CN116535422A - 具有五元芳杂环并哌啶/高哌啶的hpk1抑制剂及其制备方法及用途 - Google Patents
具有五元芳杂环并哌啶/高哌啶的hpk1抑制剂及其制备方法及用途 Download PDFInfo
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- CN116535422A CN116535422A CN202210093995.5A CN202210093995A CN116535422A CN 116535422 A CN116535422 A CN 116535422A CN 202210093995 A CN202210093995 A CN 202210093995A CN 116535422 A CN116535422 A CN 116535422A
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- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
本发明涉及具有五元芳杂环并哌啶/高哌啶的HPK1抑制剂及其制备方法及用途。具体地,本发明化合物具有式1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抗肿瘤方面的用途。
Description
技术领域
本发明涉及药物领域,具体地涉及具有五元芳杂环并哌啶/高哌啶的HPK1抑制剂及其制备方法及用途。
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,是靶向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,本发明公开一类结构新颖、高抑制活性的HPK1抑制剂。
发明内容
本发明的目的在于提供一种式1所示化合物及其制备方法和其在抗肿瘤方面的用途。
本发明的第一方面,提供了一种化合物,所述化合物为式1所示化合物、或其立体异构体、药学上可接受的盐或溶剂合物,
其中,
X选自下组:CH、N;
A1、A2独立地选自下组:S、N、CH2、CH、NH、O;
A3选自下组:C、CH、N;
为含1、2或3个选自N、O或S的杂原子的5元杂芳基;
R1选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基-取代或未取代的C1-C6亚烷基-、取代或未取代的C3-C8环烷基-(C=O)-、含1、2或3个选自N、O或S的杂原子的4-8元杂环基并取代或未取代的C3-C8环烷基-(C=O)-、取代或未取代的C1-C6烷基-(C=O)-、取代或未取代的C2-C6烯基-(C=O)-、取代或未取代的C2-C6炔基-(C=O)-、Rb-(取代或未取代的C1-C3亚烷基)-(C=O)-、取代或未取代的-S(=O)2-、
所述取代独立地指被选自下组的1、2、3或4个取代基取代:氢、卤素、羟基、-N(C1-C3烷基)2、-NH2、氰基、-(C1-C3亚烷基)-OH、-(C1-C3亚烷基)-CN、C1-C3烷基、卤代C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
Rb选自下组:氢、卤素、羟基、氨基、氰基、C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
m为0、1、2或3;
n为0、1、2或3;
p为0、1、2或3。
在另一优选例中,
X为CH;
A1、A2独立地选自下组:S、N、CH、NH、O;
A3选自下组:C、N。
在另一优选例中,选自下组:/>
在另一优选例中,
R1选自下组:H、取代或未取代的C1-C3烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6环烷基-取代或未取代的C1-C3亚烷基-、取代或未取代的C3-C6环烷基-(C=O)-、含1、2或3个选自N、O或S的杂原子的4-6元杂环基并取代或未取代的C3-C6环烷基-(C=O)-、取代或未取代的C1-C3烷基-(C=O)-、取代或未取代的C2-C4烯基-(C=O)-、取代或未取代的C2-C4炔基-(C=O)-、Rb-(取代或未取代的C1-C3亚烷基)-(C=O)-、取代或未取代的-S(=O)2-、
所述取代独立地指被选自下组的1、2、3或4个取代基取代:氢、卤素、羟基、-N(C1-C3烷基)2、-NH2、氰基、-(C1-C3亚烷基)-OH、-(C1-C3亚烷基)-CN、C1-C3烷基、卤代C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
Rb选自下组:氢、卤素、羟基、氨基、氰基、C1-C3烷基、C3-C6环烷基;
m为0、1、2或3;
n为0、1、2或3。
在另一优选例中,所述卤代C1-C3烷基为F代C1-C3烷基,优选全F代C1-C3烷基。
在另一优选例中,所述卤代C1-C3烷基为全卤代C1-C3烷基。
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安全有效量的本发明第一方面所述的化合物。
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,所述药物用于治疗肿瘤。
在另一优选例中,所述肿瘤选自下组:乳腺癌、结直肠癌、血液学恶性肿瘤、肺癌、黑色素瘤、卵巢癌、胰腺癌、肾脏癌症。
在另一优选例中,所述肺癌为非小细胞肺癌;
所述肾脏癌症为肾细胞癌。
本发明的第四方面,提供了一种HPK1抑制剂,包含一种或多种本发明第一方面所述的化合物。
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。
具体实施方式
本发明人经过长期而深入的研究,通过结构优化,获得了一种结构新颖、具备优异HPK1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。
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。
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1所示化合物、或其立体异构体、药学上可接受的盐或溶剂合物,
其中,各基团如上文所定义。
在另一优选例中,所述的化合物中,X、A1、A2、A3、R1、Rb、m、n中任一个分别独立地为本发明所述具体化合物中所对应的基团。
在另一优选例中,所述化合物优选为各实施例所制备化合物。
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。
应理解,本发明化合物可采用实施例所示方法制备,还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
应理解,本发明化合物的制备工艺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安全有效量的所述的化合物。
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(如CAR-T细胞疗法)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)所述化合物具有显著优异的HPK1抑制活性;
(2)所述化合物结构新颖、易于制备。
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用Bruke 400或700型仪测定;碳酸钾,三乙胺,氢氧化钠,硫酸钠,氢氧化钠和盐酸购于国药集团化学试剂有限公司,其余试剂由上海毕得医药科技有限公司生产。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。
制备实施例
以下制备例示例性的制备了本发明的部分式1化合物,各化合物分别以A1至A28表示。
1.化合物A1的合成
