化合物的制备方法和用途。生物学实验表明，本发明的化合物对PI3K具有较好的抑制活性；同时本发明化合物对多种肿瘤细胞增殖均具有较好的抑制活性，其中某些化合物比CAL‑101和IPI‑145展示更好的抗增殖活性；并且本发明的化合物还具有较好的抗炎效果。
Description
技术领域
本发明涉及取代喹唑啉-4-酮类化合物及其制备方法和用途，属于化学医药领域。
背景技术
磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)属于脂激酶家族成员，是细胞内重要的信号转导分子，在PI3K/AKT/mTOR信号转导通路中扮演着关键角色，能够介导体内的磷酸化过程进而影响细胞的生长、增殖、分化、迁移、凋亡等过程。已有研究发现PI3K通路的失调涉及到多种疾病，如癌症、糖尿病、血栓、类风湿性关节炎、PI3Kδ过度活化综合征和哮喘，PI3K已经成为了潜力巨大的药物治疗靶点。
目前已知的PI3K抑制剂主要分为I型，II型和III型，其中研究最多的是能被细胞表面受体激活的Ⅰ型PI3K。根据催化域(p110)以活性异二聚体形式与之结合的调节亚基的类型，I型进一步细分为IA(PI3Kα，β和δ)和IB(PI3Kγ)。IA类PI3K介导受体酪氨酸激酶(RTK)的信号转导，而PI3Kγ主要由G蛋白偶联受体(GPCR)激活。PI3Kα和β在全身组织中普遍存在，而PI3Kδ和γ主要存在于造血系统、上皮细胞和中枢神经系统(CNS)中1-3。PI3K通路的失调(例如过表达)与所有的I型PI3K相关。其中PI3Kα的突变与肿瘤的发生发展有关；PI3Kβ能够激活血小板，与血栓性疾病的发展有关，并且在PTEN缺失的肿瘤中，PI3Kβ会促进肿瘤的恶变；PI3Kγ和PI3Kδ主要与免疫系统和造血系统有关，与免疫、血液肿瘤以及炎症的发生密切有关。Ⅱ型PI3K主要影响膜运输，Ⅲ型PI3K成员Vps34可影响细胞的胞吞作用和囊泡运输，调节细胞自噬，也可通过mTOR来介导细胞的信号转导。
发明内容
本发明的目的在于提供取代喹唑啉-4-酮类化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其结构如式Ⅰ所示：
环A选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烯基、取代或未取代的杂环烯基；
环B选自取代或未取代的5元环烷基、取代或未取代的5～9元杂环烷基，所述杂环烷基含有1个杂原子，杂原子为N；
R1、R2、R3、R4独立的选自氢、卤素、C1～C6烷基、-C≡C-R6；
R5选自取代或未取代的杂芳基；
R6选自C1～C6烷基取代的5～6元杂芳基。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物：
环A选自取代或未取代的5～6元芳基、取代或未取代的5～6元杂芳基、取代或未取代的5～6元杂环烷基、取代或未取代的5～6元杂环烯基，所述杂芳基、杂环烷基和杂环烯基均有1～2个杂原子，所述杂原子为N、O或S；
优选的，环A选自取代或未取代的6元芳基、取代或未取代的6元杂芳基、取代或未取代的6元杂环烷基、取代或未取代的5元杂环烯基，所述杂芳基、杂环烷基和杂环烯基均有1～2个杂原子，所述杂原子为N、O或S；
更优选的，环A选自苯基、取代的苯基、吡啶基、取代的吡啶基、吗啉基、取代的吗啉基、四氢吡喃基、取代的四氢吡喃基、噻唑啉基、取代的噻唑啉基，所述取代的苯基、取代的吡啶基、取代的吗啉基、取代的四氢吡喃基和取代的噻唑啉基均有至少一个选自下组的取代基：卤素、C1～C6烷基、卤素取代的C1～C6烷基、C1～C6烷氧基、卤素取代的C1～C6烷氧基、
最优选的，环A选自苯基、吡啶基、吗啉基、甲基取代的吡啶基、四氢吡喃基、噻唑林基、取代的苯基，所述取代的苯基有至少一个选自下组的取代基：卤素、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物：
R1、R2、R3、R4独立的选自氢、卤素、C1～C3烷基、-C≡CR6；
优选的，R1、R2、R3、R4同时为氢，或者R1、R2、R3同时为氢，R4选自卤素、C1～C3烷基、-C≡CR6；
最优选的，R1、R2、R3、R4同时为氢，或者R1、R2、R3同时为氢，R4选自卤素、甲基、-C≡C-R6。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物：
R6选自C1～C6烷基取代的5元杂芳基，所述杂芳基有1～2个杂原子，杂原子为N；
优选的，R6选自C1～C3烷基取代的5元杂芳基，所述杂芳基有1～2个杂原子，杂原子为N；
更优选的，R6选自C1～C3烷基取代的吡唑基；
最优选的，R6选自甲基取代的吡唑基。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物：
R5选自取代或未取代的6～9元杂芳基，所述杂芳基有1～4个杂原子，杂原子为N或S；优选的，R5选自
其中，X选自CH或N，Y选自O或S，R7、R8、R9、R10独立的选自氢、-NH2、氰基、卤素、C1～C3烷基、取代或未取代的吡唑基、取代或未取代的苯基、取代或未取代的茚基，所述取代的吡唑基、取代的苯基和取代的茚基有至少一个选自下组的取代基：卤素、羟基、甲磺酰氨基、氨基磺酰氨基；
最优选的，R5选自
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下式Ⅱ：
R11、R12、R13、R14、R15独立的选自氢、卤素、C1～C3烷基。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，具有以下两种结构：
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下：
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下式Ⅲ：
R16、R17、R18、R19独立的选自氢、卤素、C1～C3烷基。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，具有以下两种结构：
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下：
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下式Ⅳ：
R20、R21、R22独立的选自氢、卤素、C1～C3烷基、-OR23、＝CH2、酮基；
R23选自氰基、C2～C3烯基。
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，具有以下两种结构：
其中，上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，结构式如下：
本发明还提供了上述化合物的制备方法，包括以下步骤：
其中，X表示卤素；
(1)将M1与M2溶于有机溶剂，惰性气体保护下加入催化剂反应后得到M3；
(2)M3与M4反应，经萃取、洗涤、干燥后得到M5；
(3)将M5溶于有机溶剂，加入强酸反应，反应结束后加入碱性溶液中和至弱碱性，经萃取、浓缩、柱层析纯化得到M6；
(4)将M6与M7溶于有机溶剂中，加入碱反应，反应结束后，经萃取、洗涤、浓缩、柱层析纯化后得到式Ⅰ。
其中，上述的制备方法，满足以下至少一项：
步骤(1)中，所述有机溶剂为吡啶；
步骤(1)中，所述惰性气体为氮气；
步骤(1)中，所述催化剂为亚磷酸三苯酯；
步骤(1)中，所述M1与M2的摩尔比为1：1；
步骤(1)中，所述反应的温度为60～75℃；
步骤(2)中，所述M3与M4的摩尔比为1：1～1.2；
