CN116217561A - 一类具有二甲基异吲哚酮结构的新型激酶抑制剂及其制备方法和用途 - Google Patents
一类具有二甲基异吲哚酮结构的新型激酶抑制剂及其制备方法和用途 Download PDFInfo
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- CN116217561A CN116217561A CN202111463141.3A CN202111463141A CN116217561A CN 116217561 A CN116217561 A CN 116217561A CN 202111463141 A CN202111463141 A CN 202111463141A CN 116217561 A CN116217561 A CN 116217561A
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- 238000002360 preparation method Methods 0.000 title abstract description 50
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- 229940043355 kinase inhibitor Drugs 0.000 title abstract 2
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- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
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Abstract
本发明涉及一类具有二甲基异吲哚酮结构的新型激酶抑制剂及其制备方法和用途。具体地，本发明化合物具有式I所示结构，其中各基团和取代基的定义如说明书中所述；本发明还公开了所述化合物的制备方法及其在预防和/或治疗HPK1相关疾病方面的用途。
Description
技术领域
本发明涉及医药领域，具体地涉及一类具有二甲基异吲哚酮结构的HPK1抑制剂及其制备方法和用途。
背景技术
造血祖细胞激酶1(HPK1)是MAP4K家族的成员之一，隶属丝氨酸/苏氨酸蛋白激酶类。HPK1是一种免疫抑制调节激酶，主要在造血细胞，包括早期造血祖细胞表达。
在T细胞中，HPK1是T细胞受体(TCR)的负信号调节剂。TCR激活后，胞质HPK1被募集到细胞膜附近，活化的HPK1磷酸化衔接蛋白SLP76，继而激活SLP76并作为负调节蛋白14-3-3π的停靠位点，最终导致TCR信号复合物的不稳定，达到下调TCR信号的作用。此外，HPK1激酶活性可以抑制CD4+T细胞、CD8+T细胞和树突状细胞(DC)的免疫功能，通过抑制HPK1激酶活性来引发抗肿瘤免疫反应。HPKl还可以通过由肿瘤分泌的前列腺素(PGE2)被激活，从而有助于肿瘤细胞发生免疫逃逸。此外，HPKl还可以通过抑制AP-1来促进肿瘤细胞增殖以及肿瘤细胞的侵袭和转移。由此可见，HPK1是TCR信号的重要调节蛋白，主导T细胞介导的免疫反应，是抗肿瘤免疫的重要并有潜力的靶点。
目前针对该靶点尚未有药物上市，本项发明公开具有二甲基异吲哚酮结构的新型HPK1抑制剂，该类化合物对HPK1具有强的抑制活性。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和其在抑制HPK1活性方面的用途。
本发明的第一方面，提供了一种化合物，所述化合物为式I所示化合物、或其药学上可接受的盐、溶剂合物，
其中，
Q为C时，
为双键，A环为
或者
Q为N时，
为单键，A环为
R1选自下组：组A、组B；
组A为取代或未取代的含1、2或3个选自N、O、S的杂原子的5-6元杂芳基，所述取代指被选自下组的1、2或3个取代基取代：卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、-(C1-C3亚烷基)-O-(C1-C3亚烷基)-OH；
组B选自下组：-CO-NH-(C1-C3亚烷基)-O-(C1-C3亚烷基)-C1-C6烷氧基、-CO-NH-(C1-C3亚烷基)-O-(C1-C3亚烷基)-OH、-CO-NH-(1、2或3个R’取代或未取代的C1-C8烷基)、-CO-NH-(1、2或3个R’取代或未取代的C3-C6环烷基)、-COO-(C1-C6烷基)；
各R’独立地选自下组：卤素、羟基、氰基、氨基、-(C1-C3亚烷基)-OH、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C3烷基氨基、C1-C3烷基酰(胺)基、C1-C3烷基磺酰(胺)基、C3-C6环烷基、卤代C3-C6环烷基、1、2或3个R”取代或未取代的含1、2或3个选自N、O、S的杂原子的4-8元杂环基；
各R”独立地选自下组：C1-C6烷基、卤素、氰基、氨基、羟甲基、氰基甲基、卤代C1-C6烷基；
R2、R3独立地选自下组：无、氢、卤素、卤代C1-C2烷基、C1-C2烷氧基、卤代C1-C2烷氧基；
R4、R5独立地选自下组：氢、C1-C3烷基；或者R4和R5形成3-6元环烷基；
X、Y分别独立地选自下组：CH、N；
W选自下组：NH、N-(1、2或3个R’取代或未取代的C1-C6烷基)。
在另一优选例中，所述含1、2或3个选自N、O、S的杂原子的4-8元杂环基为选自下组的结构：单环、稠合环、桥环、螺环。
在另一优选例中，所述化合物为式I-1所示化合物：
其中，各基团如上文所定义。
在另一优选例中，所述化合物为式I-2所示化合物：
其中，各基团如上文所定义。
在另一优选例中，R1为含1、2或3个选自N、O、S的杂原子的5-6元杂芳基；
X、Y均为CH；
R2、R3均为氢或R2单独为F；
W为NH；
R4、R5独立地为C1-C3烷基。
在另一优选例中，所述含1、2或3个选自N、O、S的杂原子的5-6元杂芳基为
在另一优选例中，所述药学上可接受的盐选自下组：无机酸盐、有机酸盐、烷基磺酸盐、芳基磺酸盐。
在另一优选例中，所述无机酸盐选自下组：盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐。
在另一优选例中，所述有机酸盐选自下组：甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐。
在另一优选例中，所述烷基磺酸盐选自下组：甲基磺酸盐、乙基磺酸盐。
在另一优选例中，所述芳基磺酸盐选自下组：苯磺酸盐、对甲苯磺酸盐。
在另一优选例中，所述溶剂合物为所述化合物与选自下组的溶剂的溶剂合物：水、乙醇、异丙醇、乙醚、丙酮。
在另一优选例中，所述化合物选自下组：
本发明的第二方面，提供了一种药物组合物，包含药学上可接受的载体和一种或多种预防和/或治疗有效量的本发明第一方面所述化合物。
本发明的第三方面，提供了一种本发明第一方面所述化合物的用途，用于制备药物，所述药物用于预防和/或治疗HPK1相关疾病。
在另一优选例中，所述HPK1相关疾病为肿瘤。
在另一优选例中，所述肿瘤包括但不限于选自下组的肿瘤：结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、肾癌、头颈癌、淋巴瘤、白血病、黑色素瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是化合物K的水溶解性标准曲线回归方程。
图2是本发明化合物S4的水溶解性标准曲线回归方程。
图3是本发明化合物S16的水溶解性标准曲线回归方程。
图4是本发明化合物S26的水溶解性标准曲线回归方程。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种对于HPKl激酶具有高抑制活性的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C1-C3烷基”、“C1-C8烷基”具有类似含义。
在本发明中，术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C3-C6环烷基”具有类似含义。