步骤1:将化合物1a(350mg,0.67mmol),化合物1b(187.43mg,0.80mmol),碳酸钠(213.03mg,2.01mmol),1,1'-双(二苯基膦)二茂铁(37.14mg,0.07mmol)溶于1,4-二氧六环(20mL)和水(5mL)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=10:1),得240.33mg黄色油状液体(产率:65.4%)。MS(ESI):[M+H]+m/z 549.2。[化合物1a的合成参考文献:WO 2019/206049]
步骤2::将化合物1c(200mg,0.36mmol),铁粉(101.78mg,1.82mmol),氯化铵(97.49mg,1.82mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=60:1),得103.9mg白色固体(产率:54.9%)。
步骤3:将化合物1d(90mg,0.17mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=20:1),得18.3mg白色固体(产率:23.9%)。1H NMR(400MHz,CDCl3)δ8.14(d,J=1.8Hz,1H),7.57(d,J=1.8Hz,1H),7.47(s,1H),7.40(t,J=2.1Hz,0.39H),7.38(t,J=2.3Hz,0.58H),7.36–7.30(m,2H),5.08(s,2H),5.03(s,2H),3.68(s,2H),2.96(t,J=5.8Hz,2H),2.84(t,J=5.7Hz,2H),2.52(s,3H),1.61(s,6H)。
2.化合物A2的合成
步骤1:将化合物1a(315mg,0.6mmol),化合物2a(231mg,0.72mmol),碳酸钠(191.7mg,1.8mmol),1,1'-双(二苯基膦)二茂铁(33.4mg,0.06mmol)溶于1,4-二氧六环(8mL)和水(2mL)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=10:1),得120mg黄色油状液体(产率:31.4%)。1H NMR(400MHz,CDCl3)δ8.48(d,J=1.7Hz,1H),8.09(s,1H),7.48(s,1H),7.43–7.37(m,2H),7.34(d,J=2.5Hz,1H),5.28(s,2H),5.11(dd,J=5.6,3.2Hz,1H),4.71(s,2H),3.97(dt,J=10.5,4.8Hz,1H),3.79(s,2H),3.51(dt,J=11.1,5.0Hz,1H),2.96(s,2H),1.64–1.45(m,21H)。
步骤2:将化合物2b(120mg,0.19mmol),铁粉(52.8mg,0.95mmol),氯化铵(50.6mg,0.95mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=10:1),得105mg白色固体(产率:91.8%)。
步骤3:将化合物2c(80mg,0.13mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=180:1),得20.4mg白色固体(产率:29.62%)。1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.58(s,1H),7.50(s,1H),7.42(d,J=6.5Hz,1H),7.35(d,J=6.2Hz,2H),5.19–5.08(m,4H),4.64(s,2H),3.77(s,2H),2.91(s,2H),1.63(s,6H),1.50(s,9H)。
步骤4:将化合物2d(100mg,0.19mmol)溶于DCM(二氯甲烷,5mL)中,搅拌下逐滴加入TFA(三氟乙酸,5mL),室温反应1h。待反应完毕后,旋干反应体系,不需进一步纯化,得78.6mg黄色油状液体(产率:97.31%)。
步骤5:将化合物2e(78.6mg,0.19mmol),2,2-二氟环丙羧酸(29.7mg,0.24mmol),HATU(N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲,142.1mg,0.38mmol)溶于DMF(N,N-二甲基甲酰胺,5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得16.2mg白色固体(产率:16.52%)。1H NMR(400MHz,CDCl3)δ8.12(d,J=1.8Hz,1H),7.61(d,J=1.8Hz,0.33H),7.57(d,J=1.8Hz,0.71H),7.49(s,1H),7.43–7.40(m,1H),7.38–7.32(m,2H),5.39(s,2H),5.12(s,2H),4.93–4.79(m,2H),4.09–3.85(m,2H),3.06–3.01(m,1.55H),2.97–2.94(m,0.69H),2.69–2.56(m,1H),2.25–2.17(m,1H),1.79–1.68(m,1H),1.63(s,6H)。
3.化合物A3的合成
将化合物2e(60mg,0.14mmol),3-氧杂双环[3.1.0]己烷-6-羧酸(23.8mg,0.19mmol),HATU(108.5mg,0.29mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得17.3mg白色固体(产率:22.85%)。1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.58(s,0.3H),7.55(s,0.7H),7.48(s,1H),7.44–7.39(m,1H),7.38–7.31(m,2H),5.20(s,2H),5.11(s,2H),4.85(s,0.7H),4.80(s,1.4H),3.97–3.94(m,4H),3.79(d,J=8.4Hz,2H),2.99(s,1.3H),2.91(s,0.7H),2.51(br,2H),2.22(s,2H),1.84(t,J=3.4Hz,0.7H),1.77(s,0.3H),1.63(s,6H)。
4.化合物A4的合成
将化合物2e(60mg,0.14mmol),3-氰基丙酸(18.4mg,0.19mmol),HATU(108.5mg,0.29mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得13.5mg白色固体(产率:18.86%)。1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.57(d,J=1.6Hz,0.36H),7.54(d,J=1.8Hz,0.72H),7.49(s,1H),7.41(m,1H),7.38–7.31(m,2H),5.20(s,2H),5.11(s,2H),4.82(s,1.46H),4.66(s,0.72H),3.98(t,J=5.8Hz,0.73H),3.78(t,J=5.8Hz,1.44H),2.99(t,J=5.9Hz,1.45H),2.93(t,J=5.9Hz,0.75H),2.87–2.70(m,4H),1.63(s,6H)。
5.化合物A5的合成
将化合物2e(60mg,0.14mmol),1-三氟甲基环丙烷-1-甲酸(28.6mg,0.19mmol),HATU(108.5mg,0.29mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得11.2mg白色固体(产率:14.11%)。1H NMR(700MHz,CDCl3)δ8.08(d,J=1.7Hz,1H),7.62(s,1H),7.49(s,1H),7.44–7.42(m,1H),7.36(d,J=1.0Hz,1.16H),7.35(d,J=1.3Hz,0.86H),5.75(s,2H),5.14(s,2H),4.86(s,2H),4.04(s,2H),2.99(s,2H),1.63(s,6H),1.40(t,J=6.5Hz,2H),1.25(s,2H)。
6.化合物A6的合成
