CN112142731B - 一种2,4-二取代嘧啶衍生物及其制备方法和用途 - Google Patents
一种2,4-二取代嘧啶衍生物及其制备方法和用途 Download PDFInfo
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
本发明属于化学医药领域,具体涉及2,4‑二取代嘧啶衍生物及其制备方法和用途。本发明提供了一种2,4‑二取代嘧啶衍生物,其结构如式Ⅳ所示。本发明还提供了上述2,4‑二取代嘧啶衍生物的制备方法及其用途。本发明提供的2,4‑二取代嘧啶衍生物既可以作为具有JAK2和FLT3双功能靶点的激酶抑制剂,又可以是具有单独的JAK2或者FLT3功能靶点的激酶抑制剂,为制备多靶点抑制剂提供了新的选择。
Description
技术领域
本发明属于化学医药领域,具体涉及2,4-二取代嘧啶衍生物及其制备方法和用途。特别是涉及一种2,4-二取代嘧啶衍生物作为贾纳斯酪氨酸激酶2以及FMS样的酪氨酸激酶3(JAK2-FLT3)抑制剂的应用。
背景技术
骨髓增殖性肿瘤(myeloproliferative neoplasms,MPNs)是一组起源于多能造血干细胞的恶性骨髓增殖性疾病,表现为髓系细胞一系或多系的过度增殖,进而外周血一系或多系增多,有形成血栓、髓外造血、骨髓纤维化及转化为急性白血病的趋势。这类疾病包括真性红细胞增多症(polycythaemia vera,PV)、原发性血小板增多症(primarythrombocytosis,PT)和原发性骨髓纤维化(primary myelofibrosis,PMF)。
目前的临床治疗方法仍不能治愈MPNs类疾病。近年来的研究发现,贾纳斯激酶(JAK)家族中的JAK2激酶在MPNs中起着重要作用。JAK-信号转换器和转录激活因子(JAK-STAT)通路通过细胞因子介导信号传递,控制多种细胞的存活、增殖和分化。而JAK2磷酸化、下游STAT磷酸化以及基因转录的激活会最终导致红细胞和髓细胞增殖、分化和存活的增加。现已有多种JAK2抑制剂在进行临床试验,其中JAK2抑制剂Ruxolitinib已被FDA批准用于骨髓纤维化,其余如Lestaurtinib(CEP701),CYT-387,LY2784544,BMS-911543等仍在进行临床研究。
此外,最新的研究表明,FMS样酪氨酸激酶3(FLT3)突变也与MPNs息息相关:ITD(内部串联重复)突变敲入小鼠FLT3后,可导致小鼠产生骨髓增生性疾病。FLT3是一种受体酪氨酸激酶,它在造血祖细胞的发育过程中起着至关重要的作用。急性髓细胞白血病(AML)患者中约有30%发现激活的FLT3内串联重复(ITD)突变,而这是导致疾病复发的高危因素。小分子FLT3抑制剂已经作为单一药物或者组合化疗在进行临床试验,然而到目前为止,这些候选药物要么没有产生足够的初始反应,要么不能维持治疗效益,其原因主要是由于继发性的耐药性。临床资料也表明病人治疗后外周血白血病细胞急剧下降,但骨髓反应却几乎没有,这些失败的可能机制之一是可能存在独立的替代生存途径,白血病细胞可以通过进一步的遗传突变或代谢适应。这些途径可能包括mTOR-PI3K-Akt,JAK-STAT或Ras-MAPK。同时抑制这些途径可能将使白血病细胞摆脱FLT3的限制。
在这基础上,同时靶向JAK2通路则有以下几个优点:(a)AML病例中几乎没有发现JAK2突变,(b)在AML中发现磷酸化-JAK2升高,(c)在FLT3-TKI耐药株FLT3-ITD中,JAK信号的负调节器即细胞因子1/2/3的抑制物会被显著下调。同时,有证据表明,抑制JAK2-FLT3两个信号通路可以增强具有FLT3-ITD突变的AML患者的临床疗效。基于此,JAK2/FLT3双靶点抑制剂治疗MPNs也逐渐成为研发热点,目前已有JAK2/FLT3双靶点抑制剂Fedratinib被FDA批准优先用于骨髓纤维化,大环结构化合物Pacritinib也在进行临床三期研究(用于治疗骨髓纤维化)。然而,现有的JAK2/FLT3双靶点抑制剂酶活性较差,口服生物利用度不高,仍不能满足医疗需求,因此,开发出选择性更好、活性更高、具有更好体内药代属性的抑制剂是目前研发的热点。
发明内容
本发明提供了一种具有JAK2和FLT3双功能靶点的2,4-二取代嘧啶衍生物。
上述2,4-二取代嘧啶衍生物,其结构如式Ⅳ所示:
其中,X为N或CH;R22为C1~C6烷基;
R1、R2独立的为-H、卤素、-OH、C1~C10烷基或C1~C10烷氧基;
A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C10环烷基、取代或未取代的C1~C10烷基、C2~C10炔基、取代或未取代的C2~C10烯基、 所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基或C1~C10氧羰基;所述取代的C2~C10烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C10烷氧基、C1~C10氧羰基或m、n=0~2;
R5为C1~C10烷氧基、取代或未取代的C2~C10烯基、取代或未取代的C1~C10烷基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基、C1~C10氧羰基、所述取代的C2~C10烯基为-H、-OH、卤素、-CN、苯基或
R6、R7独立的为-H、C1~C10烷基或卤素取代的苯基;
R10、R11独立的-H或C1~C10烷基;
R12~R16独立的为-H、C1~C10烷基或-CF3;
R17~R21独立的为-H、C1~C10烷基或-CF3。
作为本发明的优选方案,上述2,4-二取代嘧啶衍生物,R22为C1~C4烷基。
作为本发明的优选方案,上述2,4-二取代嘧啶衍生物,其结构如式Ⅰ所示:
其中,X为N或CH;
R1、R2独立的为-H、卤素、-OH、C1~C10烷基或C1~C10烷氧基;
A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C10环烷基、取代或未取代的C1~C10烷基、C2~C10炔基、取代或未取代的C2~C10烯基、 所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基或C1~C10氧羰基;所述取代的C2~C10烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C10烷氧基、C1~C10氧羰基或m、n=0~2;
R5为C1~C10烷氧基、取代或未取代的C2~C10烯基、取代或未取代的C1~C10烷基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基、C1~C10氧羰基、所述取代的C2~C10烯基为-H、-OH、卤素、-CN、苯基或
R6、R7独立的为-H、C1~C10烷基或卤素取代的苯基;
R10、R11独立的-H或C1~C10烷基;
R12~R16独立的为-H、C1~C10烷基或-CF3;
R17~R21独立的为-H、C1~C10烷基或-CF3。
作为本发明的优选方案,上述2,4-二取代嘧啶衍生物,R1、R2独立的为-H、卤素、-OH、C1~C8烷基或C1~C8烷氧基。
优选的,R1、R2独立的为-H、卤素、-OH、C1~C6烷基或C1~C6烷氧基。
进一步优选的,R1、R2独立的为-H、卤素、-OH、C1~C4烷基或C1~C4烷氧基。
更优选的,R1、R2独立的为-H、卤素或C1~C4烷基。
最优选的,R1、R2独立的为-H、-F或甲基。
优选的,上述2,4-二取代嘧啶衍生物中,A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C8环烷基、取代或未取代的C1~C8烷基、C2~C8炔基、C2~C10烯基、取代的C2~C8烯基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基或C1~C8氧羰基;所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C8烷氧基、C1~C8氧羰基或m、n=0~2。
进一步优选的,A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C6烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基或C1~C6氧羰基;所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C6烷氧基、C1~C6氧羰基或m、n=0~2。
更进一步优选的,A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C4烷氧基、C1~C4氧羰基或m、n=0~2。
更优选的,A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、 所述取代的C1~C6烷基的取代基为-H、-OH、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、C1~C4氧羰基或m、n=0或1。
最优选的,A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、 所述取代的C1~C6烷基的取代基为-H、-OH、-CN、乙氧基或所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、m、n=0或1。
优选的,上述2,4-二取代嘧啶衍生物中,R5为C1~C8烷氧基、取代或未取代的C2~C8烯基、取代或未取代的C1~C8烷基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基、C1~C8氧羰基、 所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C8烷基;R12~R16独立的为-H、C1~C8烷基或-CF3。
进一步优选的,R5为C1~C6烷氧基、取代或未取代的C2~C6烯基、取代或未取代的C1~C6烷基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基、C1~C6氧羰基、所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C6烷基;R12~R16独立的为-H、C1~C6烷基或-CF3。
更优选的,R5为C1~C6烷氧基、C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基、C1~C4氧羰基、所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C4烷基;R12~R16独立的为-H、C1~C4烷基或-CF3。
最优选的,R5为C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、-CN、 所述取代的C2~C4烯基的取代基为-H、苯基或R10、R11独立的-H或C1~C4烷基。
优选的,上述2,4-二取代嘧啶衍生物中,R6、R7独立的为-H、C1~C8烷基或卤素取代的苯基。
进一步优选的,R6、R7独立的为-H、C1~C6烷基或卤素取代的苯基。
更优选的,R6、R7独立的为-H、C1~C4烷基或氯取代的苯基。
作为本发明的优选技术方案,上述2,4-二取代嘧啶衍生物,其结构如式Ⅱ所示:
其中,R4为C3~C10环烷基、取代或未取代的C1~C10烷基、C2~C10炔基、取代或未取代的C2~C10烯基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基或C1~C10氧羰基;所述取代的C2~C10烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C10烷氧基、C1~C10氧羰基或m、n=0~2;
R5为C1~C10烷氧基、取代或未取代的C2~C10烯基、取代或未取代的C1~C10烷基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基、C1~C10氧羰基、所述取代的C2~C10烯基为-H、-OH、卤素、-CN、苯基或
R6、R7独立的为-H、C1~C10烷基或卤素取代的苯基;
R10、R11独立的-H或C1~C10烷基;
R12~R16独立的为-H、C1~C10烷基或-CF3;
R17~R21独立的为-H、C1~C10烷基或-CF3。
优选的,上述2,4-二取代嘧啶衍生物中,R4为C3~C8环烷基、取代或未取代的C1~C8烷基、C2~C8炔基、C2~C10烯基、取代的C2~C8烯基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基或C1~C8氧羰基;所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C8烷氧基、C1~C8氧羰基或m、n=0~2。
进一步优选的,R4为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C6烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基或C1~C6氧羰基;所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C6烷氧基、C1~C6氧羰基或m、n=0~2。
更进一步优选的,R4为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C4烷氧基、C1~C4氧羰基或m、n=0~2。
更优选的,R4为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、C1~C4氧羰基或m、n=0或1。
最优选的,R4为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、-CN、乙氧基或所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、m、n=0或1。
优选的,上述2,4-二取代嘧啶衍生物中,R5为C1~C8烷氧基、取代或未取代的C2~C8烯基、取代或未取代的C1~C8烷基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基、C1~C8氧羰基、 所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C8烷基;R12~R16独立的为-H、C1~C8烷基或-CF3。
进一步优选的,R5为C1~C6烷氧基、取代或未取代的C2~C6烯基、取代或未取代的C1~C6烷基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基、C1~C6氧羰基、所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C6烷基;R12~R16独立的为-H、C1~C6烷基或-CF3。
