CN111527088A - 作为激酶抑制剂的氨基-甲基哌啶衍生物 - Google Patents
作为激酶抑制剂的氨基-甲基哌啶衍生物 Download PDFInfo
- Publication number
- CN111527088A CN111527088A CN201880083535.6A CN201880083535A CN111527088A CN 111527088 A CN111527088 A CN 111527088A CN 201880083535 A CN201880083535 A CN 201880083535A CN 111527088 A CN111527088 A CN 111527088A
- Authority
- CN
- China
- Prior art keywords
- amino
- pyrimidin
- pyrazol
- pyrrolo
- methylpiperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
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Abstract
本发明涉及由化学式(1)表示的化合物或其药学上可接受的盐。根据本发明的化合物可用于预防或治疗受益于激酶抑制作用的疾病。
Description
技术领域
本发明涉及具有激酶抑制活性的氨基-甲基哌啶衍生物、其制备方法及其用途。
背景技术
蛋白激酶是催化其他蛋白质的特定残基磷酸化的酶,并且在将细胞外信号转导至细胞核的信号转导途径中起重要作用。此外,它涉及体内的多种疾病。在炎性疾病、自身免疫疾病、增殖性疾病或过度增殖性疾病和/或免疫介导的疾病的发病或发展中,有多种证据表明T细胞(或T淋巴细胞)和B细胞(或B-淋巴细胞)起重要作用。
Janus激酶(下文称为“JAK”)是细胞质蛋白酪氨酸激酶,其在调节淋巴-造血系统中的细胞功能中起关键作用。已知细胞因子在调节炎症、免疫和正常细胞功能中起重要作用,并且JAK通过酪氨酸磷酸化激活STAT(Signal Transducer and Activators ofTranscription,信号转导和转录激活因子)蛋白,以提供细胞因子的快速信号传导途径。已知JAK/STAT信号传导与过敏、哮喘、自身免疫疾病(例如,移植排斥、类风湿性关节炎、肌萎缩侧索硬化、多发性硬化等)、实体癌、血癌(例如,白血病、淋巴瘤等)有关。
JAK家族分为四种成员:JAK1、JAK2、JAK3和TYK2。JAK家族的成员彼此配对,以介导来自各种细胞因子的信号。它包括与造血生长因子信号传导相关的JAK2和JAK1,并且TYK2和JAK2的组合对于干扰素信号传导是重要的并且有助于宿主耐受。JAK2可诱导贫血、血小板减少、白细胞减少,特别是当JAK2参与造血生长因子信号传导并引起过度抑制时。
已发现JAK1、JAK2和TYK2的表达广泛分布,而JAK3的表达局限于淋巴细胞并且与IL-2、IL-4、IL-7、IL-9、IL-15和IL-21受体的成员的常见γ链,特别是IL-2家族的常见γ链的信号传导相关。一旦细胞因子结合,受体就会在附近携带相邻的JAK3,这会诱导β-链C-末端的自身磷酸化。结果,它引起STAT蛋白的激活,这是将信号重新传递到细胞核的重要步骤。JAK3通过该过程控制多种细胞因子的信号途径。这使得JAK3成为免疫抑制的有吸引力的靶标。
B细胞在自身免疫疾病和/或炎性疾病的发展中起重要作用。减少B细胞的基于蛋白质的治疗剂,例如Rituxan对于自身抗体诱导的炎性疾病,例如类风湿性关节炎是有效的。因此,在B细胞激活中起作用的蛋白激酶抑制剂是用于治疗B细胞介导的疾病,例如用于产生自身抗体的有用治疗剂。
通过B细胞受体(BCR)的信号转导调节多种B细胞应答,包括增殖和分化成成熟抗体产生细胞。BCR是B细胞活性的重要调节因素,并且异常信号转导可导致致病性自身抗体的形成,这引起多种自身免疫和/或炎性疾病以及失调的B细胞的增殖。
布鲁顿酪氨酸激酶(下文称为“BTK”)是B细胞的发育、激活、信号传导和存活的重要调节剂。BTK参与通过将多种细胞外配体与其细胞表面受体结合而启动的信号转导途径。在连接B细胞抗原受体(BCR)后,通过蛋白酪氨酸激酶Lyn和Syk的同时作用,BTK的活性是诱导磷脂酶C-γ2介导的钙动员所必需的。因此,抑制BTK可以是阻断B细胞介导的疾病的发病过程的有用治疗方法。
如上所述,Janus激酶和基于TEC的激酶在与炎性疾病、自身免疫疾病、增殖性疾病或过度增殖性疾病和免疫介导的疾病的发展有关的T细胞和/或B细胞的激活中起重要作用。因此,有效抑制这些疾病的物质的开发可用作相关治疗剂。可以治疗和预防的疾病的具体示例包括癌症、移植排斥、多发性硬化、类风湿性关节炎、银屑病关节炎、牛皮癣、哮喘、过敏性皮炎、特应性皮炎、湿疹、I型糖尿病、糖尿病并发症、溃疡性结肠炎、克罗恩病、自身免疫性甲状腺疾病、全身性脱毛、干燥综合症等。
JAK3激酶抑制剂托法替尼(tasocitinib,CP-690550)(辉瑞公司)目前已被批准并销售用于治疗类风湿性关节炎。此外,BTK激酶抑制剂依鲁替尼(ibrutinib,PCI-32765)(Pharmacyclics公司)处于临床阶段,但在临床病例中已报道了严重的副作用,例如皮疹和腹泻。因此,需要开发一种更稳定和有效的抑制JAK和/或BTK的物质(参见Nat RevRheumatol.2009Jun 5(6)317-24;Expert Opin Investig Drugs.2014Aug 23(8)1067-77;Drug Discov Today 2014Aug19(8)1200-4;WO2002/096909;WO2010-009342)。
因此,本发明人发现了一种具有优异抑制活性的新的氨基-甲基哌啶衍生物作为激酶抑制剂,由此完成了本发明。
发明内容
【技术问题】
本发明的一个目的是提供一种对激酶,特别是对酪氨酸激酶具有抑制能力的氨基-甲基哌啶,其制备方法及其用途。
本发明的另一个目的是提供包含氨基-甲基哌啶衍生物作为活性成分的药物组合物。
【技术方案】
为了实现上述目的,本文提供了由以下化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
其中,在化学式1中,
X1是N-R1、O或S,
X2是CH或N,
R1是C1-5烷基、C3-6环烷基或取代有(叔丁氧羰基)氨基的C1-5烷基,
R2是氢、C1-5烷基或卤素,并且
R3是氢或C1-5烷基。
优选地,R1是甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、新戊基、环丙基、环丁基、环戊基、环己基或2-((叔丁氧羰基)氨基)乙基。
优选地,R2是氢、甲基、溴、氟或氯。
优选地,R3是氢、甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基或新戊基。
优选地,X1是N-R1,X2是CH。
化学式1表示的化合物的代表性实例如下:
1)1-((2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