将化合物2e(60mg,0.14mmol),3,3-二氟环丁烷羧酸(23.3mg,0.19mmol),HATU(108.5mg,0.29mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得16.3mg白色固体(产率:21.21%)。1H NMR(700MHz,CDCl3)δ8.10(d,J=1.8Hz,0.66H),8.09(d,J=1.8Hz,0.32H),7.62(d,J=1.8Hz,0.32H),7.57(d,J=1.8Hz,0.68H),7.49(s,1H),7.44–7.41(m,1H),7.36–7.34(m,2H),5.58(s,2H),5.13(d,J=2.9Hz,2H),4.83(s,1.43H),4.62(s,0.64H),3.98(t,J=5.8Hz,0.65H),3.74(t,J=5.8Hz,1.44H),3.20–3.16(m,0.77H),3.14–3.10(m,0.35H),3.03–2.96(m,2H),2.97–2.89(m,1H),2.84–2.73(m,2H),1.63(s,6H)。
7.化合物A7的合成
步骤1:将化合物2e(160mg,0.38mmol),化合物7a(112.4mg,0.49mmol),HATU(289.3mg,0.76mmol)溶于DMF(10mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=25:1),得73.5mg白色固体(产率:30.67%)。1H NMR(700MHz,CDCl3)δ8.13(s,1H),7.57(s,1H),7.49(s,1H),7.41(d,J=6.8Hz,1H),7.35(d,J=7.6Hz,2H),5.33(s,2H),5.12(s,2H),4.87–4.75(m,2H),3.96(t,J=5.8Hz,2H),3.69(d,J=10.9Hz,1H),3.57(s,1H),3.46(d,J=11.4Hz,2H),3.03–2.91(m,2H),2.55(s,2H),2.17(s,1H),2.09(s,1H),1.62(s,6H),1.47(s,9H)。
步骤2:将化合物7b(50mg,0.08mmol)溶于DCM(5mL)中,搅拌下逐滴加入TFA(5mL),室温反应1h。待反应完毕后,用饱和碳酸氢钠溶液把反应体系调成中性,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得18.7mg白色固体(产率:44.52%)。1H NMR(700MHz,CDCl3)δ8.16(s,1H),7.53(s,1H),7.46(s,1H),7.40(m,1H),7.36–7.31(m,2H),5.07(s,2H),5.03(s,2H),4.89(s,0.71H),4.78(s,1.31H),3.97(t,J=5.7Hz,1.33H),3.94(t,J=6.0Hz,0.78H),3.19(d,J=11.1Hz,2H),3.10(d,J=11.0Hz,2H),3.00(t,J=5.7Hz,1.36H),2.90(s,0.70H),2.10(s,2H),1.96(s,0.64H),1.94(s,0.39H),1.62(s,6H)。
8.化合物A8的合成
将化合物2e(143mg,0.34mmol),甲氧基乙酸(39.8mg,0.44mmol),HATU(258.6mg,0.68mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得28.7mg白色固体(产率:17.1%)。1H NMR(700MHz,CDCl3)δ8.13(s,0.62H),8.12(s,0.31H),7.56(s,0.34H),7.53(s,0.67H),7.46(s,1H),7.39(s,0.42H),7.38(s,0.56H),7.32(m,2H),5.17(s,2H),5.08(s,2H),4.79(s,1.39H),4.72(s,0.69H),4.21(s,1.36H),4.17(s,0.69H),3.95(t,J=5.5Hz,0.69H),3.80(t,J=5.7Hz,1.37H),3.44(s,2H),3.42(s,1H),2.96(t,J=5.1Hz,1.42H),2.93(s,0.79H),1.62(s,6H)。
9.化合物A9的合成
将化合物2e(96.7mg,0.23mmol),乙醇酸(22.7mg,0.30mmol),HATU(178.9mg,0.17mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得11.2mg白色固体(产率:10.2%)。1H NMR(700MHz,CDCl3)δ8.05(s,0.62H),8.05(s,0.39H),7.48(s,0.38H),7.45(s,0.71H),7.40(s,1H),7.32(s,0.46H),7.32(s,0.63H),7.29–7.22(m,2H),5.11(s,2H),5.01(s,2H),4.77(s,1.46H),4.40(s,0.74H),4.22(s,1.47H),4.16(s,0.79H),3.94(t,J=5.9Hz,0.75H),3.53(t,J=5.8Hz,1.60H),2.88(s,2H),1.54(s,6H)。
10.化合物A10的合成
将化合物2e(109.3mg,0.26mmol),D-苏糖酸钾(46.0mg,0.34mmol),HATU(197.7mg,0.52mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=10:1),得化合物A10 21.6mg白色固体(产率:15.4%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44(d,J=1.5Hz,1H),7.43–7.42(m,0.66H),7.42–7.41(m,0.37H),7.40(q,J=1.3Hz,1H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5Hz,1H),5.16–5.05(m,2H),4.71(d,J=9.5Hz,1H),4.67(s,1H),4.46–4.42(m,2H),4.41(d,J=0.7Hz,0.79H),4.40(d,J=0.7Hz,0.2H),4.36(s,1H),4.24(t,J=7.5Hz,1H),3.97–3.89(m,1H),3.83–3.66(m,4H),2.66–2.62(m,2H),1.67(s,3H),1.62(s,3H)。
11.化合物A11的合成
将化合物2e(55mg,0.13mmol),2-溴乙醇(32.7mg,0.26mmol)和碳酸钾(36.2mg,0.26mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得26.8mg白色固体(产率:44.1%)。1H NMR(700MHz,CDCl3)δ8.16(d,J=1.8Hz,1H),7.56(d,J=1.9Hz,1H),7.50(s,1H),7.42(t,J=1.8Hz,0.44H),7.41(t,J=1.7Hz,0.59H),7.38–7.33(m,2H),5.11(s,2H),5.00(s,2H),3.88(s,2H),3.76(t,J=5.2Hz,2H),3.04(t,J=5.8Hz,2H),3.00–2.96(m,2H),2.85(t,J=5.3Hz,2H),1.63(s,6H)。
12.化合物A12的合成
将化合物2e(55mg,0.13mmol),2-(2-溴乙氧基)乙醇(44.2mg,0.26mmol)和碳酸钾(36.2mg,0.26mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得18.7mg白色固体(产率:28.12%)。1H NMR(700MHz,CDCl3)δ8.12(d,J=1.8Hz,1H),7.54(d,J=1.9Hz,1H),7.47(s,1H),7.40(t,J=2.2Hz,0.43H),7.39(t,J=2.4Hz,0.5H),7.36–7.31(m,2H),5.07(s,2H),5.04(s,2H),3.82(s,2H),3.73–3.71(m,4H),3.64–3.61(m,2H),2.98(t,J=5.6Hz,2H),2.95(t,J=5.6Hz,2H),2.83(t,J=5.4Hz,2H),1.62(s,6H)。