更优选的,R5为C1~C6烷氧基、C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基、C1~C4氧羰基、所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C4烷基;R12~R16独立的为-H、C1~C4烷基或-CF3。
最优选的,R5为C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、-CN、 所述取代的C2~C4烯基的取代基为-H、苯基或R10、R11独立的-H或C1~C4烷基。
优选的,上述2,4-二取代嘧啶衍生物中,R6、R7独立的为-H、C1~C8烷基或卤素取代的苯基。
进一步优选的,R6、R7独立的为-H、C1~C6烷基或卤素取代的苯基。
更优选的,R6、R7独立的为-H、C1~C4烷基或氯取代的苯基。
作为本发明的优选技术方案,上述2,4-二取代嘧啶衍生物,其结构如式Ⅲ所示:
其中,R1为甲基或-F;R3为C3~C10环烷基、取代或未取代的C1~C10烷基、C2~C10炔基、取代或未取代的C2~C10烯基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基或C1~C10氧羰基;所述取代的C2~C10烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C10烷氧基、C1~C10氧羰基或m、n=0~2;
R5为C1~C10烷氧基、取代或未取代的C2~C10烯基、取代或未取代的C1~C10烷基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基、C1~C10氧羰基、所述取代的C2~C10烯基为-H、-OH、卤素、-CN、苯基或
R6、R7独立的为-H、C1~C10烷基或卤素取代的苯基;
R10、R11独立的-H或C1~C10烷基;
R12~R16独立的为-H、C1~C10烷基或-CF3;
R17~R21独立的为-H、C1~C10烷基或-CF3。
优选的,上述2,4-二取代嘧啶衍生物中,R3为C3~C8环烷基、取代或未取代的C1~C8烷基、C2~C8炔基、C2~C10烯基、取代的C2~C8烯基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基或C1~C8氧羰基;所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C8烷氧基、C1~C8氧羰基或m、n=0~2。
进一步优选的,R3为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C6烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基或C1~C6氧羰基;所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C6烷氧基、C1~C6氧羰基或m、n=0~2。
更优选的,R3为C3~C6环烷基、取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C4烷氧基、C1~C4氧羰基或m、n=0~2。
更优选的,R3为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、-CN、C1~C4烷氧基或C1~C4氧羰基;所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、C1~C4氧羰基或m、n=0或1。
最优选的,R3为取代或未取代的C1~C6烷基、C2~C6炔基、C2~C10烯基、取代的C2~C4烯基、所述取代的C1~C6烷基的取代基为-H、-OH、-CN、乙氧基或所述取代的C2~C4烯基的取代基为-H、-COOH、苯基、m、n=0或1。
优选的,上述2,4-二取代嘧啶衍生物中,R5为C1~C8烷氧基、取代或未取代的C2~C8烯基、取代或未取代的C1~C8烷基、所述取代的C1~C8烷基的取代基为-H、-OH、卤素、-CN、C1~C8烷氧基、C1~C8氧羰基、 所述取代的C2~C8烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C8烷基;R12~R16独立的为-H、C1~C8烷基或-CF3。
进一步优选的,R5为C1~C6烷氧基、取代或未取代的C2~C6烯基、取代或未取代的C1~C6烷基、所述取代的C1~C6烷基的取代基为-H、-OH、卤素、-CN、C1~C6烷氧基、C1~C6氧羰基、所述取代的C2~C6烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C6烷基;R12~R16独立的为-H、C1~C6烷基或-CF3。
更优选的,R5为C1~C6烷氧基、C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、卤素、-CN、C1~C4烷氧基、C1~C4氧羰基、所述取代的C2~C4烯基的取代基为-H、-OH、卤素、-CN、苯基或R10、R11独立的-H或C1~C4烷基;R12~R16独立的为-H、C1~C4烷基或-CF3。
最优选的,R5为C2~C6烯基、取代的C2~C4烯基、C1~C6烷基、取代的C1~C4烷基、所述取代的C1~C4烷基的取代基为-H、-OH、-CN、 所述取代的C2~C4烯基的取代基为-H、苯基或R10、R11独立的-H或C1~C4烷基。
优选的,上述2,4-二取代嘧啶衍生物中,R6、R7独立的为-H、C1~C8烷基或卤素取代的苯基。
进一步优选的,R6、R7独立的为-H、C1~C6烷基或卤素取代的苯基。
更优选的,R6、R7独立的为-H、C1~C4烷基或氯取代的苯基。
本发明2,4-二取代嘧啶衍生物,结构式如下:
本发明还提供了上述2,4-二取代嘧啶衍生物的制备方法,合成路线如下:
上述2,4-二取代嘧啶衍生物制备方法包括以下步骤:
1)原料1与卤代物在碱性条件下加热反应4~8小时得到中间体1;所述的碱为碳酸铯或碳酸钾;反应的溶剂为乙腈、N,N-二甲基甲酰胺或二氧六环中的任意一种;所述原料1与卤代物的反应温度60~80℃;
2)中间体1与2,4-二取代嘧啶化合物在氮气保护及碱性条件下,通过Suzuki反应在二氧六环、水、乙醇条件下得到中间体2;所述的碱为碳酸钠或碳酸钾;反应的溶剂为二氧六环/水/乙醇混合体系、甲苯/水混合体系、1,2-二氯乙烷/水混合体系中的任意一种;所述反应温度80~95℃;反应时间为2~5小时;其中,硼酸酯的用量为1.3当量;
3)原料2与中间体2在氮气保护及碱性条件下,通过Buchwald–Hartwig偶联反应得到式中间体3;所述的碱为碳酸铯或叔丁醇钾;反应的溶剂为二氧六环、甲苯中的任意一种;所述反应温度100~110℃;反应时间为4~6小时;其中,中间体2的用量为1.2当量;
4)中间体3在酸性条件下脱掉Boc酸酐的保护得到中间体4;所述的酸为三氟乙酸或盐酸;反应的溶剂为二氯甲烷、乙酸乙酯、四氢呋喃中的任意一种;所述反应温度20~30℃;反应时间为2~5小时;
5)中间体4在碱性条件下与卤代物反应得到式I或Ⅳ化合物,中间体4在碱性条件下与酸反应得到酰胺类的式I或Ⅳ化合物;所述的碱为DIEA、碳酸钾或碳酸铯中的任意一种;反应的溶剂为二氯甲烷、N,N-二甲基甲酰胺或四氢呋喃中的任意一种;所述反应温度20~30℃;反应时间为1~2小时;
其中,X为N或CH;R22为C1~C6烷基;
R1、R2独立的为-H、卤素、-OH、C1~C10烷基或C1~C10烷氧基;
A环为5元或6元含N杂环,N原子为1个;R与A环上N相连,R为C3~C10环烷基、取代或未取代的C1~C10烷基、C2~C10炔基、取代或未取代的C2~C10烯基、 所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基或C1~C10氧羰基;所述取代的C2~C10烯基的取代基为-H、-OH、卤素、-CN、-COOH、苯基、C1~C10烷氧基、C1~C10氧羰基或m、n=0~2;
R5为C1~C10烷氧基、取代或未取代的C2~C10烯基、取代或未取代的C1~C10烷基、所述取代的C1~C10烷基的取代基为-H、-OH、卤素、-CN、C1~C10烷氧基、C1~C10氧羰基、所述取代的C2~C10烯基为-H、-OH、卤素、-CN、苯基或
R6、R7独立的为-H、C1~C10烷基或卤素取代的苯基;
R10、R11独立的-H或C1~C10烷基;
R12~R16独立的为-H、C1~C10烷基或-CF3;
R17~R21独立的为-H、C1~C10烷基或-CF3。
本发明还提供了上述2,4-二取代嘧啶衍生物包括其互变异构体、立体异构体及其所有比例的混合物,还包括其同位素取代的化合物。
本发明还提供了上述2,4-二取代嘧啶衍生物药学上可接受的盐。其中与酸成盐是指,通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸或高氯酸等。有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围,能适于用来与人类和其他哺乳动物的组织接触,而没有不当毒性、刺激、过敏反应等,其在对受者给药时能直接或间接地提供本发明的化合物或化合物的前药。
本发明还提供了上述2,4-二取代嘧啶衍生物药学上可接受的水合物。术语“水合物”表示进一步通过非共价分子间作用力结合化学计量或非化学计量的水的化合物。
本发明还提供了上述2,4-二取代嘧啶衍生物药学上可接受的多晶型物。术语“多晶型物”表示化合物或其复合物的固体结晶形式,其可以通过物理方法,例如X.射线粉末衍射图或红外光谱进行表征。
本发明还提供了上述2,4-二取代嘧啶衍生物药学上可接受的药物组合物,这种药物组合物是由式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐或水合物添加药学上可以接受的辅助性成分制备而成的制剂。所述的辅助性成分如环糊精、精氨酸或葡甲胺。所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、(C1-4烷基)-α-环糊精、(C1-4烷基)-β-环糊精、(C1-4烷基)-γ-环糊精、(羟基-C1-4烷基)-α-环糊精、(羟基-C1-4烷基)-β-环糊精、(羟基-C1-4烷基)-γ-环糊精、(羧基-C1-4烷基)-α-环糊精、(羧基-C1-4烷基)-β-环糊精、(羧基-C1-4烷基)-γ-环糊精、α-环糊精的糖类醚、β-环糊精的糖类醚、γ-环糊精的糖类醚、α-环糊精的磺丁基醚、β-环糊精的磺丁基醚和γ-环糊精的磺丁基醚。所述的辅助性成分还包含医学上可接受的载体、佐剂或媒剂。可用于药学上可接受的药物组合物还离子交换剂、氧化铝、硬脂酸铝、卵凝脂;缓冲物质包括磷酸盐、甘氨酸、精氨酸、山梨酸等。
上述药物组合物可以为液体形式或固体形式。其中,所述的液体形式可以为水溶液形式。所述的固体形式可以为粉末、颗粒、片剂或冻干粉形式。该药物组合物还含有注射用水、盐水溶液、葡萄糖水溶液、注射/输注用盐水、注射/输注用葡萄糖、格林氏溶液或含有乳酸盐的格林氏溶液。进一步的,所述制剂为片剂、胶囊、粉末、颗粒、软膏剂、溶液、混悬液、注射剂、吸入剂、凝胶、微球或气雾剂。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备JAK2抑制剂中的用途。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备FLT3抑制剂中的用途。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备JAK2-FLT3抑制剂中的用途。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备治疗和/或预防肿瘤的药物中的用途。
上述用途中,所述肿瘤包括实体瘤和/或血液瘤。
上述用途中,所述实体瘤包括:淋巴瘤、B-细胞淋巴瘤、弥漫性大B-细胞淋巴瘤、慢性淋巴细胞淋巴瘤、淋巴浆细胞淋巴瘤、卵巢癌、乳腺癌、***癌、膀胱癌、肾癌、食道癌、颈癌、胰腺癌、结直肠癌、胃癌、非小细胞肺癌、甲状腺癌、脑癌、淋巴癌、表皮过渡增生、银屑病、***癌,以及它们的组合。
上述用途,所述血液瘤包括:急性髓性白血病、慢性粒细胞白血病、骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、急性早幼粒白血病、慢性淋巴细胞白血病、慢性嗜中性白血病、急性未分化细胞白血病、骨髓发育不良综合征、骨髓增生异常、骨髓纤维化、多发性骨髓瘤、脊髓肉瘤,以及它们的组合。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物及其盐、水合物或药物组合物在制备治疗和/或预防免疫性疾病的药物中的用途。
上述用途中,所述免疫性疾病包括:牛皮癣、类风湿性关节炎、炎性肠疾病(例如,克罗恩病、溃疡性结肠炎等等)、斯耶格伦氏综合征、***、多发性硬化、***性红斑狼疮、关节强硬性椎关节炎、多肌炎、皮肤肌炎(DM)、结节性动脉周围炎(PN)、混合***病(MCTD)、硬皮病、深红斑狼疮、慢性甲状腺炎、Graves'疾病、自身免疫性胃炎、I型和II型糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少、特异性皮炎、慢性活动型肝炎、重症肌无力、移植物抗宿主疾病、艾迪生病、异常免疫应答、关节炎、皮炎、放射性皮炎等等)(尤其是牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、***、多发性硬化和***性红斑狼疮)。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备治疗和/或预防炎性相关疾病的药物中的用途。
上述用途中,所述炎性相关疾病包括:炎性肠炎疾病、急性胰炎、慢性胰腺炎、哮喘、成人呼吸窘迫综合征、慢性阻塞性肺病(COPD)、炎性骨疾病、炎性肺病、炎性肠疾病、乳糜泻、肝炎、***炎性响应综合症(SIRS)、手术后或外伤后的炎症、肺炎、肾炎、脑膜炎、膀胱炎、咽喉炎、胃粘膜损伤、脑膜炎、脊椎炎、关节炎、皮炎、慢性肺炎、支气管炎、肺梗塞形成、矽肺、肺结节病等。
式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备口服或静脉注射制剂中的用途。
为了施用目的,可以将本发明的化合物作为原料化学物质施用,或可以将其配制成药物组合物施用。本发明的药物组合物包含结构I、II、III或Ⅳ的化合物和药学上可接受的载体、稀释剂或赋形剂。存在于组合物中的结构I、II、III或Ⅳ的化合物以有效治疗所关注的具体疾病或病症的用量-即足以治疗不同癌症的且优选对于患者具有可接受的毒性用量存在。结构I、II、III或Ⅳ的化合物的JAK2和/或FLT3激酶活性可以由本领域技术人员测定,例如,如下文实施例中所述。本领域技术人员易于确定适合的浓度和剂量。
