CN116987085A - 一种PI3Kδ抑制剂及其用途 - Google Patents
一种PI3Kδ抑制剂及其用途 Download PDFInfo
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- CN116987085A CN116987085A CN202210540111.6A CN202210540111A CN116987085A CN 116987085 A CN116987085 A CN 116987085A CN 202210540111 A CN202210540111 A CN 202210540111A CN 116987085 A CN116987085 A CN 116987085A
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- Prior art keywords
- compound
- pi3k delta
- alkyl
- mmol
- delta inhibitor
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Abstract
本发明涉及一种新型的PI3Kδ抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药。本发明还提供PI3Kδ抑制剂在制备用于抑制PI3Kδ激酶活性或5治疗与PI3Kδ激酶活性相关的疾病或病症的药物中的用途。
Description
技术领域
本发明属于生物医药领域，具体涉及作为选择性PI3Kδ抑制剂的化合物、以及使用这样的化合物抑制PI3Kδ激酶活性及治疗与抑制PI3Kδ激酶活性相关的疾病或病症的方法和用途。
背景技术
PI3K称为磷脂酰肌醇-3-激酶，按照结构和底物差异可以分为三类：I类、II类和III类。I类PI3K利用磷酸肌醇4,5-二磷酸生成磷酸肌醇3,4,5-三磷酸(PIP3)，它由一个催化亚基和一个调节亚基构成，具体又可以分为IA和IB两个家族。其中IB PI3K由催化亚基P110γ与p101或p84调节亚基偶联而成。IA PI3K又可分为PI3Kα、PI3Kβ、PI3Kδ三种亚型，其催化亚基分别是p110α、p110β和p110δ，它们与p85α、p55α、p50α、p85β、p55γ五个调节亚基之一偶联成IA PI3K。PI3Kα和PI3Kβ广泛表达于多种细胞，PI3Kδ则主要表达于造血细胞和免疫细胞中，是关键的B细胞受体信号中介，与B细胞的存活、迁移、激活密切相关，在B细胞相关的自身免疫疾病和恶性血液肿瘤的发生发展中作为关键的信号分子，因而成为治疗这些疾病潜在有效的靶点。
Idelalisib、Copanlisib和Duvelisib是三款获批的PI3Kδ抑制剂。其中，吉利德研发的PI3Kδ抑制剂Idelalisib耐受性极差，有4项黑框警告，副作用几乎遍布全身，如肝脏(转氨酶升高)、消化道(腹泻、结肠炎、肠穿孔)、免疫系统(肺炎、感染)、皮肤(皮疹)以及血液(中性粒细胞减少)，在临床中更是有超过50％的治疗中止率，最终退出市场。Duvelisib则有1项黑框警告。
PI3Kδ抑制剂的出现虽然开辟了恶性血液肿瘤治疗的新局面，但由于现有的PI3Kδ抑制剂均存在较为严重的副作用，因此迫切需要开发具有高效力、高选择性、低毒性的新型PI3Kδ抑制剂。
发明内容
本发明的一个目的在于提供一类PI3Kδ抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药：
其中，
R1各自独立地选自卤素和C1-C4烷基；m为1或2；
R2选自C3-C6环烷基、C3-C6环烷基C1-C4烷基、和任选地被卤素或甲基取代的苯基或吡唑基；
R3、R4各自独立地选自H和C1-C4烷基；
R5选自C3-C8支链烷基、C1-C8卤代烷基、C1-C4烷氧基C1-C4烷基、C2-C6羟基烷基、C3-C6环烷基C1-C4烷基、4-6元杂环烷基、和4-6元杂环烷基C1-C4烷基。
在优选的实施方式中，R5选自异丙基、异丁基、戊-3-基、一卤代烷基(优选卤代乙基)、二卤代烷基(优选二卤代甲基)、1-乙氧基-乙基、羟乙基、环丙基甲基、氧杂环丁基、四氢吡喃基和吗啉基乙基。特别优选地，R5为二氟甲基。
在另外优选的实施方式中，R1选自氟和甲基。
在又一优选的实施方式中，R2选自环丙基、环丙基甲基、氟代苯基、和N-甲基-吡唑基。
在其他优选的实施方式中，R3和R4中一个为H，另一个为甲基或乙基。
另一方面，本申请还提供一种药物组合物，其包括式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药、和药学上可接受的稀释剂或载体、以及任选的其他活性成分。
在其他方面，本申请还涉及式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药在制备用于抑制PI3Kδ激酶活性或治疗与PI3Kδ激酶活性相关的疾病或病症的药物中的用途。
所述疾病或病症选自慢性淋巴细胞白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、套细胞淋巴瘤、慢性阻塞性肺病、类风湿性关节炎、系统性红斑狼疮和哮喘。
本发明还涉及抑制PI3Kδ激酶活性、或治疗与PI3Kδ激酶活性相关的疾病或病症的方法，包括对患者施用治疗有效量的式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药、或包括其的药物组合物。
附图说明
图1示出本发明的化合物12、化合物24、Linperlisib及溶媒给药后对DOHH2小鼠移植瘤模型中小鼠体重的影响。
图2示出本发明的化合物12、化合物24、Linperlisib及溶媒给药后对DOHH2小鼠移植瘤模型肿瘤大小的影响。
图3示出本发明的化合物24、比较例化合物1及溶媒给药后对MC38小鼠移植瘤模型中小鼠体重的影响。
图4示出本发明的化合物24、比较例化合物1及溶媒给药后对MC38小鼠移植瘤模型肿瘤大小的影响。
图5示出本发明的化合物24、比较例化合物1及溶媒给药后对MC38小鼠移植瘤模型肿瘤重量的影响。
具体实施方式
术语
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异戊基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
术语“氨基”是指-NH2基团。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。
术语“氨酰基”或“胺酰基”是指-CO-NH2基团。
术语“烷基氨酰基”或“烷基胺酰基”是指-CO-NH-R基团，其中R为本文定义的烷基。
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本文使用的术语“酪氨酸蛋白激酶(tyrosine protein kinase，TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《ThePharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
本文使用的IC50是指在测量这样的效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。
本文使用的GI50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本发明新型的激酶抑制剂
本发明提供一种PI3Kδ抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药：
其中，
R1各自独立地选自卤素和C1-C4烷基；m为1或2；
R2选自C3-C6环烷基、C3-C6环烷基C1-C4烷基、和任选地被卤素或甲基取代的苯基或吡唑基；
R3、R4各自独立地选自H和C1-C4烷基；
R5选自C3-C8支链烷基、C1-C8卤代烷基、C1-C4烷氧基C1-C4烷基、C2-C6羟基烷基、C3-C6环烷基C1-C4烷基、4-6元杂环烷基、和4-6元杂环烷基C1-C4烷基。