13.化合物A13的合成
将化合物2e(48mg,0.12mmol),溴代-二聚乙二醇(48.6mg,0.23mmol)和碳酸钾(31.6mg,0.23mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得28.4mg白色固体(产率:45.02%)。1H NMR(700MHz,CDCl3)δ8.09(d,J=1.8Hz,1H),7.53(d,J=1.8Hz,1H),7.46(s,1H),7.38(t,J=1.6Hz,0.44H),7.37(t,J=1.6Hz,0.54H),7.34–7.29(m,2H),5.14(s,2H),5.06(s,2H),3.83(s,2H),3.73–3.70(m,4H),3.68–3.66(m,2H),3.65–3.63(m,2H),3.62–3.59(m,2H),2.99(t,J=5.8Hz,2H),2.93(t,J=6.2Hz,2H),2.85(t,J=5.5Hz,2H),1.60(s,6H)。
14.化合物A14的合成
将化合物2e(72.5mg,0.17mmol),3-溴-1,1,1-三氟-2-丙醇(66.5mg,0.34mmol)和碳酸钾(47.7mg,0.34mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得30.5mg白色固体(产率:33.22%)。1H NMR(700MHz,DMSO-d6)δ8.05(d,J=1.9Hz,1H),7.53(m,2H),7.46(d,J=1.9Hz,1H),7.42–7.37(m,1H),7.34(d,J=7.7Hz,1H),6.34(s,2H),6.24(d,J=6.4Hz,1H),5.47(s,1H),5.23(s,2H),4.23(br,1H),3.85–3.75(m,2H),2.92(t,J=5.8Hz,2H),2.77(m,3H),2.72(m,1H),1.46(s,6H)。
15.化合物15的合成
将化合物2e(72.5mg,0.17mmol),3-溴-三氟-2-丙醇(66.5mg,0.34mmol)和碳酸钾(47.7mg,0.34mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得20.4mg白色固体(产率:22.21%)。1H NMR(700MHz,DMSO-d6)δ8.05(d,J=1.9Hz,1H),7.53(m,2H),7.46(d,J=1.9Hz,1H),7.40(t,J=8.0Hz,1H),7.34(dt,J=7.6,1.5Hz,1H),6.34(s,2H),6.25(d,J=6.4Hz,1H),5.47(s,1H),5.23(s,2H),4.23(br,1H),3.80(q,J=15.2Hz,2H),3.30(s,1H),2.92(t,J=5.8Hz,2H),2.78(s,3H),2.72(m,J=8.3Hz,1H),1.47(s,6H)。
16.化合物A16的合成
将化合物2e(60mg,0.14mmol),2-溴乙基甲基醚(39.7mg,0.29mmol)和碳酸钾(39.4mg,0.29mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=18:1),得21.6mg白色固体(产率:31.63%)。1H NMR(700MHz,CDCl3)δ8.13(s,1H),7.56(s,1H),7.44(s,1H),7.37(d,J=7.4Hz,1H),7.32(m,2H),5.06(s,4H),3.81(s,2H),3.59(t,J=5.4Hz,2H),3.37(d,J=1.3Hz,3H),2.95(d,J=4.5Hz,2H),2.94(s,2H),2.82(m,2H),1.61(s,6H)。
17.化合物A17的合成
化合物2e(48mg,0.11mmol),N,N-二甲胺基溴乙烷氢溴酸盐(34.7mg,0.23mmol)和碳酸钾(31.6mg,0.23mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得8.6mg白色固体(产率:15.32%)。1H NMR(700MHz,CDCl3)δ8.13(d,J=1.6Hz,1H),7.54(s,1H),7.49(s,1H),7.41(d,J=7.1Hz,1H),7.37-7.33(m,2H),5.14(s,2H),5.10(s,2H),3.85(s,2H),3.19(s,4H),3.01–2.97(m,2H),2.94(d,J=6.7Hz,2H),2.90(s,6H),1.62(s,6H)。
18.化合物A18的合成
将化合物2e(48mg,0.11mmol),化合物18a(45.9mg,0.23mmol)和碳酸钾(31.6mg,0.23mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得12.4mg白色固体(产率:20.09%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.43–7.42(m,0.68H),7.42–7.41(m,0.32H),7.41–7.39(m,2H),7.37(t,J=1.6Hz,0.55H),7.35(t,J=1.6Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5Hz,1H),5.16–5.04(m,2H),4.70(d,J=6.8Hz,1H),4.67(s,1H),4.05–3.93(m,3H),3.12–3.06(m,2H),3.04–2.99(m,1H),2.94–2.89(m,1H),2.72(t,J=7.1Hz,2H),2.44–2.32(m,1H),2.29–2.17(m,1H),1.92–1.80(m,1H),1.67(s,3H),1.62(s,3H)。
19.化合物A19的合成
将化合物2e(72mg,0.17mmol),3-溴-1,2-并二酚(53.1mg,0.34mmol)和碳酸钾(47.3mg,0.34mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=12:1),得18.0mg白色固体(产率:21.26%)。1H NMR(700MHz,氘代甲醇)δ8.04(d,J=1.9Hz,1H),7.55(d,J=1.8Hz,1H),7.54(s,1H),7.47(m,1H),7.37(s,1H),7.37(d,J=1.3Hz,1H),5.21(s,2H),3.94–3.84(m,3H),3.55(qd,J=11.2,5.3Hz,2H),3.05(t,J=5.8Hz,2H),2.91(t,J=5.8Hz,2H),2.79(dd,J=13.1,4.0Hz,1H),2.69(dd,J=13.0,8.0Hz,1H),1.56(s,6H)。
20.化合物A20的合成
将化合物2e(72mg,0.17mmol),化合物20a(56.5mg,0.34mmol)和碳酸钾(47.3mg,0.34mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得9.4mg白色固体(产率:10.88%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.43(m,1.65H),7.42–7.41(m,0.34H),7.41–7.40(m,1H),7.37(t,J=1.7Hz,0.57H),7.36(t,J=1.6Hz,0.42H),6.78(d,J=12.3Hz,1H),6.41(d,J=12.5Hz,1H),5.10(t,J=1.0Hz,2H),4.67(s,1H),4.05(t,J=5.4Hz,1H),3.93(s,2H),3.34(d,J=5.5Hz,2H),3.06(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.52(s,2H),1.81(s,4H),1.64(s,6H)。
21.化合物A21的合成