步骤(2)中，所述反应的温度为60～75℃；
步骤(3)中，所述有机溶剂为乙酸乙酯；
步骤(3)中，所述强酸为浓盐酸；
步骤(4)中，所述有机溶剂为正丁醇；
步骤(4)中，所述碱为三乙胺；
步骤(4)中，所述M6与M7的摩尔比为1：1～1.2；
步骤(4)中，所述反应的温度为75～85℃。
本发明还提供了一种药物组合物，由上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物为活性成分，添加药学上可接受的辅助性成分组成。
本发明还提供了上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物在制备PI3K抑制剂中的用途；优选的，所述PI3K抑制剂为PI3Kδ抑制剂、PI3Kγ抑制剂、PI3Kα抑制剂或PI3Kβ抑制剂。
本发明还提供了上述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物在制备预防和/或治疗与PI3K相关疾病的药物中的用途。
其中，上述的用途，所述与PI3K相关疾病为肿瘤和炎性疾病；优选的，所述肿瘤为白血病、霍奇金氏淋巴瘤、骨髓增生症、非霍奇金氏淋巴瘤、多发性骨髓瘤、乳腺癌、肉瘤、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、肝癌、卵巢癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤或皮肤癌；所述炎性疾病为过敏、哮喘、类风湿性关节炎、骨关节炎、过敏性结膜炎、过敏性角膜炎、慢性阻塞性肺病、红斑狼疮、牛皮癣、多发性硬化症或晚期肾病。
术语定义：
本发明提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
术语“烷基”是直链或支链的饱和烃基的基团。C1～C6烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。
术语“环烷基”是指不包含杂原子的饱和的环状烃基，其可以是单环结构，也可以是多环结构，例如：环丙烷基(3元)、环己烷基(6元)。
术语“杂环烷基”是指“环烷基”中的碳原子被杂原子取代，杂原子选自磷、硫、氧和/或氮，单环杂环基包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、吡喃基、四氢呋喃基等；多环杂环基包括螺环、稠环和桥环的杂环基。
术语“烯基”是指由碳和氢原子组成的至少含有一个双键的直链或支链的烃链基团，例如：乙烯基、丙烯基、丁烯基、戊烯基、戊二烯基、己烯基。
术语“环烯基”是指由碳和氢原子组成的至少含有一个双键的环烃基，例如环丙烯、环戊烯、环己烯。
术语“杂环烯基”是指“环烯基”中的碳原子被杂原子取代，杂原子选自磷、硫、氧和/或氮，例如噻唑啉基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠环基团，芳基可以是完全芳香族的基团，例如苯基、萘基、蒽基、菲基等。
术语“杂芳基”是指“芳基”中的碳原子被杂原子取代，杂原子选自磷、硫、氧和/或氮，例如吡啶、吡唑、嘧啶、苯并吡唑、吡啶并吡唑、嘧啶并吡唑等。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“药学上可接受的盐”是指本发明化合物的有机盐和无机盐，优选无机盐、药学上可接受的无毒的酸形成的盐，包括但不限于，与氨基反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、硝酸盐,有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、盐酸盐、油酸盐、硬脂酸盐、抗坏血酸盐、甲酸盐、硼酸盐、樟脑酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、苹果酸盐等。
术语“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缔合物。形成溶剂化物的溶剂包括，但不限于，水、异丙醇、乙醇、甲醇、二甲基亚砜、乙酸乙酯、乙酸等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅助性成分，是指除活性成分以外包含在剂型中的物质，所述的辅助性成分如环糊精、精氨酸或葡甲胺。所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、(C1-4烷基)-α-环糊精、(C1-4烷基)-β-环糊精、(C1-4烷基)-γ-环糊精、(羟基-C1-4烷基)-α-环糊精、(羟基-C1-4烷基)-β-环糊精、(羟基-C1-4烷基)-γ-环糊精、(羧基-C1-4烷基)-α-环糊精、(羧基-C1-4烷基)-β-环糊精、(羧基-C1-4烷基)-γ-环糊精、α-环糊精的糖类醚、β-环糊精的糖类醚、γ-环糊精的糖类醚、α-环糊精的磺丁基醚、β-环糊精的磺丁基醚和γ-环糊精的磺丁基醚。所述的辅助性成分还包含医学上可接受的载体、佐剂或媒剂。可用于药学上可接受的药物组合物还离子交换剂、氧化铝、硬脂酸铝、卵凝脂；缓冲物质包括磷酸盐、甘氨酸、精氨酸、山梨酸等。
本发明公开了一类式I的化合物，药效学实验结果显示，本发明的化合物能够作用于PI3K靶点，可作为肿瘤或炎症的单一治疗剂，或者与其他抗肿瘤或抗炎药物联用，从而达到提高对肿瘤或炎症的疗效并降低剂量和毒性的目的。
本发明的化合物潜在地可用于治疗多种疾病，特别是包括但不限于自身免疫疾病，自身炎症性疾病，过敏性疾病，病理学免疫性疾病，呼吸系统疾病，如哮喘和COPD，移植排斥，恶性肿瘤(如血源性或实体瘤)。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
CLJ-1的制备
步骤a：中间体N-Boc-L-八氢吲哚-2-羧酸(SM1)的制备
将L-八氢吲哚-2-羧酸(2.00g,1eq,11.80mmol)溶于二氯甲烷，向溶液中加入三乙胺(3.30mL,2eq,23.60mmol)，室温搅拌10min，加入Boc酸酐(2.70mL,1eq,11.80mmol)，室温继续反应2-3h后，加入饱和氯化铵溶液20mL，萃取分离收集有机层，无水硫酸钠干燥，减压浓缩，残留物未进一步纯化直接用于下一步。
步骤b：SM4的制备
在氮气保护下将2-氨基-6-氯苯甲酸(2.03g,1eq,11.80mmol)与N-Boc-L-八氢吲哚-2-羧酸(3.18g,1eq,11.80mmol)溶于吡啶，向混合液中注入亚磷酸三苯酯(7.75mL,2.5eq,29.5mmol)，升温至70℃，反应通过TLC检测，待反应结束，缓慢滴加苯胺(1.32mL,1.2eq,11.8mmol)至反应液，70℃过夜反应。次日将反应液均匀分散于乙酸乙酯与水中，萃取，有机层再以水洗涤1次后，收集有机层，减压浓缩溶剂至干，残留物未经进一步纯化直接溶于乙酸乙酯，并向混合液中注入适量浓盐酸，常温反应2-3h后直接加入1M NaOH溶液，条件PH为弱碱性，萃取分离收集有机层，减压浓缩，残留物经硅胶柱层析纯化，得到浅黄色固体粉末SM5，收率54％。
1HNMR(400MHz,DMSO-d6)δ7.78(t,J＝8.0Hz,1H),7.66(dd,J＝8.2,1.2Hz,1H),7.60–7.51(m,4H),7.49–7.44(m,2H),3.72(dt,J＝9.9,5.5Hz,1H),2.84(q,J＝4.8Hz,1H),1.87–1.74(m,2H),1.71–1.59(m,2H),1.53–1.38(m,4H),1.35(d,J＝5.2Hz,1H),1.27–1.09(m,2H).ESI-MS m/z:379.8[M+H]+.