在优选的实施方式中，R5选自异丙基、异丁基、戊-3-基、一卤代烷基(优选卤代乙基)、二卤代烷基(优选二卤代甲基)、1-乙氧基-乙基、羟乙基、环丙基甲基、氧杂环丁基、四氢吡喃基和吗啉基乙基。特别优选地，R5为二氟甲基。
在另外优选的实施方式中，R1选自氟和甲基。
在又一优选的实施方式中，R2选自环丙基、环丙基甲基、氟代苯基和N-甲基-吡唑基。
在其他优选的实施方式中，R3和R4中一个为H，另一个为甲基或乙基。
对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文也描述了此化合物的药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药。
在优选的实施方式中，本发明涉及以下表1的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药。
表1
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐，通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱或无机碱配位，可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、溶剂化物和/或多晶型物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明提供的PI3Kδ抑制剂，当吡唑基上的R5取代基为较大位阻基团(如卤代烷基或者其它支链烷基、环烷基烷基、杂环烷基等)时，与现有技术的化合物相比无论是在蛋白水平还是在细胞水平，对PI3Kδ磷酸化的抑制更为显著。
本发明的药物用途
本发明的式(I)的化合物、或其药学可接受盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药，能抑制PI3Kδ激酶活性，达到治疗与PI3Kδ激酶活性相关的疾病或病症的目的。
因此，本申请涉及式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药在制备用于抑制PI3Kδ激酶活性、或治疗与PI3Kδ激酶活性相关的疾病或病症的药物中的用途。
所述疾病或病症选自慢性淋巴细胞白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、套细胞淋巴瘤、慢性阻塞性肺病、类风湿性关节炎、系统性红斑狼疮和哮喘。
在本发明的实施方式中，可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)。但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中，本文提供的是本文描述的PI3Kδ抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
中间体的制备
中间体1：2-(1-氯丙基)-3-环丙基-5-氟代喹唑啉-4(3H)-酮的合成
步骤1：向2-氨基-6-氟苯甲酸(5.0g,32.2mmol,1.0eq)四氢呋喃溶液(50mL)中加入环丙基胺(2.21g,38.7mmol,1.2eq)、HATU(14.71g,38.7mol,1.2eq)和DIPEA(8.33g,64.5mmol,2.0eq)。室温下搅拌反应16小时，减压蒸除溶剂，残余物用乙酸乙酯稀释并依次用饱和食盐水、水洗涤有机层，无水Na2SO4干燥30min，过滤、浓缩、石油醚打浆过滤得到类白色固体，LC-MS(ESI)：195.1(M+H)+。
步骤2：0℃下，向2-氯丁酸(3.84g,35.42mmol,1.0eq)的无水四氢呋喃溶液(40mL)中滴加草酰氯(COCl2)(5.40g,42.5mmol,1.2eq)及催化量的DMF(0.06mL)。滴加完成后，反应液升至室温(25℃)，反应两小时后直接用于下一步反应。
步骤3：0℃下，将上述步骤1得到的中间体(32.2mmol,1.0eq)溶于无水四氢呋喃(60mL)中，向其中加入DIPEA(12.49g,96.6mmol,3.0eq)及步骤2得到的酰氯(35.42mmol,1.1eq)。搅拌反应2小时，浓缩反应液至干，残余物用二氯甲烷稀释，依次用饱和食盐水、水洗涤有机相，无水硫酸钠干燥，过滤浓缩得到固体化合物，LC-MS(ESI):285(M+H)+。
步骤4：将步骤3得到的中间体(32.2mmol,1.0eq)溶于乙腈，向其中加入HMDS(25.82g,160mmol，5.0eq))和氯化锌(21.81g,160mmol,5.0eq)，于90℃搅拌反应16小时后，减压蒸除溶剂，残余物用二氯甲烷稀释，过滤，将滤液浓缩至干，柱层析(3-6％乙酸乙酯的石油醚混合溶液)得到5.4g白色固体化合物中间体1。
LC-MS(ESI):281.7(M+H)+。
通过上述方法合成如表2所列的中间体：
表2
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中间体14：3-(1-(1-乙氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺的合成
步骤1:向3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(5.0g,19.2mmol,1.0eq)加入1,4-二氧六环/水(50mL/16mL)的混合溶液，向其中加入1-(1-乙氧基乙基)-4-吡唑硼酸频哪醇酯(7.01g,28.7mmol,1.5eq)，氮气置换两次，氮气氛围下加入Pd(PPh3)4(3.32g,2.87mmol,0.15eq)，K2CO3(5.29g,38.3mmol,2.0eq)，加完后氮气置换5次，随后升温至135℃反应24小时。减压浓缩除去溶剂，向残余物中加水(200mL)，搅拌2小时，过滤，二氯甲烷洗涤滤饼2次，得到类白色固体化合物中间体14。LC-MS(ESI):274.3(M+H)+。
通过上述方法合成如表3所列的中间体：
表3
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实施例1.
将中间体1(2g,7.5mmol,1.0eq)溶于DMF(20mL)中，向其中加入中间体14(2.26g,9.0mmol,1.2eq)以及K2CO3(2.07g,15.0mmol,2.0eq)，然后升温至60℃搅拌反应6小时。向反应液中加入水，有大量固体析出。搅拌15分钟后，过滤，水洗滤饼3次，收集滤饼，柱层析分离(含0-8％MeOH的二氯甲烷混合溶液)得白色固体化合物1共2.1g，收率57％。1H NMR(500MHz,DMSO-d6)δ8.28-8.22(m,2H),7.80-7.75(m,2H),7.45(dd,J＝8.2,1.0Hz,1H),7.27(ddt,J＝10.9,8.2,1.3Hz,1H),6.49(dd,J＝9.1,5.0Hz,1H),5.59(q,J＝5.9Hz,1H),3.49-3.39(m,1H),3.27(ddd,J＝7.1,6.0,3.5Hz,1H),2.49-2.34(m,2H),2.17-2.09(m,1H),1.62(d,J＝6.0Hz,3H),1.21-1.08(m,3H),1.04(td,J＝7.0,1.0Hz,3H),0.89(td,J＝7.3,1.3Hz,3H),0.81-0.74(m,1H)。
实施例2.
参考实施例1的合成方法，由中间体13(2g,6.7mmol,1.0eq)与中间体21(2.02g,8.03mmol,1.2eq)合成得到化合物2，为白色固体1.8g，收率53％。1H NMR(500MHz,DMSO-d6)δ8.51(s,1H),8.26(s,1H),8.00(s,1H),7.95-7.57(m,3H),7.10(s,2H),6.52(dd,J＝9.1,5.0Hz,1H),2.39(ddd,J＝14.0,9.0,7.2Hz,1H),2.16(td,J＝6.9,3.5Hz,1H),1.26-1.07(m,3H),0.91(t,J＝7.3Hz,3H),0.81(tt,J＝9.9,5.2Hz,1H).LC-MS(ESI):513.2(M+H)+.
实施例3.