将化合物2e(60.5mg,0.14mmol),1-环丙基溴甲烷甲腈(50.1mg,0.29mmol)和碳酸钾(39.8mg,0.29mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得17.3mg白色固体(产率:23.41%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42(m,1.71H),7.42–7.41(m,0.35H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.58H),7.36(t,J=1.6Hz,0.43H),6.78(d,J=12.3Hz,1H),6.41(d,J=12.5Hz,1H),5.10(t,J=1.0Hz,2H),4.67(s,1H),3.99(s,2H),3.11(t,J=7.1Hz,2H),2.83(s,2H),2.71(t,J=7.1Hz,2H),2.18–2.04(m,4H),1.64(s,6H)。
22.化合物A22的合成
将化合物2e(60.5mg,0.14mmol),化合物22a(47.2mg,0.29mmol)和碳酸钾(39.8mg,0.29mmol)溶于干燥的乙腈(10mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得12.0mg白色固体(产率:16.56%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.48–7.44(m,1H),7.43(d,J=1.5Hz,1H),7.42–7.41(m,0.63H),7.41–7.39(m,1.34H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.41H),6.78(d,J=12.5Hz,1H),6.44(d,J=12.3Hz,1H),5.08(t,J=1.0Hz,2H),4.67(s,1H),3.90(s,2H),3.43(s,2H),3.03(t,J=7.0Hz,2H),2.73(t,J=7.0Hz,2H),2.38(s,2H),1.93–1.82(m,4H),1.64(s,6H)。
23.化合物A23的合成
步骤1:将化合物23a(300mg,1.08mmol),氰酸钾(262.5mg,3.24mmol)溶于乙醇(9mL)和水(1mL)的混合溶液中,78℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=60:1),得68.5mg红色油状液体(产率:26.43%)。1H NMR(400MHz,CDCl3)δ9.10(s,1H),3.95(s,1H),3.75(t,J=7.1Hz,2H),3.71(s,1H),2.39(t,J=7.1Hz,2H),1.46(s,9H)。
步骤2:将化合物23b(50mg,0.21mmol),三溴氧磷(298.3mg,1.04mmol)溶于吡啶(5mL)中,110℃回流2h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=200:1),得16mg红色油状液体(产率:25.36%)。1H NMR(400MHz,CDCl3)δ4.47(s,2H),3.77(t,J=7.0Hz,2H),2.98(t,J=7.1Hz,2H),1.46(s,9H)。
步骤3:将化合物1a(280mg,0.54mmol),化合物23c(194.9mg,0.64mmol),碳酸钠(170.4mg,1.61mmol),1,1'-双(二苯基膦)二茂铁(29.7mg,0.05mmol)溶于1,4-二氧六环(8ml)和水(2ml)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=12:1),得76.8mg黄色油状液体(产率:23.2%)。1H NMR(400MHz,CDCl3)δ8.72(d,J=1.4Hz,1H),7.81(d,J=1.4Hz,1H),7.48(t,J=7.5Hz,1H),7.43–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.27–5.14(m,2H),4.94(t,J=6.9Hz,1H),4.48(d,J=4.9Hz,2H),3.75(q,J=7.0Hz,2H),3.73–3.58(m,2H),2.98(m,2H),1.80–1.67(m,2H),1.65–1.53(m,10H),1.47(s,9H)。
步骤4:将化合物23d(60mg,0.10mmol),铁粉(27.1mg,0.48mmol),氯化铵(25.9mg,0.48mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=10:1),得43.5mg白色固体(产率:76.2%)。1H NMR(700MHz,CDCl3)δ8.31(d,J=1.4Hz,1H),7.52(d,J=1.5Hz,1H),7.48–7.44(m,2H),7.41(ddq,J=6.4,1.6,0.8Hz,1H),7.36(dt,J=7.3,1.6Hz,1H),6.51(d,J=12.4Hz,1H),5.99(d,J=12.5Hz,1H),5.18–5.04(m,2H),4.94(t,J=7.0Hz,1H),4.46(d,J=8.6Hz,2H),3.79–3.60(m,4H),2.98(m,2H),1.80–1.67(m,2H),1.65–1.54(m,10H),1.47(s,9H)。
步骤5:将化合物23e(40mg,0.07mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=20:1),得12.8mg白色固体(产率:46.6%)。1H NMR(400MHz,CDCl3)δ8.14(d,J=1.8Hz,1H),7.57(d,J=1.8Hz,1H),7.47(s,1H),7.39(m,1H),7.36-7.31(m,2H),5.05(d,J=18.6Hz,4H),3.68(s,2H),2.90(m,5H),2.52(s,3H),1.61(s,6H)。
步骤6:将化合物23f(11.2mg,0.03mmol),[1-(溴甲基)环丙基]乙腈(9.6mg,0.06mmol)和碳酸钾(7.7mg,0.06mmol)溶于干燥的乙腈(5mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得4.3mg白色固体(产率:31.2%)。1H NMR(500MHz,CDCl3)δ8.32(d,J=1.4Hz,1H),7.52(d,J=1.6Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42(m,0.65H),7.42–7.41(m,0.35H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.55H),7.36(t,J=1.6Hz,0.43H),6.52(d,J=12.4Hz,1H),6.12(d,J=12.5Hz,1H),5.11(t,J=1.0Hz,2H),4.67(s,1H),3.84(s,2H),3.09(t,J=7.1Hz,2H),2.92–2.88(m,2H),2.56(s,2H),2.39(s,2H),1.93–1.83(m,4H),1.64(s,6H)。
24.化合物24的合成
步骤1:将化合物23a(300mg,1.08mmol),尿素(194.3mg,3.24mmol),醋酸铵(249.4mg,3.24mmol),醋酸(0.19mL,3.24mmol)溶于水(10mL)中,100℃回流12h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=40:1),得98.2mg红色油状液体(产率:38.05%)。
步骤2:将化合物24a(95mg,0.39mmol),三溴氧磷(569.1mg,1.99mmol)溶于吡啶(5ml)中,110℃回流2h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=80:1),得48.7mg黄色油状液体(产率:40.59%)。1HNMR(400MHz,CDCl3)δ4.24(s,2H),3.70(t,J=7.1Hz,2H),2.68(t,J=7.1Hz,2H),1.46(s,9H)。