2)1-((2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
3)1-((2S,5R)-5-((2-((1-异丁基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
4)1-((2S,5R)-5-((2-((1-环戊基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
5)2-(4-((4-((3R,6S)-1-丙烯酰基-6-甲基哌啶-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基氨基甲酸叔丁酯,
6)1-((2S,5R)-5-((5-氯-2-(异噻唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
7)1-((2S,5R)-5-((5-氯-2-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
8)1-((2S,5R)-5-((5-氯-2-((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
9)1-((2S,5R)-5-((5-氯-2-((1-环丙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
10)1-((2S,5R)-5-((2-(1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,和
11)1-((2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮。
此外,本发明的化合物可以以盐的形式,尤其是药学上可接受的盐的形式存在。作为盐,可以使用本领域常用的盐,例如由药学上可接受的游离酸形成的酸加成盐,但不限于此。本文所用的术语“药学上可接受的盐”是指化学式1表示的化合物的任何有机或无机加成盐,其浓度由于对患者相对无毒且无害而具有有效作用,并且其副作用不会降低上述化合物的有益功效。
药学上可接受的盐可通过常规方法使用无机酸或有机酸获得。例如,药学上可接受的盐可以通过将化学式1表示的化合物溶解在水混溶性有机溶剂(例如丙酮、甲醇、乙醇或乙腈)中,然后加入有机酸或无机酸,并过滤和干燥沉淀的晶体来制备。可替代地,可以通过对来自加酸的反应混合物中的溶剂或过量的酸进行减压,然后干燥残余物,或者通过添加不同的有机溶剂,然后过滤沉淀的盐来制备。此时,优选的盐可包括衍生自以下各项的盐:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸等。
在制备化学式1的化合物或其药学上可接受的盐或溶剂化物中,可以使用化学式1的化合物的药学上不可接受的盐或溶剂化物作为中间体。
根据本发明的化学式1的化合物不仅包括其药学上可接受的盐,而且包括可由该化学式1的化合物制备的所有溶剂化物和水合物,并且还包括所有可能的立体异构体。由化学式1表示的化合物的溶剂化物、水合物和立体异构体可以使用常规方法由化学式1的化合物制备和使用。
此外,根据本发明的由化学式1表示的化合物可以以结晶形式或以非结晶形式制备,并且当由化学式1表示的化合物以结晶形式制备时,该化合物可以可选地水合化或溶剂化。在本发明中,由化学式1表示的化合物不仅可以包括化学计量的水合物,也可以包括含有多种量的水的化合物。根据本发明的由化学式1表示的化合物的溶剂化物包括化学计量的溶剂化物和非化学计量的溶剂化物。
此外,作为示例,本发明可以通过下面的反应方案1制备由化学式1表示的化合物。
[反应方案1]
(在反应方案1中,X1至X2和R1至R3如上文所限定,Z是卤素,并且优选地Z为氯)。
步骤i是通过使由化学式1-1表示的化合物与由化学式1-2表示的化合物反应来制备由化学式1-3表示的化合物的步骤。该反应优选在氢化钠或二异丙基乙胺的存在下,于0℃或更低温度或者于室温至高温下进行,并且溶剂优选为四氢呋喃、乙醇或二甲基甲酰胺。
步骤ii是通过使由化学式1-3表示的化合物与胺反应来制备由化学式1-4表示的化合物的步骤。该反应优选在配体、钯催化剂或碱的存在下于100℃至120℃下进行,或者在三氟乙酸的存在下于高温下进行,并且溶剂优选为1,4-二噁烷、叔丁醇或2-丁醇。
步骤iii是移除由化学式1-4表示的化合物的保护基的反应,该步骤是制备由化学式1-5表示的化合物的步骤。该反应优选在氢气的存在下通过钯来进行,或者在酸性条件下于高温下进行,优选在6N盐酸条件下进行。
步骤iv是通过使由化学式1-5表示的化合物与酰氯反应来制备由化学式1表示的化合物的步骤。该反应优选在三乙胺或碳酸氢钠的存在下于-20℃至0℃下进行。此外,溶剂优选为二氯甲烷或四氢呋喃与水的混合物。
此外,如反应方案1所示,也可以以由化学式1-3表示的化合物、由化学式1-6表示的化合物、由化学式1-7表示的化合物和由化学式1表示的化合物的顺序制备,并且除了反应物之外,每个步骤iii、iv和ii与上述相同。
此外,作为示例,本发明可通过以下反应方案2制备由化学式1表示的化合物。
[反应方案2]
(在反应方案2中,X1至X2以及R1至R3如上文所限定,PG是作为保护基团的氢吡喃基或2-(三甲基硅烷基)乙氧基甲基,并且Z是卤素。优选地,Z为氯)。
步骤v是通过使由化学式1-1表示的化合物与保护基团反应来制备由化学式2-2表示的化合物的步骤。该反应优选在酸性条件下使用二氢吡喃来进行,或者在碱性条件下使用2-(三甲基硅烷基)乙氧基甲基氯来进行,并且溶剂优选为二氯甲烷或二甲基甲酰胺。
步骤vi是由化学式2-2表示的化合物制备由化学式2-3表示的化合物的步骤,该步骤除了反应物之外,与反应方案1的步骤i相同。
步骤vii是通过使由化学式2-3表示的化合物和R3-I反应来制备由化学式2-4表示的化合物的步骤。该反应优选在碱的存在下进行,优选在氢化钠的存在下于0℃或更低温度下或者在室温下进行,并且溶剂优选为二甲基甲酰胺。
步骤viii是由化学式2-4表示的化合物制备由化学式2-5表示的化合物的步骤,该步骤除了反应物之外,与反应方案1的步骤ii相同。
步骤ix是移除化学式2-5表示的化合物的保护基团的反应,该步骤是制备由化学式2-6表示的化合物的步骤。该反应优选在酸性条件下(优选三氟乙酸)、于高温下进行,或者在碱性条件下通过氟化物优选四丁基氟化铵来进行,并且溶剂优选为甲醇、四氢呋喃或1,4-二噁烷。
步骤x是由化学式2-6表示的化合物制备由化学式1表示的化合物的步骤,该步骤除了反应物之外,与反应方案1的步骤iv相同。
根据本发明的另一个实施方式,提供了的用于预防或治疗受益于激酶抑制作用的疾病的药物组合物,该药物组合物包含由化学式1表示的化合物、或其药学上可接受的盐、水合物、溶剂化物或异构体作为活性成分。
在这种情况下,与激酶抑制作用相关的疾病包括炎性疾病、自身免疫疾病、增殖性疾病或过度增殖性疾病,以及免疫介导的疾病、癌症、肿瘤等。
本文所用的术语“预防”是指通过给药本发明的组合物来延迟或抑制上述疾病的发生、扩散或复发的任何行为,并且本文所用的术语“治疗”是指通过给药本发明的组合物可以更好地改善或改变上述疾病的症状的任何行为。