在本发明中，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中，术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8元杂环基，包括(但并不限于)如下基团：
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语1-6个指1、2、3、4、5或6个。其他类似术语各自独立地具有类似含义。术语“多个”指2-6个，如2、3、4、5或6个。
应理解，当某一基团同时存在于化合物的多个不同位置时，其在各位置的定义是相互独立的，可以相同也可以不同。亦即，术语“选自下组：”与术语“各独立地选自下组：”具有相同含义。
化合物
本发明提供了一种化合物，所述化合物为式I所示化合物、或其药学上可接受的盐、溶剂合物，
其中，各基团如上文定义。
在另一优选例中，所述的化合物中，各基团中任一个分别独立地为所述具体化合物中所对应的基团。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
在另一优选例中，所述式I化合物中，各基团独立地为各具体化合物中对应基团。
应理解，本发明化合物的制备工艺流程中，所用原料和试剂如无特殊说明，均可通过商业途径购买。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含药学上可接受的载体和一种或多种预防和/或治疗有效量的所述化合物。
由于本发明化合物具有优异的抗肿瘤活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
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、瘤内、直肠、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)填料或增容剂，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。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物具有更优的溶解度(尤其是水溶解度)；
(2)所述化合物具有更优的HPK1抑制活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
1H-NMR和13C-NMR用Bruke 400，600或700型仪测定；N,N-二异丙基乙胺[DIPEA]、氢氧化钠、氢化钠、硫酸钠、盐酸、三乙胺、硝酸铈铵、碘甲烷、氨基甲酸叔丁酯、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)、醋酸钯、N-甲基吡咯烷酮、氯化铵、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽[Xantphos]购于J&K Chemica百灵威化学试剂公司、中国医药试剂有限公司和韶远科技有限公司。所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得；除说明外，所有反应均是在氮气保护下进行并TLC跟踪，后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程；产品的纯化除说明外均使用硅胶(200-300目)柱色谱法；其中硅胶(200-300目)由青岛海洋化工厂生产，GF-254薄层硅胶板由烟台江友硅胶开发有限公司生产。
一、化合物的制备
1.制备实施例1
化合物1c的合成：将2,4-二氯嘧啶-5-羧酸乙酯(10.0g,45.2mmol)装入配备有搅拌棒的500mL圆底烧瓶中，加入100mL乙腈室温搅拌10分钟使其完全溶解。向其中加入DIPEA(15.8mL,90.0mmol)，搅拌五分钟，然后加入(S)-2-氨基-2-苯基乙醇(6.52g，47.5mmol)。将所得混合物在室温搅拌3小时。反应结束后，用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，PE:EA＝2:1～1:1得到所需产物(12.4g,84％产率)，为白色固体。1H NMR(400MHz,氘代氯仿)δ9.18(br d,J＝7.8Hz,1H),8.72(s,1H),7.45-7.39(m,4H),7.38-7.32(m,1H),5.51(dt,J＝8.0,4.9Hz,1H),4.47-4.35(m,2H),4.07-3.96(m,2H),2.06(br d,J＝7.5Hz,1H),1.42(t,J＝7.2Hz,3H)。MS-ESI(m/z)C15H16ClN3O3[M+H]+calcd for：321.1.Found 321.1
化合物1e的合成：将(S)-2-氯-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-甲酸乙酯(321.1mg,1mmol)和5-氨基-2,3-二氢异吲哚-1-酮(222.2mg,1.5mmol)溶解于N-甲基-2-吡咯烷酮(2mL)中。向其中添加1N 1,4-二氧六环/HCl溶液(0.102mL,0.102mmol)，80℃油浴条件下搅拌过夜。反应完全后用，将反应混合物用三乙胺淬灭反应并用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥，旋干得油状产物(390.1mg,产率90％)。1H NMR(400MHz,氘代氯仿)δ8.72(s,1H),7.81(d,J＝7.5Hz,1H),7.45–7.34(m,3H),7.23(m,3H),6.83(dd,J＝7.5,1.5Hz,1H),6.30(s,1H),5.20(s,1H),4.89(s,1H),4.81(m,1H),4.74(d,J＝1.8Hz,2H),4.55(m,1H),4.22(dd,J＝12.3,6.9Hz,1H),4.08(dd,J＝12.4,7.0Hz,1H),3.71(m,1H),2.96(s,1H),1.34(t,J＝8.0Hz,3H).
化合物S1的合成：将(S)-2-(2,3-二氢异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-甲酸乙酯(454.1mg,1mmol)溶于10mL乙醇中，室温下缓慢加入水合肼(90mg,1.5mmol)。将所得混合物在80℃的封管中搅拌12小时。反应结束后，用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩，得到(S)-2-(2,3-二氢异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-碳酰肼(439.7mg,99％产率)，未经纯化直接投下一步。
在室温条件下将(S)-2-(2,3-二氢异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-碳酰肼(439.7mg,0.99mmol)溶于2mL乙酸中，室温搅拌五分钟后，添加三乙氧基甲烷(1.44g,9.9mmol)。将所得混合物在100℃搅拌过夜。反应结束后，用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，PE:EA＝2:1～1:1得到所需产物(332.9mg,74％产率)，为白色固体。1H NMR(400MHz,氘代二甲基亚砜)δ10.08(s,1H),9.35(s,1H),8.94(d,J＝7.3Hz,1H),8.66(s,1H),8.33(s,1H),7.88(s,1H),7.60(d,J＝8.1Hz,1H),7.50(d,J＝8.3Hz,1H),7.43(d,J＝7.4Hz,2H),7.36(t,J＝7.6Hz,2H),7.25(t,J＝7.2Hz,1H),5.41-5.36(m,1H),5.24(t,J＝4.9Hz,1H),4.41(d,J＝17.5Hz,1H),4.26(d,J＝17.5Hz,1H),3.97-3.87(m,1H),3.82-3.72(m,1H).