参考实施例1的合成方法，由中间体13(2g,6.7mmol,1.0eq)与中间体18(1.95g,8.03mmol,1.2eq)合成得到化合物3，为白色固体1.5g，收率44％。1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.06(s,1H),7.83(ddd,J＝10.2,9.0,2.9Hz,1H),7.68(s,1H),7.65-7.53(m,1H),6.50(dd,J＝9.0,5.0Hz,1H),4.54(p,J＝6.6Hz,1H),2.37(ddd,J＝13.9,9.0,7.2Hz,1H),2.11(dq,J＝9.6,3.5,2.7Hz,1H),1.44(dd,J＝6.6,1.3Hz,6H),1.26-1.06(m,4H),0.89(t,J＝7.3Hz,3H),0.78(ddd,J＝12.3,6.3,3.8Hz,1H).LC-MS(ESI):505.2(M+H)+.
实施例4.
参考实施例1的合成方法，由中间体1(0.2g,0.71mmol)与中间体17(0.22g,0.78mmol)合成得到化合物4，为白色固体79mg，收率21％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.11(d,J＝0.7Hz,1H),7.78(td,J＝8.2,5.4Hz,1H),7.72(d,J＝0.7Hz,1H),7.45(dd,J＝8.1,1.0Hz,1H),7.27(ddd,J＝11.0,8.2,1.0Hz,1H),6.47(dd,J＝9.1,5.0Hz,1H),4.44(td,J＝10.3,5.0Hz,1H),3.99-3.92(m,2H),3.48-3.40(m,2H),2.48-2.34(m,2H),2.08(td,J＝6.9,3.4Hz,1H),2.04-1.97(m,4H),1.21-1.08(m,3H),0.89(t,J＝7.4Hz,3H),0.80-0.73(m,1H)。
实施例5.
参考实施例1的合成方法，由中间体1(0.2g,0.71mmol)与中间体18(0.21g,0.85mmol)合成得到化合物5，为白色固体0.13g，收率37％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.07(d,J＝0.8Hz,1H),7.78(td,J＝8.2,5.5Hz,1H),7.69(d,J＝0.7Hz,1H),7.45(dd,J＝8.2,1.0Hz,1H),7.27(ddd,J＝11.0,8.2,1.1Hz,1H),6.47(dd,J＝9.2,5.0Hz,1H),4.55(p,J＝6.6Hz,1H),2.47-2.35(m,2H),2.12-2.06(m,1H),1.44(dd,J＝6.7,1.4Hz,6H),1.20-1.08(m,3H),0.88(t,J＝7.4Hz,3H),0.77(dp,J＝8.0,5.2,4.5Hz,1H)。
实施例6.
参考实施例1的合成方法，由中间体1(0.2g,0.71mmol)与中间体19(0.27g,0.85mmol)合成得到化合物6，为白色固体0.21g，收率50％，1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),8.12(s,1H),7.78(td,J＝8.2,5.4Hz,1H),7.67(s,1H),7.45(dd,J＝8.2,1.0Hz,1H),7.28(dd,J＝10.9,8.2Hz,1H),6.47(dd,J＝9.1,5.0Hz,1H),4.27(t,J＝6.5Hz,2H),3.51(t,J＝4.6Hz,4H),2.72(t,J＝6.5Hz,2H),2.48-2.32(m,6H),2.06(td,J＝6.9,3.4Hz,1H),1.13(tdd,J＝17.0,8.2,5.5Hz,3H),0.90(t,J＝7.4Hz,3H),0.77(td,J＝8.4,7.8,4.2Hz,1H)。
实施例7.
参考实施例1的合成方法，由中间体1(0.2g,0.71mmol)与中间体20(0.21g,0.85mmol)合成得到化合物7，为白色固体89mg，收率25.6％，1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),8.12(s,1H),7.78(td,J＝8.2,5.4Hz,1H),7.67(s,1H),7.45(dd,J＝8.2,1.0Hz,1H),7.28(dd,J＝10.9,8.2Hz,1H),6.47(dd,J＝9.1,5.0Hz,1H),4.27(t,J＝6.5Hz,2H),3.51(t,J＝4.6Hz,4H),2.72(t,J＝6.5Hz,2H),2.48-2.32(m,6H),2.06(td,J＝6.9,3.4Hz,1H),1.13(tdd,J＝17.0,8.2,5.5Hz,3H),0.90(t,J＝7.4Hz,3H),0.77(td,J＝8.4,7.8,4.2Hz,1H)。
实施例8.
参考实施例1的合成方法，由中间体1(0.2g,0.71mmol)与中间体21(0.21g,0.85mmol)合成得到化合物8，为白色固体0.11g，收率32％，1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.26(d,J＝5.6Hz,1H),8.02(s,1H),7.95-7.66(m,2H),7.43(d,J＝8.2Hz,1H),7.27(dd,J＝10.4,8.3Hz,1H),7.10(s,1H),6.49(dd,J＝9.1,5.0Hz,1H),2.49-2.43(m,1H),2.43-2.33(m,1H),2.20-2.10(m,1H),1.22-1.16(m,1H),1.16-1.06(m,2H),0.90(t,J＝7.3Hz,3H),0.83-0.75(m,1H)。
实施例9.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体18(0.21g,0.85mmol)合成得到化合物9，为白色固体0.12g，收率36％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.06(s,1H),7.80-7.62(m,4H),6.98(s,1H),6.50(dd,J＝9.1,5.0Hz,1H),4.60-4.46(m,1H),2.48-2.42(m,1H),2.42-2.32(m,1H),2.20-2.09(m,1H),1.43(dd,J＝6.6,1.3Hz,6H),1.26-1.07(m,3H),0.88(t,J＝7.3Hz,3H),0.84-0.75(m,1H)。
实施例10.
参考实施例1的合成方法，由中间体4(0.2g,0.74mmol)与中间体18(0.22g,0.90mmol)合成得到化合物10，为白色固体0.14g，收率42％，1H NMR(500MHz,DMSO)δ8.24(s,1H),8.07(s,1H),7.80-7.65(m,4H),6.73(s,2H),6.71(t,J＝6.6Hz,1H),4.61-4.49(m,1H),2.19-2.09(m,1H),1.84(d,J＝6.6Hz,3H),1.44(d,J＝6.5Hz,6H),1.26-1.15(m,1H),1.14-1.03(m,2H),0.80(dd,J＝8.3,3.4Hz,1H)。
实施例11.
参考实施例1的合成方法，由中间体5(0.2g,0.0.68mmol)与中间体18(0.2g,0.81mmol)合成得到化合物11，为白色固体0.16g，收率48％，1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.09(s,1H),7.83(td,J＝8.2,5.5Hz,1H),7.70(s,1H),7.55(d,J＝8.1Hz,1H),7.32(dd,J＝10.6,8.4Hz,1H),7.00(s,1H),6.10(dd,J＝9.2,5.1Hz,1H),4.55(dq,J＝13.3,6.6Hz,1H),4.08(dd,J＝14.5,5.6Hz,1H),3.77(dd,J＝14.5,7.6Hz,1H),2.46(d,J＝8.9Hz,1H),2.42-2.34(m,1H),1.43(dd,J＝6.6,1.5Hz,6H),0.75(t,J＝7.3Hz,3H),0.53(s,1H),0.36(tt,J＝10.3,5.1Hz,2H),0.18-0.06(m,1H),0.02(d,J＝4.9Hz,1H)。
实施例12.