可以通过用于类似用途的可接受的活性剂施用模式施用纯形式或适合的药物组合物形式的本发明化合物或其药学上可接受的盐。可以通过合并本发明的化合物与适合的药学上可接受的载体、稀释剂或赋形剂制备本发明的药物组合物,且可以将它们配制成固体、半固体、液体或气体形式,例如片剂、胶囊、粉末、颗粒、软膏剂、溶液、混悬液、注射剂、吸入剂、凝胶、微球和气雾剂。这类药物组合物的典型施用途径包括、但不限于口服、局部、透皮、吸入、胃肠外、舌下、直肠、***和鼻内。本文所用的术语胃肠外包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。可以配制本发明的药物组合物,以便在将组合物适合于患者时允许其中包含的活性成分是生物可利用的。施用于受试者或患者的组合物可以采取一个或多个剂量单元的形式,例如,其中片剂可以是单一剂量单元,且气雾剂形式的本发明的化合物的容器可以承载多个剂量单元。制备这类剂型的确切方法是已知的或对于本领域技术人员而言显而易见;例如,参见Remington:The Science and Practice of Pharmacy,第20版(Philadelphia College of Pharmacy and Science,2000)。在任何情况下,所施用的组合物包含治疗有效量的本发明的化合物或其药学上可接受的盐,其用于治疗根据本发明的教导所关注的疾病或病症。
本发明的药物组合物可以为固体或液体形式。在一个方面,载体是颗粒,使得组合物例如是片剂或粉末形式。载体可以是液体,其中组合物为,例如口服糖浆剂、可注射液体或气雾剂,例如,其用于吸入施用。
当欲用于口服施用时,所述药物组合物优选是固体或液体形式,其中在本文认可为固体或液体的形式中包括半固体、半液体、混悬液和凝胶形式。
作为用于口服施用的固体组合物,可以将药物组合物配制成粉末、颗粒、压制片、丸剂、胶囊、口香糖、糯米纸囊剂等形式。这类固体组合物典型地包含一种或多种惰性稀释剂或可食用载体。此外,可以存在如下成分的一种或多种:粘合剂,例如羧甲基纤维素、乙基纤维素、微晶纤维素、黄蓍树胶或明胶;赋形剂,例如淀粉、乳糖或糊精;崩解剂,例如藻酸、藻酸钠、Primogel、玉米淀粉等;润滑剂,例如硬脂酸镁或氢化植物油;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精:矫味剂,例如薄荷、水杨酸甲酯或橙香精;和着色剂。
当药物组合物是胶囊形式时,例如,明胶胶囊,它除包含上述类型的物质外,还可以包含液体载体,例如聚乙二醇或油。
药物组合物可以是液体形式,例如,酸剂、糖浆剂、溶液、乳剂或混悬液。作为两个实例,液体可以用于口服施用或通过注射递送。当欲用于口服施用时,除本发明的化合物外,优选的组合物还包含甜味剂、防腐剂、染料/着色剂和增味剂的一种或多种。在欲通过注射施用的组合物中,可以包括表面活性剂、防腐剂、湿润剂、分散剂、助悬剂、缓冲剂、稳定剂和等渗剂的一种或多种。
本发明的液体组合物,无论它们是溶液、混悬液还是其它类似形式,都可以包括如下辅料的一种或多种:无菌稀释剂,例如注射用水、盐水溶液,优选生理盐水、林格液和等渗氯化钠,固定油,例如可以充当溶剂或助悬介质的合成单酸甘油酯类或二脂酰甘油酯类、聚乙二醇、甘油、丙二醇或其它溶剂;抗菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;鳌合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐:和用于调整张度的试剂,例如氯化钠或葡萄糖。可以将胃肠外制剂包封在安瓿、一次性注射器或多剂量玻璃或速率制成的小瓶中。生理盐水是优选的辅料。可注射药物组合物优选是无菌的。
欲用于胃肠外或口服施用的本发明液体药物组合物应当包含一定量的本发明的化合物,使得可以得到适合的剂量。
本发明的药物组合物预先用于局部施用,在这种情况中,载体可以适当地包含溶液、乳剂、软育剂或凝胶基质。例如,所述基质可以包含如下成分的一种或多种:凡士林油、羊毛脂、聚乙二醇、蜂蜡、矿物油、稀释剂例如水和醇和乳化剂和稳定剂。药物组合物中可以存在增稠剂,以便局部施用。如果预期透皮施用,则组合物可以包括透皮贴剂或离子透入装置。
本发明的药物组合物欲用于例如可以以栓剂形式直肠施用,它在直肠中融化并且释放药物。用于直肠施用的组合物可以包含作为适合的无刺激性赋形剂的含油基质。这种基质包括、但不限于羊毛脂、可可脂和聚乙二醇。
本发明的药物组合物可以包括各种材料,其改变固体或液体剂型的物理形式。例如,该组合物可以包括在活性成分周围形成包衣壳的材料。形成包衣壳的材料典型地是惰性的且可以选自,例如糖、虫胶和其它肠溶包衣衣料。或者,可以将活性成分包装在明胶胶囊中。
固体或液体形式的本发明的药物组合物可以包括结合本发明的化合物且由此有助于化合物递送的试剂。可以在这种能力方面起作用的适合的试剂包括单克隆抗体或多克隆抗体、蛋白质或脂质体。
本发明的药物组合物可以由可以作为气雾剂施用的剂量单元组成。术语气雾剂用于表示从胶体性质的那些到由加压包装组成的***的范围的各种***。递送可以通过液化或加压气体或通过分配活性成分的适合的泵***进行。本发明化合物的气雾剂可以以单相、双相或三相***的形式递送,以便递送活性成分。所递送的气雾剂包括必要的容器、启动器、阀、子容器(subcontainer)等,它们一起可以形成药盒。本领域技术人员无需过度实验可以确定优选的气雾剂。
本发明还提供了上述式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物、其盐、水合物或药物组合物在制备口服或静脉注射制剂中的用途。所述的口服或静脉注射制剂至少包含一种式I~III、Ⅳ所示的2,4-二取代嘧啶衍生物及其盐、水合物或药物组合物以及任意的赋形剂和/或佐剂。
本发明提供的2,4-二取代嘧啶衍生物既可以作为具有JAK2和FLT3双功能靶点的激酶抑制剂,又可以是具有单独的JAK2或者FLT3功能靶点的激酶抑制剂,为制备治疗和/或预防肿瘤、炎性疾病、免疫性疾病的药物提供了新的选择。
具体实施方式
实施例1 6-羟丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(CLJ-100)的制备
步骤1:1-丙基吡唑-4-硼酸频哪醇酯(式2化合物)的合成
将4-硼酸频哪醇酯(1.9g,10mmol),2-碘丙烷(3.4g,20mmol),碳酸铯(6.5g,20mmol)加入到乙腈(50ml)中,于80℃的油浴内反应2小时。反应结束后,趁热过滤并将滤液浓缩,得到式2化合物。
步骤2:2-氯-5-甲基-4-(1-异丙基-1H-吡唑-4-基)嘧啶(式3化合物)的合成将式2化合物(1.9g,10mmol)、2,4-二氯-5-氟嘧啶(1.7g,10mmol)、碳酸钾(3.4g,25mmol)和dppf(Pd2Cl2)(0.75g,1mmol)加入到250mL三颈瓶内,加入二氧六环/乙醇/水=7:3:4(共计70mL)作为溶剂,置换氮气三次后转入85℃的油浴内反应2小时。反应结束后将反应液浓缩至干后,拌样经硅胶柱分离,即得到式3化合物,为类白色固体。1H NMR(500MHz,Chloroform-d)δ:8.43(d,J=8.1Hz,1H),8.14(t,J=1.7Hz,1H),7.46(t,J=1.7Hz,1H),4.78(m,1H),0.99(d,J=8.0Hz,6H).
步骤3:6-Boc-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(式5化合物)的合成
将2-氨基-N-Boc-5,6,7,8-四氢萘啶(2.5g,10mmol),2-氯-5-甲基-4-(1-异丙基-1H-吡唑-4-基)嘧啶(2.7g,10mmol),碳酸铯(6.5g,20mmol),Pd2DBA3(260mg,1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(520mg,2mmol)到二氧六环(50ml)中,置换氮气后于103℃的油浴内反应2小时。反应结束后,趁热过滤并将滤液浓缩,粗硅胶拌样后经flash柱分离(EA)得到式5化合物。
步骤4:N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(式6化合物)的合成
将6-Boc-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(2.3g,5mmol)加入到二氯甲烷(50ml)中,加入三氟乙酸(1.2g,10mmol),室温反应1h,反应结束后,减压蒸馏除去溶剂,得到式6化合物。
步骤5:6-羟丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(CLJ-100)的合成
将N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-5,6,7,8-四氢萘啶-2-胺(350mg,1mmol)加入到乙腈(20ml)中,加入3-溴丙醇(180mg,1.3mmol),碳酸铯(650mg,2mmol),室温反应1h,反应结束后,加水40ml,并用二氯甲烷萃取,减压蒸馏有机相,粗品以***打浆得到终产物CLJ-100。1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.38–8.30(m,2H),8.11(t,J=4.2Hz,2H),7.47(d,J=8.5Hz,1H),4.63(h,J=6.6Hz,1H),4.44(d,J=38.4Hz,1H),3.55–3.44(m,4H),2.80(t,J=5.9Hz,2H),2.73(t,J=6.1Hz,2H),2.54(d,J=7.1Hz,2H),2.33(s,3H),1.72–1.64(m,2H),1.48(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.93,158.01,157.82,152.89,151.72,139.55,136.47,129.69,123.47,120.45,117.59,110.21,59.81,55.19,54.71,53.83,50.98,32.20,30.45,23.03,17.19.m/z:408.5230[M+H]+.
实施例2 2-羟乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺醇(CLJ-101)的制备
CLJ-101的合成同实施例1,用6-氨基-N-Boc-1,2,3,4-四氢异喹啉替代2-氨基-N-Boc-5,6,7,8-四氢萘啶,2-碘乙醇替代3-溴-1-丙醇可得终产物CLJ-101。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.29(d,J=22.7Hz,2H),8.08(s,1H),7.65(d,J=2.3Hz,1H),7.46(dd,J=8.3,2.3Hz,1H),6.94(d,J=8.4Hz,1H),4.62(h,J=6.6Hz,1H),4.46(s,1H),3.67–3.46(m,4H),2.80(d,J=5.8Hz,2H),2.71(t,J=5.8Hz,2H),2.57(t,J=6.2Hz,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.88,159.00,157.63,139.42,139.31,134.44,129.38,127.92,126.71,120.74,118.31,116.72,116.35,60.74,59.30,56.07,53.83,51.64,29.63,23.03,17.15.m/z:393.5070[M+H]+.
实施例3 2-羟乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-氟-6-胺(CLJ-102)的制备
CLJ-102的嘧啶部分合成同实施例2;
芳香胺部分合成如下:
步骤1:4-氟苯乙胺三氟乙酰胺(式2化合物)的合成
将4-氟苯乙胺(7g,50mmol),三乙胺(13g,125mmol)溶于二氯甲烷(100mL)中,滴加三氟乙酸酐(12.6g,60mmol),室温反应30min,加入大量水(约200mL)剧烈搅拌,分液,减压蒸馏浓缩有机相,并以***打浆,得到式2化合物。
步骤2:7-氟-1,2,3,4-四氢异喹啉三氟乙酰胺(式3化合物)的合成
将4-氟苯乙胺三氟乙酰胺(4.7g,20mmol)溶于浓硫酸(20ml)中,加入冰乙酸(5ml)和多聚甲醛(1.8g,20mmol),室温反应4h,待反应完毕后,将浓硫酸加入到大量冰水中,以二氯甲烷萃取后浓缩,并以正己烷/***(1:1)打浆,得到式3化合物。
步骤3:7-氟-6-硝基-1,2,3,4-四氢异喹啉三氟乙酰胺(式4化合物)的合成将4-氟-1,2,3,4-四氢异喹啉三氟乙酰胺(4.9g,20mmol)溶于浓硫酸(20ml)中,并在0摄氏度条件下将硝酸钾(3g,30mmol)的浓硫酸(20ml)溶液缓慢滴入,滴加完毕后继续反应2h,待反应完毕后,将浓硫酸加入到大量冰水中,抽滤干燥后以正己烷/***(1:1)打浆,得到式4化合物。
步骤4:7-氟-6-硝基-1,2,3,4-四氢异喹啉(式5化合物)的合成
将4-氟-5-硝基-1,2,3,4-四氢异喹啉三氟乙酰胺(4.4g,15mmol)溶于甲醇(40ml)中,加入浓盐酸5mL,60摄氏度反应1h,待反应完毕后,调至中性并抽滤,干燥后得到式5化合物。
步骤5:N-Boc-7-氟-6-硝基-1,2,3,4-四氢异喹啉(式6化合物)的合成
将4-氟-5-硝基-1,2,3,4-四氢异喹啉(2g,10mmol)加入到乙腈(50ml)中,随后加入碳酸钾(2.8g,20mmol)和Boc酸酐(5ml),60摄氏度条件下反应1h,待反应完毕后,加入大量水并以二氯甲烷萃取,将有机相减压蒸馏浓缩后以***打浆得到式6化合物。
步骤6:2-N-Boc-7-氟-6-氨基-1,2,3,4-四氢异喹啉(式7化合物)的合成式8化合物、CLJ-102的合成同实施例2,用7-氟-6-氨基-N-Boc-1,2,3,4-四氢异喹啉替代6-氨基-N-Boc-1,2,3,4-四氢异喹啉。1H NMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.26(d,J=25.6Hz,2H),8.01(s,1H),7.67(d,J=8.0Hz,1H),6.92(d,J=11.5Hz,1H),4.61(p,J=6.7Hz,1H),4.54(s,1H),3.82–3.42(m,4H),2.96–2.63(m,4H),2.55(t,J=6.5Hz,2H),2.30(s,3H),1.46(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO)δ:159.91,159.09,157.81,154.07,151.66,139.34,130.75,129.94,129.42,123.69,120.56,116.87,113.15,60.46,59.27,55.69,53.82,51.37,28.78,23.02,17.08.m/z:411.4974[M+H]+.