2.制备实施例2
化合物2b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.75(s,1H),7.82(d,J＝7.5Hz,1H),7.42(d,J＝1.6Hz,1H),7.40–7.34(m,2H),7.23(m,3H),6.83(dd,J＝7.5,1.5Hz,1H),6.19(s,1H),5.20(s,1H),4.90(s,1H),4.77(tt,J＝7.0,1.0Hz,1H),4.38–4.25(m,2H),4.28–4.18(m,2H),4.10(dd,J＝12.4,7.0Hz,1H),2.96(s,1H),2.31(dq,J＝12.3,8.0Hz,2H),2.03(m,2H),1.34(t,J＝8.0Hz,3H),0.81(t,J＝8.0Hz,6H).
化合物S2的合成：合成步骤同S1。1H NMR(500MHz,氘代氯仿)δ8.43(s,1H),7.80(d,J＝7.5Hz,1H),7.68(s,1H),7.45–7.38(m,3H),7.23(m,3H),6.83(dd,J＝7.5,1.5Hz,1H),6.22(s,1H),5.20(s,1H),4.99–4.90(m,2H),4.35(dd,J＝12.4,7.0Hz,1H),4.17(dd,J＝12.4,7.0Hz,1H),2.96(s,1H),2.30–2.18(m,2H),2.09(m,2H),0.93(t,J＝8.0Hz,6H).
3.制备实施例3
化合物S3的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.76(s,1H),7.84(d,J＝7.5Hz,1H),7.42(d,J＝1.6Hz,1H),7.37(m,2H),7.23(m,3H),6.83(m,1H),6.25(s,1H),5.20(s,1H),5.08(s,1H),4.83–4.76(m,1H),4.40–4.27(m,3H),4.08(dd,J＝12.4,7.0Hz,1H),2.96(s,1H),1.74(s,3H),1.70(s,3H),1.34(t,J＝8.0Hz,3H).MS-ESI(m/z)C25H27N5O4[M+H]+calcd for：461.20.Found 461.20.
4.制备实施例4
化合物S4的合成：合成步骤同S1。1H NMR(700MHz,氘代甲醇)δ8.95(s,1H),8.65(s,1H),7.76(s,1H),7.66(dd,J＝8.3,1.8Hz,1H),7.59(d,J＝8.3Hz,1H),7.45(d,J＝7.4Hz,1H),7.39(t,J＝7.8Hz,1H),7.28(t,J＝7.4Hz,1H),5.55–5.47(m,1H),4.02(dd,J＝11.3,4.5Hz,1H),3.94(dd,J＝11.4,6.4Hz,1H),1.52(s,3H),1.51(s,3H).
5.制备实施例5
化合物5b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.73(s,1H),7.71(d,J＝7.5Hz,1H),7.42(d,J＝1.5Hz,1H),7.29–7.18(m,5H),6.83(dd,J＝7.5,1.5Hz,1H),6.03(s,1H),5.20(s,1H),4.74(s,1H),4.47–4.37(m,2H),4.40–4.30(m,1H),4.28(dd,J＝12.4,6.9Hz,1H),4.05(dd,J＝12.4,6.9Hz,1H),2.96(s,1H),1.34(t,J＝8.0Hz,3H),1.14–1.06(m,2H),0.86–0.77(m,2H)。
化合物S5的合成：合成步骤同S5。1H NMR(700MHz,氘代甲醇)δ8.95(s,1H),8.65(s,1H),7.69–7.62(m,2H),7.44(d,J＝7.6Hz,3H),7.38(t,J＝7.7Hz,2H),7.28(t,J＝7.4Hz,1H),5.55–5.42(m,1H),4.00(dd,J＝11.3,4.5Hz,1H),3.93(dd,J＝11.4,6.4Hz,1H),1.60–1.53(m,2H),1.48-1.38(m,2H).
6.制备实施例6
化合物6b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.73(s,1H),7.70(d,J＝7.5Hz,1H),7.42(d,J＝2.0Hz,1H),7.29–7.18(m,5H),6.83(dd,J＝7.5,2.0Hz,1H),5.20(s,1H),4.77(s,1H),4.48–4.39(m,1H),4.42–4.34(m,1H),4.37–4.24(m,1H),4.05(dd,J＝12.4,7.0Hz,1H),3.08(s,3H),2.96(s,1H),1.66(s,3H),1.60(s,3H),1.34(t,J＝8.0Hz,3H).
化合物S6的合成：合成步骤同S1。1H NMR(700MHz,氘代氯仿)δ9.04(d,J＝7.7Hz,1H),8.60(s,1H),8.42(s,1H),7.77(s,1H),7.72(d,J＝8.1Hz,1H),7.68(s,1H),7.50(dd,J＝8.3,1.9Hz,1H),7.44–7.39(m,4H),7.34–7.30(m,1H),5.56(m,1H),4.08–4.04(m,2H),3.02(s,3H),1.46(s,6H).
7.制备实施例7
化合物7b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.76(s,1H),7.85(d,J＝7.4Hz,1H),7.42(d,J＝2.1Hz,1H),7.38–7.32(m,2H),7.23(qd,J＝3.9,1.7Hz,3H),6.83(dd,J＝7.5,2.0Hz,1H),5.20(s,1H),5.05(s,1H),4.88(m,1H),4.55(dq,J＝12.5,8.0Hz,1H),4.48–4.33(m,2H),4.36–4.26(m,2H),4.15–3.97(m,2H),2.96(s,1H),1.66(s,3H),1.60(s,3H),1.34(t,J＝8.0Hz,3H).
化合物S7的合成：合成步骤同S1。1H NMR(700MHz,氘代甲醇)δ8.96(s,1H),8.67(s,1H),7.83(s,1H),7.69(dd,J＝8.4,1.8Hz,1H),7.64(d,J＝8.4Hz,1H),7.45(d,J＝7.5Hz,2H),7.38(t,J＝7.8Hz,2H),7.30–7.26(m,1H),5.61–5.48(m,1H),4.23(q,J＝9.3Hz,2H),4.02(dd,J＝11.4,4.5Hz,1H),3.94(dd,J＝11.3,6.4Hz,1H),1.54(s,3H),1.52(s,3H).