参考实施例1的合成方法，由中间体4(0.2g,0.75mmol)与中间体21(0.23g,0.90mmol)合成得到化合物12，为白色固体0.23g，收率64％，1H NMR(500MHz,DMSO)δ8.53(s,1H),8.26(s,1H),8.02(s,1H),7.88(d,J＝58.8Hz,1H),7.78-7.68(m,3H),7.14(s,2H),6.74(q,J＝6.6Hz,1H),2.19(t,J＝6.7Hz,1H),1.87(d,J＝6.6Hz,3H),1.20(dd,J＝9.3,3.7Hz,1H),1.10(d,J＝5.4Hz,2H),0.83(dd,J＝8.4,3.4Hz,1H)。
实施例13.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体21(0.21g,0.85mmol)合成得到化合物13，为白色固体0.13g，收率37％，1H NMR(500MHz,DMSO)δ8.52(s,1H),8.26(s,1H),8.01(s,1H),7.87(d,J＝58.8Hz,1H),7.77-7.67(m,3H),7.13(s,2H),6.53(d,J＝14.1Hz,1H),2.48(dd,J＝10.0,4.8Hz,1H),2.44-2.37(m,1H),2.25-2.19(m,1H),1.22(dd,J＝11.5,7.1Hz,1H),1.19-1.10(m,2H),0.91(t,J＝7.3Hz,3H),0.87-0.80(m,1H)。
实施例14.
参考实施例1的合成方法，由中间体4(0.2g,0.75mmol)与中间体20(0.22g,0.89mmol)合成得到化合物14，为白色固体0.11g，收率32％，1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),8.01(s,1H),7.79-7.65(m,4H),6.96(s,1H),6.70(q,J＝6.6Hz,1H),4.89(t,J＝5.6Hz,1H),4.18(t,J＝5.5Hz,2H),3.74(q,J＝5.6Hz,2H),2.11(tt,J＝7.2,4.2Hz,1H),1.84(d,J＝6.6Hz,3H),1.21-1.13(m,1H),1.08(q,J＝6.5Hz,2H),0.79(dt,J＝9.5,4.1Hz,1H)。
实施例15.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体20(0.21g,0.85mmol)合成得到化合物15，为白色固体0.2g，收率58％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.01(s,1H),7.79-7.62(m,4H),6.99(s,1H),6.50(dd,J＝9.1,5.0Hz,1H),4.88(t,J＝5.6Hz,1H),4.18(t,J＝5.5Hz,2H),3.74(q,J＝5.6Hz,2H),2.48-2.43(m,1H),2.38(dt,J＝21.2,7.3Hz,1H),2.20-2.11(m,1H),1.15(dddd,J＝20.4,16.7,8.0,4.9Hz,3H),0.89(t,J＝7.3Hz,3H),0.82-0.75(m,1H)。
实施例16.
参考实施例1的合成方法，由中间体11(0.2g,0.59mmol)与中间体21(0.18g,0.71mmol)合成得到化合物16，为白色固体0.18g，收率33％，1H NMR(500MHz,DMSO-d6)δ8.57(d,J＝12.1Hz,1H),8.06(s,1H),8.03-7.90(m,2H),7.86-7.57(m,2H),7.53-7.37(m,1H),7.28-6.97(m,2H),6.88(ddt,J＝22.0,15.2,8.3Hz,2H),6.28-6.15(m,1H),6.02(dq,J＝33.9,6.6Hz,1H),1.74(d,J＝6.5Hz,3H)。
实施例17.
参考实施例1的合成方法，由中间体10(0.2g,0.76mmol)与中间体21(0.23g,0.91mmol)合成得到化合物17，为白色固体0.17g，收率47％，1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.25(s,1H),8.01(s,1H),7.81(t,J＝58.7Hz,1H),7.61(t,J＝7.7Hz,1H),7.42(d,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),7.12(s,1H),6.69(q,J＝6.6Hz,1H),2.72(s,3H),2.15-2.03(m,1H),1.84(d,J＝6.7Hz,3H),1.17-1.11(m,1H),1.10-1.01(m,2H),0.74(dd,J＝7.3,3.2Hz,1H)。
实施例18.
参考实施例1的合成方法，由中间体10(0.2g,0.76mmol)与中间体18(0.22g,0.91mmol)合成得到化合物18，为白色固体0.15g，收率42％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.07(s,1H),7.68(s,1H),7.62(t,J＝7.8Hz,1H),7.44(d,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),6.99(s,1H),6.67(q,J＝6.6Hz,1H),4.54(dt,J＝13.3,6.7Hz,1H),2.72(s,3H),2.05-1.98(m,1H),1.82(d,J＝6.7Hz,3H),1.44(dd,J＝6.6,1.2Hz,6H),1.14(dd,J＝8.6,3.9Hz,1H),1.09-0.99(m,2H),0.75-0.64(m,1H)。
实施例19.
参考实施例1的合成方法，由中间体5(0.2g,0.68mmol)与中间体21(0.2g,0.81mmol)合成得到化合物19，为白色固体0.15g，收率45％，1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.33(s,1H),8.03(s,1H),7.93-7.66(m,2H),7.54(d,J＝8.2Hz,1H),7.32(dd,J＝10.9,8.2Hz,1H),7.26-7.05(m,1H),6.13(dd,J＝9.2,5.2Hz,1H),4.09(dd,J＝14.5,5.7Hz,1H),3.81(dd,J＝14.6,7.5Hz,1H),2.49-2.45(m,1H),2.43-2.36(m,1H),0.79(t,J＝7.3Hz,3H),0.59(d,J＝7.2Hz,1H),0.43-0.34(m,2H),0.20-0.11(m,1H),0.09-0.04(m,1H)。
实施例20.
参考实施例1的合成方法，由中间体5(0.2g,0.68mmol)与中间体20(0.2g,0.81mmol)合成得到化合物20，为白色固体0.11g，收率33％，1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.04(d,J＝0.8Hz,1H),7.83(td,J＝8.2,5.4Hz,1H),7.70(d,J＝0.8Hz,1H),7.55(dd,J＝8.2,1.0Hz,1H),7.36-7.28(m,1H),6.10(dd,J＝9.2,5.2Hz,1H),4.88(t,J＝5.6Hz,1H),4.18(t,J＝5.5Hz,2H),4.08(dd,J＝14.6,5.7Hz,1H),3.84-3.77(m,1H),3.74(q,J＝5.6Hz,2H),2.48-2.44(m,1H),2.39(ddd,J＝15.2,7.9,5.9Hz,1H),0.77(t,J＝7.3Hz,3H),0.56(d,J＝7.0Hz,1H),0.41-0.33(m,2H),0.13(dq,J＝8.4,2.7,1.8Hz,1H),0.06-0.00(m,1H)。
实施例21.