实施例4 2-羟丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-103)的制备
CLJ-103的合成同实施例2,用3-碘丙醇替代2-碘乙醇可得到终产物CLJ-103。1HNMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.27(d,J=25.6Hz,2H),8.00(s,1H),7.66(d,J=8.0Hz,1H),6.94(d,J=11.5Hz,1H),4.62(p,J=6.7Hz,1H),4.54(s,1H),3.81–3.43(m,4H),2.95–2.64(m,4H),2.53(t,J=6.5Hz,2H),2.30(s,3H),1.57(m,2H),1.46(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO)δ:159.89,159.00,157.64,139.46,139.31,134.46,129.39,127.83,126.75,120.74,118.30,116.75,116.36,59.96,55.86,55.56,53.83,51.25,30.34,29.66,23.04,17.15。m/z:407.5340[M+H]+.
实施例5 2-羟丁基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-104)的制备
CLJ-104的合成同实施例2,用4-溴-1-丁醇替代2-碘乙醇可得到终产物CLJ-104。1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.29(d,J=23.0Hz,2H),8.08(s,1H),7.64(d,J=2.3Hz,1H),7.46(dd,J=8.3,2.3Hz,1H),6.95(d,J=8.4Hz,1H),4.63(q,J=6.6Hz,1H),4.56(d,J=26.0Hz,1H),3.56–3.35(m,4H),2.80(t,J=5.9Hz,2H),2.63(t,J=5.8Hz,2H),2.43(t,J=7.0Hz,2H),2.31(s,3H),1.55(q,J=7.2Hz,2H),1.48(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.03,158.27,158.19,140.86,139.50,131.80,129.78,127.32,121.05,120.48,118.02,117.76,116.99,60.49,60.22,55.58,53.89,52.27,49.47,29.86,29.68,25.74,23.02,22.91,21.01,17.16.m/z:421.2638[M+H]+.
实施例6 2-羟戊基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-105)的制备
CLJ-105的合成同实施例2,用5-溴-1-戊醇替代2-碘乙醇可得到终产物CLJ-105。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.3Hz,1H),6.95(d,J=8.3Hz,1H),4.63(p,J=6.7Hz,1H),4.34(s,1H),3.40(t,J=5.7Hz,2H),2.80(t,J=5.9Hz,2H),2.63(t,J=5.9Hz,2H),2.43(t,J=7.3Hz,2H),2.31(s,3H),1.58–1.41(m,10H),1.35(qd,J=9.8,8.4,4.5Hz,2H).m/z:435.2794[M+H]+.
实施例7 2-羟乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-氟嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-106)的制备
CLJ-106的合成同实施例2,用2,4-二氯-5-氟嘧啶替代2,4-二氯-5-甲基嘧啶可得到终产物CLJ-106。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.49(d,J=2.9Hz,1H),8.38(s,1H),8.08(s,1H),7.62(s,1H),7.48(d,J=8.3Hz,1H),6.99(d,J=8.4Hz,1H),4.66(td,J=14.4,13.9,7.2Hz,2H),3.83–3.50(m,4H),2.78(d,J=66.0Hz,6H),1.48(d,J=6.7Hz,6H).m/z:397.2074[M+H]+.
实施例8 2-羟丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-氟嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-107)的制备
CLJ-107的合成同实施例7,用3-碘-1-丙醇替代2-碘乙醇得到终产物CLJ-107。1HNMR(400MHz,DMSO-d6)δ:10.24(s,1H),9.68(s,1H),8.53(d,J=3.0Hz,1H),8.40(d,J=2.0Hz,1H),8.10(d,J=1.1Hz,1H),7.76(d,J=2.2Hz,1H),7.60(dd,J=8.4,2.2Hz,1H),7.14(d,J=8.5Hz,1H),4.67(p,J=6.6Hz,1H),4.25(d,J=36.4Hz,2H),3.37(s,4H),3.24(t,J=8.1Hz,2H),3.12(s,2H),1.94(dq,J=11.9,6.0Hz,2H),1.48(d,J=6.6Hz,6H).13CNMR(101MHz,DMSO)δ:156.98,149.96,147.48,146.97,146.18,139.09,138.86,134.51,128.24,126.82,118.38,116.85,115.73,59.94,55.80,55.52,54.00,51.18,30.28,29.56,22.94.m/z:411.2230[M+H]+.
实施例9 2-羟丁基-N-(4-(1-异丙基-1H-吡唑-4-基)5-氟嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-108)的制备
CLJ-108的合成同实施例8,用4-溴-1-丁醇替代3-碘-1-丙醇得到终产物CLJ-108。1H NMR(400MHz,DMSO-d6)δ:9.48(s,1H),8.49(d,J=3.0Hz,1H),8.38(d,J=1.9Hz,1H),8.08(d,J=1.3Hz,1H),7.60(d,J=2.2Hz,1H),7.46(dd,J=8.3,2.2Hz,1H),6.98(d,J=8.4Hz,1H),4.68(h,J=6.6Hz,1H),4.56(s,1H),3.42(t,J=6.3Hz,2H),2.81(t,J=5.9Hz,2H),2.64(t,J=5.8Hz,2H),2.44(t,J=7.1Hz,2H),1.60–1.40(m,10H).13C NMR(101MHz,DMSO)δ:157.01,149.95,147.47,146.97,145.96,139.05,138.85,134.58,129.78,128.38,126.82,118.39,116.83,115.73,61.22,58.22,55.74,54.00,51.11,31.13,29.61,23.80,22.95.m/z:425.2387[M+H]+.
实施例10 2-羟戊基-N-(4-(1-异丙基-1H-吡唑-4-基)5-氟嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-109)的制备
CLJ-109的合成同实施例9,用5-溴-1-戊醇替代4-溴-1-丁醇得到终产物CLJ-109。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.49(d,J=3.0Hz,1H),8.38(d,J=1.6Hz,1H),8.08(s,1H),7.59(s,1H),7.46(dd,J=8.4,1.9Hz,2H),6.98(d,J=8.3Hz,1H),4.67(dt,J=13.3,6.6Hz,2H),4.35(t,J=4.9Hz,2H),3.50(s,1H),3.44–3.37(m,5H),2.86–2.75(m,4H),2.66(s,0H),2.44(d,J=5.0Hz,1H),1.58–1.40(m,8H),1.33(dt,J=15.3,7.1Hz,3H).m/z:439.2543[M+H]+.
实施例11 2-羟乙酰基-N-(4-(1-异丙基-1H-吡唑-4-基)5-氟嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-110)的制备
CLJ-110的合成同实施例10,用2-羟基乙酰氯替代5-溴-1-戊醇得到CLJ-120。1HNMR(400MHz,DMSO-d6)δ:9.55(d,J=4.7Hz,1H),8.44(d,J=45.8Hz,2H),8.09(s,1H),7.68(s,1H),7.55(t,J=6.6Hz,1H),7.11(dd,J=13.3,8.1Hz,1H),4.76–4.42(m,4H),4.19(d,J=5.2Hz,2H),3.64(dt,J=51.4,5.8Hz,2H),2.83(dt,J=28.2,5.8Hz,2H),1.48(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO)δ:170.87,156.92,150.02,147.54,146.90,146.25,139.54,138.88,134.92,129.87,126.97,126.44,118.39,117.31,115.71,60.74,54.01,43.89,41.70,29.42,22.96.m/z:411.1867[M+H]+.
实施例12 2-羟乙酰基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-111)的制备
CLJ-111的合成同实施例11,用2,4-二氯-5-甲基嘧啶替代2,4-二氯-5-氟嘧啶得到终产物CLJ-111。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J=4.8Hz,1H),8.30(d,J=20.6Hz,2H),8.09(s,1H),7.74(s,1H),7.55(d,J=7.4Hz,1H),7.09(dd,J=13.7,8.2Hz,1H),4.72–4.44(m,4H),4.18(d,J=5.5Hz,2H),3.64(dt,J=50.9,5.8Hz,2H),2.92–2.73(m,2H),2.31(s,3H),1.48(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO)δ:170.86,159.90,158.92,157.69,139.95,139.33,134.83,129.45,126.90,125.90,120.67,118.22,117.22,116.59,60.74,53.84,43.89,41.72,29.48,23.04,17.16.m/z:407.2117[M+H]+.
实施例13 2-丙酰胺甲酰基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-112)的制备
CLJ-112的合成同实施例12,用丙基异氰酸酯替代2-羟基乙酰氯得到终产物CLJ-112。1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.30(d,J=22.9Hz,2H),8.09(s,1H),7.71(d,J=2.2Hz,1H),7.54(dd,J=8.4,2.2Hz,1H),7.03(d,J=8.3Hz,1H),6.50(t,J=5.5Hz,1H),4.63(hept,J=6.7Hz,1H),4.43(s,2H),3.55(t,J=5.8Hz,2H),3.02(q,J=7.8,7.0Hz,2H),2.76(t,J=5.8Hz,2H),2.32(s,3H),1.46(dd,J=18.8,6.9Hz,8H),0.84(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.88,157.67,139.70,139.32,135.21,129.43,126.99,126.60,120.70,118.43,117.08,116.51,53.83,45.50,42.47,41.44,29.22,23.56,23.04,17.15,11.87.m/z:434.2590[M+H]+.
实施例14 2-(3-氯苯胺甲酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-113)的制备
CLJ-113的合成同实施例13,用3-氯苯基异氰酸酯替代丙基异氰酸酯得到终产物CLJ-113。1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.73(s,1H),8.31(d,J=21.9Hz,2H),8.09(s,1H),7.72(d,J=26.0Hz,2H),7.57(d,J=8.3Hz,1H),7.45(d,J=8.3Hz,1H),7.26(t,J=8.1Hz,1H),7.09(d,J=8.4Hz,1H),6.98(d,J=7.9Hz,1H),4.61(d,J=16.3Hz,3H),3.71(t,J=5.8Hz,2H),2.85(t,J=5.9Hz,2H),2.32(s,3H),1.49(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.69,155.14,142.73,139.93,139.34,135.07,133.20,130.35,129.44,126.68,126.38,121.69,120.70,119.38,118.38,118.27,117.16,116.57,53.84,45.80,41.95,29.27,23.04,17.16.m/z:502.2044[M+H]+.
实施例15 2-乙酰胺甲酰基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-114)的制备
CLJ-114的合成同实施例14,用乙基异氰酸酯替代3-氯苯基异氰酸酯得到终产物CLJ-114。1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.30(d,J=22.7Hz,2H),8.08(s,1H),7.70(d,J=2.2Hz,1H),7.53(dd,J=8.3,2.3Hz,1H),7.03(d,J=8.3Hz,1H),6.49(t,J=5.4Hz,1H),4.62(h,J=6.5Hz,1H),4.41(s,2H),3.54(t,J=5.8Hz,2H),3.08(dt,J=12.5,6.3Hz,2H),2.75(t,J=5.9Hz,2H),2.31(s,3H),1.48(d,J=6.6Hz,6H),1.03(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.80,157.67,139.71,139.32,135.21,129.43,126.95,126.59,120.70,118.43,117.08,116.51,53.83,45.46,41.38,35.38,29.23,23.04,17.15,16.15.m/z:420.2434[M+H]+.
实施例16 2-乙酰甲基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-115)的制备
CLJ-115的合成同实施例15,用1-氯丙酮替代乙基异氰酸酯得到终产物CLJ-115。1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J=24.3Hz,2H),8.09(s,1H),7.67(d,J=2.2Hz,1H),7.47(dd,J=8.4,2.3Hz,1H),6.94(d,J=8.4Hz,1H),4.63(hept,J=6.6Hz,1H),3.53(s,2H),2.82(t,J=5.8Hz,2H),2.68(t,J=5.8Hz,2H),2.31(s,3H),2.13(s,3H),1.48(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO)δ:207.56,159.90,158.99,157.64,139.55,139.32,134.09,129.40,127.42,126.69,120.72,118.38,116.80,116.40,67.91,55.46,53.83,51.13,29.50,28.01,23.04,17.15.m/z:405.2325[M+H]+.
实施例17 2-氨甲酰甲基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-116)的制备
CLJ-116的合成同实施例16,用1-氯丙酰胺替代1-氯丙酮酯得到终产物CLJ-116。1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J=23.8Hz,2H),8.09(s,1H),7.68(d,J=2.2Hz,1H),7.48(dd,J=8.4,2.2Hz,1H),7.20(dd,J=38.0,3.0Hz,2H),6.96(d,J=8.4Hz,1H),4.63(hept,J=6.7Hz,1H),3.61(s,2H),3.03(s,2H),2.86(t,J=5.8Hz,2H),2.71(t,J=5.8Hz,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:172.30,159.91,158.98,157.64,139.56,139.32,134.19,129.41,127.44,126.71,120.71,118.37,116.78,116.41,61.74,55.65,53.83,51.34,29.54,23.05,17.15.m/z:406.2277[M+H]+.