8.制备实施例8：
化合物8b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.76(s,1H),7.84(d,J＝7.5Hz,1H),7.42(d,J＝2.1Hz,1H),7.40–7.34(m,2H),7.25-7.21(m,3H),6.83(dd,J＝7.5,2.0Hz,1H),5.20(s,1H),5.04(s,1H),4.78(m,1H),4.44–4.26(m,3H),4.19(m,1H),4.09(dd,J＝12.4,7.0Hz,1H),3.76–3.66(m,2H),3.70–3.61(m,2H),3.37(s,3H),2.96(s,1H),1.66(s,3H),1.60(s,3H),1.34(t,J＝8.0Hz,3H).
化合物S8的合成：合成步骤同S1。1H NMR(500MHz,氘代氯仿)δ9.06(s,1H),9.01(s,1H),8.33(s,1H),7.76(d,J＝7.5Hz,1H),7.71(dd,J＝7.5,1.5Hz,1H),7.65(d,J＝11.7Hz,1H),7.47(d,J＝1.5Hz,1H),7.30(m,5H),5.00–4.91(m,1H),4.15(m,J＝12.3,7.0,6.1Hz,1H),4.04(m,1H),3.88–3.79(m,2H),3.79–3.71(m,1H),3.71–3.58(m,2H),3.27(s,2H),1.79(s,2H),1.74(s,2H).
9.制备实施例9：
化合物9b的合成：合成步骤同1e。1H NMR(500MHz,氘代氯仿)δ8.76(s,1H),7.82(d,J＝7.5Hz,1H),7.41(dd,J＝6.8,2.6Hz,3H),7.23(m,3H),6.83(dd,J＝7.5,2.0Hz,1H),5.20(s,1H),5.08(s,1H),4.94–4.85(m,2H),4.39(dd,J＝12.4,7.0Hz,1H),4.26(m,2H),4.13(m,1H),3.94–3.79(m,2H),3.53(m,1H),2.96(s,1H),1.66(s,3H),1.61(s,3H),1.44(dd,J＝2.6,1.3Hz,1H),1.34(t,J＝8.0Hz,3H).
化合物S9的合成：合成步骤同S1。1H NMR(500MHz,氘代氯仿)δ9.06(s,1H),9.01(s,1H),8.33(s,1H),7.77(d,J＝7.5Hz,1H),7.71(dd,J＝7.5,1.6Hz,1H),7.65(d,J＝11.7Hz,1H),7.47(d,J＝1.5Hz,1H),7.35–7.24(m,5H),5.00–4.91(m,1H),4.35(t,J＝6.6Hz,1H),4.15(m,J＝12.3,7.0,6.1Hz,1H),4.04(m,J＝12.4,7.1,6.1Hz,1H),3.88–3.82(m,1H),3.85–3.78(m,1H),3.81–3.69(m,2H),3.67–3.58(m,1H),1.79(s,2H),1.74(s,2H).
10.制备实施例10：
化合物10a的合成：合成步骤同1e。将(S)-2-(2,3-二甲基异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-甲酸乙酯(461.1mg,1mmol)溶于10mL乙醇中，室温下缓慢加入水合肼(90mg,1.5mmol)。将所得混合物在80℃的封管中搅拌12小时。反应结束后，用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩，得到(S)-2-(2,3-二甲基异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-碳酰肼(442.5mg,99％产率)，未经纯化直接投下一步。
化合物S10的合成：将(S)-2-(2,3-二甲基异吲哚-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-碳酰肼(442.5mg,0.99mmol)溶于5mL DMF中，室温下缓慢加入三氟乙酸酐(838mg,4mmol)，搅拌五分钟后加入DIPEA(258mg,2mmol)将所得混合物在45℃的条件下搅拌6小时。反应结束后，用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩，得到S10(467.9mg,90％产率).1H NMR(500MHz,氘代氯仿)δ8.81(d,J＝7.4Hz,1H),8.66(d,J＝0.9Hz,1H),7.78–7.71(m,1H),7.66(d,J＝8.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.45(d,J＝7.7Hz,2H),7.38(t,J＝7.5Hz,2H),7.28(t,J＝7.6Hz,1H),5.51(t,J＝5.4Hz,1H),4.03(dd,J＝11.3,4.4Hz,1H),3.94(dd,J＝11.3,6.2Hz,1H),1.51(s,3H),1.50(s,3H).
11.制备实施例11：
化合物S11的合成：合成步骤同S10。1H NMR(500MHz,氘代氯仿)δ8.90(d,J＝7.4Hz,1H),8.74–8.64(m,1H),7.74(s,1H),7.65(d,J＝8.3Hz,1H),7.60(d,J＝8.3Hz,1H),7.49–7.42(m,2H),7.42–7.35(m,2H),7.31–7.27(m,1H),7.27–7.14(m,1H),5.54-5.50(m,1H),4.02(dd,J＝11.4,4.4Hz,1H),3.94(dd,J＝11.4,6.3Hz,1H),1.52(s,3H),1.50(s,3H).
12.制备实施例12：
化合物S12的合成:合成步骤同S10。1H NMR(500MHz,氘代氯仿)δ8.40(s,1H),7.83(d,J＝7.4Hz,1H),7.44–7.33(m,3H),7.23(m,3H),6.83(dd,J＝7.5,1.5Hz,1H),6.25(s,1H),5.20(s,1H),5.05(s,1H),4.77(m,1H),4.66(d,J＝12.5Hz,1H),4.39–4.27(m,2H),4.08(dd,J＝12.4,7.0Hz,1H),3.69–3.61(m,2H),3.23(m,2H),2.96(s,1H),1.97(t,J＝1.9Hz,1H),1.74(s,3H),1.70(s,3H).
13.制备实施例13：
化合物S13的合成：合成步骤同S10。1H NMR(400MHz,氘代甲醇)δ8.58(s,1H),7.67(d,J＝1.7Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.55(d,J＝8.4Hz,1H),7.42–7.33(m,4H),7.29-7.21(m,1H),5.44–5.26(m,1H),4.56(s,1H),3.93(dd,J＝11.2,4.4Hz,1H),3.83(dd,J＝11.2,6.2Hz,1H),3.23-3.21(m,4H),3.02-2.98(m,4H),1.48(s,3H),1.46(s,3H).