步骤c：终产物的获得
将SM5(0.100g,1eq,0.263mmol)与4-氯吡咯并嘧啶(0.049g,1.2eq,0.316mmol)溶于正丁醇，并向反应液中加入三乙胺(110μL,3eq,0.790mmol)，升温至80℃，反应通过TLC检测，待反应结束，减压浓缩，残留物加入乙酸乙酯，混合液用水和饱和氯化钠溶液洗涤，收集有机层，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化得白色固体粉末，收率70％。
1HNMR(400MHz,Chloroform-d)δ10.73(s,1H),8.14(s,1H),7.88(d,J＝8.0Hz,1H),7.67–7.34(m,8H),7.03(d,J＝3.5Hz,1H),4.71(dd,J＝9.4,7.4Hz,1H),4.33(q,J＝7.7Hz,1H),2.39–2.23(m,4H),1.99–1.93(m,1H),1.79–1.66(m,3H),1.59(d,J＝13.1Hz,1H),1.50–1.39(m,2H).ESI-MS m/z:496.1[M+H]+.
实施例2、化合物CLJ-2的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2-氨基-6-氯嘌呤，得到终产物CLJ-2。1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.92(d,J＝7.8Hz,1H),7.70(s,1H),7.67–7.55(m,5H),7.51–7.47(m,2H),7.43–7.39(m,1H),4.93(dt,J＝11.6,6.2Hz,1H),4.52(t,J＝8.5Hz,1H),2.39(d,J＝12.2Hz,1H),2.30–2.04(m,4H),1.81(dd,J＝12.6,6.2Hz,1H),1.75–1.58(m,4H),1.45(s,1H),1.27(t,J＝12.7Hz,2H).ESI-MS m/z:512.1[M+H]+.
实施例3、化合物CLJ-3的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为4-氨基-2-氯嘧啶，得到终产物CLJ-3。1H NMR(400MHz,DMSO-d6)δ7.80–7.35(m,10H),6.22(d,J＝53.2Hz,2H),4.26(dd,J＝9.1,7.0Hz,1H),4.19–4.03(m,1H),2.12(s,3H),2.02–1.91(m,1H),1.84(s,1H),1.63(q,J＝17.0,13.9Hz,3H),1.44(d,J＝12.5Hz,1H),1.23(d,J＝4.0Hz,2H).ESI-MSm/z:472.2[M+H]+.
实施例4、化合物CLJ-4的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2-氯-3-氰基吡啶得到终产物CLJ-4。1HNMR(400MHz,DMSO-d6)δ8.71(dd,J＝4.9,1.9Hz,1H),8.48(dd,J＝7.7,1.9Hz,1H),8.31(dd,J＝4.7,1.9Hz,1H),7.85(dd,J＝7.7,1.9Hz,1H),7.68–7.63(m,3H),7.60(dd,J＝8.5,6.8Hz,2H),7.48(ddd,J＝7.9,6.5,1.6Hz,2H),4.46(ddd,J＝17.3,10.7,6.8Hz,2H),2.32–2.10(m,4H),1.90–1.81(m,1H),1.75(d,J＝12.7Hz,1H),1.69–1.55(m,2H),1.46(d,J＝13.0Hz,1H),1.40–1.26(m,1H),1.22–1.14(m,1H).ESI-MS m/z:482.1[M+H]+.
实施实5、化合物CLJ-5的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2-氯-4-甲基吡啶得到终产物CLJ-5。1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝53.1Hz,1H),7.76(s,1H),7.59–7.47(m,5H),7.39(dd,J＝6.8,2.2Hz,1H),7.22(d,J＝7.6Hz,1H),6.25(d,J＝5.0Hz,1H),4.49(s,1H),4.33–4.18(m,1H),2.36–2.17(m,6H),1.92(dd,J＝7.3,5.1Hz,1H),1.81–1.66(m,3H),1.60–1.48(m,3H),1.41(t,J＝7.4Hz,1H).ESI-MS m/z:472[M+H]+.
实施例6、化合物CLJ-6的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为6-氯嘌呤得到终产物CLJ-6。1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.13(d,J＝13.7Hz,2H),7.80–7.75(m,1H),7.65–7.58(m,3H),7.57–7.48(m,3H),7.39(dd,J＝8.2,1.2Hz,1H),4.88(dt,J＝11.3,6.2Hz,1H),4.49(dd,J＝9.3,7.4Hz,1H),2.29(q,J＝10.6,9.8Hz,2H),2.23–2.12(m,2H),1.78–1.60(m,4H),1.48(s,1H),1.43–1.33(m,2H).ESI-MS m/z:498[M+H]+.
实施实7、化合物CLJ-7的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为4-氯-1H-吡唑并[3,4-d]嘧啶得到终产物CLJ-7。1H NMR(400MHz,Chloroform-d)δ12.20(s,1H),8.26(s,1H),7.95(s,1H),7.84–7.80(m,1H),7.66–7.45(m,5H),7.39(dd,J＝8.0,0.9Hz,2H),4.72(dd,J＝9.5,7.5Hz,1H),4.23(dd,J＝10.2,6.6Hz,1H),2.44–2.26(m,4H),2.01(dt,J＝11.7,6.8Hz,1H),1.91(d,J＝12.1Hz,1H),1.49–1.32(m,3H).ESI-MS m/z:498.0[M+H]+.
实施实8、化合物CLJ-8的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为4-氯咪唑[4,5-C]吡啶得到终产物CLJ-8。1H NMR(500MHz,Chloroform-d)δ8.10–8.03(m,2H),7.61–7.53(m,2H),7.51–7.43(m,4H),7.35–7.29(m,2H),7.03(d,J＝7.5Hz,1H),3.63(d,J＝5.8Hz,1H),2.73(ddd,J＝16.7,7.0,2.7Hz,1H),2.29(ddd,J＝16.8,3.7,1.4Hz,1H),2.07(ddd,J＝9.8,6.6,3.4Hz,1H),1.54–1.41(m,2H),1.29–1.22(m,1H),1.20–1.10(m,2H),1.09–0.98(m,1H),0.90–0.72(m,2H),0.54–0.42(m,1H).ESI-MS m/z:497.1[M+H]+.
实施例9、化合物CLJ-9的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2-氯-7H-吡咯并[2,3-d]嘧啶得到终产物CLJ-9。1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.91(s,1H),7.81(t,J＝8.0Hz,1H),7.70(dd,J＝8.2,1.2Hz,1H),7.66–7.59(m,2H),7.44(ddd,J＝14.5,10.7,7.8Hz,5H),6.64(d,J＝3.6Hz,1H),3.63(d,J＝5.8Hz,1H),3.17(d,J＝5.2Hz,1H),2.73(ddd,J＝16.8,7.0,2.6Hz,1H),2.34–2.27(m,1H),2.08(dt,J＝9.7,3.5Hz,1H),1.47(dq,J＝15.8,5.5Hz,2H),1.31–1.23(m,1H),1.14(d,J＝13.1Hz,2H),1.08–0.98(m,1H),0.80–0.71(m,1H),0.48(qd,J＝10.8,10.4,5.3Hz,1H).ESI-MS m/z:497.2[M+H]+.