实施例18 2-(2-乙氧基乙基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-117)的制备
CLJ-117的合成同实施例17,用2-乙氧基氯乙烷替代1-氯丙酰胺得到终产物CLJ-117。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.30(d,J=22.7Hz,2H),8.08(s,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.94(d,J=8.3Hz,1H),4.63(hept,J=6.7Hz,1H),3.61–3.51(m,4H),3.46(q,J=7.0Hz,2H),2.79(d,J=5.8Hz,2H),2.70(t,J=5.8Hz,2H),2.64(t,J=6.0Hz,2H),2.31(s,3H),1.49(d,J=6.7Hz,6H),1.12(t,J=7.0Hz,3H).13CNMR(101MHz,DMSO)δ:159.87,159.01,157.63,139.46,139.32,134.35,129.35,127.83,126.68,120.76,118.31,116.74,116.34,68.48,65.94,57.73,56.03,53.83,51.59,29.65,23.02,17.15,15.62.m/z:421.2638[M+H]+.
实施例19 2-氰甲基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-118)的制备
CLJ-118的合成同实施例18,用氯乙腈替代2-乙氧基氯乙烷得到终产物CLJ-118。1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J=21.8Hz,2H),8.09(s,1H),7.69(d,J=2.3Hz,1H),7.51(dd,J=8.3,2.2Hz,1H),7.00(d,J=8.4Hz,1H),4.63(hept,J=6.7Hz,1H),3.91(s,2H),3.62(s,2H),2.86(d,J=6.0Hz,2H),2.77(d,J=5.7Hz,2H),2.32(s,3H),1.49(d,J=6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.87,158.97,157.66,139.77,139.34,133.54,129.35,126.77,126.45,120.74,118.35,116.96,116.47,116.34,53.85,53.79,49.74,45.59,29.43,23.01,17.16.m/z:388.2171[M+H]+.
实施例20 2-炔丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-119)的制备
CLJ-119的合成同实施例19,用3-氯丙炔替代氯乙腈得到终产物CLJ-119。1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.30(d,J=22.4Hz,2H),8.09(s,1H),7.75–7.61(m,1H),7.56–7.42(m,1H),6.98(d,J=8.4Hz,1H),4.63(p,J=6.7Hz,1H),3.59(s,2H),3.51–3.40(m,2H),3.23–3.13(m,1H),2.84(s,2H),2.72(s,2H),2.32(s,3H),1.49(d,J=6.7Hz,6H).m/z:387.2219[M+H]+.
实施例21 2-烯丙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-120)的制备
CLJ-120的合成同实施例20,用烯丙基氯替代3-氯丙炔得到终产物CLJ-120。1HNMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.33(s,1H),8.27(d,J=0.8Hz,1H),8.08(s,1H),7.66(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.95(d,J=8.3Hz,1H),5.91(ddt,J=16.6,10.2,6.3Hz,1H),5.26(dq,J=17.2,1.7Hz,1H),5.18(ddt,J=10.1,2.2,1.2Hz,1H),4.62(h,J=6.7Hz,1H),3.48(s,2H),3.12(dt,J=6.4,1.4Hz,2H),2.81(t,J=5.9Hz,2H),2.65(t,J=5.8Hz,2H),2.31(s,3H),1.49(d,J=6.6Hz,6H).m/z:389.2375[M+H]+.
实施例22 2-(3-甲基-2-丁烯基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-121)的制备
CLJ-121的合成同实施例21,用1-氯-3-甲基-2-丁烯替代烯丙基氯得到终产物CLJ-121。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.95(d,J=8.4Hz,1H),5.28(td,J=7.4,6.9,3.9Hz,1H),4.63(hept,J=6.6Hz,1H),3.47(s,2H),3.06(d,J=6.8Hz,2H),2.80(t,J=5.9Hz,2H),2.64(t,J=5.8Hz,2H),2.31(s,3H),1.74(d,J=1.5Hz,3H),1.66(d,J=1.4Hz,3H),1.49(d,J=6.6Hz,6H).m/z:417.2688[M+H]+.
实施例23 2-(2-戊炔基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-122)的制备
CLJ-122的合成同实施例22,用1-氯-2-戊炔替代1-氯-3-甲基-2-丁烯得到终产物CLJ-122。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.4Hz,2H),8.09(s,1H),7.66(s,1H),7.48(d,J=8.4Hz,1H),6.98(d,J=8.3Hz,1H),4.63(dt,J=13.5,6.8Hz,1H),3.57(s,2H),3.38(d,J=22.7Hz,2H),2.83(t,J=5.7Hz,2H),2.70(t,J=5.9Hz,2H),2.32(s,3H),2.22(d,J=7.6Hz,2H),1.49(d,J=6.7Hz,6H),1.10(q,J=7.4,6.9Hz,3H).m/z:415.2332[M+H]+.
实施例24 2-(2-丁炔基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-123)的制备
CLJ-123的合成同实施例23,用1-氯-2-丁炔替代1-氯-2-戊烯得到终产物CLJ-123。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.66(d,J=2.3Hz,1H),7.48(dd,J=8.4,2.2Hz,1H),6.97(d,J=8.4Hz,1H),4.63(hept,J=6.7Hz,1H),3.38(q,J=2.4Hz,2H),2.82(t,J=5.8Hz,2H),2.70(t,J=5.9Hz,2H),2.32(s,3H),1.83(t,J=2.3Hz,3H),1.49(d,J=6.6Hz,6H).m/z:401.2375[M+H]+.
实施例25 2-(苯丙烯基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-124)的制备
CLJ-124的合成同实施例24,用肉桂基氯替代1-氯-2-丁炔得到终产物CLJ-124。1HNMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.2Hz,2H),8.09(s,1H),7.68(d,J=2.2Hz,1H),7.54–7.42(m,3H),7.34(t,J=7.6Hz,2H),7.28–7.22(m,1H),6.96(d,J=8.4Hz,1H),6.61(d,J=15.9Hz,1H),6.39(dt,J=15.9,6.4Hz,1H),4.63(hept,J=6.7Hz,1H),3.54(s,2H),3.31–3.21(m,2H),2.84(t,J=5.8Hz,2H),2.71(t,J=5.8Hz,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).m/z:467.2688[M+H]+.
实施例26 2-(4-烯基戊酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-125)的制备
步骤1:2-(4-烯基戊酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-125)的制备
将N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(348mg,1mmoL),HATU(380mg,1mmoL),N,N-二异丙基乙胺(320mg,2.5mmoL),4-戊烯酸(100mg,1mmoL)加入到二氯甲烷(20mL)中,室温搅拌30分钟,减压浓缩除去溶剂,加粗硅胶拌样,以二氯甲烷/甲醇体系经硅胶柱分离得到终产品CLJ-125。1H NMR(400MHz,DMSO-d6)δ:9.28(d,J=4.7Hz,1H),8.30(d,J=20.9Hz,2H),8.08(s,1H),7.76–7.69(m,1H),7.54(t,J=8.6Hz,1H),7.09(dd,J=8.4,4.7Hz,1H),5.93–5.80(m,1H),5.11–5.01(m,1H),4.99–4.91(m,1H),4.69–4.50(m,3H),3.67(t,J=5.9Hz,2H),2.89–2.81(m,1H),2.75(t,J=5.9Hz,1H),2.29(d,J=14.7Hz,5H),1.48(d,J=6.7Hz,6H).m/z:431.2481[M+H]+.
实施例27 2-(3-氰基丙酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-126)的制备
CLJ-126的合成同实施例26,用3-氰基丙酸替代4-戊烯酸得到终产物CLJ-126。1HNMR(400MHz,DMSO-d6)δ:9.30(d,J=5.3Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J=5.7,2.3Hz,1H),7.62–7.50(m,1H),7.29(s,1H),7.10(dd,J=11.5,8.4Hz,1H),6.72(s,1H),4.71–4.46(m,3H),3.68(q,J=6.5Hz,2H),2.88(q,J=6.0,5.3Hz,1H),2.75(t,J=6.0Hz,1H),2.61(t,J=7.0Hz,2H),2.34(d,J=11.9Hz,5H),1.49(d,J=6.7Hz,6H).m/z:430.2277[M+H]+.
实施例28 (E)-2-(3,7-二甲基-2,6-戌二烯基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-127)的制备
CLJ-127的合成同实施例24,用香叶基溴替代1-氯-2-丁炔得到终产物CLJ-127。1HNMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.1Hz,2H),8.08(s,1H),7.66(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.94(d,J=8.3Hz,1H),5.31–5.24(m,1H),5.15–5.03(m,1H),4.63(p,J=6.6Hz,1H),3.51(s,2H),3.11(s,2H),2.81(d,J=5.9Hz,2H),2.68(s,2H),2.31(s,3H),2.17–1.98(m,4H),1.66(d,J=1.4Hz,6H),1.59(d,J=1.3Hz,3H),1.49(d,J=6.7Hz,6H).m/z:485.3314[M+H]+.
实施例29 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸甲酯(CLJ-128)的制备
CLJ-128的合成同实施例28,用(E)-4-溴-2-丁烯酸甲酯替代香叶基溴得到终产物CLJ-128。1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.33(s,1H),8.29(s,1H),8.08(s,1H),7.67(d,J=2.2Hz,1H),7.52–7.44(m,1H),6.96(d,J=8.8Hz,2H),6.10(d,J=15.7Hz,1H),4.63(hept,J=6.7Hz,1H),3.68(s,3H),3.52(s,2H),2.83(t,J=5.8Hz,2H),2.68(t,J=5.8Hz,2H),2.32(s,3H),1.49(d,J=6.6Hz,6H).m/z:447.2430[M+H]+.
实施例30 2-(5-烯己基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-129)的制备
CLJ-129的合成同实施例29,用6-溴-1-己烯替代(E)-4-溴-2-丁烯酸甲酯得到终产物CLJ-129。1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.33(d,J=0.7Hz,1H),8.27(d,J=0.7Hz,1H),8.08(d,J=0.7Hz,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.95(d,J=8.4Hz,1H),5.82(ddt,J=16.9,10.2,6.6Hz,1H),5.03(dq,J=17.2,1.7Hz,1H),4.96(ddt,J=10.2,2.3,1.2Hz,1H),4.63(p,J=6.6Hz,1H),3.47(s,2H),2.80(t,J=5.8Hz,2H),2.63(t,J=5.8Hz,2H),2.44(t,J=7.2Hz,2H),2.35–2.28(m,3H),2.07(q,J=7.1Hz,2H),1.58–1.37(m,10H).m/z:431.2845[M+H]+.
实施例31 2-(3-烯丁基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-130)的制备
CLJ-130的合成同实施例30,用4-溴-1-丁烯替代6-溴-1-己烯得到终产物CLJ-130。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.96(d,J=8.3Hz,1H),5.86(ddt,J=17.0,10.2,6.7Hz,1H),5.10(dq,J=17.2,1.7Hz,1H),5.00(ddt,J=10.3,2.4,1.3Hz,1H),4.63(hept,J=6.6Hz,1H),3.51(s,2H),2.80(t,J=5.9Hz,2H),2.67(t,J=5.8Hz,2H),2.34–2.25(m,5H),1.49(d,J=6.7Hz,6H).m/z:403.2532[M+H]+.
实施例32 2-(4-烯戊基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-131)的制备
CLJ-131的合成同实施例31,用5-溴-1-戊烯替代4-溴-1-丁烯得到终产物CLJ-131。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.33(d,J=0.7Hz,1H),8.27(d,J=0.7Hz,1H),8.11–8.06(m,1H),7.65(d,J=2.2Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),6.95(d,J=8.4Hz,1H),5.86(ddt,J=16.9,10.1,6.6Hz,1H),5.08–4.94(m,2H),4.63(p,J=6.7Hz,1H),3.48(s,2H),2.80(t,J=5.8Hz,2H),2.64(t,J=5.8Hz,2H),2.44(t,J=7.3Hz,2H),2.31(s,3H),2.09(tdd,J=6.6,5.3,1.4Hz,2H),1.62(p,J=7.4Hz,2H),1.49(d,J=6.7Hz,6H).m/z:417.2688[M+H]
实施例33 2-(2-甲基-2-戊烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-132)的制备
CLJ-132的合成同实施例26,用2-甲基-2-戊烯酸替代4-戊烯酸得到终产物CLJ-132。1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.30(d,J=23.2Hz,2H),8.09(s,1H),7.75(s,1H),7.56(d,J=8.4Hz,1H),7.07(d,J=8.3Hz,1H),5.51(t,J=7.4Hz,1H),4.59(d,J=28.3Hz,3H),3.68(t,J=6.0Hz,2H),2.69(s,5H),2.31(s,3H),2.10(p,J=7.4Hz,2H),1.76(s,3H),1.48(d,J=6.8Hz,6H).m/z:445.2638[M+H]
实施例34 2-(3-苯甲酰基丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-133)的制备
CLJ-133的合成同实施例33,用3-苯甲酰基丙烯酸替代2-甲基-2-戊烯酸得到终产物CLJ-133。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=2.2Hz,1H),8.33(s,1H),8.28(s,1H),8.13–8.02(m,3H),7.85–7.79(m,1H),7.76(d,J=2.2Hz,1H),7.74–7.68(m,1H),7.64–7.50(m,4H),7.15(dd,J=8.5,4.3Hz,1H),4.73(d,J=36.9Hz,2H),4.63(p,J=6.7Hz,1H),3.83(dt,J=11.2,5.9Hz,2H),2.88(dt,J=23.7,6.0Hz,2H),2.32(s,3H),1.49(dd,J=6.7,1.9Hz,6H).m/z:507.2430[M+H].