14.制备实施例14：
化合物14a的合成：将(461.2mg,1mmol)溶解于THF(6mL)和水(3mL)混合溶剂中，搅拌五分钟后，添加氢氧化钠(80mg,2mmol)。将所得混合物在室温条件下搅拌2h。添加另外80mg的氢氧化钠，并继续搅拌过夜。LCMS分析指示起始物质的消耗。将溶液用2N HCl水溶液中和至pH～6。将反应混合物用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥，旋干得淡黄色固体(402.8mg,产率93％)。1H NMR(400MHz,氘代二甲基亚砜)δ9.67(br,1H),8.59(s,1H),8.01(s,1H)，7.72(d,J＝8.4Hz,1H)，7.61(d,J＝8.4Hz,1H)，7.42-7.33(m,4H)，7.28-7.23(m,1H)，5.33(br，1H),3.86(dd,J＝11.0,4.8Hz,1H)，3.80(dd,J＝10.6,5.9Hz,1H)，1.59(s,3H)，1.55(s,3H)。
化合物S14的合成:在氮气氛围下将TBTU(96.3mg,0.3mmol)、((S)-2-(3,3-二甲基-异吲哚啉-1-酮)氨基)-4-((2-羟基-1-苯基乙基)氨基)嘧啶-5-甲酸(43.3mg,0.1mmol)、2-(2-甲氧基乙氧基)乙胺(17.85mg,0.15mmol)和DIPEA(1.13mL,0.45mmol)溶于3mL DMF中，室温搅拌2h，反应完全后，将反应混合物用乙酸乙酯萃取,合并有机相用饱和食盐水洗，无水硫酸钠干燥,旋干得白色固体(49.66mg,产率93％)。1H NMR(400MHz,氘代甲醇)δ8.44(s,1H),7.69(d,J＝1.7Hz,1H),7.62–7.52(m,2H),7.39(d,J＝1.8Hz,1H),7.37(s,2H),7.39–7.30(m,2H),7.28–7.19(m,1H),5.35(dd,J＝6.3,4.6Hz,1H),3.92(dd,J＝11.2,4.5Hz,1H),3.84(dd,J＝11.2,6.4Hz,1H),3.66–3.58(m,4H),3.61–3.49(m,4H),3.36(s,2H),1.74(s,3H),1.70(s,3H).
15.制备实施例15：
化合物S15的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.51(s,1H),7.67(d,J＝8.2Hz,1H),7.64(s,1H),7.49(d,J＝8.2Hz,1H),7.35(t,J＝7.6Hz,2H),7.34–7.30(m,2H),7.27(t,J＝7.2Hz,1H),5.42–5.26(m,1H),4.31-4.24(m,1H),3.94(dd,J＝11.5,4.2Hz,1H),3.87(dd,J＝12.0,6.0Hz,1H),3.77(dd,J＝13.8,3.8Hz,1H),3.51-3.44(m,1H),1.52(s,3H),1.50(s,3H).
16.制备实施例16
化合物S16的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.46(s,1H),7.70(d,J＝1.8Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.58(d,J＝8.4Hz,1H),7.42–7.39(m,2H),7.37(t,J＝7.7Hz,2H),7.26(t,J＝7.2Hz,1H),5.47–5.30(m,1H),4.54-4.35(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.93–3.84(m,2H),3.60-3.40(m,1H),1.51(s,3H),1.49(s,3H),1.29(m,6H).
17.制备实施例17：
化合物S17的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.49(s,1H),7.70(s,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.39(d,J＝7.2Hz,2H),7.37(d,J＝7.4Hz,2H),7.27–7.24(m,1H),5.56–5.22(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.90–3.83(m,3H),3.74(t,J＝13.0Hz,2H),1.50(s,3H),1.49(s,3H).
18.制备实施例18：
化合物S18的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.39(s,1H),7.73(d,J＝1.5Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.40(d,J＝7.4Hz,2H),7.36(t,J＝7.7Hz,2H),7.25(t,J＝7.3Hz,1H),5.45–5.25(m,1H),3.94(dd,J＝11.3,4.6Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.37(s,3H),3.31(s,2H),3.21(s,2H),1.50(s,3H),1.49(s,3H),0.97(s,6H).
19.制备实施例19：
化合物S19的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.42(s,1H),7.71(d,J＝1.9Hz,1H),7.61(d,J＝8.4Hz,1H),7.57(d,J＝8.4Hz,1H),7.41(d,J＝7.6Hz,2H),7.37(t,J＝7.7Hz,2H),7.26(t,J＝7.3Hz,1H),5.37(t,J＝5.4Hz,1H),3.94(dd,J＝11.2,4.6Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.55(t,J＝6.6Hz,2H),3.34(t,J＝7.2Hz,2H),1.67-1.61(m,2H),1.55-1.52(m,2H),1.50(s,3H),1.49(s,3H),1.43-1.37(m,6H).
20.制备实施例20：
化合物S20的合成：合成步骤同S14。1H NMR(500MHz,氘代氯仿)δ9.06(s,1H),8.70(s,1H),8.31–8.25(m,2H),7.89(d,J＝11.9Hz,1H),7.76(dd,J＝7.5,1.5Hz,1H),7.72(d,J＝7.5Hz,1H),7.46(d,J＝1.5Hz,1H),7.35–7.25(m,5H),4.95(m,1H),4.16(m,1H),4.04(m,1H),3.84(t,J＝6.1Hz,1H),3.61–3.47(m,2H),3.30–3.12(m,2H),1.85–1.67(m,8H),1.67–1.39(m,4H),1.39–1.26(m,4H).
21.制备实施例21：
化合物S21的合成：合成步骤同S14。1H NMR(500MHz,氘代甲醇)δ8.45(s,1H),7.69(d,J＝1.8Hz,1H),7.64–7.51(m,2H),7.43–7.30(m,4H),7.28–7.19(m,1H),5.36(dd,J＝6.4,4.7Hz,1H),4.78-4.51(m,1H),3.92(m,1H),3.87–3.47(m,5H),1.74(s,3H),1.72(s,3H).