步骤3:将化合物1a(185mg,0.35mmol),化合物24b(128.4mg,0.42mmol),碳酸钠(112.6mg,1.06mmol),1,1'-双(二苯基膦)二茂铁(19.6mg,0.04mmol)溶于1,4-二氧六环(8ml)和水(2ml)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=6:1),得58.3mg黄色油状液体(产率:26.7%)。1H NMR(400MHz,CDCl3)δ8.80(d,J=1.4Hz,1H),8.02(d,J=1.4Hz,1H),7.50(t,J=7.4Hz,1H),7.43–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.24–5.16(m,2H),4.94(t,J=6.9Hz,1H),4.26(s,2H),3.76–3.67(m,1H),3.66–3.55(m,3H),2.64(td,J=7.0,1.6Hz,2H),1.79–1.67(m,2H),1.66–1.53(m,10H),1.47(s,9H)。
步骤4:将化合物24c(48mg,0.08mmol),铁粉(21.7mg,0.39mmol),氯化铵(20.8mg,0.39mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=3:1),得28.6mg白色固体(产率:62.6%)。1H NMR(400MHz,CDCl3)δ8.42(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.46(t,J=7.3Hz,1H),7.44–7.39(m,2H),7.36(dt,J=7.3,1.6Hz,1H),6.14(d,J=12.3Hz,1H),5.67(d,J=12.5Hz,1H),5.17–5.03(m,2H),4.94(t,J=7.0Hz,1H),4.25(s,2H),3.76–3.68(m,1H),3.68–3.56(m,3H),2.64(td,J=7.0,1.6Hz,2H),1.80–1.66(m,2H),1.67–1.52(m,10H),1.47(s,9H)。
步骤5:将化合物24d(25mg,0.04mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=12:1),得9.1mg白色固体(产率:53.1%)。1H NMR(400MHz,CDCl3)δ8.40(d,J=1.4Hz,1H),7.54(d,J=1.6Hz,1H),7.46–7.41(m,1H),7.40(p,J=1.3Hz,1H),7.39–7.35(m,2H),6.14(d,J=12.4Hz,1H),5.67(d,J=12.5Hz,1H),5.09(t,J=1.0Hz,2H),4.67(s,1H),4.39(d,J=7.6Hz,2H),3.20(q,J=7.0Hz,2H),2.91–2.82(m,2H),2.65(dt,J=12.4,7.2Hz,1H),1.64(s,6H)。
步骤6:将化合物24e(8.5mg,0.02mmol),L-环丙基甘氨酸(3.2mg,0.03mmol),HATU(16.0mg,0.04mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得4.30mg白色固体(产率:40.8%)。1H NMR(500MHz,CDCl3)δ8.41(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42(m,0.66H),7.42–7.41(m,0.36H),7.41–7.39(m,1H),7.37(t,J=1.6Hz,0.56H),7.36(t,J=1.6Hz,0.43H),6.13(d,J=12.3Hz,1H),5.83(d,J=12.3Hz,1H),5.15–5.07(m,2H),4.97–4.91(m,1H),4.67(s,1H),4.60–4.54(m,1H),4.33(s,2H),3.73–3.69(m,2H),3.67–3.61(m,1H),2.71–2.64(m,2H),2.27–2.18(m,1H),1.67(s,3H),1.62(s,3H),1.55–1.44(m,2H),1.41–1.29(m,2H)。
25.化合物25的合成
步骤1:将化合物1a(240mg,0.46mmol),化合物25a(166.6mg,0.55mmol),碳酸钠(146.1mg,1.38mmol),1,1'-双(二苯基膦)二茂铁(25.5mg,0.05mmol)溶于1,4-二氧六环(8mL)和水(2mL)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=6:1),得172.3mg黄色油状液体(产率:60.7%)。1H NMR(400MHz,CDCl3)δ8.34(d,J=1.4Hz,1H),7.57(d,J=1.4Hz,1H),7.50(t,J=7.4Hz,1H),7.44–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),6.78(s,1H),5.21(dt,J=1.9,1.0Hz,2H),4.94(t,J=6.9Hz,1H),4.40(d,J=1.8Hz,2H),3.83(td,J=7.1,1.2Hz,2H),3.74–3.68(m,1H),3.66–3.58(m,3H),1.78–1.67(m,2H),1.65–1.54(m,10H),1.47(s,9H)。[中间体25a的合成参考WO 2020/089456 Al]
步骤2:将化合物25b(150mg,0.24mmol),铁粉(67.8mg,1.21mmol),氯化铵(64.9mg,1.21mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=3:1),得53.6mg白色固体(产率:37.6%)。1H NMR(400MHz,CDCl3)δ8.33(d,J=1.6Hz,1H),7.46(t,J=7.3Hz,1H),7.43–7.39(m,3H),7.36(dt,J=7.3,1.6Hz,1H),6.61(s,1H),6.44(d,J=12.3Hz,1H),6.00(d,J=12.5Hz,1H),5.10(qt,J=12.5,0.9Hz,2H),4.94(t,J=7.0Hz,1H),4.41(d,J=4.2Hz,2H),3.84(td,J=7.1,2.0Hz,2H),3.75–3.58(m,4H),1.79–1.67(m,2H),1.65–1.53(m,10H),1.47(s,9H)。
步骤3:将化合物25c(48.6mg,0.08mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=12:1),得12.8mg白色固体(产率:38.4%)。
步骤4:将化合物25d(12.0mg,0.03mmol),3-(溴甲基)-1,1-二氟环戊烷(11.4mg,0.06mmol)和碳酸钾(7.9mg,0.06mmol)溶于干燥的乙腈(5mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得5.3mg白色固体(产率:35.62%)。1H NMR(500MHz,CDCl3)δ8.34(d,J=1.6Hz,1H),7.47(t,J=7.3Hz,1H),7.44–7.42(m,0.68H),7.42–7.41(m,0.33H),7.41(d,J=1.6Hz,1H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.56H),7.36(t,J=1.6Hz,0.43H),6.58(s,1H),6.45(d,J=12.5Hz,1H),6.13(d,J=12.5Hz,1H),5.11(s,2H),4.67(s,1H),4.00–3.92(m,2H),3.66(d,J=12.6Hz,2H),2.92–2.85(m,2H),2.56–2.46(m,2H),2.33–2.23(m,1H),2.13–1.80(m,4H),1.79–1.70(m,2H),1.67(s,3H),1.62(s,3H)。