实施例35 2-(5-烯己酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-134)的制备
CLJ-134的合成同实施例34,用5-己烯酸替代3-苯甲酰基丙烯酸得到终产物CLJ-134。1H NMR(400MHz,DMSO-d6)δ:9.29(d,J=5.0Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J=8.0,2.2Hz,1H),7.59–7.52(m,1H),7.10(dd,J=8.5,4.8Hz,1H),5.83(ddtd,J=16.6,9.8,6.5,3.1Hz,1H),5.06–4.95(m,2H),4.68–4.60(m,1H),4.56(d,J=14.9Hz,2H),3.67(q,J=5.8Hz,2H),2.80(dt,J=39.4,6.0Hz,2H),2.41(t,J=7.4Hz,2H),2.32(s,3H),2.07(q,J=7.8Hz,2H),1.63(td,J=7.7,5.1Hz,2H),1.49(d,J=6.7Hz,6H).m/z:445.2638[M+H]+.
实施例36 2-(2-甲基烯丙基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-135)的制备
CLJ-135的合成同实施例31,用3-溴-2-甲基丙烯替代4-溴-1-丁烯得到终产物CLJ-135。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.32(s,1H),8.26(s,1H),8.09(s,1H),7.67(d,J=2.2Hz,1H),7.48(dd,J=8.3,2.3Hz,1H),6.94(d,J=8.4Hz,1H),4.97–4.85(m,2H),4.62(p,J=6.7Hz,1H),3.42(s,2H),2.98(s,2H),2.81(t,J=5.9Hz,2H),2.58(t,J=5.8Hz,2H),2.31(s,3H),1.73(s,3H),1.48(d,J=6.7Hz,6H).m/z:403.2532[M+H]+.
实施例37 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(CLJ-136)的制备
步骤1:(E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(CLJ-136)的合成
将(E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸甲酯(446.6mg,1mmol)加入到甲醇(5mL)中,并加入氢氧化钠水溶液(2mmol/L,2.5mL),50℃加热反应2h,用稀盐酸调至中性,抽滤干燥得到终产品CLJ-136。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.4Hz,2H),8.08(s,1H),7.67(d,J=2.3Hz,1H),7.48(dd,J=8.3,2.2Hz,1H),6.96(d,J=8.4Hz,1H),6.79(dt,J=15.6,5.9Hz,1H),6.02–5.94(m,1H),4.62(h,J=6.6Hz,1H),3.51(s,2H),3.27(d,J=5.5Hz,2H),3.18(s,1H),2.83(t,J=5.8Hz,2H),2.67(t,J=5.8Hz,2H),2.31(s,3H),1.49(d,J=6.6Hz,6H).m/z:433.2274[M+H]+.
实施例38 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸丙酰胺(CLJ-137)的制备
步骤1:(E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸丙酰胺(CLJ-137)的合成
将(E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(432mg,1mmol),丙胺(120mg,2mmol),N,N-二异丙基乙胺(320mg,2.5mmol),HATU(380mg,1mmol),加入到二氯甲烷(10mL)中,室温反应1h,抽滤干燥得到终产品CLJ-137。1H NMR(400MHz,DMSO-d6)δ:9.23(s,1H),8.30(d,J=21.5Hz,2H),8.08(s,1H),8.01(s,1H),7.68(s,1H),7.48(d,J=8.3Hz,1H),6.97(d,J=8.4Hz,1H),6.63(dt,J=15.3,5.9Hz,1H),6.13(d,J=15.4Hz,1H),4.63(p,J=6.6Hz,1H),3.57(d,J=39.5Hz,3H),3.08(d,J=6.3Hz,2H),2.85(s,2H),2.71(d,J=22.4Hz,2H),2.32(s,3H),1.43(s,8H),1.27(s,2H),0.86(s,4H).m/z:474.2903[M+H]+.
实施例39 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(哌啶-1-基乙胺)酰胺(CLJ-138)的制备
CLJ-138的合成同实施例38,用1-(2-氨乙基)哌啶替代丙胺得到终产物CLJ-138。1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.33(s,1H),8.27(s,1H),8.09(s,2H),7.68(d,J=2.2Hz,1H),7.48(dd,J=8.3,2.2Hz,1H),6.96(d,J=8.3Hz,1H),6.67(dt,J=15.4,5.9Hz,1H),6.14(d,J=15.5Hz,1H),4.62(h,J=6.6Hz,1H),3.53(s,2H),3.29–3.21(m,3H),2.87–2.81(m,2H),2.69(d,J=8.0Hz,2H),2.32(s,3H),1.49(d,J=6.6Hz,12H).m/z:543.3482[M+H]+.
实施例40 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸叔丁酰胺(CLJ-139)的制备
CLJ-139的合成同实施例39,用叔丁胺替代1-(2-氨乙基)哌啶得到终产物CLJ-139。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.0Hz,2H),8.09(s,1H),7.71–7.56(m,2H),7.48(dd,J=8.3,2.2Hz,1H),6.96(d,J=8.4Hz,1H),6.58(dt,J=15.4,5.9Hz,1H),6.15(dd,J=15.4,1.6Hz,1H),4.63(p,J=6.6Hz,1H),3.50(s,2H),3.26–3.15(m,2H),2.84(t,J=5.8Hz,2H),2.66(t,J=5.8Hz,2H),2.32(s,3H),1.49(d,J=6.6Hz,6H),1.29(s,9H).m/z:488.3060[M+H]+.
实施例41 (E)-4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸二乙酰胺(CLJ-140)的制备
CLJ-140的合成同实施例40,用二乙胺替代叔丁胺得到终产物CLJ-140。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J=22.5Hz,2H),8.08(s,1H),7.67(d,J=2.2Hz,1H),7.48(dd,J=8.4,2.2Hz,1H),6.96(d,J=8.4Hz,1H),6.71(dt,J=15.1,6.0Hz,1H),6.61–6.52(m,1H),4.63(hept,J=6.7Hz,1H),3.52(s,2H),3.38(s,3H),3.30–3.25(m,2H),2.83(t,J=5.9Hz,2H),2.68(t,J=5.8Hz,2H),2.32(s,3H),1.49(d,J=6.7Hz,6H),1.17–0.99(m,7H).m/z:488.3062[M+H]+.
实施例42 2-氰甲基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-141)的制备
CLJ-141的嘧啶部分合成同实施例19;芳香胺部分的合成同实施例3步骤3,用1,2,3,4-四氢异喹啉替代7-氟-1,2,3,4-四氢异喹啉三氟乙酰胺,后处理以石油醚/乙酸乙酯(5:1)过硅胶柱可得。1H NMR(400MHz,DMSO-d6)δ:9.25(s,1H),8.30(d,J=21.5Hz,2H),8.09(s,1H),7.65(d,J=2.3Hz,1H),7.50(dd,J=8.3,2.2Hz,1H),7.04(d,J=8.4Hz,1H),4.63(hept,J=6.7Hz,1H),3.93(s,2H),3.68(s,2H),2.84–2.71(m,4H),2.32(s,3H),1.49(d,J=6.6Hz,6H).m/z:388.2171[M+H]+.
实施例43 2-(2-甲基-2-戊烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-142)的制备
CLJ-142的合成同实施例33,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-142。1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.31(d,J=21.1Hz,2H),8.09(s,1H),7.74(s,1H),7.55–7.49(m,1H),7.08(d,J=8.3Hz,1H),5.53(t,J=7.3Hz,1H),4.62(d,J=6.3Hz,3H),3.68(t,J=5.9Hz,2H),2.76(t,J=6.0Hz,2H),2.11(p,J=7.5Hz,2H),1.78(s,3H),1.49(d,J=6.7Hz,6H),0.99(t,J=7.5Hz,3H).m/z:445.2638[M+H]+.
实施例44 2-羟丁基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-143)的制备
CLJ-143的合成同实施例5,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-143。1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.30(d,J=24.4Hz,2H),8.08(s,1H),7.62(d,J=2.3Hz,1H),7.46(dd,J=8.2,2.3Hz,1H),7.00(d,J=8.3Hz,1H),4.62(dq,J=13.4,6.7Hz,2H),3.43(t,J=6.3Hz,2H),2.73(d,J=5.7Hz,2H),2.64(t,J=5.8Hz,2H),2.46(t,J=7.0Hz,2H),2.32(s,3H),1.62–1.43(m,11H).m/z:421.2638[M+H]+.
实施例45 2-丁基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-144)的制备
CLJ-144的合成同实施例19,用1-溴丁烷替代氯乙腈得到终产物CLJ-144。1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.29(d,J=23.5Hz,2H),8.09(s,1H),7.65(s,1H),7.47(d,J=7.7Hz,1H),6.94(d,J=8.2Hz,1H),4.70–4.56(m,J=6.8Hz,1H),3.46(s,2H),2.79(s,2H),2.61(s,2H),2.41(s,2H),2.31(s,3H),1.48(d,J=6.8Hz,8H),1.31(p,J=7.3Hz,2H),0.90(t,J=7.2Hz,3H).m/z:405.2688[M+H]+.
实施例46 2-羟乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-氟6-胺(CLJ-145)的制备
CLJ-145的合成同实施例3,用4-溴正丁醇替代2-碘乙醇得到终产物CLJ-145。1HNMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.30(s,1H),8.23(s,1H),8.02(s,1H),7.68(d,J=8.1Hz,1H),6.93(d,J=11.5Hz,1H),4.61(p,J=6.7Hz,1H),4.54(s,1H),3.50(s,2H),3.42(d,J=6.3Hz,2H),2.78(t,J=5.9Hz,2H),2.64(t,J=5.9Hz,2H),2.44(t,J=7.0Hz,2H),2.30(s,3H),1.58–1.41(m,10H).m/z:439.2543[M+H]+.
实施例47 (E)-4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(CLJ-146)的制备
CLJ-146的合成同实施例37,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-146。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J=20.0Hz,2H),8.07(s,1H),7.60(d,J=2.2Hz,1H),7.48(dd,J=8.3,2.2Hz,1H),7.02(d,J=8.3Hz,1H),6.82(dt,J=15.6,5.9Hz,1H),5.99(d,J=15.6Hz,1H),4.61(h,J=6.7Hz,1H),3.57(s,2H),3.29(s,2H),2.72(dt,J=36.8,5.9Hz,4H),2.31(s,3H),1.49(d,J=6.7Hz,6H).m/z:433.2274[M+H]+.
实施例48 (E)-4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸异丁酰胺(CLJ-147)的制备
CLJ-147的合成同实施例41,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉,异丁胺替代二乙胺得到终产物CLJ-147。1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.30(d,J=19.8Hz,1H),8.07(s,1H),7.99(t,J=5.8Hz,1H),7.61(d,J=1.6Hz,1H),7.48(dt,J=13.7,6.8Hz,1H),7.02(d,J=8.4Hz,1H),6.64(dt,J=15.5,5.8Hz,1H),6.17(d,J=15.5Hz,1H),4.75–4.49(m,1H),3.59(s,1H),3.28(d,J=5.5Hz,1H),2.96(t,J=6.3Hz,1H),2.78(d,J=5.1Hz,1H),2.70(s,1H),2.31(s,1H),1.77–1.65(m,1H),1.48(d,J=6.7Hz,3H),0.86(d,J=6.7Hz,3H).m/z:488.3060[M+H]+.
实施例49 (E)-4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸二乙酰胺(CLJ-148)的制备
CLJ-148的合成同实施例48,用二乙胺替代异丁胺得到终产物CLJ-148。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J=20.9Hz,2H),8.07(s,1H),7.60(d,J=1.7Hz,1H),7.49(dd,J=8.3,2.1Hz,1H),7.02(d,J=8.4Hz,1H),6.71(dt,J=15.0,6.0Hz,1H),6.59(s,1H),4.62(s,1H),3.58(s,2H),3.42–3.27(m,8H),2.76(d,J=5.2Hz,2H),2.69(d,J=5.1Hz,2H),1.09(dt,J=28.2,6.9Hz,6H).m/z:488.3062[M+H]+.