22.制备实施例22：
化合物S22的合成：合成步骤同S14。1H NMR(500MHz,氘代氯仿)δ8.44(s,1H),7.71(s,1H),7.66–7.55(m,2H),7.49–7.33(m,4H),7.26(s,1H),5.36(s,1H),3.94(dd,J＝11.3,4.6Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.32-3.30(m,2H),1.64(q,J＝7.4Hz,2H),1.51(s,3H),1.49(s,3H),0.99(t,J＝7.4Hz,3H).
23.制备实施例23：
化合物S23的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.47(s,1H),7.71(d,J＝2.1Hz,1H),7.62(dd,J＝8.3,1.8Hz,1H),7.56(d,J＝8.3Hz,1H),7.41(d,J＝7.5Hz,2H),7.36(t,J＝7.7Hz,2H),7.26(t,J＝7.3Hz,1H),5.49–5.22(m,1H),3.93(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.71(t,J＝5.8Hz,2H),3.48(t,J＝5.8Hz,2H),1.50(s,3H),1.48(s,3H).
24.制备实施例24：
化合物S24的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.46(s,1H),7.71(s,1H),7.66–7.52(m,2H),7.46–7.32(m,4H),7.26(t,J＝7.3Hz,1H),5.49–5.18(m,1H),4.07–3.87(m,1H),3.90–3.81(m,1H),3.72–3.68(m,2H),3.66(t,J＝5.5Hz,2H),3.59(t,J＝4.7Hz,2H),3.56(t,J＝5.5Hz,2H),1.50(s,3H),1.49(s,3H).
25.制备实施例25：
化合物S25的合成：合成步骤同S14。1H NMR(500MHz,氘代甲醇)δ8.47(s,1H),7.71(d,J＝1.9Hz,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.40(d,J＝7.3Hz,2H),7.37(t,J＝7.8Hz,2H),7.26(t,J＝7.3Hz,1H),5.42–5.32(m,1H),4.75–4.61(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.84-3.72(m,1H),3.74–3.69(m,1H),3.69–3.63(m,1H),3.61-3.55(m,1H),1.50(s,3H),1.48(s,3H).
26.制备实施例26：
化合物S26的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.44(s,1H),7.72(d,J＝1.8Hz,1H),7.61(dd,J＝8.3,1.8Hz,1H),7.56(d,J＝8.3Hz,1H),7.41(d,J＝7.5Hz,2H),7.37(t,J＝7.7Hz,2H),7.26(t,J＝7.3Hz,1H),5.40–5.27(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.2,6.3Hz,1H),3.73(t,J＝4.7Hz,4H),3.41(t,J＝6.8Hz,2H),3.00-2.98(m,1H),2.62-2.54(m,5H),1.92–1.75(m,2H),1.50(s,3H),1.48(s,3H).
27.制备实施例27：
化合物S27的合成：合成步骤同S14。1H NMR(500MHz,氘代氯仿)δ8.70(s,1H),7.84(d,J＝7.5Hz,1H),7.42(d,J＝1.6Hz,1H),7.38–7.32(m,2H),7.23(qd,J＝3.9,1.8Hz,3H),6.83(dd,J＝7.5,1.5Hz,1H),6.25(s,1H),6.11(s,1H),5.20(s,1H),5.06(s,1H),4.82–4.74(m,1H),4.35(dd,J＝12.4,7.0Hz,1H),4.07(dd,J＝12.3,6.9Hz,1H),3.68(m,1H),3.14(m,1H),2.96(s,1H),2.87–2.62(m,5H),2.24(s,3H),2.23–2.10(m,5H),2.14–1.98(m,1H),1.89(m,1H),1.74(s,3H),1.70(s,3H).
28.制备实施例28：
化合物S28的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.46(s,1H),7.72(d,J＝1.8Hz,1H),7.61(dd,J＝8.3,1.8Hz,1H),7.56(d,J＝8.3Hz,1H),7.41(d,J＝7.3Hz,2H),7.36(t,J＝7.7Hz,2H),7.26(t,J＝7.3Hz,1H),5.45–5.32(m,1H),4.32(td,J＝8.0,6.4Hz,1H),3.96–3.90(m,2H),3.90–3.84(m,2H),3.63(d,J＝5.4Hz,2H),2.40-2.30(m,1H),2.25–2.10(m,1H),1.50(s,3H),1.48(s,3H),1.36-1.30(m,1H).
29.制备实施例29：
化合物S29的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.44(s,1H),7.72(s,1H),7.62(dd,J＝8.3,1.9Hz,1H),7.57(d,J＝8.3Hz,1H),7.43–7.39(m,2H),7.37(t,J＝7.6Hz,2H),7.26(t,J＝7.3Hz,1H),5.43–5.30(m,1H),3.94(dd,J＝11.3,4.6Hz,1H),3.86(dd,J＝11.3,6.5Hz,1H),3.35(t,J＝7.2Hz,2H),1.75–1.66(m,2H),1.58–1.53(m,2H),1.50(s,3H),1.49(s,3H),1.21(s,6H).
30.制备实施例30：
化合物S30的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.51(s,1H),7.90(s,1H),7.70(s,1H),7.62–7.56(m,2H),7.47–7.34(m,4H),7.26(t,J＝7.1Hz,1H),5.38(s,1H),4.64(d,J＝7.2Hz,2H),4.59(d,J＝6.7Hz,2H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.4,6.5Hz,1H),3.75(d,J＝4.2Hz,2H),1.51(s,3H),1.49(s,3H).
31.制备实施例31：
化合物S31的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.43(s,1H),7.72(d,J＝1.8Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.41(d,J＝7.3Hz,2H),7.37(t,J＝7.8Hz,2H),7.26(t,J＝7.8Hz,1H),5.46–5.22(m,1H),3.93(dd,J＝11.3,4.6Hz,1H),3.86(dd,J＝11.3,6.5Hz,1H),3.76–3.66(m,2H),3.59(t,J＝6.0Hz,2H),3.57–3.53(m,2H),3.47(t,J＝6.7Hz,2H),1.95-1.83(m,2H),1.50(s,3H),1.49(s,3H).