参考实施例1的合成方法，由中间体6(0.2g,0.68mmol)与中间体18(0.2g,0.81mmol)合成得到化合物21，为白色固体0.12g，收率34％，1H NMR(500MHz,DMSO-d6)δ8.32(s,1H),8.08(s,1H),7.86-7.80(m,2H),7.75(td,J＝8.7,3.1Hz,1H),7.69(s,1H),6.13(dd,J＝9.2,5.2Hz,1H),4.54(p,J＝6.7Hz,1H),4.14(dd,J＝14.5,5.7Hz,1H),3.81(dd,J＝14.5,7.6Hz,1H),1.43(dd,J＝6.6,2.0Hz,6H),0.76(t,J＝7.3Hz,3H),0.55(d,J＝7.6Hz,1H),0.38(ddd,J＝20.1,9.4,4.6Hz,2H),0.13(dq,J＝10.0,4.6Hz,1H),0.03(dq,J＝10.0,4.9Hz,1H)。
实施例22.
参考实施例1的合成方法，由中间体12(0.2g,0.65mmol)与中间体21(0.2g,0.78mmol)合成得到化合物22，为白色固体0.10g，收率31％，1H NMR(500MHz,DMSO)δ8.52(s,1H),8.13(s,1H),8.00(s,1H),7.92(dd,J＝9.3,5.4Hz,1H),7.86-7.62(m,3H),7.31(d,J＝1.9Hz,1H),7.03(s,2H),6.19(q,J＝6.7Hz,1H),5.71(s,1H),3.59(s,3H),1.74(d,J＝6.7Hz,3H)。
实施例23.
参考实施例1的合成方法，由中间体9(0.2g,0.65mmol)与中间体21(0.2g,0.78mmol)合成得到化合物23，为白色固体0.12g，收率35％，1H NMR(500MHz,DMSO)δ8.54(s,1H),8.11(s,1H),8.02(s,1H),7.92-7.86(m,1H),7.84-7.66(m,3H),7.49(s,1H),7.00(s,3H),6.11(q,J＝6.6Hz,1H),3.54(s,3H),1.74(d,J＝6.7Hz,3H)。
实施例24.
参考实施例1的合成方法，由中间体8(0.2g,0.70mmol)与中间体21(0.21g,0.84mmol)合成得到化合物24，为白色固体0.14g，收率40％，1H NMR(500MHz,DMSO)δ8.52(s,1H),8.26(d,J＝5.5Hz,1H),8.01(s,1H),7.96-7.68(m,2H),7.63(dt,J＝16.2,8.0Hz,1H),7.13(s,2H),6.73(q,J＝6.6Hz,1H),2.22-2.06(m,1H),1.86(d,J＝6.7Hz,3H),1.28-1.18(m,1H),1.13-1.04(m,2H),0.81(tdd,J＝16.9,9.0,3.5Hz,1H)。
实施例25.
参考实施例1的合成方法，由中间体7(0.2g,0.74mmol)与中间体21(0.22g,0.88mmol)合成得到化合物25，为白色固体0.17g，收率52％，1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.25(s,1H),8.06-7.98(m,2H),7.95-7.63(m,3H),6.73(q,J＝6.7Hz,1H),2.18(dq,J＝7.0,3.5,3.0Hz,1H),1.86(d,J＝6.6Hz,3H),1.22-1.17(m,1H),1.09(d,J＝6.8Hz,2H),0.83(dt,J＝9.9,4.7Hz,1H)。
实施例26.
参考实施例1的合成方法，由中间体2(1.0g,3.56mmol)与中间体16(1.13g,4.27mmol)合成得到化合物26，为白色固体1.2g，收率66％。MS(ESI)：[M+H]508.9511。
实施例27.
参考实施例1的合成方法，由中间体6(0.2g,0.68mmol)与中间体22(0.22g,0.82mmol)合成得到化合物27，为白色固体0.13g，收率38％，1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.89(dd,J＝8.5,2.9Hz,1H),7.84-7.77(m,2H),7.70(s,1H),7.46(td,J＝8.7,2.9Hz,1H),6.13(dd,J＝8.6,6.1Hz,1H),5.60(s,2H),4.29(dd,J＝14.5,6.1Hz,1H),4.00-3.84(m,2H),2.73-2.46(m,2H),1.97-1.79(m,4H),1.09-0.99(m,1H),0.94(t,J＝7.3Hz,3H),0.80(dd,J＝12.8,7.3Hz,6H),0.67-0.53(m,2H),0.49-0.34(m,2H)。
实施例28.
参考实施例1的合成方法，由中间体6(0.2g,0.68mmol)与中间体15(0.2g,0.8mmol)合成得到化合物28，为白色固体0.12g，收率34％，1H NMR(500MHz,CDCl3)δ8.42(s,1H),7.94-7.85(m,3H),7.79(dd,J＝8.9,4.9Hz,1H),7.46(td,J＝8.6,3.0Hz,1H),6.13(dd,J＝8.6,6.1Hz,1H),5.59(s,2H),5.51-5.44(m,1H),5.12-5.02(m,4H),4.29(dd,J＝14.5,6.1Hz,1H),3.90(dd,J＝14.6,7.3Hz,1H),2.58(ddt,J＝35.8,13.9,7.0Hz,2H),1.06-0.98(m,1H),0.94(t,J＝7.3Hz,3H),0.66-0.52(m,2H),0.49-0.36(m,2H)。
实施例29.
参考实施例1的合成方法，由中间体6(0.2g,0.68mmol)与中间体24(0.21g,0.82mmol)合成得到化合物29，为白色固体0.17g，收率50％，1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.88(dd,J＝8.5,2.8Hz,1H),7.83(s,1H),7.79(dd,J＝9.0,4.9Hz,1H),7.77(s,1H),7.45(td,J＝8.7,2.9Hz,1H),6.12(dd,J＝8.5,6.1Hz,1H),5.78(s,2H),4.29(dd,J＝14.5,6.0Hz,1H),4.01(d,J＝7.0Hz,2H),3.88(dd,J＝14.6,7.3Hz,1H),2.67-2.49(m,2H),1.34-1.28(m,1H),1.05-0.97(m,1H),0.94(t,J＝7.3Hz,3H),0.67(d,J＝7.3Hz,2H),0.64-0.53(m,2H),0.47-0.42(m,1H),0.41-0.35(m,3H)。
实施例30.