实施例50 (E)-4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸(3-三氟甲基苯乙胺)酰胺(CLJ-149)的制备
CLJ-149的合成同实施例49,用3-三氟甲基苯乙胺替代二乙胺得到终产物CLJ-149。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.64(t,J=6.0Hz,1H),8.29(d,J=20.6Hz,2H),8.07(s,1H),7.69–7.52(m,5H),7.49(dd,J=8.3,2.0Hz,1H),7.02(d,J=8.4Hz,1H),6.72(dt,J=15.5,5.7Hz,1H),6.21(d,J=15.5Hz,1H),4.61(dt,J=13.3,6.6Hz,1H),4.44(d,J=5.9Hz,2H),3.58(s,2H),3.28(d,J=5.4Hz,2H),2.77(d,J=5.4Hz,2H),2.69(d,J=5.3Hz,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).
m/z:590.2777[M+H]+.
实施例51 (E)-4-二甲氨基-1-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)-2-丁烯酸(CLJ-150)的制备
CLJ-150的合成同实施例26,用4-二甲氨基-2-丁烯酸替代4-戊烯酸得到终产物CLJ-150。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J=5.2Hz,1H),8.30(d,J=20.8Hz,2H),8.09(s,1H),7.75(d,J=6.4Hz,1H),7.56(t,J=9.0Hz,1H),7.10(t,J=8.8Hz,1H),6.85(d,J=15.1Hz,1H),6.70–6.56(m,1H),4.71(s,1H),4.65–4.57(m,2H),3.77(dt,J=18.4,5.8Hz,2H),3.51(d,J=6.6Hz,2H),2.84(dt,J=28.8,6.0Hz,2H),2.32(s,3H),1.49(d,J=6.6Hz,6H).m/z:460.2747[M+H]+.
实施例52 2-氰乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-151)的制备
CLJ-151的合成同实施例19,用3-氯丙腈替代2-氯乙腈得到终产物CLJ-151。1HNMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J=22.7Hz,2H),8.08(s,1H),7.67(d,J=2.2Hz,1H),7.48(dd,J=8.3,2.2Hz,1H),6.95(d,J=8.3Hz,1H),4.63(hept,J=6.7Hz,1H),2.76(ddt,J=20.6,9.8,5.7Hz,8H),2.31(s,3H),1.48(d,J=6.6Hz,6H).m/z:402.2328[M+H]+.
实施例53 2-(3-苯甲酰基丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-152)的制备
CLJ-152的合成同实施例34,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-152。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=3.6Hz,1H),8.34(s,1H),8.28(d,J=7.3Hz,1H),8.12–8.01(m,3H),7.85–7.75(m,2H),7.73–7.67(m,1H),7.62–7.50(m,4H),7.10(d,J=8.3Hz,1H),4.79(d,J=40.6Hz,2H),4.61(dq,J=13.3,6.7Hz,1H),3.82(dt,J=10.9,5.9Hz,2H),2.82(dt,J=24.6,5.9Hz,2H),2.32(d,J=4.6Hz,3H),1.48(dd,J=16.7,6.6Hz,6H).m/z:507.2430[M+H]+.
实施例54 2-氰乙基-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-153)的制备
CLJ-153的合成同实施例52,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-153。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J=24.5Hz,2H),8.07(s,1H),7.60(d,J=2.2Hz,1H),7.48(dd,J=8.3,2.3Hz,1H),7.01(d,J=8.3Hz,1H),4.63(p,J=6.7Hz,1H),3.63(s,2H),2.76(dq,J=15.2,4.9Hz,8H),2.31(s,3H),1.49(d,J=6.6Hz,6H).m/z:402.2328[M+H]+.
实施例55 2-(3-苯基丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-154)的制备
CLJ-154的合成同实施例53,用3-苯基丙烯酸替代3-苯甲酰基丙烯酸可得终产品CLJ-154。1H NMR(400MHz,DMSO-d6)δ:9.32(d,J=6.4Hz,1H),8.37(d,J=17.1Hz,1H),8.29(s,1H),8.10(s,1H),7.91–7.69(m,3H),7.55(d,J=15.1Hz,2H),7.41(q,J=6.6Hz,4H),7.10(d,J=8.0Hz,1H),4.95(s,1H),4.74(s,1H),4.64(dt,J=13.9,7.7Hz,1H),3.88(dt,J=55.8,5.8Hz,2H),2.81(dt,J=33.6,5.8Hz,2H),2.28(s,3H),1.55–1.42(m,6H).m/z:479.2481[M+H]+.
实施例56 2-(3-苯基丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-155)的制备
CLJ-155的合成同实施例53,6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-155。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=3.6Hz,1H),8.31(d,J=21.8Hz,2H),8.10(s,1H),7.82–7.70(m,3H),7.63–7.50(m,2H),7.48–7.31(m,4H),7.14(d,J=8.4Hz,1H),4.95–4.57(m,3H),3.88(dt,J=55.9,5.8Hz,2H),2.87(dt,J=32.1,5.9Hz,2H),2.32(s,3H),1.49(d,J=6.6Hz,6H).m/z:479.2483[M+H]+.
实施例57 2-(3-(4-甲基苯甲酰基)丙酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-156)的制备
CLJ-156的合成同实施例56,用3-(4-甲基苯甲酰基)丙酸替代3-苯基丙烯酸可得终产物CLJ-156。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J=5.9Hz,1H),8.31(d,J=20.9Hz,2H),8.09(d,J=1.7Hz,1H),7.88(d,J=8.0Hz,2H),7.75(dd,J=11.7,1.8Hz,1H),7.61–7.51(m,1H),7.33(d,J=7.8Hz,2H),7.11(dd,J=25.0,8.4Hz,1H),4.71–4.49(m,3H),3.71(dt,J=35.7,5.9Hz,2H),3.24(t,J=6.2Hz,2H),2.95–2.71(m,4H),2.35(d,J=24.3Hz,6H),1.49(d,J=6.6Hz,6H).m/z:523.2743[M+H]+.
实施例58 2-(2-甲基苯丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-157)的制备
CLJ-157的合成同实施例57,用2-甲基苯丙烯酸替代3-(4-甲基苯甲酰基)丙酸可得终产物CLJ-157。1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.31(d,J=21.5Hz,2H),8.09(s,1H),7.76(s,1H),7.56(d,J=8.4Hz,1H),7.42(d,J=4.5Hz,4H),7.32(pd,J=5.7,3.9,3.3Hz,1H),7.11(d,J=8.5Hz,1H),6.58(s,1H),4.63(d,J=6.0Hz,3H),3.77(t,J=5.8Hz,2H),2.88(t,J=5.9Hz,2H),2.32(s,3H),2.06(s,3H),1.48(d,J=6.6Hz,6H).m/z:493.2638[M+H]+.
实施例59 2-(3-(4-甲基苯甲酰基)丙酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-158)的制备
CLJ-158的合成同实施例57,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-158。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J=15.6Hz,1H),8.42–8.22(m,2H),8.08(d,J=5.5Hz,1H),7.88(d,J=7.8Hz,2H),7.77(dd,J=35.8,2.1Hz,1H),7.53(td,J=8.3,2.2Hz,1H),7.33(d,J=7.9Hz,2H),7.09(t,J=8.1Hz,1H),4.77–4.53(m,3H),3.71(dt,J=33.7,5.9Hz,2H),3.24(s,2H),2.88–2.64(m,4H),2.44–2.23(m,6H),1.48(dd,J=6.6,5.0Hz,6H).m/z:523.2743[M+H]+.
实施例60 2-(2-甲基苯丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-159)的制备
CLJ-159的合成同实施例58,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-159。1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.30(d,J=20.3Hz,2H),8.08(s,1H),7.77(s,1H),7.53(dd,J=8.4,2.2Hz,1H),7.45–7.37(m,4H),7.31(tq,J=5.4,3.5,2.4Hz,1H),7.10(d,J=8.4Hz,1H),6.58(d,J=1.9Hz,1H),4.65(d,J=36.4Hz,3H),3.76(t,J=5.9Hz,2H),2.81(t,J=6.0Hz,2H),2.31(s,3H),2.11–1.99(m,3H),1.47(dd,J=7.1,3.6Hz,6H).m/z:493.2638[M+H]+.
实施例61 2-(3-(4-甲基苯甲酰基)丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-6-胺(CLJ-160)的制备
CLJ-160的合成同实施例57,用3-(4-甲基苯甲酰基)丙烯酸替代3-(4-甲基苯甲酰基)丙酸得到终产物CLJ-160。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=2.1Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.96(dd,J=8.3,2.8Hz,2H),7.84–7.72(m,2H),7.59–7.48(m,2H),7.39(d,J=8.0Hz,2H),7.14(dd,J=8.5,3.8Hz,1H),4.79–4.58(m,3H),3.82(dt,J=10.1,5.9Hz,2H),2.88(dt,J=23.6,6.0Hz,2H),2.40(s,3H),2.32(s,3H),1.48(dd,J=6.7,1.7Hz,6H).m/z:521.2587[M+H]+.
实施例62 2-(3-(4-甲基苯甲酰基)丙烯酰基)-N-(4-(1-异丙基-1H-吡唑-4-基)5-甲基嘧啶-2-基)-1,2,3,4-四氢异喹啉-7-胺(CLJ-161)的制备
CLJ-161的合成同实施例61,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉得到终产物CLJ-161。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=3.4Hz,1H),8.39–8.21(m,2H),8.08(d,J=10.4Hz,1H),7.96(dd,J=8.0,4.3Hz,2H),7.88–7.68(m,2H),7.61–7.47(m,2H),7.38(dd,J=8.1,4.2Hz,2H),7.10(d,J=8.3Hz,1H),4.94–4.49(m,3H),3.82(dt,J=9.7,5.9Hz,2H),2.81(dt,J=24.2,5.9Hz,2H),2.40(d,J=3.7Hz,3H),2.32(d,J=4.5Hz,3H),1.48(dd,J=16.3,6.7Hz,6H).m/z:521.2587[M+H]+.
实施例63 4-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁酸甲酯(CLJ-162)的制备
CLJ-162的合成同实施例29,用4-溴丁酸甲酯替代(E)-4-溴-2-丁烯酸甲酯可得到终产物CLJ-162。1H NMR(400MHz,DMSO-d6)δ:9.18(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.64(s,1H),7.46(d,J=8.4Hz,1H),6.95(d,J=8.3Hz,1H),4.62(dt,J=13.2,6.6Hz,1H),3.57(d,J=9.1Hz,3H),3.46(s,2H),2.78(d,J=5.3Hz,2H),2.62(t,J=5.6Hz,2H),2.44(t,J=6.9Hz,2H),2.36(t,J=7.2Hz,2H),2.31(s,3H),1.83–1.74(m,2H),1.48(d,J=6.6Hz,6H).m/z:449.2587[M+H]+.
实施例64 (E)-4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁烯酸甲酯(CLJ-163)的制备
CLJ-163的合成同实施例29,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉可得到终产物CLJ-163。1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.32(s,1H),8.26(d,J=5.5Hz,1H),8.07(d,J=6.0Hz,1H),7.61(s,1H),7.50–7.45(m,1H),7.00(t,J=9.9Hz,1H),6.93(dt,J=15.7,5.8Hz,1H),6.10(d,J=15.7Hz,1H),4.62(dt,J=13.3,6.6Hz,1H),3.68(s,3H),3.58(s,2H),3.32–3.29(m,2H),2.75(d,J=5.1Hz,2H),2.67(t,J=5.4Hz,2H),2.30(d,J=9.3Hz,3H),1.48(d,J=6.7Hz,6H).m/z:447.2430[M+H]+.
实施例65 4-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)丁酸甲酯(CLJ-164)的制备
CLJ-164的合成同实施例64,用4-溴丁酸甲酯替代(E)-4-溴-2-丁烯酸甲酯可得到终产物CLJ-164。1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.61(s,1H),7.45(dd,J=8.3,1.8Hz,1H),6.99(d,J=8.3Hz,1H),4.62(dp,J=12.9,6.4Hz,1H),3.56(s,3H),3.52(s,2H),2.71(d,J=5.3Hz,2H),2.62(t,J=5.6Hz,2H),2.46(t,J=6.9Hz,2H),2.36(t,J=7.2Hz,2H),2.30(d,J=11.3Hz,3H),1.79(p,J=7.1Hz,2H),1.47(dd,J=11.7,5.9Hz,6H).m/z:449.2587[M+H]+.
实施例66 4-二甲氨基-1-(6-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)-2-丁酰胺(CLJ-165)的制备
CLJ-165的合成同实施例51,用4-二甲氨基丁酸替代(E)-4-二甲氨基-2-丁烯酸可得到终产物
CLJ-165。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J=6.4Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.75(dd,J=10.1,2.2Hz,1H),7.56(ddd,J=14.8,8.4,2.2Hz,1H),7.10(d,J=8.4Hz,1H),4.68–4.54(m,3H),3.68(dt,J=12.1,5.9Hz,2H),3.09–2.99(m,2H),2.88(s,8H),2.56–2.51(m,2H),2.32(s,3H),1.87(p,J=7.0Hz,2H),1.48(d,J=6.6Hz,6H).m/z:462.2903[M+H]+.