32.制备实施例32：
化合物S32的合成：合成步骤同S14。1H NMR(700MHz,氘代甲醇)δ8.43(s,1H),7.72(d,J＝2.2Hz,1H),7.61(d,J＝9.6Hz,1H),7.56(d,J＝8.4Hz,1H),7.41(d,J＝7.7Hz,2H),7.37(t,J＝7.5Hz,2H),7.26(t,J＝7.2Hz,1H),5.49–5.25(m,1H),3.94(dd,J＝11.3,4.6Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.65-3.59(m,2H),3.38(t,J＝6.8Hz,2H),1.89-1.84(m,2H),1.85-1.72(m,2H),1.50(s,3H),1.49(s,3H).
33.制备实施例33：
33a的合成参照专利CN 106795162 A。
化合物S33的合成：合成步骤同1e。1H NMR(700MHz,氘代甲醇)δ9.71(s,1H),9.08(d,J＝6.7Hz,1H),8.64(s,1H),8.24(s,1H),8.09(s,1H),7.40(d,J＝7.5Hz,2H),7.35(t,J＝7.7Hz,2H),7.23(t,J＝7.3Hz,1H),5.26(t,J＝4.9Hz,1H),5.18(q,J＝5.5Hz,1H),4.33(q,J＝7.0Hz,2H),3.87-3.82(m,1H),3.73-3.64(m,1H),1.77(s,3H),1.75(s,3H),1.34(t,J＝7.1Hz,3H).
34.制备实施例34：
化合物S34的合成：合成步骤同S10。1H NMR(500MHz,氘代氯仿)δ8.40(s,1H),7.79(s,1H),7.44-7.42(m,2H),7.25-7.21(m,3H),6.68(s,1H),6.47(s,1H),6.23(s,1H),6.11(s,1H),5.20(s,1H),4.99-4.95(m,1H),4.39(dd,J＝12.4,7.1Hz,1H),4.16(dd,J＝12.5,7.0Hz,1H),2.96(s,1H),1.67(s,3H),1.63(s,3H).
35.制备实施例35
化合物S35的合成：合成步骤同S10。1H NMR(500MHz,氘代氯仿)δ8.40(s,1H),7.32–7.26(m,2H),7.29–7.18(m,3H),6.68(s,1H),6.47(s,1H),6.11(s,1H),5.67(s,1H),5.20(s,1H),4.71–4.64(m,1H),4.33(dd,J＝12.4,7.1Hz,1H),4.09(dd,J＝12.4,7.0Hz,1H),2.96(s,1H),1.67(s,3H),1.63(s,3H).
36.制备实施例36
化合物S36的合成：合成步骤同S10。1H NMR(500MHz,氘代氯仿)δ8.42(s,1H),7.45–7.38(m,2H),7.25-7.21(m,3H),6.66(d,J＝20.0Hz,1H),6.47(s,1H),6.23(s,1H),6.11(s,1H),5.20(s,1H),4.50-496(m,1H),4.39(dd,J＝12.5,7.0Hz,1H),4.16(dd,J＝12.5,7.0Hz,1H),2.96(s,1H),1.67(s,3H),1.63(s,3H).
37.制备实施例37
化合物S37的合成：合成步骤同S4。 1H NMR(700MHz,氘代甲醇)δ8.95(s,1H),8.65(s,1H),7.79–7.72(m,1H),7.66(dd,J＝8.3,1.8Hz,1H),7.59(d,J＝8.3Hz,1H),7.52–7.41(m,2H),7.39(t,J＝7.8Hz,2H),5.55–5.47(m,1H),4.02(dd,J＝11.3,4.5Hz,1H),3.94(dd,J＝11.4,6.4Hz,1H),1.52(s,3H),1.51(s,3H)。
38.制备实施例38
化合物S38的合成：合成步骤同S16。1H NMR(700MHz,氘代甲醇)δ8.46(s,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.58(d,J＝8.4Hz,1H),7.42–7.39(m,2H),7.37(t,J＝7.7Hz,2H),7.26(t,J＝7.2Hz,1H),5.47–5.30(m,1H),4.54-4.35(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.93–3.84(m,2H),3.60-3.40(m,1H),1.51(s,3H),1.49(s,3H),1.29(m,6H).
39.制备实施例39
化合物S39的合成：合成步骤同S17。1H NMR(700MHz,氘代甲醇)δ8.49(s,1H),7.70(d,J＝1.9Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.42–7.34(m,3H),7.28–7.23(m,1H),5.38(dd,J＝6.5,4.4Hz,1H),3.94(dd,J＝11.4,4.5Hz,1H),3.90–3.81(m,3H),3.75(t,J＝13.0Hz,2H),1.49(d,J＝11.4Hz,6H)。
40.制备实施例40
化合物S40的合成：合成步骤同S25。1H NMR(700MHz,氘代甲醇)δ8.47(s,1H),7.71(d,J＝1.9Hz,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.40(d,J＝7.3Hz,2H),7.37(t,J＝7.8Hz,2H),5.42–5.32(m,1H),4.75–4.61(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.84-3.72(m,1H),3.74–3.69(m,1H),3.69–3.63(m,1H),3.61-3.55(m,1H),1.50(s,3H),1.48(s,3H)。
41.制备实施例41
化合物S41的合成：合成步骤同S26。1H NMR(700MHz,氘代甲醇)δ8.44(s,1H),7.72(d,J＝1.8Hz,1H),7.61(dd,J＝8.3,1.8Hz,1H),7.56(d,J＝8.3Hz,1H),7.41(d,J＝7.5Hz,2H),7.37(t,J＝7.7Hz,2H),5.40–5.27(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.2,6.3Hz,1H),3.73(t,J＝4.7Hz,4H),3.41(t,J＝6.8Hz,2H),3.00-2.98(m,1H),2.62-2.54(m,5H),1.92–1.75(m,2H),1.50(s,3H),1.48(s,3H)。
42.制备实施例42