根据标准药学实践,本发明的药物组合物可以配制成用于口服或肠胃外给药的类型。除活性成分外,这些制剂可含有添加剂,例如药学上可接受的载体,佐剂或稀释剂。
合适的载体包括例如生理盐水、聚乙二醇、乙醇、植物油和肉豆蔻酸异丙酯等。稀释剂包括例如乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和/或甘氨酸等,但不限于此。此外,本发明的化合物可以溶解在制备注射溶液中通常使用的油、丙二醇或其他溶剂中。此外,本发明化合物可以配制成用于局部施用的软膏(ointment)或乳膏(cream)。
本发明的化合物的药物剂型可包括以其药学上可接受的盐或溶剂化物的形式使用该化合物,以及单独或作为与其他药学活性化合物的组合和/或合适的混合物使用所述化合物。
通过将化合物溶解、悬浮或乳化在水溶性溶剂,例如生理盐水、5%葡萄糖或非水溶剂(例如合成脂肪酸甘油酯、高级脂肪酸酯或丙二醇)中,可将本发明化合物配制成注射溶液。本发明的制剂可包括常规添加剂,例如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂。
本发明化合物的优选剂量可根据患者的病情和体重、疾病的严重程度、药物的类型、给药的途径和持续时间而变化,但可以由本领域技术人员合适地选择。然而,为了达到理想的效果,本发明化合物可以每天以0.0001mg/kg(体重)~100mg/kg(体重),并且优选0.001mg/kg(体重)~100mg/kg(体重)的剂量给药。可以通过口服或肠胃外途径每天一次或者每天以分剂量进行给药。根据给药方法,组合物可含有0.001wt%至99wt%,优选0.01wt%至60wt%的本发明的化合物。
根据本发明的药物组合物可以通过多种途径施用至哺乳动物,例如大鼠、小鼠、家畜、人。施用可以通过所有可能的方法进行,例如口服、直肠、静脉内、肌肉内、皮下、子宫内膜内、脑室内注射。
【有益效果】
根据本发明的由化学式1表示的化合物、或其药学上可接受的盐、水合物、溶剂化物或异构体可以有效地用于预防或治疗与激酶抑制作用相关的疾病。
具体实施方式
下面,将通过实施例更详细地描述本发明。然而,提供这些实施例仅用于说明的目的,不应理解为将本发明的范围限制于这些实施例。
实施例1:制备1-((2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
步骤1:制备(2S,5R)-5-((2,5-二氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将2,4,5-三氯-7H-吡咯并[2,3-d]嘧啶(11.1g,50.0mmol)溶解于乙醇(10.0mL),然后向其中加入N,N-二异丙基乙胺(26.1mL,150.0mmol)和(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄基酯(14.9g,60.0mmol)。在110℃下,搅拌反应混合物12小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到19.9g(产率:91.7%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.40-7.20(m,5H),7.03(s,1H),5.18-5.06(m,2H),4.50-4.30(m,2H),4.16-4.04(m,1H),2.94-2.85(m,1H),1.95-1.77(m,3H),1.70-1.60(m,1H),1.24-1.20(m,3H)。
步骤2:制备(2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2S,5R)-5-((2,5-二氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(19.9g,46.0mmol)和1-乙基-1H-吡唑-4-胺(3.9g,35.0mmol)溶解在2-丁醇(190.0mL)中。加入三氟乙酸(3.2mL,42.0mmol),随后在110℃下使反应混合物反应12小时,然后浓缩溶剂。通过加入溶解于甲醇中的7N氨溶液来中和反应产物,然后通过柱色谱分离残余物,得到4.7g(产率:26.5%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.90(s,1H),7.51(s,1H),7.40-7.20(m,5H),6.78(s,1H),5.18-5.06(m,2H),4.54-4.38(m,2H),4.27-4.10(m,1H),4.10-4.00(m,2H),2.94-2.85(m,1H),1.99-1.70(m,4H),1.43-1.35(m,3H),1.28-1.20(m,3H)。
步骤3:制备5-氯-N2-(1-乙基-1H-吡唑-4-基)-N4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺
将溶解在甲醇中的6N盐酸溶液(47.0mL,过量)加入到(2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(4.7g,9.5mmol)中。在80℃下搅拌6小时后,浓缩反应产物,然后无需分离而进行下一反应。
步骤4:制备1-((2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
将5-氯-N2-(1-乙基-1H-吡唑-4-基)-N4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(3.3g,9.0mmol)和碳酸氢钠(599.8mg,6.9mmol)溶解于四氢呋喃/蒸馏水(15.0mL/3.0mL),然后在℃下向其中加入丙烯酰氯(720.0μL,9.0mmol)。在0℃下搅拌反应混合物1小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到1.4mg(产率:36.8%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.95(s,1H),7.50(s,1H),6.94-6.55(m,2H),6.33-6.06(m,1H),5.86-5.53(m,1H),4.56-4.14(m,2H),4.13-4.00(m,2H),3.14-2.67(m,1H),2.18-2.12(m,1H),2.04-1.98(m,1H),1.97-1.76(m,3H),1.46-1.38(m,3H),1.37-1.17(m,3H)。
实施例2:制备1-((2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用2,4-二氯-7H-吡咯并[2,3-d]嘧啶代替实施例1中的2,4,5-三氯-7H-吡咯并[2,3-d]嘧啶之外,以与实施例1相同的方式得到5.4mg(产率:46.1%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.96-7.91(m,1H),7.52-7.47(m,1H),6.88-6.57(m,2H),6.40-6.38(m,1H),6.23-6.13(m,1H),5.79-5.56(m,1H),4.47-4.07(m,4H),3.00-2.70(m,1H),2.01-1.81(m,4H),1.44-1.41(m,3H),1.35-1.34(m,1H),1.26-1.22(m,2H)。