实施例10、化合物CLJ-10的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2,6-二氯嘌呤得到终产物CLJ-10。1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.15(s,1H),7.86(d,J＝8.4Hz,1H),7.68–7.62(m,2H),7.62–7.56(m,2H),7.51(dd,J＝7.9,1.5Hz,2H),7.40(dd,J＝8.2,1.2Hz,1H),4.86(dt,J＝11.7,6.1Hz,1H),4.50–4.44(m,1H),2.35(d,J＝20.0Hz,2H),2.19(dd,J＝20.8,8.2Hz,2H),1.92(dt,J＝12.9,6.9Hz,1H),1.77–1.68(m,2H),1.28(dd,J＝24.8,13.1Hz,3H).ESI-MS m/z:532.4[M+H]+.
实施例11、化合物CLJ-11的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为2,4-二氯嘧啶得到终产物CLJ-11。1H NMR(400MHz,Chloroform-d)δ8.99–8.95(m,2H),8.02(d,J＝6.0Hz,1H),7.62–7.56(m,2H),7.32(t,J＝7.9Hz,2H),7.10(t,J＝7.4Hz,1H),6.32(d,J＝6.1Hz,1H),4.65(d,J＝8.9Hz,1H),3.84(s,1H),2.85–2.71(m,1H),2.14(dt,J＝14.3,7.7Hz,1H),1.96–1.84(m,2H),1.81–1.68(m,2H),1.63–1.48(m,4H),1.28–1.18(m,1H).ESI-MS m/z:492.4[M+H]+.
实施例12、化合物CLJ-12的制备
制备方法同是实施例1，将步骤c中的4-氯吡咯并嘧啶替换为4-氨基-5-氰基-6-氯嘧啶得到终产物CLJ-12。1H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.64(d,J＝7.9Hz,1H),7.60–7.47(m,5H),7.42(dd,J＝7.6,1.4Hz,1H),7.22(dt,J＝7.2,1.9Hz,1H),5.37(s,2H),4.65(t,J＝8.5Hz,1H),4.51(dt,J＝11.7,6.1Hz,1H),2.36(s,1H),2.31–2.12(m,3H),1.86(d,J＝18.4Hz,2H),1.76–1.64(m,2H),1.54(s,1H),1.34(dt,J＝14.4,8.1Hz,2H).ESI-MS m/z:498[M+H]+.
实施例13、化合物CLJ-13的制备
制备方法同实施例1，将SM1替换为可直接购买的(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧酸，并将骤c中的4-氯吡咯并嘧啶替换为2-氨基-6-氯嘌呤，得到终产物CLJ-13。1H NMR(400MHz,DMSO-d6)δ8.05–7.86(m,1H),7.80–7.37(m,8H),5.62(d,J＝48.6Hz,2H),4.78(dd,J＝8.6,3.9Hz,1H),4.18(dd,J＝57.1,10.8Hz,1H),3.81(t,J＝10.1Hz,1H),2.08–1.83(m,2H),0.76–0.29(m,4H).ESI-MS m/z:484.9[M+H]+.
实施例14、化合物CLJ-14的制备
制备方法同实施例1。
CLJ-14,1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.09(s,1H),7.77(dt,J＝8.2,1.4Hz,1H),7.69–7.52(m,5H),7.50–7.46(m,2H),7.41(dd,J＝8.2,1.2Hz,1H),7.12(dd,J＝3.5,2.2Hz,1H),4.78(dd,J＝8.1,4.5Hz,1H),4.03(dd,J＝8.3,6.1Hz,1H),3.92(d,J＝9.4Hz,1H),2.10–2.00(m,2H),0.87–0.74(m,2H),0.64(pd,J＝5.7,3.4Hz,2H).ESI-MS m/z:468.9[M+H]+.
实施例15、化合物CLJ-15的制备
制备方法同实施例1，将4-氯吡咯并嘧啶替换为6-氯嘌呤，得到终产物。
CLJ-15,1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),7.92(s,1H),7.84(d,J＝7.9Hz,1H),7.67–7.58(m,2H),7.53(dd,J＝6.5,2.9Hz,3H),7.44–7.39(m,2H),7.21(d,J＝6.5Hz,1H),5.05(dd,J＝8.2,5.3Hz,1H),4.44–4.34(m,2H),4.03–3.90(m,2H),0.75–0.59(m,4H).ESI-MS m/z:469.9[M+H]+.
实施例16、化合物CLJ-16的制备
制备方法同实施例1，将4-氯吡咯并嘧啶替换为4-氨基-5-氰基-6-氯嘧啶，得到终产物。CLJ-16,1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.63–7.43(m,7H),7.19(s,1H),6.55(s,2H),5.04(s,1H),4.27–4.15(m,1H),3.91(d,J＝39.4Hz,3H),0.82(s,1H),0.64(d,J＝25.4Hz,2H),0.51(s,1H).ESI-MS m/z:469.9[M+H]+.
实施例17、化合物CLJ-17的制备
制备方法同实施例1，将4-氯吡咯并嘧啶替换为2,4-二氨基-6-氯嘧啶，得到终产物。
CLJ-17,1H NMR(400MHz,Chloroform-d)δ7.73(dd,J＝8.2,1.3Hz,1H),7.65(t,J＝8.0Hz,1H),7.54(dd,J＝7.8,1.3Hz,1H),7.46(pd,J＝7.8,6.8,2.4Hz,4H),7.33–7.30(m,2H),3.72(t,J＝2.2Hz,2H),2.48(t,J＝2.2Hz,2H),1.25(s,1H),0.47–0.42(m,4H).ESI-MS m/z:459.9[M+H]+.
实施例18、化合物CLJ-18的制备
步骤a：HM1的制备
将Boc-L-羟脯氨酸(1g,1eq)溶于四氢呋喃，反应瓶至于冰浴中，待温度降至0℃左右，加入60％的NaH(0.52g,3eq)，冰浴搅拌10min，缓慢滴加溴甲腈(0.63mL,2eq)，滴加结束后撤去冰浴，室温反应过夜，次日向反应液缓慢滴加冰水淬灭，并加入乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，减压浓缩，残留物未经进一步纯化直接用于下一步。剩余步骤的制备方法同实施例1，将将4-氯吡咯并嘧啶替换为2-氨基-6-氯嘌呤得到终产品CLJ-18。1HNMR(400MHz,DMSO-d6)δ12.23(s,1H),10.20(s,1H),7.80–7.48(m,3H),7.28(t,J＝7.7Hz,2H),7.02(t,J＝7.4Hz,1H),5.87(ddd,J＝16.1,10.7,5.2Hz,1H),5.65(s,1H),5.24(d,J＝17.2Hz,1H),5.12(d,J＝10.4Hz,1H),4.71(d,J＝99.0Hz,1H),4.31(s,1H),3.99(q,J＝7.8,6.3Hz,2H),3.53–3.35(m,2H),2.26(s,1H).ESI-MS m/z:513.1[M+H]+.