化合物S42的合成：合成步骤同S31。1H NMR(500MHz,氘代氯仿)δ8.47(s,1H),7.71(d,J＝1.9Hz,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.40(d,J＝7.3Hz,2H),7.37(t,J＝7.8Hz,2H),5.42–5.32(m,1H),4.75–4.61(m,1H),3.94(dd,J＝11.3,4.5Hz,1H),3.86(dd,J＝11.3,6.4Hz,1H),3.84-3.72(m,1H),3.74–3.69(m,1H),3.69–3.63(m,1H),3.61-3.55(m,1H),1.50(s,3H),1.48(s,3H)。
二.化合物S4与文献化合物K化合物水溶性测试
1.实验方法
仪器：高效液相色谱；电子天平ME204E；水浴恒温振荡器SHA-C。
材料：0.45μm微孔滤膜；甲醇(AR)；超纯水；加水溶解即可。
实验方法：
(1)标准储备液的配制
取1.00mg化合物于10mL容量瓶中，用甲醇定容，配制100μg/mL的储备液，把配好的储备液分别稀释，配制2-5个浓度的样品用来建立标准曲线。
(2)标准曲线的建立
精密移取各浓度的标准品到测试瓶中，以相应的溶剂作空白，用HPLC测试每一个样品各浓度下的吸光度值A。以吸光度值A为纵坐标，浓度C为横坐标绘制标准曲线，计算回归方程。
从图1方程计算可知：化合物K的溶解度为7.36ug/ml。
从图2方程计算可知：化合物S4的溶解度为60.4ug/ml，是化合物K的8倍。
从图3方程计算可知：化合物S16的溶解度为590ug/ml，是化合物K的80倍。
从图4方程计算可知：化合物S26的溶解度为856ug/ml，是化合物K的116倍。
三.化合物对HPK1酶的抑制活性
试剂、耗材与仪器：
实验中所用激酶和底物购自Promega公司；反应微孔板购自PerkinElmer公司。实验读板用多功能酶标仪为Molecular Devices公司产品，型号：SpectraMax Paradigm；实验用水为国药集团产蒸馏水。阳性化合物GNE-1858购自MedChemExpress(MCE)公司。
化合物配制：
化合物12000g离心5min，加入DMSO配制成10-2M储液,涡旋均匀后超声10min待用，-40℃保存。测试时将化合物用DMSO从储液稀释到所测试浓度的100倍(体系中DMSO浓度为1％)。
试验方法：
1.酶促反应：
384孔板中，加入2μL酶和1μL不同浓度化合物，同时设置不加激酶和化合物的0％激酶活性对照孔和不加化合物的100％激酶活性对照孔，室温孵育10min。继续加入2μL ATP+底物的混合液(底物终浓度100μg/mL，ATP终浓度10μM)，37℃孵育1h。
2.检测反应：
每孔加入5μL ADP-GloTM Reagent,室温孵育40min，去除未反应ATP。每孔加入10μlKinase Detection Reagent，室温孵育30-60min，使反应中生成的ADP转化为ATP。
3.读板：
检测荧光信号(luminescence：integration time 0.5s)。
4.计算：
通过平均RLU值表示0％激酶活性(无酶和化合物)和100％激酶活性(无化合物)来计算每个孔的抑制率，IC50值采用GraphPad Prism软件计算求得。抑制率计算公式如下：
表1实施例中部分化合物对HPK1酶活性的抑制作用
| 化合物 | IC50 *(nM) |
| S4 | 11.7 |
| S16 | 42.7 |
| S26 | 30.9 |
| 化合物K | 54.1 |
本发明获得一类具有二甲基异吲哚酮的新型HPK1抑制剂，该类化合物对HPK1具有强的抑制活性，并且与阳性化合物K相比，具有显著提升的水溶解性，具有进一步研发前景。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种化合物，其特征在于，所述化合物为式I所示化合物、或其药学上可接受的盐、溶剂合物，
其中，
Q为C时，
为双键，A环为
或者
Q为N时，
为单键，A环为
R1选自下组：组A、组B；
组A为取代或未取代的含1、2或3个选自N、O、S的杂原子的5-6元杂芳基，所述取代指被选自下组的1、2或3个取代基取代：卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、-(C1-C3亚烷基)-O-(C1-C3亚烷基)-OH；
组B选自下组：-CO-NH-(C1-C3亚烷基)-O-(C1-C3亚烷基)-C1-C6烷氧基、-CO-NH-(C1-C3亚烷基)-O-(C1-C3亚烷基)-OH、-CO-NH-(1、2或3个R’取代或未取代的C1-C8烷基)、-CO-NH-(1、2或3个R’取代或未取代的C3-C6环烷基)、-COO-(C1-C6烷基)；
各R’独立地选自下组：卤素、羟基、氰基、氨基、-(C1-C3亚烷基)-OH、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C3烷基氨基、C1-C3烷基酰(胺)基、C1-C3烷基磺酰(胺)基、C3-C6环烷基、卤代C3-C6环烷基、1、2或3个R”取代或未取代的含1、2或3个选自N、O、S的杂原子的4-8元杂环基；
各R”独立地选自下组：C1-C6烷基、卤素、氰基、氨基、羟甲基、氰基甲基、卤代C1-C6烷基；
R2、R3独立地选自下组：无、氢、卤素、卤代C1-C2烷基、C1-C2烷氧基、卤代C1-C2烷氧基；
R4、R5独立地选自下组：氢、C1-C3烷基；或者R4和R5形成3-6元环烷基；
X、Y分别独立地选自下组：CH、N；
W选自下组：NH、N-(1、2或3个R’取代或未取代的C1-C6烷基)。
2.如权利要求1所述化合物，其特征在于，所述化合物为式I-1所示化合物：
其中，各基团如权利要求1所定义。
3.如权利要求1所述化合物，其特征在于，所述化合物为式I-2所示化合物：
其中，各基团如权利要求1所定义。
4.如权利要求2所述化合物，其特征在于，
R1为含1、2或3个选自N、O、S的杂原子的5-6元杂芳基；
X、Y均为CH；
R2、R3均为氢或R2单独为F；
W为NH；
R4、R5独立地为C1-C3烷基。
5.如权利要求1所述化合物，其特征在于，所述含1、2或3个选自N、O、S的杂原子的5-6元杂芳基为
6.如权利要求1所述化合物，其特征在于，所述药学上可接受的盐选自下组：无机酸盐、有机酸盐、烷基磺酸盐、芳基磺酸盐。
7.如权利要求1所述化合物，其特征在于，所述化合物选自下组：
8.一种药物组合物，其特征在于，包含药学上可接受的载体和一种或多种预防和/或治疗有效量的权利要求1所述化合物。
9.一种权利要求1所述化合物的用途，其特征在于，用于制备药物，所述药物用于预防和/或治疗HPK1相关疾病。
10.如权利要求9所述用途，其特征在于，所述HPK1相关疾病为肿瘤。
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