实施例3:制备1-((2S,5R)-5-((2-((1-异丁基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
步骤1:制备(2S,5R)-5-((2-氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2R,5S)-5-氨基-2-甲基哌啶-1-羧酸苄基酯(10.0g,40.27mmol)溶解于乙醇(500.0mL)中,然后向其中加入N,N-二异丙基乙胺(35.1mL,201.4mmol)和2,4-二氯-7H-吡咯并[2,3-d]嘧啶(9.1g,48.3mmol)。在110℃下,搅拌反应混合物12小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到14.6mg(产率:90.7%)标题化合物。
1H NMR(500MHz,CDCl3)δ11.00(s,1H),7.48-7.30(m,5H),7.03(s,1H),6.38(s,1H),5.41-4.93(m,2H),4.63-4.41(m,2H),4.22-4.19(m,1H),2.77-2.75(m,1H),2.09-2.06(m,1H),1.98-1.83(m,1H),1.78-1.45(m,2H),1.39-1.10(m,3H)。
步骤2:制备2-氯-N-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
将(2S,5R)-5-((2-氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(14.4g,36.0mmol)溶解于乙醇(500.0mL)中,然后向其中加入钯/碳(1.4g),并密封反应器。使用真空泵除去反应器内的空气,并通过氢气置换进行钯为媒介的氢化反应。使反应在室温下进行约3小时后,通过硅藻土过滤器除去钯,并在减压下浓缩乙醇。无需进一步纯化,得到6.9g(产率:60.2%)标题化合物。
步骤3:制备1-((2S,5R)-5-((2-氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
将2-氯-N-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(6.8g,25.7mmol)和碳酸氢钠(4.3g,51.3mmol)溶解于四氢呋喃/蒸馏水(300.0mL/30.0mL)中,然后在0℃下向其中加入丙烯酰氯(2.1mL,25.7mol)。在0℃下,搅拌反应混合物1小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到3.3mg(产率:40.2%)标题化合物。
1H NMR(500MHz,CDCl3)δ11.82(s,1H),7.08-7.06(m,1H),6.95-6.48(m,1H),6.45-6.16(m,2H),5.74-5.72(m,1H),5.50(s,1H),5.02(s,1H),4.46(s,1H),4.11-4.09(m,1H),2.88(s,1H),2.10-2.08(m,1H),1.95-1.61(m,4H),1.45-1.03(m,3H)。
步骤4:制备1-((2S,5R)-5-((2-((1-异丁基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
向1-((2S,5R)-5-((2-氯-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮(100.0mg,0.3mmol)和1-异丁基-1H-吡唑-4-胺(45.3mg,0.3mmol)中加入叔丁醇(2.0mL)。向其中加入三(二苄基二丙酮)二钯(28.6mg,0.03mmol)、2-二环己基膦基2',4',6'-三异丙基联苯(22.4mg,0.05mmol)和碳酸钾(86.4mg,0.6mmol),在150℃下,搅拌混合物2至3小时,然后冷却至室温。加入乙酸乙酯,然后加入蒸馏水,分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到15.0mg(产率:11.4%)标题化合物。
1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.82(s,1H),7.53-7.44(m,1H),6.74(s,1H),6.65-6.62(m,1H),6.40(s,1H),6.33-6.30(m,1H),6.24(s,1H),5.70-5.68(m,1H),5.03(s,1H),4.72-4.70(m,1H),4.34(s,1H),4.17-4.06(m,1H),3.94-3.73(m,2H),2.86(s,2H),2.28-2.07(m,3H),1.95-1.81(m,1H),1.79-1.58(m,6H),1.40-1.15(m,8H),1.00-0.83(m,6H)。
实施例4:制备1-((2S,5R)-5-((2-((1-环戊基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用1-环戊基-1H-吡唑-4-胺代替实施例3中的1-异丁基-1H-吡唑-4-胺之外,以与实施例3相同的方式得到25.8mg(产率:18.4%)标题化合物。
1H NMR(500MHz,CDCl3)δ9.09(s,1H),7.86(s,1H),7.50-7.48(m,1H),6.75-6.53(m,2H),6.44(s,1H),6.32-6.29(m,1H),6.21(s,1H),5.67(s,1H),4.99(s,1H),4.74-4.70(m,1H),4.58-4.55(m,1H),2.82(s,1H),2.45-2.21(m,1H),2.12-1.56(m,6H),1.32-1.07(m,4H),0.92-0.76(m,3H)。
实施例5:制备2-(4-((4-((3R,6S)-1-丙烯酰基-6-甲基哌啶-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基氨基甲酸叔丁酯
除了使用(2-(4-氨基-1H-吡唑-1-基)乙基)氨基甲酸叔丁酯代替实施例3中的1-异丁基-1H-吡唑-4-胺之外,以与实施例3相同的方式得到111.5mg(产率:69.7%)标题化合物。
1H NMR(500MHz,CDCl3)δ9.00(s,1H),7.82-7.79(m,1H),7.50(s,1H),6.71(s,1H),6.65-6.59(m,1H),6.33-6.29(m,1H),6.23(s,1H),5.72-5.69(m,1H),4.14-4.10(m,4H),3.52-3.48(m,2H),2.04-2.02(m,2H),1.95-1.60(m,4H),1.50-1.47(m,9H),1.22-1.19(m,3H)。