实施例19、实施例20、实施例21分别为CLJ-19、CLJ-20、CLJ-21的制备，制备方法同实施例18，CLJ-19、CLJ-20、CLJ-21分别将2-氨基-6-氯嘌呤替换为4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶得到终产品。
CLJ-19，1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.17(s,1H),8.06(s,1H),7.59(d,J＝8.0Hz,2H),7.32–7.24(m,2H),7.16(t,J＝2.8Hz,1H),7.05–6.99(m,1H),6.62(s,1H),5.89(ddt,J＝17.3,10.5,5.3Hz,1H),5.26(dq,J＝17.2,1.8Hz,1H),5.13(dq,J＝10.4,1.6Hz,1H),4.89(s,1H),4.36(d,J＝5.6Hz,1H),4.15(s,1H),4.04(ddt,J＝5.7,2.9,1.6Hz,2H),4.00–3.95(m,1H),2.42(s,1H),2.18(s,1H).ESI-MS m/z:497.1[M+H]+.
CLJ-20，1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),10.19(s,1H),8.15(s,2H),7.60(d,J＝8.1Hz,2H),7.28(t,J＝7.7Hz,2H),7.02(t,J＝7.4Hz,1H),5.88(ddt,J＝16.2,10.5,5.3Hz,1H),5.24(dd,J＝17.2,2.1Hz,1H),5.12(d,J＝10.3Hz,1H),4.87(s,1H),4.65(d,J＝11.3Hz,1H),4.35(s,1H),4.15(d,J＝11.9Hz,1H),4.01(t,J＝4.9Hz,2H),2.45(s,1H),2.14(s,1H).ESI-MS m/z:498.1[M+H]+.
CLJ-21，1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),7.94(s,1H),7.58–7.54(m,2H),7.28(t,J＝7.9Hz,3H),7.07–7.00(m,1H),5.90(ddt,J＝17.3,10.6,5.3Hz,1H),5.26(dq,J＝17.2,1.8Hz,1H),5.15(dq,J＝10.4,1.5Hz,1H),4.84(s,1H),4.30(s,1H),4.08–3.97(m,3H),3.87(d,J＝11.3Hz,1H),2.39(s,1H),2.05(s,1H).ESI-MS m/z:498.1[M+H]+.
实施例22、化合物CLJ-22的制备
制备方法同实施例1，将SM1替换为可直接购买的N-BOC-4-亚甲基-L-脯氨酸，并将骤c中的4-氯吡咯并嘧啶替换为2-氨基-6-氯嘌呤，得到终产物CLJ-22。1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),7.96–7.24(m,9H),5.22–4.78(m,4H),4.56–4.35(m,1H),2.88(dd,J＝26.3,16.2Hz,1H),2.75–2.59(m,1H).ESI-MS m/z:470.9[M+H]+.
实施例23，实施例24，实施例25，实施例26，分别为CLJ-23、CLJ-24、CLJ-25、CLJ-26的制备，制备方法同实施例1，CLJ-24、CLJ-25、CLJ-26分别将4-氯吡咯并嘧啶替换为6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶、2,4-二氨基-6-氯嘧啶，得到终产物。
CLJ-23，1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.12(s,1H),7.77(dt,J＝8.1,1.5Hz,1H),7.70–7.64(m,1H),7.63–7.54(m,4H),7.46(dd,J＝7.8,1.2Hz,1H),7.33(dd,J＝8.2,1.2Hz,1H),7.18(dd,J＝3.6,2.2Hz,1H),6.70(dd,J＝3.6,1.7Hz,1H),5.19(s,1H),5.05(s,1H),4.88(dd,J＝9.3,2.5Hz,1H),4.80(d,J＝14.1Hz,1H),4.69(d,J＝14.1Hz,1H),2.91(d,J＝16.2Hz,1H),2.79–2.69(m,1H).ESI-MS m/z:454.9[M+H]+.
CLJ-24，1H NMR(400MHz,DMSO-d6)δ12.98(d,J＝18.8Hz,1H),8.29–8.14(m,2H),7.83–7.26(m,8H),5.64(d,J＝9.4Hz,1H),5.15(d,J＝15.4Hz,1H),5.01(d,J＝13.0Hz,1H),4.96–4.87(m,1H),4.53(q,J＝16.0Hz,1H),2.95(t,J＝16.1Hz,1H),2.75(s,1H).ESI-MS m/z:455.9[M+H]+.
CLJ-25，1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.70–7.46(m,8H),7.29(s,2H),5.14(d,J＝2.9Hz,1H),5.04–4.99(m,1H),4.84(d,J＝9.3Hz,1H),4.68(s,2H),2.89–2.80(m,1H),2.64(dd,J＝16.0,9.6Hz,1H).ESI-MS m/z:455.9[M+H]+.
CLJ-26，1H NMR(400MHz,DMSO-d6)δ7.77(t,J＝8.0Hz,1H),7.64(dd,J＝8.2,1.2Hz,1H),7.62–7.46(m,6H),4.83(dt,J＝5.3,2.3Hz,2H),3.79–3.68(m,2H),3.26–3.20(m,1H),2.60–2.52(m,1H),2.26(dd,J＝16.4,7.6Hz,1H).ESI-MS m/z:445.9[M+H]+.
实施例27、化合物CLJ-27的制备
制备方法同实施例1，将SM1替换为可直接购买的N-Boc-4-氧代-L-脯氨酸，并将骤c中的4-氯吡咯并嘧啶替换为4-氨基-5-氰基-6-氯嘧啶，得到终产物CLJ-22。1H NMR(500MHz,Chloroform-d)δ8.80(s,1H),7.65(dd,J＝6.9,2.7Hz,1H),7.59–7.47(m,3H),7.35–7.30(m,2H),7.26–7.20(m,2H),6.96(t,J＝7.0Hz,1H),5.80(s,2H),4.56(d,J＝9.5Hz,1H),4.39(d,J＝9.5Hz,1H),2.72(dd,J＝18.8,7.0Hz,1H),2.45(dd,J＝18.7,6.9Hz,1H).ESI-MS m/z:457.9[M+H]+.
实施例28、实施例29、实施例30的制备方法同实施例18，将溴甲睛替换为溴丙烯，CLJ-28、CLJ-29、CLJ-30分别使用4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶替换2-氨基-6-氯嘌呤，得到终产品。
CLJ-28，1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.09(s,1H),7.79(dd,J＝7.8,2.0Hz,1H),7.67–7.59(m,3H),7.57–7.50(m,2H),7.50–7.46(m,1H),7.42–7.38(m,1H),7.16(dd,J＝3.6,2.4Hz,1H),5.83–5.72(m,1H),5.14(dq,J＝17.3,1.8Hz,1H),5.06(dq,J＝10.4,1.5Hz,1H),4.62(t,J＝7.4Hz,1H),4.48(s,1H),4.28(dd,J＝10.8,4.9Hz,1H),3.98–3.87(m,3H),2.40–2.33(m,1H),2.15–2.08(m,1H).ESI-MS m/z:499.1[M+H]+.