26.化合物26的合成
步骤1:将化合物1a(303.6mg,0.58mmol),化合物26a(232.4mg,0.70mmol),碳酸钠(184.8mg,1.74mmol),1,1'-双(二苯基膦)二茂铁(32.2mg,0.06mmol)溶于1,4-二氧六环(8mL)和水(2mL)的混合溶液中。氮气置换多次,90℃回流6h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=6:1),得204.6mg黄色油状液体(产率:54.26%)。1H NMR(400MHz,CDCl3)δ8.35(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.48(t,J=7.4Hz,1H),7.44–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.24–5.17(m,2H),4.94(t,J=6.9Hz,1H),3.74–3.66(m,3H),3.64(tt,J=7.0,2.4Hz,3H),2.94(td,J=7.1,3.5Hz,2H),2.71(dt,J=11.9,7.1Hz,2H),1.79–1.67(m,2H),1.65–1.53(m,10H),1.45(s,9H)。[中间体26a的合成参考Eur.J.Med.Chem.86(2014)438-448]
步骤2:将化合物26b(200mg,0.31mmol),铁粉(86.1mg,1.54mmol),氯化铵(82.5mg,1.54mmol)溶于75%乙醇(10mL)中。70℃回流4h。待反应完毕后,用水淬灭反应,硅藻土过滤,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(PE:EA=3:1),得118.4mg白色固体(产率:62.07%)。1H NMR(400MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.46(t,J=7.3Hz,1H),7.44–7.38(m,3H),7.36(dt,J=7.3,1.6Hz,1H),6.78(d,J=12.4Hz,1H),6.27(d,J=12.5Hz,1H),5.15–5.04(m,2H),4.94(t,J=6.9Hz,1H),3.79–3.57(m,6H),2.94(td,J=7.1,3.5Hz,2H),2.72(t,J=7.1Hz,2H),1.81–1.66(m,2H),1.66–1.52(m,10H),1.45(s,9H)。
步骤3:将化合物26c(112.5mg,0.18mmol)溶于四氢呋喃(4mL)中,将圆底烧瓶置于冰水浴中并逐滴加入干燥的4.0M盐酸(1mL),氮气置换多次,室温反应3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=12:1),得42.3mg白色固体(产率:53.54%)。
步骤4:将化合物26d(35.6mg,0.08mmol),2-溴乙醇(20.5mg,0.16mmol)和碳酸钾(22.6mg,0.16mmol)溶于干燥的乙腈(5mL)中,氮气置换多次,80℃回流3h。待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=15:1),得17.6mg白色固体(产率:44.89%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.48–7.43(m,2H),7.42–7.39(m,2H),7.37(t,J=1.6Hz,0.57H),7.35(t,J=1.5Hz,0.42H),6.78(d,J=12.5Hz,1H),6.44(d,J=12.3Hz,1H),5.08(t,J=1.0Hz,2H),4.67(s,1H),4.03(t,J=7.6Hz,1H),3.59(q,J=7.1Hz,2H),3.01(t,J=7.1Hz,2H),2.95(t,J=7.1Hz,2H),2.79(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.63(t,J=7.1Hz,2H),1.64(s,6H)。
27.化合物27的合成
步骤1:将化合物2e(180mg,0.43mmol),(1R,2R)-2-氟-环丙甲酸(57.9mg,0.56mmol),HATU(325.5mg,0.86mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=20:1),得17.6mg白色固体(产率:8.11%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.5Hz,1H),7.48–7.44(m,2H),7.44–7.42(m,0.73H),7.42–7.41(m,0.32H),7.41–7.39(m,1H),7.37(t,J=1.6Hz,0.57H),7.36(t,J=1.6Hz,0.42H),6.78(d,J=12.3Hz,1H),6.41(d,J=12.4Hz,1H),5.15–5.05(m,2H),4.84(q,J=7.0Hz,0.5H),4.75(q,J=7.0Hz,0.5H),4.67(s,1H),4.42(d,J=12.6Hz,2H),3.69(q,J=7.2Hz,2H),2.66–2.58(m,2H),2.26–2.14(m,1H),2.11–2.02(m,1H),2.02–1.92(m,1H),1.67(s,3H),1.62(s,3H)。
28.化合物28的合成
将化合物2d(131.16mg,0.31mmol),化合物28a(55.2mg,0.41mmol),HATU(237.2mg,0.62mmol)溶于DMF(5mL)中,室温反应2h,待反应完毕后,用水淬灭反应,随后用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析(DCM:MeOH=10:1),得32.7mg白色固体(产率:23.71%)。1H NMR(500MHz,CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44(d,J=1.5Hz,1H),7.44–7.42(m,0.68H),7.42–7.41(m,0.37H),7.41–7.39(m,1H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5Hz,1H),5.15–5.05(m,2H),4.71(d,J=9.5Hz,1H),4.67(s,1H),4.45–4.43(m,1H),4.43(s,1H),4.41(d,J=0.7Hz,0.77H),4.40(d,J=0.7Hz,0.2H),4.36(s,1H),4.24(t,J=7.5Hz,1H),3.97–3.88(m,1H),3.78–3.65(m,4H),2.67–2.60(m,2H),1.67(s,3H),1.62(s,3H)。
29.化合物29的合成同化合物4
1H NMR(700MHz,CDCl3)δ8.16(d,J=1.8Hz,0.58H),8.13(d,J=1.8Hz,0.37H),7.58(d,J=1.8Hz,0.40H),7.51(d,J=1.8Hz,1H),7.50(s,0.60H),7.44–7.39(m,1H),7.39–7.31(m,2H),5.12(s,0.82H),5.11(s,1.25H),5.03(s,1.15H),5.02(s,0.80H),4.82(s,0.80H),4.64(s,1.23H),3.97(t,J=5.7Hz,1.26H),3.76(t,J=5.7Hz,0.80H),2.94(t,J=5.6Hz,0.81H),2.90–2.87(m,1.27H),2.84–2.78(m,2H),2.77–2.71(m,2H),2.52(s,0.38H),2.39(s,0.57H),1.63(s,6H)。
30.化合物30的合成同化合物7