实施例6:制备1-((2S,5R)-5-((5-氯-2-(异噻唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用异噻唑-4-胺代替在实施例1中的1-乙基-1H-吡唑-4-胺之外,以与实施例1相同的方式得到5.9mg(产率:25.6%)标题化合物。
1H NMR(500MHz,CD3OD)δ8.95-8.80(m,1H),8.62-8.50(m,1H),6.90-6.60(m,2H),6.33-6.10(m,1H),5.80-5.60(m,1H),4.65-4.08(m,2H),3.18-2.70(m,1H),2.10-1.75(m,5H),1.30-1.20(m,3H)。
实施例7:制备1-((2S,5R)-5-((5-氯-2-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用1-(2,2-二氟乙基)-1H-吡唑-4-胺代替实施例1中的1-乙基-1H-吡唑-4-胺之外,以与实施例1相同的方式得到9.9mg(产率:39.3%)标题化合物。
1H NMR(500MHz,CD3OD)δ8.15-7.95(m,1H),7.70-7.50(m,1H),6.90-6.55(m,2H),6.30-5.95(m,2H),5.80-5.55(m,1H),4.60-4.38(m,3H),4.30-4.10(m,1H),3.18-2.65(m,1H),2.05-1.65(m,5H),1.40-1.20(m,3H)。
实施例8:制备1-((2S,5R)-5-((5-氯-2-((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用1-(2,2,2-三氟乙基)-1H-吡唑-4-胺代替实施例1中的1-乙基-1H-吡唑-4-胺之外,以与实施例1相同的方式得到9.2mg(产率:35.3%)标题化合物。
1H NMR(500MHz,CD3OD)δ8.17-8.12(m,1H),7.58-7.55(m,1H),6.86-6.72(m,2H),6.28-6.18(m,1H),5.79-5.66(m,1H),4.82-4.81(m,2H),4.50-4.48(m,1H),4.26-4.15(m,1H),3.05-2.77(m,1H),2.01-1.83(m,4H),1.35-1.23(m,4H)。
实施例9:制备1-((2S,5R)-5-((5-氯-2-((1-环丙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
除了使用1-环丙基-1H-吡唑-4-胺代替实施例1中的1-乙基-1H-吡唑-4-胺之外,以与实施例1相同的方式得到5.0mg(产率:21.0%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.98(s,1H),7.48(s,1H),6.82-6.64(m,2H),6.21-6.18(m,1H),5.75-5.61(m,1H),4.58-4.56(m,1H),4.26-4.19(m,1H),3.52-3.50(m,1H),3.05-2.77(m,1H),2.05-1.82(m,4H),1.36-1.31(m,4H),1.03-0.98(m,4H)。
实施例10:制备1-((2S,5R)-5-((2-(1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
步骤1:制备2,4-二氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(400.0mg,2.1mmol)和氢化钠(93.6mg,2.3mmol)溶解在N,N-二甲基甲酰胺(4.0mL)中,然后在0℃下,搅拌混合物10分钟。向反应混合物中加入2-(三甲基硅烷基)乙氧基甲基氯(415.0μL,2.3mmol),然后在0℃下,搅拌30分钟。向混合物中加入乙酸乙酯后,加入蒸馏水,并分出有机层。用硫酸钠处理分离的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到585.0mg(产率:86.4%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.66-7.65(m,1H),6.72-6.71(m,1H),5.63(s,2H),3.59-3.56(m,2H),0.91-0.88(m,2H),0.07(s,9H)。
步骤2:制备(2S,5R)-5-((2-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将苄基(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸酯(390.1mg,1.6mmol)、2,4-二氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(500.0mg,1.6mmol)和N,N-二异丙基(821.0μL,4.7mmol)溶解在乙醇(3.0mL)中,然后将温度升至150℃并搅拌混合物12小时。在减压下浓缩溶液,通过柱色谱分离所得残余物,得到717.8mg(产率:86.2%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.40-7.29(m,5H),7.13-7.12(m,1H),6.61-6.60(m,1H),5.48(s,2H),5.18-5.12(m,2H),4.49-4.47(m,1H),4.36-4.34(m,1H),4.12-4.10(m,1H),3.54-3.53(m,2H),2.85-2.80(m,1H),1.93-1.70(m,3H),1.25-1.22(m,4H),0.88-0.85(m,2H),0.07(s,9H)。
步骤3:制备(2S,5R)-5-((6-氯-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2S,5R)-5-((2-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(170.0mg,0.3mmol)溶解在N,N-二甲基甲酰胺(2.0mL)中,然后加入氢化钠(25.7mg,0.6mmol),随后在0℃下搅拌10分钟。然后,加入甲基碘(30.0μL,0.5mmol),并在0℃下进一步搅拌2小时。向混合物中加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到165.2mg(产率:94.7%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.35-7.23(m,5H),7.13-7.07(m,1H),6.61-6.58(m,1H),5.47(s,2H),5.17-5.06(m,2H),4.61-4.60(m,1H),4.46-4.44(m,1H),3.54-3.50(m,2H),3.25(s,3H),3.17-3.14(m,1H),2.15-2.12(m,1H),1.87-1.65(m,3H),1.24-1.21(m,4H),0.88-0.84(m,2H),0.07(s,9H)。