CLJ-29，1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),8.22–8.11(m,2H),7.54(dddd,J＝46.4,26.4,14.7,7.8Hz,8H),5.74(ddt,J＝15.6,9.9,5.0Hz,1H),5.17–5.00(m,2H),4.73–4.59(m,1H),4.42(s,1H),4.22(dt,J＝18.6,8.8Hz,1H),3.87(q,J＝7.6,6.4Hz,3H),2.40–2.27(m,1H),2.14(t,J＝11.1Hz,1H).ESI-MS m/z:500.1[M+H]+.
CLJ-30，1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.73–7.46(m,8H),7.28(s,2H),5.76(ddt,J＝17.3,10.6,5.4Hz,1H),5.15–5.03(m,2H),4.58(s,1H),4.39(s,1H),4.15(d,J＝9.5Hz,1H),3.93–3.81(m,3H),2.27(ddd,J＝12.7,7.5,4.9Hz,1H),2.07(d,J＝10.1Hz,1H).ESI-MS m/z:500.1[M+H]+.
实施例31、实施例32、实施例33、实施例34，分别为CLJ-31、CLJ-32、CLJ-33、CLJ-34的制备，制备方法同实施例1，将SM1替换为可直接购买的N-Boc-4,4-二氟-L-脯氨酸，CLJ-31、CLJ-32、CLJ-33、CLJ-34最后一步的原料分别替换为2-氨基-6-氯嘌呤、4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶，得到终产品。
CLJ-31，1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.85–7.37(m,8H),5.83(d,J＝54.6Hz,2H),4.98(d,J＝77.9Hz,1H),4.57–4.06(m,2H),2.84(d,J＝16.5Hz,1H),2.45(d,J＝4.6Hz,1H).ESI-MS m/z:494.9[M+H]+.
CLJ-32，1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.17(s,1H),7.77(dd,J＝8.2,1.8Hz,1H),7.70–7.55(m,6H),7.50(dd,J＝7.9,1.2Hz,1H),7.40(dd,J＝8.2,1.2Hz,1H),7.23(dd,J＝3.6,2.4Hz,1H),4.88(dd,J＝9.2,5.2Hz,1H),4.56(ddd,J＝23.2,19.5,9.7Hz,2H),2.88(qd,J＝14.6,5.2Hz,1H),2.71–2.57(m,1H).ESI-MS m/z:478.9[M+H]+.
CLJ-33，1H NMR(400MHz,DMSO-d6)δ13.11(d,J＝31.9Hz,1H),8.44–7.30(m,10H),4.96(d,J＝60.1Hz,1H),4.55(d,J＝58.6Hz,1H),4.22(d,J＝14.1Hz,1H),3.03–2.85(m,1H),2.62(d,J＝37.2Hz,1H).ESI-MS m/z:479.9[M+H]+.
CLJ-34，1H NMR(400MHz,Chloroform-d)δ12.05(s,1H),8.07(s,1H),7.64–7.53(m,5H),7.48(ddd,J＝15.8,7.9,1.4Hz,2H),7.19(dd,J＝6.9,2.7Hz,1H),5.92(s,2H),5.11(s,1H),4.55(dd,J＝16.7,6.4Hz,2H),2.60–2.44(m,2H).ESI-MS m/z:479.9[M+H]+.
实施例35、实施例36、实施例37、实施例38分别为CLJ-35、CLJ-36、CLJ-37、CLJ-38的制备，制备方法同实施例1，将SM1替换为可直接购买的(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸，CLJ-35、CLJ-36、CLJ-37、CLJ-38最后一步的原料分别替换为2-氨基-6-氯嘌呤、4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶，得到终产品。
CLJ-35，1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.05(d,J＝106.1Hz,1H),7.76–7.34(m,8H),5.59(d,J＝59.0Hz,2H),5.17(d,J＝40.6Hz,1H),4.53(s,1H),2.13(s,1H),1.93(dd,J＝14.5,7.3Hz,2H),1.74(s,1H),1.57(d,J＝6.2Hz,3H).ESI-MS m/z:472.9[M+H]+.
CLJ-36，1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.08(s,1H),7.78(dd,J＝8.0,2.2Hz,1H),7.67–7.44(m,7H),7.38(dd,J＝8.2,1.2Hz,1H),7.18–7.14(m,1H),4.55(dt,J＝36.5,7.1Hz,2H),2.19(q,J＝7.7Hz,1H),2.05(q,J＝8.2Hz,2H),1.85(t,J＝8.4Hz,1H),1.61(d,J＝6.2Hz,3H).ESI-MS m/z:456.9[M+H]+.
CLJ-37，1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.25–8.10(m,2H),7.84–7.45(m,7H),7.38(d,J＝6.0Hz,1H),5.19(d,J＝61.5Hz,1H),4.54(d,J＝32.2Hz,1H),2.22(t,J＝6.6Hz,1H),2.12–1.91(m,2H),1.83(d,J＝8.3Hz,1H),1.67–1.55(m,3H).ESI-MS m/z:457.9[M+H]+.
CLJ-38，1H NMR(400MHz,DMSO-d6)δ8.41(s,2H),8.01(s,1H),7.73–7.61(m,2H),7.56(dd,J＝16.6,7.4Hz,2H),7.53–7.46(m,2H),7.18(s,2H),4.66(dt,J＝7.2,3.6Hz,1H),4.50(t,J＝7.5Hz,1H),2.12(s,1H),2.01(dt,J＝14.7,6.7Hz,2H),1.91(s,1H),1.82(s,1H),1.56(d,J＝6.2Hz,3H).ESI-MS m/z:457.9[M+H]+.
实施例39、实施例40、实施例41、实施例42、实施例43、实施例44分别为CLJ-39、CLJ-40、CLJ-41、CLJ-42、CLJ-43、CLJ-44的制备，制备方法同实施例1，将SM3替换为可直接购买的间三氟甲氧基苯胺，CLJ-39、CLJ-40、CLJ-41、CLJ-42、CLJ-43、CLJ-44最后一步的原料分别替换为4-氯-1H-吡唑并[3,4-d]嘧啶、2-氨基-6-氯嘌呤、4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶、2,6-二氯嘌呤，得到终产品。
CLJ-39，1H NMR(400MHz,Chloroform-d)δ8.97(s,1H),8.18(s,1H),7.51–7.46(m,2H),7.30(t,J＝7.9Hz,2H),7.12–7.07(m,1H),5.73(s,2H),4.94(dd,J＝7.8,5.0Hz,1H),4.79(td,J＝6.7,4.7Hz,1H),2.54(dt,J＝12.5,6.2Hz,1H),2.24(dt,J＝12.2,7.3Hz,1H),2.14–2.07(m,1H),1.97(ddd,J＝12.0,7.0,4.7Hz,1H),1.46(d,J＝6.3Hz,3H).ESI-MS m/z:322.2[M+H]+.