参考实施例1的合成方法，由中间体5(0.2g,0.68mmol)与中间体15(0.21g,0.81mmol)合成得到化合物30，为白色固体0.12g，收率34％，1H NMR(500MHz,CDCl3)δ8.41(s,1H),7.92(s,1H),7.88(s,1H),7.65(dd,J＝14.8,6.8Hz,1H),7.57(d,J＝8.1Hz,1H),7.16-7.07(m,1H),6.11(dd,J＝8.6,6.0Hz,1H),5.63(s,2H),5.52-5.45(m,1H),5.13-5.02(m,4H),4.26(dd,J＝14.6,6.1Hz,1H),3.85(dd,J＝14.6,7.3Hz,1H),2.71-2.45(m,2H),1.06-0.98(m,1H),0.94(t,J＝7.3Hz,3H),0.64-0.53(m,2H),0.42(dtt,J＝15.4,10.4,5.2Hz,2H)。
实施例31.
参考实施例1的合成方法，由中间体5(0.2g,0.68mmol)与中间体22(0.22g,0.82mmol)合成得到化合物31，为白色固体0.13g，收率39％，1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.80(s,1H),7.71(s,1H),7.66(td,J＝8.1,5.3Hz,1H),7.59(d,J＝7.9Hz,1H),7.11(dd,J＝10.0,8.6Hz,1H),6.10(dd,J＝8.7,6.0Hz,1H),5.62(s,2H),4.26(dd,J＝14.6,6.1Hz,1H),3.99-3.90(m,1H),3.84(dd,J＝14.6,7.4Hz,1H),2.72-2.46(m,2H),1.96-1.81(m,4H),1.08-0.98(m,1H),0.95(t,J＝7.4Hz,3H),0.81(td,J＝7.3,4.8Hz,6H),0.64-0.53(m,2H),0.47-0.36(m,2H)。
实施例32.
参考实施例1的合成方法，由中间体5(0.2g,0.68mmol)与中间体23(0.21g,0.82mmol)合成得到化合物32，为白色固体0.13g，收率38％，1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.78(s,1H),7.70(s,1H),7.65(td,J＝8.1,5.4Hz,1H),7.57(d,J＝8.0Hz,1H),7.11(dd,J＝9.8,8.4Hz,1H),6.09(dd,J＝8.6,6.0Hz,1H),5.71(s,2H),4.25(dd,J＝14.6,6.1Hz,1H),4.03-3.88(m,2H),3.84(dd,J＝14.6,7.3Hz,1H),2.70-2.47(m,2H),2.24(dp,J＝13.6,6.8Hz,1H),1.05-0.97(m,1H),0.96-0.88(m,9H),0.63-0.52(m,2H),0.47-0.35(m,2H)。
实施例33.
参考实施例1的合成方法，由中间体6(0.2g,0.68mmol)与中间体23(0.21g,0.82mmol)合成得到化合物33，为白色固体0.15g，收率50％，1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.88(dd,J＝8.5,2.8Hz,1H),7.80(dd,J＝8.9,4.9Hz,1H),7.77(s,1H),7.69(s,1H),7.45(td,J＝8.7,2.9Hz,1H),6.12(dd,J＝8.5,6.1Hz,1H),5.69(s,2H),4.29(dd,J＝14.5,6.1Hz,1H),3.94(dd,J＝7.2,4.2Hz,2H),3.89(dd,J＝14.6,7.3Hz,1H),2.70-2.47(m,2H),2.23(dp,J＝13.6,6.8Hz,1H),1.07-0.97(m,1H),0.97-0.88(m,9H),0.64-0.53(m,2H),0.41(ddq,J＝25.4,10.2,4.9Hz,2H)。
实施例34.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体15(0.22g,0.85mmol)合成得到化合物34，为白色固体0.14g，收率36％，1H NMR(500MHz,CDCl3)δ8.36(s,1H),7.87(d,J＝1.1Hz,2H),7.82(dd,J＝8.4,2.8Hz,1H),7.70(dd,J＝8.9,4.9Hz,1H),7.42(td,J＝8.7,2.9Hz,1H),6.62(dd,J＝8.4,6.2Hz,1H),5.72(s,2H),5.54-5.41(m,1H),5.16-4.99(m,4H),2.65-2.46(m,2H),2.45-2.34(m,1H),1.52-1.41(m,1H),1.34-1.22(m,2H),1.01(t,J＝7.3Hz,3H),0.92(ddd,J＝21.3,13.2,5.5Hz,1H)。
实施例35.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体23(0.22g,0.85mmol)合成得到化合物35，为白色固体0.150g，收率47％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.06(s,1H),7.80-7.63(m,4H),6.98(s,1H),6.50(dd,J＝9.1,5.0Hz,1H),3.95(d,J＝7.2Hz,2H),2.46(dd,J＝9.9,4.7Hz,1H),2.42-2.34(m,1H),2.19-2.09(m,2H),1.22-1.06(m,3H),0.89(t,J＝7.4Hz,3H),0.85(d,J＝6.7Hz,6H),0.79(dt,J＝9.6,3.9Hz,1H)。
实施例36.
参考实施例1的合成方法，由中间体4(0.2g,0.74mmol)与中间体23(0.23g,0.88mmol)合成得到化合物36，为白色固体0.14g，收率42％，1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.88-7.60(m,4H),6.98(s,1H),6.70(q,J＝6.6Hz,1H),3.95(d,J＝7.2Hz,2H),2.19-2.06(m,2H),1.84(d,J＝6.7Hz,3H),1.21-1.14(m,1H),1.13-1.03(m,2H),0.85(d,J＝6.7Hz,6H),0.82-0.75(m,1H)。
实施例37.
参考实施例1的合成方法，由中间体4(0.2g,0.74mmol)与中间体22(0.24g,0.88mmol)合成得到化合物37，为白色固体0.12g，收率35％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.12(s,1H),7.79-7.64(m,4H),6.71(q,J＝6.6Hz,1H),4.16-3.94(m,1H),2.17(qd,J＝7.4,3.7Hz,1H),1.84(d,J＝6.6Hz,3H),1.83-1.71(m,4H),1.22-1.14(m,1H),1.13-1.05(m,2H),0.84-0.78(m,1H),0.70(t,J＝7.3Hz,6H)。
实施例38.
参考实施例1的合成方法，由中间体3(0.2g,0.71mmol)与中间体22(0.23g,0.88mmol)合成得到化合物38，为白色固体0.14g，收率40％，1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),8.12(s,1H),7.86-7.58(m,4H),6.88(s,1H),6.51(dd,J＝9.1,5.0Hz,1H),4.16-3.96(m,1H),2.48-2.43(m,1H),2.38(dt,J＝21.2,7.4Hz,1H),2.19(ddd,J＝11.5,6.9,4.4Hz,1H),1.89-1.70(m,4H),1.22-1.18(m,1H),1.18-1.09(m,2H),0.88(t,J＝7.3Hz,3H),0.83-0.77(m,1H),0.70(t,J＝7.3Hz,6H)。
实施例39.