步骤4:制备(2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将叔丁醇(4.0mL)加入至(2S,5R)-5-((6-氯-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(165.2mg,0.3mol)和1-乙基-1H-吡唑-4-胺(30.4mg,0.3mmol)。向其中加入三(二苄基二丙酮)二钯(13.9mg,0.02mmol)、2-二环己基膦基-2',4',6'-三异丙基联苯(14.5mg,0.03mmol)和碳酸钾(92.3mg,0.7mmol),在150℃下搅拌混合物12小时,然后冷却至室温。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到149.4mg(产率:79.5%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.93(s,1H),7.54-7.21(m,6H),6.87-6.83(m,1H),6.53-6.51(m,1H),5.49(s,2H),5.19-5.05(m,2H),4.49-4.48(m,1H),4.13-4.07(m,3H),3.25(s,3H),3.15-3.10(m,1H),2.15-2.11(m,1H),1.93-1.75(m,4H),1.43-1.40(m,3H),1.28-1.24(m,3H),0.90-0.87(m,2H),0.01(s,9H)。
步骤5:制备(2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯(133.5mg,0.2mmol)、乙二胺(43.7μL,0.6mmol)和溶解在四氢呋喃溶液中的1.0M四丁基氟化铵(647.1μL,0.6mmol)溶解于四氢呋喃(2.0mL)中,然后在160℃下,将混合物搅拌12小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到72.3mg(产率:68.6%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.82(s,1H),7.47(s,1H),7.35-7.19(m,5H),6.74-6.71(m,1H),6.40-6.38(m,1H),5.15-5.01(m,2H),4.83-4.80(m,1H),4.43-4.41(m,1H),4.03-4.00(m,3H),3.22(s,3H),3.09-3.06(m,1H),1.82-1.65(m,3H),1.36-1.34(m,3H),1.25-1.21(m,4H)。
步骤6:制备N2-(1-乙基-1H-吡唑-4-基)-N4-甲基-N4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺
向(2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯(72.3mg,0.1mmol)和钯/碳(7.0mg)中加入甲醇,然后用氢气替换空气,并在室温下搅拌混合物12小时。在减压下通过硅藻土过滤后,在减压下浓缩残余物,得到53.0mg(产率:100.0%)标题化合物,无需进一步分离即可进行下一步反应。
步骤7:制备1-((2S,5R)-5-((2-(1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
将N2-(1-乙基-1H-吡唑-4-基)-N4-甲基-N4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(53.0mg,0.1mmol)和碳酸氢钠(37.3mg,0.4mmol)溶解在四氢呋喃/蒸馏水(0.75mL/0.25mL),然后在0℃下,向其中加入丙烯酰氯(12.0μL,0.1mmol)。在室温下,搅拌反应混合物1小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到29.0mg(产率:48.0%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.90(s,1H),7.55(s,1H),6.84-6.61(m,1H),6.26-6.19(m,1H),5.75-5.68(m,1H),4.63-4.61(m,1H),4.51-4.42(m,1H),4.13-4.01(m,3H),3.41-3.06(m,4H),2.21-2.18(m,1H),1.88-1.81(m,3H),1.44-1.41(m,3H),1.35-1.30(m,3H)。
实施例11:制备1-((2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
步骤1:制备3,4,6-三氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶
将3,4,6-三氯-1H-吡唑并[3,4-d]嘧啶(600.0mg,2.7mmol)、二氢吡喃(735.0μL,8.1mmol)和对甲苯磺酸(51.1mg,0.3mmol)溶解在二氯甲烷(10.0mL)中,然后在120℃下搅拌2小时。在减压下浓缩反应混合物,然后通过柱色谱分离所得残余物,得到715.9mg(产率:86.7%)标题化合物。
1H NMR(500MHz,CD3OD)δ5.98-5.95(m,1H),4.05-4.02(m,1H),3.81-3.76(m,1H),2.46-2.43(m,1H),2.14-2.10(m,1H),1.98-1.95(m,1H),1.82-1.62(m,3H)。
步骤2:制备苄基(2S,5R)-5-((3,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸酯
将(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄基酯(242.2mg,1.0mmol)、3,4,6-三氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(300.0mg,1.0mmol)和N,N-二异丙基(203.9μL,1.2mmol)溶解在乙醇(2.0mL)中,然后在190℃下,搅拌5小时。在减压下浓缩反应产物,并随后通过柱色谱分离所得残余物,得到446.3mg(产率:92.0%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.39-7.29(m,5H),5.80-5.78(m,1H),5.18-5.10(m,2H),4.48-4.46(m,1H),4.29-4.22(m,2H),4.04-4.02(m,1H),3.78-3.75(m,1H),3.02-3.00(m,1H),2.41-2.33(m,1H),2.08-1.61(m,9H),1.25-1.22(m,3H)。