CLJ-40，1H NMR(400MHz,Chloroform-d)δ7.73–7.65(m,1H),7.64–7.55(m,2H),7.49(dt,J＝14.2,8.0Hz,2H),7.42–7.34(m,4H),7.25–7.14(m,1H),4.60(dt,J＝18.3,9.0Hz,2H),2.47–2.28(m,2H),2.24–2.12(m,2H),1.77(dt,J＝47.0,17.2Hz,6H),1.40–1.34(m,1H).ESI-MS m/z:597[M+H]+.
CLJ-41，1H NMR(400MHz,Chloroform-d)δ11.97(s,1H),8.16(d,J＝2.4Hz,1H),7.86(d,J＝7.2Hz,1H),7.62(dt,J＝28.1,8.2Hz,1H),7.49–7.34(m,4H),7.23–7.16(m,1H),7.06(d,J＝3.5Hz,1H),6.47(d,J＝3.6Hz,1H),4.71–4.60(m,1H),4.36(q,J＝7.9Hz,1H),2.44–2.26(m,4H),2.00–1.69(m,4H),1.67–1.56(m,1H),1.47–1.30(m,2H).ESI-MS m/z:581[M+H]+.
CLJ-42，1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.92(s,1H),7.80(d,J＝8.2Hz,1H),7.61(dt,J＝16.7,8.2Hz,1H),7.52–7.33(m,5H),7.20(d,J＝17.9Hz,1H),5.02(dt,J＝11.6,6.3Hz,1H),4.72–4.59(m,1H),2.50(s,1H),2.46–2.36(m,1H),2.33–2.20(m,2H),1.96(dt,J＝12.5,6.7Hz,1H),1.77(ddd,J＝36.4,18.7,8.4Hz,5H),1.62–1.53(m,1H).ESI-MS m/z:582[M+H]+.
CLJ-43，1H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.63–7.48(m,4H),7.47–7.36(m,2H),7.22–7.12(m,1H),5.70(s,2H),4.65–4.48(m,2H),2.44–2.15(m,4H),1.92–1.52(m,6H),1.28(d,J＝9.0Hz,1H).ESI-MS m/z:582[M+H]+.
CLJ-44，1H NMR(400MHz,Chloroform-d)δ8.06–8.03(m,1H),7.88(d,J＝2.7Hz,1H),7.71–7.64(m,1H),7.59(dd,J＝9.4,6.9Hz,1H),7.51(ddd,J＝8.5,7.5,1.2Hz,1H),7.45–7.36(m,4H),5.04–4.94(m,1H),4.59(ddd,J＝9.4,7.5,5.4Hz,1H),2.51–2.35(m,3H),2.33–2.27(m,1H),2.00–1.93(m,1H),1.77(dt,J＝34.5,17.7Hz,5H),1.57(d,J＝11.1Hz,1H).ESI-MS m/z:616.4[M+H]+.
CLJ-45至CLJ-91的制备方法同实施例1，CLJ-45至CLJ-49将SM3替换为间氟苯胺，CLJ-50将SM3替换为2-氨基-2-噻唑啉，CLJ-51替换为4-氨基四氢吡喃，CLJ-52至CLJ-56将SM3替换为间氨基吡啶，CLJ-57-CLJ-61将SM3替换为N-氨基吗啉，CLJ-62至CLJ-66将SM3替换为3,5-二氟苯胺，CLJ-66至CLJ-71将SM2替换为2-氨基-6-氟苯甲酸，将SM3替换为3,5-二氟苯胺，CLJ-72至CLJ-76将SM1替换为可以购买的(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸，将SM3替换为间氟苯胺，CLJ-77至CLJ81将SM1替换为可以购买的(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸，将SM3替换为3,5-二氟苯胺，CLJ-82至CLJ-86将SM1替换为可以购买的(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸，将SM3替换间氨基吡啶，CLJ-87至CLJ-91将SM1替换为可以购买的(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸，将SM3替换为N-氨基吗啉，获得关键中间体，中间体分别和2-氨基-6-氯嘌呤、4-氯吡咯并嘧啶、6-氯嘌呤、4-氨基-5-氰基-6-氯嘧啶、2,4-二氨基-6-氯-5-氰基嘧啶反应获得终产品。结果表征如下：
药效学试验部分
以下代表性实验(不限于此)用于分析本发明化合物的生物活性
(1)检测化合物在酶水平对PI3Kα、β、γ、δ四个亚型的抑制活性
实验方法
本实验中所采用的激酶活性测试方法基本相同，只是根据不同的激酶及对应的不同底物，采取不同的浓度以达到最佳的检测范围。
PI3K抑制活性实验方法：40mMTris，pH7.4，10mMMgC12，0.1mg/ml BSA，1mM DTT，10μMATP，PI3K激酶，激酶底物；同时加入不同浓度的待筛化合物，组成50uL的反应体系，在30℃下反应40分钟，后用荧光素酶的方法检测体系内的ADP含量，再反应5分钟后，在MD-SpectralMax M5多功能酶标仪上检测化学发光信号，化学发光信号值强度与酶活性抑制成正比。检测到的化学发光信号值，代入如下公式：
酶活性百分率(％)＝(0D值给药孔-0D值本底)/(OD值对照孔-OD值本底)×100％
药物浓度按照三倍浓度梯度稀释，每个浓度均检测两个复孔。将药物浓度作为横坐标，各浓度对应的酶活性百分率为纵坐标，使用Graphpad Prism5做非线性回归，计算得到各测试化合物的IC50值。
部分实例实验结果见表1和表2。
表1部分化合物在不同浓度下对PI3K四个亚型的抑制活性
“▲”代表在设定浓度下抑制率大于50％，“”代表在设定浓度下抑制率小于50％。
表2部分化合物对PI3K四个亚型的IC50值
“+++”代表IC50范围在0-50nM，“++”代表IC50范围在50-100nM，“+”代表IC50范围在100-200nM，“-”代表IC50范围在200-500nM，“--”代表IC50范围500-1000nM，“---”代表IC50＞1000nM。
结果表明，本发明受试化合物对PI3K具有较好的抑制活性。
(2)检测化合物对肿瘤及炎症相关细胞的增殖抑制活性
实验方法
将处于对数生长期的细胞(包括但不限于细胞株OCI-AML2、Daudi、Raji、Jurkat)以一定数量接种于96孔板(200uL/孔)，培养24小时使之贴壁后加药。每个药物浓度设3个复孔，并设相应的调零孔及空白对照。药物作用72小时后，贴壁细胞加入50％TCA(50uL/孔)，4℃固定1小时，倒掉固定液，用蒸馏水洗5次，自然干燥。每孔加入100μL 4mg/mL SRB，室温染色15分钟，弃之，用1％冰醋酸洗5次，自然干燥。最后每孔加入150uL 10mMTris溶液，摇匀，用可调波长式微孔板酶标仪(VERSAmaxTM，Molecular Device)在565nm波长下测定0D值。结果统计分析得出抑制率或IC50值,结果见表3。
实验结果如下：
表3部分化合物的体外细胞实验结果
“※※※※”代表IC50≤10μM；“※※※”代表IC50范围为10-20μM；“※※”代表IC50范围为20-50μM；“※”代表IC50≥50μM。
结果表明，本发明的受试化合物对OCI-AML2、Daudi、JurKat、Raji细胞增殖均具有较好的抑制活性，其中某些化合物比CAL-101和IPI-145展示更好的抗增殖活性，是一种新型的、潜在的和具备治疗PI3K相关疾病潜力的抑制剂。
Claims (20)