参考实施例1的合成方法，由中间体4(0.2g,0.74mmol)与中间体24(0.22g,0.88mmol)合成得到化合物39，为白色固体0.15g，收率44％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.10(s,1H),7.80-7.64(m,4H),7.07(dd,J＝106.0,54.9Hz,1H),6.71(q,J＝6.6Hz,1H),4.00(d,J＝7.2Hz,2H),2.16-2.08(m,1H),1.84(d,J＝6.7Hz,3H),1.31-1.26(m,1H),1.19(dd,J＝10.4,4.3Hz,1H),1.12-1.03(m,2H),0.82-0.73(m,1H),0.56-0.47(m,2H),0.38(q,J＝4.9Hz,2H)。
实施例40.
参考实施例1的合成方法，由中间体4(0.2g,0.75mmol)与中间体15(0.23g,0.9mmol)合成得到化合物40，为白色固体0.14g，收率38％，1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.10(s,1H),7.80-7.64(m,4H),7.07(dd,J＝106.0,54.9Hz,1H),6.71(q,J＝6.6Hz,1H),4.00(d,J＝7.2Hz,2H),2.16-2.08(m,1H),1.84(d,J＝6.7Hz,3H),1.31-1.26(m,1H),1.19(dd,J＝10.4,4.3Hz,1H),1.12-1.03(m,2H),0.82-0.73(m,1H),0.56-0.47(m,2H),0.38(q,J＝4.9Hz,2H)。
比较例化合物1.
参考实施例1的合成方法制备比较例化合物1。
实施例41.体外抑制活性(酶活)测定
体外酶活实验测定化合物对PI3K家族Ⅰ型激酶(PI3Kδ，储液浓度5.9mM)的IC50值。蛋白激酶PI3Kδ购自Invitrogen(美国)；底物PIP2:3PS、PI及ADP-Glo试剂盒购自Promega(美国)。分别取用试剂盒中的蛋白稀释液稀释至一定浓度的蛋白激酶PI3Kδ5.4μL(终浓度为1ng/μL)，分别与梯度稀释(用试剂盒中反应缓冲液作溶剂稀释)的化合物各1μL混合，室温孵育1小时(化合物终浓度分别为10μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM)；加入底物(底物终浓度0.01mg/mL)混合，将混合体系室温反应1小时；最后加入8μL检测试剂，25℃孵育40分钟，采用MD SpectraMax I3X酶标仪(Molecular Devices，美国)读取荧光值。基于读取的荧光数值采用Prism 8.0(GraphPad Software,San Diego,CA)作图，计算本发明的化合物12、24，比较例化合物1、TGR-1202(购自中国MCE)对所测试蛋白激酶PI3Kδ的IC50值，如下表4所示。
表4
| IC50:nM | IC50:nM | IC50:nM | |||
| TGR-1202 | 48.4 | 化合物10 | 6.85 | 化合物19 | 18.1 |
| 化合物2 | 2.15 | 化合物11 | 10.99 | 化合物20 | 22.6 |
| 化合物3 | 3.15 | 化合物12 | 2.59 | 化合物21 | 15.4 |
| 化合物5 | 14.5 | 化合物13 | 14.1 | 化合物24 | 2.12 |
| 化合物7 | 15.4 | 化合物16 | 3.96 | 化合物39 | 24 |
| 化合物8 | 16.8 | 化合物17 | 3.72 | 化合物40 | 23.7 |
| 化合物9 | 13.2 | 化合物18 | 3.63 | 比较例化合物1 | 34 |
实验表明，本发明的化合物是针对PI3Kδ具有很强的抑制活性，特别是将吡唑环上取代基替换成更大位阻基团(如卤代烷基或者其它支链烷基等)时，其对PI3Kδ的抑制活性显著提升。
实施例42.细胞中PI3Kδ抑制活性检测
本实施例使用PI3Kδ高表达的人淋巴瘤细胞系Jeko-1细胞(购自南京科佰生物科技有限公司)进行，具体为：将细胞铺于6孔板中，每孔5×105个细胞，将不同浓度的本发明化合物(溶于DMSO中)加入到6孔板中，反应体系中化合物的最终浓度分别为0.03μM、0.1μM、0.3μM、1μM、3μM、10μM。然后在培养箱中孵育2小时，收集细胞，提取蛋白，采用western blot方法检测各组AKT(PI3Kδ的直接下游蛋白)T473位点的磷酸化水平(其中使用的抗体购自CST，Cat:4060S，美国)，用GAPDH作为内参，然后通过Image J软件进行定量，用Graphad 8.0作图，计算EC50值，如表5所示。
表5
| 化合物 | EC50:nM | 化合物 | EC50:nM | 化合物 | EC50:nM |
| 比较例化合物1 | 460 | 化合物9 | 80 | 化合物13 | 100 |
| 化合物5 | 83 | 化合物10 | 80 | 化合物14 | 150 |
| 化合物7 | 85 | 化合物11 | 97 | 化合物15 | 128 |
| 化合物8 | 85 | 化合物12 | 80 | 化合物24 | 46 |
实验结果显示，本申请的化合物与比较例化合物1相比，对PI3Kδ磷酸化抑制更为显著。
实施例43.细胞中PI3Kα、PI3Kβ、PI3Kγ抑制活性检测
本实施例使用PI3Kα高表达的人乳腺癌细胞系SK-Br-3细胞(购自南京科佰生物科技有限公司)、PI3Kβ高表达的人乳腺癌细胞MDA-MB-468(购自南京科佰生物科技有限公司)、PI3Kγ高表达的小鼠淋巴瘤细胞RAW264.4(购自南京科佰生物科技有限公司)进行，具体为：将细胞铺于6孔板中，每孔5×105个细胞，将不同浓度的本发明化合物(溶于DMSO中)加入到6孔板中，反应体系中化合物的最终浓度分别为0.03μM、0.1μM、0.3μM、1μM、3μM、10μM。然后在培养箱中孵育2小时，收集细胞，提取蛋白，采用western blot方法检测各组AKT(PI3K不同亚型的直接下游蛋白)T473位点的磷酸化水平(其中使用的抗体购自CST，Cat:4060S，美国)，用GAPDH作为内参，然后通过Image J软件进行定量，用Graphad 8.0作图，计算EC50值，如表6所示。
表6
实验结果显示，本申请的化合物对PI3K其它亚型如PI3Kα、PI3Kβ、PI3Kγ磷酸化的EC50均＞1000nM，说明本申请的化合物对PI3K其它亚型磷酸化均无抑制作用，而对PI3Kδ磷酸化有较强的抑制作用，证明本发明的化合物能够选择性地抑制PI3Kδ的活性。