步骤3:制备(2S,5R)-5-((3,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2S,5R)-5-((3,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄基酯(200.0mg,0.4mmol)溶解在N,N-二甲基甲酰胺(2.0mL),然后向其中加入氢化钠(30.8mg,0.8mmol),且随后在0℃下搅拌5分钟。加入甲基碘(40.0μL,0.6mmol),并在0℃下搅拌6小时。加入蒸馏水后,在减压下过滤混合物,得到205.4mg(产率:100.0%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.36-7.31(m,5H),5.87-5.85(m,1H),5.14-5.09(m,2H),4.47-4.45(m,2H),4.18-4.13(m,1H),4.03-4.01(m,1H),3.79-3.77(m,1H),3.32(s,3H),3.18-3.16(m,1H),2.39-1.59(m,10H),1.28-1.26(m,3H)。
步骤4:制备(2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯
将(2S,5R)-5-((3,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯(200.0mg,0.4mmol)和1-乙基-1H-吡唑-4-胺(32.0mg,0.3mmol)溶解在2-丁醇(3.0mL)中,然后向其中加入三氟乙酸(26.5μL,0.3mmol),并在200℃下使反应物反应6小时。浓缩反应产物,并随后通过加入7N氨/甲醇溶液中和,并且通过柱色谱分离残余物,得到92.3mg(产率:61.1%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.92-7.89(m,1H),7.56-7.53(m,1H),7.37-7.24(m,5H),5.18-5.04(m,2H),4.59-4.45(m,2H),4.17-4.07(m,3H),3.29(s,3H),3.18-3.16(m,1H),2.17-2.13(m,1H),1.88-1.76(m,3H),1.45-1.42(m,3H),1.28-1.25(m,3H)。
步骤5:制备3-氯-N6-(1-乙基-1H-吡唑-4-基)-N4-甲基-N4-((3R,6S)-6-甲基哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺
将(2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-羧酸苄基酯(39.0mg,0.1mmol)和三氟乙酸(3.0mL)溶解在2-丁醇(1.0mL)中,然后在190℃下搅拌18小时。浓缩反应产物,然后通过加入7N氨/甲醇溶液进行中和,并在减压下浓缩以得到29.0mg(产率:100.0%)标题化合物,无需进一步分离即可进行下一步反应。
步骤6:制备1-((2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
将3-氯-N6-(1-乙基-1H-吡唑-4-基)-N4-甲基-N4-((3R,6S)-6-甲基哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(29.0mg,0.1mmol)和碳酸氢钠(38.8mg,0.2mmol)溶解在四氢呋喃/蒸馏水(0.75mL/0.25mL)中,然后在0℃向其中加入丙烯酰氯(6.0μL,0.1mmol)。在室温下,搅拌反应混合物1小时。加入乙酸乙酯,然后加入蒸馏水,并分出有机层。用硫酸钠处理分出的有机层,过滤并在减压下浓缩。通过柱色谱分离残余物,得到13.1mg(产率:39.7%)标题化合物。
1H NMR(500MHz,CD3OD)δ7.84-7.83(m,1H),7.48(s,1H),6.84-6.52(m,2H),6.45-6.44(m,1H),6.24-6.06(m,1H),5.77-5.56(m,1H),4.59-4.41(m,1H),4.11-3.91(m,3H),3.34(s,3H),3.29-3.00(m,1H),2.18-2.11(m,1H),1.85-1.72(m,3H),1.42-1.38(m,3H),1.34-1.33(m,1H),1.25-1.23(m,3H)。
实验例1:对JAK3和BTK酶的抑制活性的测量
通过在ADP Glow(Glo)平台上的体外分析测量实施例中制备的化合物的JAK3和BTK激酶抑制活性。
具体地,使用从Promega购得的JAK3激酶检测试剂盒(Promega,V9441)和BTK激酶检测试剂盒(Promega,V9071)来测量对JAK3和BTK激酶的抑制活性。纯化的重组人JAK3和BTK用1×激酶反应缓冲液(JAK3:40mM Tris-Cl,pH 7.5,20mM MgCl2,0.1mg/mL BSA和50μMDTT/BTK:40mM Tris-Cl,pH 7.5,20mM MgCl2,0.1mg/mL BSA,2mM MnCl2和50μM DTT)稀释并加入到96孔板中(JAK3:每个反应的最终浓度为4ng/BTK:每个反应的最终浓度为8ng)。对前述实施例中制备的化合物进行处理,使其最终成为1%DMSO水性溶液,并且将在共计25μL的反应物中含有ATP(JAK3:最终浓度为5μM/BTK:最终浓度为10μM)和0.2μg/μL的多(Glu4,Tyr1)肽(JAK3和BTK最终浓度)的底物混合物加入到96孔板中以启动酶促反应。在温育(30℃)1小时后,加入等体积(每个反应25μL)的ADP Glo,并在室温下温育(30℃)40分钟。然后,加入激酶检测试剂(每个反应50μL)并在室温下温育(30℃)30分钟。根据ADP Glo激酶检测试剂盒的说明,通过化学发光测量激酶活性,并计算根据本发明的化合物的抑制活性。为了分析每种化合物的结果,使用了Microsoft Excel,并通过SigmaPlot软件计算IC50值。结果显示在下表1中。此外,为了进行比较,以相似的方式评价了托法替尼和依鲁替尼。
【表1】
实施例编号 | JAK3 IC<sub>50</sub>(nM) | BTK IC<sub>50</sub>(nM) |
1 | 0.3 | 1.2 |
2 | 0.4 | 1.3 |
3 | 1.8 | 3.5 |
4 | 2.2 | 5.4 |
5 | 1.2 | 5.3 |
6 | 0.6 | 3.4 |
7 | 0.3 | 1.6 |
8 | 0.3 | 1.8 |
9 | 0.3 | 2.0 |
10 | 2.4 | 3.3 |
11 | 5.7 | 0.9 |
托法替尼 | 3.5 | - |
依鲁替尼 | - | 0.6 |
实验例2:JAK3介导的细胞测定(HT-2/IL-2测定)