实施例67 4-二甲氨基-1-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)-2-丁酰胺(CLJ-166)的制备
CLJ-166的合成同实施例66,用7-氨基-2-N-BOC-1,2,3,4-四氢异喹啉替代6-氨基-2-N-BOC-1,2,3,4-四氢异喹啉可得到终产物CLJ-166。1H NMR(400MHz,DMSO-d6)δ:9.31(d,J=12.8Hz,1H),8.34(d,J=8.0Hz,1H),8.28(s,1H),8.09(d,J=1.9Hz,1H),7.76(d,J=2.7Hz,1H),7.52(dd,J=8.4,2.4Hz,1H),7.09(dd,J=8.4,4.3Hz,1H),4.63(dd,J=7.7,5.3Hz,3H),3.68(dt,J=14.1,5.9Hz,2H),3.09–2.99(m,2H),2.82(t,J=5.9Hz,1H),2.76(s,6H),2.74–2.67(m,1H),2.55(dd,J=13.4,6.8Hz,2H),2.32(d,J=2.5Hz,3H),1.88(p,J=7.0Hz,2H),1.49(d,J=6.6Hz,6H).m/z:462.2903[M+H]+.
实施例68 (E)-4-二甲氨基-1-(7-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-1,2,3,4-四氢异喹啉-2-基)-2-丁烯酰胺(CLJ-167)的制备
CLJ-167的合成同实施例67,用(E)-4-二甲氨基-2-丁烯酸替代4-二甲氨基丁酸可得到终产物CLJ-167。1H NMR(400MHz,DMSO-d6)δ:9.32(d,J=10.3Hz,1H),8.34(d,J=5.4Hz,1H),8.28(s,1H),8.10(s,1H),7.76(d,J=13.3Hz,1H),7.54(dd,J=8.3,2.3Hz,1H),7.10(d,J=8.4Hz,1H),6.95(dd,J=23.4,15.0Hz,1H),6.65(dt,J=14.7,6.8Hz,1H),4.79(s,1H),4.69(s,1H),4.63(q,J=6.7Hz,1H),3.79(dt,J=15.3,5.9Hz,2H),3.68(d,J=6.9Hz,2H),2.79(dt,J=30.7,5.8Hz,2H),2.63(s,6H),2.32(s,3H),1.50(d,J=6.7Hz,6H).m/z:460.2747[M+H]+.
实施例69 (R)-5-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)-异吲哚啉-2-吡咯啉甲酰胺(CLJ-168)的制备
CLJ-168的合成同实施例26,用5-氨基异吲哚啉替代1,2,3,4-四氢异喹啉,(R)-2-吡咯啉甲酸替代4-戊烯酸可得。1H NMR(400MHz,DMSO-d6)δ:9.42(d,J=4.7Hz,1H),8.34(s,1H),8.29(s,1H),8.10(d,J=2.6Hz,1H),7.93(t,J=3.0Hz,1H),7.64(dd,J=8.4,2.0Hz,1H),7.25(t,J=8.5Hz,1H),4.87(ddd,J=74.2,28.4,14.4Hz,3H),4.64(dt,J=20.2,6.0Hz,2H),3.80(q,J=7.5Hz,1H),3.01(dt,J=10.9,6.0Hz,1H),2.74–2.60(m,1H),2.32(s,3H),2.15–2.01(m,1H),1.76–1.59(m,3H),1.49(d,J=1.1Hz,3H),1.48(d,J=1.2Hz,3H).m/z:432.2512[M+H]+.
实施例70 (R)-5-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)吲哚啉-2-吡咯啉甲酰胺(CLJ-169)的制备
CLJ-169的合成同实施例69,用5-氨基吲哚啉替代5-氨基异吲哚啉可得。1H NMR(400MHz,DMSO-d6)δ:9.28(s,1H),8.32(s,1H),8.26(s,1H),8.08(s,1H),7.99(d,J=8.7Hz,1H),7.79(s,1H),7.51(d,J=8.8Hz,1H),4.63(p,J=6.8Hz,1H),4.23(q,J=9.1Hz,1H),4.06(q,J=9.1Hz,1H),3.86(t,J=6.9Hz,1H),3.38(q,J=7.0Hz,1H),3.17(t,J=8.3Hz,2H),3.10–2.97(m,1H),2.79–2.64(m,1H),2.31(s,3H),2.17–2.00(m,1H),1.84–1.60(m,3H),1.48(d,J=6.5Hz,6H).m/z:432.2512[M+H]+.
实施例71 5-((4-(1-异丙基-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)吲哚啉-3-吗啉丙酰胺(CLJ-170)的制备
CLJ-170的合成同实施例70,用3-吗啉丙酸替代(R)-2-吡咯啉甲酸可得。1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.98(d,J=8.8Hz,1H),7.77(s,1H),7.50(d,J=8.9Hz,1H),4.62(h,J=6.6Hz,1H),4.10(t,J=8.5Hz,2H),3.61(s,4H),3.44(s,2H),3.16(t,J=8.3Hz,2H),2.66(s,4H),2.48(s,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).m/z:476.2774[M+H]+.
药理活性实验以下代表性实验(不限于此)用于分析本发明化合物的生物活性
MTT法测MV4-11、MOLM-13和SET-2细胞增殖抑制实验
测试本发明受试化合物对癌细胞活力的影响,MV4-11、MOLM-13及SET-2购自ATCC(美国模式培养物集存库),MV4-11和MOLM-13为人白血病细胞系,表达FLT3受体,并包含FLT3-ITD突变;SET-2为原发性血小板增多症细胞,持续表达JAK2受体,并包含V617F突变。
MV4-11、MOLM-13和SET-2细胞装于96孔培养皿中,介质为100μL IMDM,包含10%胎牛血清(购于草原绿野生物公司,100mL/瓶,-20℃密闭冻存),每孔有10000-15000个细胞,受试化合物在100%DMSO(二甲基亚砜)中制备,加入到细胞中,获得浓度为100nM到0.032nM(按照5倍稀释浓度的6个浓度点),空白对照组每孔加入100μL新鲜培养基,溶剂对照组每孔加入等体积含与药物最高实验浓度等量DMSO的新鲜培养基,每组设置3-5个平行孔,在37℃5%CO2中培养72h。在终点时,向每个孔中加入20μL MTT(5mg/mL),并将细胞再孵育1-3小时。用20%SDS处理过夜后,在分光光度计(Molecular Devices,Sunnyvale,USA)上获得波长570nM的吸光度OD值。
按抑制率=[(溶剂对照组平均OD值-实验组平均OD值)/(溶剂对照组平均OD值–空白对照组平均OD值)]×100%,计算各实验组抑制率。
计算出各浓度化合物对细胞增殖活性的抑制率后,将化合物处理浓度与其对应的抑制率用Graphpadprism软件拟合剂量-响应曲线,并拟合IC50值。测定结果见表1。
体外激酶活性测定实验
在一个反应管内,依次加入缓冲液(8mM MOPS,pH 7.0,0.2mM EDTA,10mM MnCl2),待测激酶、待测激酶的底物,10mM醋酸镁和γ33P-ATP溶液,以及不同浓度的化合物,然后向反应中加入MgATP以启动酶反应过程,并在室温下孵育40分钟。最终用5微升的3%磷酸盐缓冲液终止反应,并把10微升的反应液滴定到Filtermat A膜上,用75mM的磷酸盐溶液洗三次,每次5分钟,再用甲醇洗一次,最后干燥Filtermat A膜并对其进行闪烁计数,闪烁计数值的大小反映了底物被磷酸化的程度,从而可以表征激酶活性抑制情况。激酶活性@500nM表明在500nM水平对酶的抑制率(%),数据由Eurofins公司测得。测定结果见表1。
表1受试化合物对细胞增殖抑制的IC50值和激酶活性
结果表明,本发明的大部分受试化合物对MV4-11、MOLM-13和SET-2细胞增殖具有较好的抑制活性,同时对JAK2和FLT3也具有较好的活性,是一种新型的、潜在的和具备治疗JAK2-FLT3-ITD相关疾病潜力的抑制剂。
将活性好的受试化合物优选出来进行FLT3和JAK家族激酶半数抑制活性IC50值的测定,在一个反应管内,依次加入缓冲液(8mM MOPS,pH 7.0,0.2mM EDTA,10mM MnCl2),待测激酶、待测激酶的底物,10mM醋酸镁和γ33P-ATP溶液,以及不同浓度的化合物,然后向反应中加入MgATP以启动酶反应过程,并在室温下孵育40分钟。最终用5微升的3%磷酸盐缓冲液终止反应,并把10微升的反应液滴定到Filtermat A膜上,用75mM的磷酸盐溶液洗三次,每次5分钟,再用甲醇洗一次,最后干燥Filtermat A膜并对其进行闪烁计数,闪烁计数值的大小反映了底物被磷酸化的程度,从而可以表征激酶活性抑制情况。结果如表2。
表2本发明优选化合物对JAK1/2/3和FLT3激酶抑制剂活性
结果表明,本发明优选化合物CLJ-118、CLJ-128、CLJ-144具有较好的体外酶学抑制活性,以及良好的选择性。
Claims (15)
2.权利要求1所述的2,4-二取代嘧啶衍生物药学上可接受的盐。
3.药物组合物,是由权利要求1所述的2,4-二取代嘧啶衍生物或权利要求2所述的盐添加药学上可以接受的辅助性成分制备而成的制剂。
4.根据权利要求3所述的药物组合物,所述制剂为片剂、胶囊、粉末、颗粒、软膏剂、溶液、混悬液、注射剂、吸入剂、凝胶、微球或气雾剂。
5.根据权利要求3所述的药物组合物,所述制剂为口服或静脉注射制剂。
6.权利要求1所述的2,4-二取代嘧啶衍生物、权利要求2所述的盐或权利要求3~5任一项所述的药物组合物在制备JAK2抑制剂中的用途。
7.权利要求1所述的2,4-二取代嘧啶衍生物、权利要求2所述的盐或权利要求3~5任一项所述的药物组合物在制备FLT3抑制剂中的用途。
8.权利要求1所述的2,4-二取代嘧啶衍生物、权利要求2所述的盐或权利要求3~5任一项所述的药物组合物在制备治疗或/和预防肿瘤的药物中的用途。
9.根据权利要求8所述的用途,所述肿瘤包括实体瘤和/或血液瘤;所述实体瘤包括:淋巴瘤、卵巢癌、乳腺癌、***癌、膀胱癌、肾癌、食道癌、颈癌、胰腺癌、结直肠癌、胃癌、非小细胞肺癌、甲状腺癌、脑癌、表皮过渡增生、银屑病和/或***癌;所述血液瘤包括:急性髓性白血病、慢性粒细胞白血病、骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、急性早幼粒白血病、慢性淋巴细胞白血病、慢性嗜中性白血病、急性未分化细胞白血病、骨髓发育不良综合征、骨髓增生异常、骨髓纤维化、多发性骨髓瘤和/或脊髓肉瘤。
10.根据权利要求9所述的用途,所述淋巴瘤包括B-细胞淋巴瘤、弥漫性大B-细胞淋巴瘤、慢性淋巴细胞淋巴瘤、淋巴浆细胞淋巴瘤和/或淋巴癌。
11.权利要求1所述的2,4-二取代嘧啶衍生物、权利要求2所述的盐或权利要求3~5任一项所述的药物组合物在制备治疗或/和预防免疫性疾病的药物中的用途。
12.根据权利要求11所述的用途,所述免疫性疾病包括:牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、***、多发性硬化、***性红斑狼疮、关节强硬性椎关节炎、多肌炎、皮肤肌炎、结节性动脉周围炎、混合***病、硬皮病、深红斑狼疮、慢性甲状腺炎、Graves'疾病、自身免疫性胃炎、I型和II型糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少、特异性皮炎、慢性活动型肝炎、重症肌无力、移植物抗宿主疾病、艾迪生病、异常免疫应答、关节炎和/或放射性皮炎。
13.根据权利要求12所述的用途,所述免疫性疾病包括:牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、***、多发性硬化和/或***性红斑狼疮。
14.权利要求1所述的2,4-二取代嘧啶衍生物、权利要求2所述的盐或权利要求3~5任一项所述的药物组合物在制备治疗或/和预防炎性相关疾病的药物中的用途。
15.根据权利要求14所述的用途,所述炎性相关疾病包括:急性胰炎、慢性胰腺炎、哮喘、成人呼吸窘迫综合征、慢性阻塞性肺病、炎性骨疾病、炎性肺病、炎性肠疾病、乳糜泻、肝炎、***炎性响应综合症、手术后或外伤后的炎症、肾炎、膀胱炎、咽喉炎、胃粘膜损伤、脑膜炎、脊椎炎、关节炎、皮炎和/或支气管炎。
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