实施例44.DOHH2细胞小鼠移植瘤模型上体内药效检测
在本实施例中，分别测试化合物12、化合物24及对照化合物Linperlisib(购自MedChemExpress，中国)在DOHH2细胞(购自ATCC)的小鼠移植瘤模型中的实验结果。
实验步骤如下：
(1)从江苏集萃药康生物科技股份有限公司购买饲养6周龄的C57BL/6J雄性小鼠，饲养于SPF级实验室中，饮水及垫料均经高压消毒无菌处理，有关小鼠的所有操作均在无菌条件下进行。
(2)第0天分别在所有小鼠左侧背部皮下分别注入约1×106个DOHH2细胞(购自ATCC)。
(3)从第6天开始，每天口服给药对应组小鼠：含5％(v/v)DMSO、10％(v/v)丙二醇(购自中国西安天正药用辅料)和10％(v/v)HS-15(聚乙二醇-15-羟基硬脂酸酯，购自德国巴斯夫)的溶媒每天一次(5只小鼠)；剂量为50mg/kg鼠重的化合物12每天一次(各5只小鼠)；剂量为50mg/kg鼠重的化合物24每天一次(各5只小鼠)；剂量为50mg/kg鼠重的Linperlisib每天一次(5只小鼠)。各组口服给药的体积均相等。
(4)从第0天(开始，每天用游标卡尺测量皮下肿瘤的长/宽，并每天记录小鼠体重，分别确定化合物12、化合物24及对照化合物Linperlisib对小鼠体重的影响。
(5)统计内皮下肿瘤生长趋势，肿瘤体积计算方法：长×宽×宽/2mm3。
实验结果如图1和2所示。化合物12、化合物24及对照化合物Linperlisib在小鼠移植瘤模型中，表现出很好的抑制小鼠肿瘤的效果，且随着用药天数的增加，化合物12、化合物24对小鼠肿瘤的抑制作用愈发显著，并且优于对照化合物Linperlisib的效果。
实施例45.MC38细胞小鼠移植瘤模型上体内药效检测
在本实施例中，分别测试比较例化合物1和化合物24在MC38细胞的小鼠模型中的药效。
实验步骤如下：
(1)从江苏集萃药康生物科技股份有限公司购买饲养6周龄的MC38细胞移植瘤模型使用的C57BL/6J雄性小鼠，以上小鼠均饲养于SPF级实验室中，饮水及垫料均经高压消毒无菌处理，有关小鼠的所有操作均在无菌条件下进行。
(2)第0天在C57BL/6J小鼠左侧背部皮下分别注入约1×106个MC38细胞(购自ATCC)。
(3)从第0天开始，将小鼠随机分为三组，每组5只，并开始分别进行给药，给药22天。其中，对第一组小鼠口服与给药组等体积的仅含有10％(v/v)HS-15的溶媒；对第二组和第三组小鼠分别施用剂量为30mg/kg鼠重的比较例化合物1和化合物24，每天一次。
(4)从第0天开始，每天记录小鼠体重，分别确定化合物24及比较例化合物1对小鼠体重的影响，结果参见图3。
(5)从第0天开始，每天用游标卡尺测量皮下肿瘤的长和宽，分别统计各组小鼠皮下肿瘤生长趋势，肿瘤体积计算方法：长×宽×宽/2mm3，结果参见图4。
(6)给药22天后，将小鼠安乐死，取下肿瘤并称重，结果参见图5。
本实施例的结果示于图3-图5中。其中，图3示出在MC38细胞小鼠移植瘤模型中，不同处理组中的小鼠平均体重(在图中显示为相对体重：以给药开始时的小鼠重量为基准计算的百分数)随时间的变化；图4示出在MC38细胞小鼠移植瘤模型中，不同处理组中的肿瘤的平均大小(在图中显示为肿瘤绝对大小)随时间的变化；图5示出在MC38细胞小鼠移植瘤模型中，不同处理组中的小鼠在用药后第14天的平均肿瘤重量和计算出的抑瘤率(TGI)。
图4的实验结果显示，在MC38细胞小鼠移植瘤模型中，化合物24的小组表现出非常好的抑制小鼠肿瘤的效果。图5的实验结果显示，对于化合物24的小组，在MC38细胞小鼠移植瘤模型中用药后第22天的抑瘤率高达86.7％(见图5)，其中抑瘤率(TGI)＝(对照组肿瘤的重量-实验组肿瘤的重量)/对照组肿瘤的重量。这说明本发明的化合物24在MC38细胞动物模型中能够明显抑制肿瘤的生长。另外，图3的结果还表明，化合物24不仅有效地抑制小鼠肿瘤的生长，并且对小鼠的体重基本没有影响，表明化合物24可适用于动物给药。
本发明提供一种PI3Kδ抑制剂，其可以用于治疗受试者的携带PI3Kδ的活性相关病症。因而，本发明适于工业应用。
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。
Claims (11)
1.一种PI3Kδ抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药：
其中，
R1各自独立地选自卤素和C1-C4烷基，m为1或2；
R2选自C3-C6环烷基、C3-C6环烷基C1-C4烷基、和任选地被卤素或甲基取代的苯基或吡唑基；
R3、R4各自独立地选自H和C1-C4烷基；
R5选自C3-C8支链烷基、C1-C8卤代烷基、C1-C4烷氧基C1-C4烷基、C2-C6羟基烷基、C3-C6环烷基C1-C4烷基、4-6元杂环烷基、和4-6元杂环烷基C1-C4烷基。
2.根据权利要求1所述的PI3Kδ抑制剂，其中，R5选自异丙基、异丁基、戊-3-基、一卤代烷基、二卤代烷基、1-乙氧基-乙基、羟乙基、环丙基甲基、氧杂环丁基、四氢吡喃基或吗啉基乙基。
3.根据权利要求1所述的PI3Kδ抑制剂，其中，R5为卤代乙基或二卤代甲基。
4.根据权利要求1所述的PI3Kδ抑制剂，其中，R5为二氟甲基。
5.根据权利要求1-4中任一项所述的PI3Kδ抑制剂，其中，R1选自氟和甲基。
6.根据权利要求1-4中任一项所述的PI3Kδ抑制剂，其中，R2选自环丙基、环丙基甲基、氟代苯基、和N-甲基-吡唑基。
7.根据权利要求1-4中任一项所述的PI3Kδ抑制剂，其中，R3和R4中一个为H，另一个为甲基或乙基。
8.根据权利要求1-4中任一项所述的PI3Kδ抑制剂，其包括以下化合物或其药学可接受的盐、溶剂化物、多晶型物、酯、酸、异构体、代谢物或前药：
9.一种药物组合物，其包括如权利要求1-8中任一项所述的PI3Kδ抑制剂，以及药学上可接受的载体或赋形剂，以及任选的其它活性成分。
10.权利要求1-8中任一项所述的PI3Kδ抑制剂在制备用于抑制PI3Kδ激酶活性或治疗与PI3Kδ激酶活性相关的疾病或病症的药物中的用途。
11.根据权利要求10所述的用途，其中，所述疾病或病症选自慢性淋巴细胞白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、套细胞淋巴瘤、慢性阻塞性肺病、类风湿性关节炎、系统性红斑狼疮和哮喘。
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