通过体外分析HT-2细胞中由IL-2刺激诱导的STAT5磷酸化来测量实施例中制备的化合物在细胞水平上对JAK3激酶的抑制活性。具体地,使用从Cisbio购得的phospho-STAT5(Tyr694)检测试剂盒(Cisbio,64AT5PEG)来分析STAT5磷酸化。将HT-2细胞在无生长因子的培养基中培养2小时。将经培养的HT-2细胞以50μl分配到96孔板中,使其密度为2.5×105细胞/孔。将前述实施例中制备的化合物制备成最终为0.3%DMSO水性溶液,并用该化合物处理HT-2细胞30分钟。在化合物处理后,制备IL-2以使其最终浓度为20ng/mL,并将HT-2细胞处理10分钟。然后通过处理裂解缓冲液30分钟来破坏细胞。根据phospho-STAT5检测试剂盒的说明来测量STAT5磷酸化的水平,并计算出根据本发明的化合物的抑制活性。为了分析每种化合物的结果,使用Microsoft Excel,并通过SigmaPlot软件来计算IC50值。
实施例编号 | JAK3细胞IC<sub>50</sub>(nM) |
1 | 90.9 |
2 | 360.4 |
Claims (7)
2.根据权利要求1所述的化合物或其药学上可接受的盐,
其中,R1是甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、新戊基、环丙基、环丁基、环戊基、环己基或2-((叔丁氧羰基)氨基)乙基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,
其中,R2是氢、甲基、溴、氟或氯。
4.根据权利要求1所述的化合物或其药学上可接受的盐,
其中,R3是氢、甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基或新戊基。
5.根据权利要求1所述的化合物或其药学上可接受的盐,
其中,X1是N-R1,X2是CH。
6.根据权利要求1所述的化合物或其药学上可接受的盐,
其中,由化学式1表示的化合物是选自由以下各项组成的组中的任一项:
1)1-((2S,5R)-5-((5-氯-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
2)1-((2S,5R)-5-((2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
3)1-((2S,5R)-5-((2-((1-异丁基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
4)1-((2S,5R)-5-((2-((1-环戊基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
5)2-(4-((4-((3R,6S)-1-丙烯酰基-6-甲基哌啶-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基氨基甲酸叔丁酯,
6)1-((2S,5R)-5-((5-氯-2-(异噻唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
7)1-((2S,5R)-5-((5-氯-2-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
8)1-((2S,5R)-5-((5-氯-2-((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
9)1-((2S,5R)-5-((5-氯-2-((1-环丙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,
10)1-((2S,5R)-5-((2-(1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮,和
11)1-((2S,5R)-5-((3-氯-6-((1-乙基-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-4-基)(甲基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮。
7.一种用于预防或治疗炎性疾病、自身免疫性疾病、增殖性疾病、过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的药物组合物,所述药物组合物包含根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐。
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JP7024091B2 (ja) | 2022-02-22 |
ECSP20035588A (es) | 2020-07-31 |
SA520412334B1 (ar) | 2022-11-03 |
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KR20190080541A (ko) | 2019-07-08 |
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NZ765152A (en) | 2024-02-23 |
AU2018394996A2 (en) | 2020-07-16 |
CO2020007156A2 (es) | 2020-06-19 |
WO2019132561A1 (ko) | 2019-07-04 |
KR102577242B1 (ko) | 2023-09-11 |
AU2018394996B2 (en) | 2021-08-05 |
EP3733674A1 (en) | 2020-11-04 |
US20210188854A1 (en) | 2021-06-24 |
EP3733674B1 (en) | 2022-06-29 |
MY196572A (en) | 2023-04-19 |
CN111527088B (zh) | 2022-12-30 |
US11407754B2 (en) | 2022-08-09 |
DOP2020000111A (es) | 2020-09-30 |
SG11202004916YA (en) | 2020-06-29 |
EP3733674A4 (en) | 2021-06-09 |
CA3085160A1 (en) | 2019-07-04 |
TN2020000081A1 (en) | 2022-01-06 |
CA3085160C (en) | 2021-12-07 |
RU2756505C1 (ru) | 2021-10-01 |
PE20210549A1 (es) | 2021-03-17 |
MA51433A (fr) | 2021-04-07 |
CL2020001749A1 (es) | 2020-11-06 |
BR112020013237A2 (pt) | 2020-12-01 |
MX2020006798A (es) | 2020-09-03 |
AU2018394996A1 (en) | 2020-06-25 |
JP2021507923A (ja) | 2021-02-25 |
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