1.式Ⅰ所示的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物：
环A选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烯基、取代或未取代的杂环烯基；
环B选自取代或未取代的5元环烷基、取代或未取代的5～9元杂环烷基，所述杂环烷基含有1个杂原子，杂原子为N；
R1、R2、R3、R4独立的选自氢、卤素、C1～C6烷基、-C≡C-R6；
R5选自取代或未取代的杂芳基；
R6选自C1～C6烷基取代的5～6元杂芳基。
2.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于：
环A选自取代或未取代的5～6元芳基、取代或未取代的5～6元杂芳基、取代或未取代的5～6元杂环烷基、取代或未取代的5～6元杂环烯基，所述杂芳基、杂环烷基和杂环烯基均有1～2个杂原子，所述杂原子为N、O或S；
优选的，环A选自取代或未取代的6元芳基、取代或未取代的6元杂芳基、取代或未取代的6元杂环烷基、取代或未取代的5元杂环烯基，所述杂芳基、杂环烷基和杂环烯基均有1～2个杂原子，所述杂原子为N、O或S；
更优选的，环A选自苯基、取代的苯基、吡啶基、取代的吡啶基、吗啉基、取代的吗啉基、四氢吡喃基、取代的四氢吡喃基、噻唑啉基、取代的噻唑啉基，所述取代的苯基、取代的吡啶基、取代的吗啉基、取代的四氢吡喃基和取代的噻唑啉基均有至少一个选自下组的取代基：卤素、C1～C6烷基、卤素取代的C1～C6烷基、C1～C6烷氧基、卤素取代的C1～C6烷氧基、
最优选的，环A选自苯基、吡啶基、吗啉基、甲基取代的吡啶基、四氢吡喃基、噻唑林基、取代的苯基，所述取代的苯基有至少一个选自下组的取代基：卤素、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、
3.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于：R1、R2、R3、R4独立的选自氢、卤素、C1～C3烷基、-C≡C-R6；
优选的，R1、R2、R3、R4同时为氢，或者R1、R2、R3同时为氢，R4选自卤素、C1～C3烷基、-C≡C-R6；
最优选的，R1、R2、R3、R4同时为氢，或者R1、R2、R3同时为氢，R4选自卤素、甲基、-C≡C-R6。
4.根据权利要求3所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于：R6选自C1～C6烷基取代的5元杂芳基，所述杂芳基有1～2个杂原子，杂原子为N；
优选的，R6选自C1～C3烷基取代的5元杂芳基，所述杂芳基有1～2个杂原子，杂原子为N；
更优选的，R6选自C1～C3烷基取代的吡唑基；
最优选的，R6选自甲基取代的吡唑基。
5.根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于：R5选自取代或未取代的6～9元杂芳基，所述杂芳基有1～4个杂原子，杂原子为N或S；
优选的，R5选自
其中，X选自CH或N，Y选自O或S，R7、R8、R9、R10独立的选自氢、-NH2、氰基、卤素、C1～C3烷基、取代或未取代的吡唑基、取代或未取代的苯基、取代或未取代的茚基，所述取代的吡唑基、取代的苯基和取代的茚基有至少一个选自下组的取代基：卤素、羟基、甲磺酰氨基、氨基磺酰氨基；
最优选的，R5选自
6.根据权利要求1～5任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下式Ⅱ：
R11、R12、R13、R14、R15独立的选自氢、卤素、C1～C3烷基。
7.根据权利要求6所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，具有以下两种结构：
8.根据权利要求6所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下：
9.根据权利要求1～5任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下式Ⅲ：
R16、R17、R18、R19独立的选自氢、卤素、C1～C3烷基。
10.根据权利要求9所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，具有以下两种结构：
11.根据权利要求9所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下：
12.根据权利要求1～5任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下式Ⅳ：
R20、R21、R22独立的选自氢、卤素、C1～C3烷基、-OR23、＝CH2、酮基；
R23选自氰基、C2～C3烯基。
13.根据权利要求12所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，具有以下两种结构：
14.根据权利要求12所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物，其特征在于，结构式如下：
15.权利要求1～14任一项所述化合物的制备方法，其特征在于，包括以下步骤：
其中，X表示卤素；
(1)将M1与M2溶于有机溶剂，惰性气体保护下加入催化剂反应后得到M3；
(2)M3与M4反应，经萃取、洗涤、干燥后得到M5；
(3)将M5溶于有机溶剂，加入强酸反应，反应结束后加入碱性溶液中和至弱碱性，经萃取、浓缩、柱层析纯化得到M6；
(4)将M6与M7溶于有机溶剂中，加入碱反应，反应结束后，经萃取、洗涤、浓缩、柱层析纯化后得到式Ⅰ。
16.根据权利要求15所述的制备方法，其特征在于，满足以下至少一项：
步骤(1)中，所述有机溶剂为吡啶；
步骤(1)中，所述惰性气体为氮气；
步骤(1)中，所述催化剂为亚磷酸三苯酯；
步骤(1)中，所述M1与M2的摩尔比为1：1；
步骤(1)中，所述反应的温度为60～75℃；
步骤(2)中，所述M3与M4的摩尔比为1：1～1.2；
步骤(2)中，所述反应的温度为60～75℃；
步骤(3)中，所述有机溶剂为乙酸乙酯；
步骤(3)中，所述强酸为浓盐酸；
步骤(4)中，所述有机溶剂为正丁醇；
步骤(4)中，所述碱为三乙胺；
步骤(4)中，所述M6与M7的摩尔比为1：1～1.2；
步骤(4)中，所述反应的温度为75～85℃。
17.药物组合物，由权利要求1～14任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物为活性成分，添加药学上可接受的辅助性成分组成。
18.权利要求1～14任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物在制备PI3K抑制剂中的用途；优选的，所述PI3K抑制剂为PI3Kδ抑制剂、PI3Kγ抑制剂、PI3Kα抑制剂或PI3Kβ抑制剂。
19.权利要求1～14任一项所述的化合物、其药学上可接受的盐、其立体异构体或其溶剂化物在制备预防和/或治疗与PI3K相关疾病的药物中的用途。
20.根据权利要求19所述的用途，其特征在于：所述与PI3K相关疾病为肿瘤和炎性疾病；优选的，所述肿瘤为白血病、霍奇金氏淋巴瘤、骨髓增生症、非霍奇金氏淋巴瘤、多发性骨髓瘤、乳腺癌、肉瘤、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、肝癌、卵巢癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤或皮肤癌；所述炎性疾病为过敏、哮喘、类风湿性关节炎、骨关节炎、过敏性结膜炎、过敏性角膜炎、慢性阻塞性肺病、红斑狼疮、牛皮癣、多发性硬化症或晚期肾病。
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