1H NMR(700MHz,氘代甲醇)δ8.06–7.99(m,1H),7.52(s,1.57H),7.49(s,0.49H),7.45(s,1H),7.38–7.34(m,2H),5.18(t,J=8.6Hz,2H),4.86(s,0.86H),4.70(s,1.20H),4.04(t,J=5.4Hz,1.22H),3.93–3.87(m,0.85H),3.38(d,J=3.5Hz,0.49H),3.36(d,J=3.6Hz,0.68H),3.33(s,0.40H),3.31(s,0.50H),3.25–3.22(m,0.64H),3.24–3.21(m,0.52H),3.22–3.19(m,0.49H),3.20–3.17(m,0.35H),2.98(s,1.22H),2.84(s,0.85H),2.30(d,J=17.3Hz,0.63H),2.19–2.10(m,2.47H),1.55(s,6H)。
31.化合物31的合成同化合物8
1H NMR(700MHz,CDCl3)δ8.15(d,J=1.8Hz,0.52H),8.10(d,J=1.8Hz,0.47H),7.62(s,0.49H),7.53(s,0.51H),7.52(s,0.46H),7.50(s,0.52H),7.44–7.39(m,1H),7.39–7.32(m,2H),5.25(s,1H),5.17(s,1H),5.13(d,J=13.8Hz,2H),4.81(s,1H),4.69(s,1H),4.21(s,1H),4.20(s,1H),3.96(t,J=5.6Hz,1.23H),3.82(t,J=5.6Hz,0.94H),3.45(s,3H),2.94(t,J=5.7Hz,1H),2.90(t,J=5.8Hz,1H),2.38(s,1H),1.63(s,6H)。
测试实施例
一、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。
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-GloTMReagent,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。
表1实施例中部分化合物对HPK1酶活性的抑制作用
化合物ZYF0033在100nM浓度下对HPK1酶抑制活性为46.5%,说明在此测试条件下该化合物对HPK1酶的抑制IC50>100nM。
本发明公开一类具有五元芳杂环并哌啶/高哌啶的新型HPK1抑制剂,该类抑制剂对HPK1具有强的抑制作用,与阳性对照药化合物ZYF0033相比,本发明化合物具有显著提高的抑制活性。
二、化合物对Jurkat细胞分泌IL-2能力的影响
试剂、耗材与仪器:
实验用水为国药集团产蒸馏水;Human IL-2ELISA Kit试剂盒(#1110203)、anti-CD3(#100238)、anti-CD28(#302923)购自达科生物技术有限公司;RPMI-1640培养基(#C22400500BT)、胎牛血清(#10099141)购自Thermo Fisher Scientific公司;其他试剂均购自国药集团化学试剂有限公司;读板用全波长型酶标仪为Molecular Device公司产品,型号:SpectraMax 190。
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PBS从储液稀释到所测试浓度的20倍。
试验方法:
1)96孔板中,加入100uL anti-CD3,4℃包被过夜。
2)处于对数生长期的Jurkat细胞,按照合适密度接种至96孔培养板,每孔190uL,加入0.1μM的药物,设三复孔,并设相应浓度的溶媒对照及无细胞调零孔。
3)培养24小时后,离心收集上清,用IL-2ELISA检测试剂盒检测IL-2的分泌。
表2实施例中部分化合物对Jurkat细胞分泌IL-2能力的影响
化合物 | IL-2分泌(pg/mL) |
空白 | 163.9 |
ZYF0033 | 252.5 |
A3 | 279.1 |
A4 | 296.65 |
本发明化合物A3和A4在0.1μM的浓度下可以明显地促进Jurkat细胞分泌IL-2,活性强于阳性对照ZYF0033。
三、化合物代谢稳定性测试
本发明化合物A4和A9代谢稳定性显著强于阳性对照ZYF0033。
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1所示化合物、或其立体异构体、药学上可接受的盐或溶剂合物,
其中,
X选自下组:CH、N;
A1、A2独立地选自下组:S、N、CH2、CH、NH、O;
A3选自下组:C、CH、N;
为含1、2或3个选自N、O或S的杂原子的5元杂芳基;
R1选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基-取代或未取代的C1-C6亚烷基-、取代或未取代的C3-C8环烷基-(C=O)-、含1、2或3个选自N、O或S的杂原子的4-8元杂环基并取代或未取代的C3-C8环烷基-(C=O)-、取代或未取代的C1-C6烷基-(C=O)-、取代或未取代的C2-C6烯基-(C=O)-、取代或未取代的C2-C6炔基-(C=O)-、Rb-(取代或未取代的C1-C3亚烷基)-(C=O)-、取代或未取代的-S(=O)2-、
所述取代独立地指被选自下组的1、2、3或4个取代基取代:氢、卤素、羟基、-N(C1-C3烷基)2、-NH2、氰基、-(C1-C3亚烷基)-OH、-(C1-C3亚烷基)-CN、C1-C3烷基、卤代C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
Rb选自下组:氢、卤素、羟基、氨基、氰基、C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
m为0、1、2或3;
n为0、1、2或3;
p为0、1、2或3。
2.如权利要求1所述的化合物,其特征在于,
X为CH;
A1、A2独立地选自下组:S、N、CH、NH、O;
A3选自下组:C、N。
3.如权利要求1所述的化合物,其特征在于,选自下组:/>
4.如权利要求1所述的化合物,其特征在于,
R1选自下组:H、取代或未取代的C1-C3烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6环烷基-取代或未取代的C1-C3亚烷基-、取代或未取代的C3-C6环烷基-(C=O)-、含1、2或3个选自N、O或S的杂原子的4-6元杂环基并取代或未取代的C3-C6环烷基-(C=O)-、取代或未取代的C1-C3烷基-(C=O)-、取代或未取代的C2-C4烯基-(C=O)-、取代或未取代的C2-C4炔基-(C=O)-、Rb-(取代或未取代的C1-C3亚烷基)-(C=O)-、取代或未取代的-S(=O)2-、
所述取代独立地指被选自下组的1、2、3或4个取代基取代:氢、卤素、羟基、-N(C1-C3烷基)2、-NH2、氰基、-(C1-C3亚烷基)-OH、-(C1-C3亚烷基)-CN、C1-C3烷基、卤代C1-C3烷基、C3-C8环烷基、含1、2或3个选自N、O或S的杂原子的4-8元杂环基、含1、2或3个选自N、O或S的杂原子的5-6元杂芳基;
Rb选自下组:氢、卤素、羟基、氨基、氰基、C1-C3烷基、C3-C6环烷基;
m为0、1、2或3;
n为0、1、2或3。
5.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:
6.一种药物组合物,其特征在于,包含药学上可接受的载体和一种或多种安全有效量的权利要求1所述的化合物。
7.一种权利要求1所述化合物的用途,其特征在于,用于制备药物,所述药物用于治疗肿瘤。
8.如权利要求7所述用途,其特征在于,所述肿瘤选自下组:乳腺癌、结直肠癌、血液学恶性肿瘤、肺癌、黑色素瘤、卵巢癌、胰腺癌、肾脏癌症。
9.如权利要求8所述用途,其特征在于,所述肺癌为非小细胞肺癌;
所述肾脏癌症为肾细胞癌。
10.一种HPK1抑制剂,其特征在于,包含一种或多种权利要求1所述的化合物。
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