CN114728963A - 新型三唑吡啶衍生物和包括其的药物组合物 - Google Patents
新型三唑吡啶衍生物和包括其的药物组合物 Download PDFInfo
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- CN114728963A CN114728963A CN202080080673.6A CN202080080673A CN114728963A CN 114728963 A CN114728963 A CN 114728963A CN 202080080673 A CN202080080673 A CN 202080080673A CN 114728963 A CN114728963 A CN 114728963A
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- Prior art keywords
- pyridin
- triazolo
- phenyl
- yloxy
- acrylamide
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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其中激酶抑制活性是有益的疾病。在化学式1中,R1至R3与说明书中所限定的相同。
Description
技术领域
本发明涉及一种具有激酶抑制活性的新型三唑吡啶衍生物以及包括其的药物组合物。
背景技术
蛋白激酶是催化其他蛋白质特定残基磷酸化的酶,并在将细胞外信号转导至细胞核的信号转导途径中发挥重要作用。此外,它与体内的多种疾病有关。在炎性疾病、自身免疫性疾病、增殖性疾病或过度增殖性疾病和/或免疫介导的疾病的发作或发展中,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(以下称为“JAK”)为细胞质蛋白酪氨酸激酶,其在调节淋巴-造血系统的细胞功能中起着关键作用。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,JAK通过酪氨酸磷酸化激活STAT(信号转导和转录激活因子)蛋白,为细胞因子提供快速信号转导通路。已知JAK/STAT信号传导与过敏、哮喘、自身免疫性疾病(如,移植排斥、类风湿性关节炎、肌萎缩性侧索硬化、多发性硬化等)、实体癌、血癌(如白血病、淋巴瘤等)相关。
JAK家族分为四个成员:JAK 1、JAK 2、JAK 3和TYK 2。JAK家族的成员相互配对来介导来自多种细胞因子的信号。它包括与造血生长因子信号传导相关的JAK2和JAK1,并且TYK2和AK2的结合对干扰素信号传导很重要并有助于宿主耐受。JAK2可诱导贫血、血小板减少、白细胞减少,尤其是当JAK2参与造血生长因子信号传导并导致过度抑制时。
发现JAK1、JAK2和TYK2的表达分布广泛,而JAK3的表达局限于淋巴细胞,并与IL-2、IL-4、IL-7、IL-9、IL-15和IL-21受体的成员的常见γ链,尤其是IL-2家族的常见γ链的信号传导有关。一旦细胞因子结合,受体就会在附近携带邻近的JAK3,这会诱导β-链C-末端的自磷酸化。因此,它会导致STAT蛋白的激活,这是将信号重新传输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通路。这使得JAK3成为免疫抑制的有吸引力的靶点。
B细胞在自身免疫性和/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,例如利妥昔单抗(Rituxan)对自身抗体诱导的炎性疾病诸如类风湿性关节炎有效。因此,在B细胞激活起作用的蛋白激酶抑制剂为治疗B细胞介导的疾病,例如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,包括增殖和分化为成熟的抗体产生细胞。BCR为B细胞活性的重要调节因素,并且异常的信号转导可导致致病性自身抗体的形成,从而导致多种自身免疫性和/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”)为B细胞发育、激活、信号传导和存活的重要调节因子。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的协同作用产生的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可以成为阻断B细胞介导的疾病发病过程的有用治疗方法。
如上所述,Janus激酶和基于TEC的激酶在参与炎性疾病、自身免疫性疾病、增殖性疾病或过度增殖性疾病以及免疫介导的疾病的发展的T细胞和/或B细胞的激活中起重要作用。因此,开发有效抑制这些疾病的物质可用作为相关的治疗剂。能够治疗和预防的疾病的具体实例包括癌症、移植排斥、多发性硬化、类风湿性关节炎、银屑病关节炎、银屑病、哮喘、变应性皮炎、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、干燥综合征等。
JAK3激酶抑制剂托法替尼(CP-690550)(Pfizer)目前已获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(PCI-32765)(Pharmacyclics公司)正处于临床阶段,但在临床病例中报告了严重的副作用,如皮疹和腹泻。因此,需要开发抑制JAK和/或BTK的更稳定和有效的物质(参见Nat Rev Rheumatol.2009Jun 5(6)317-24;Expert OpinInvestig Drugs.2014Aug 23(8)1067-77;Drug Discov Today 2014Aug 19(8)1200-4;WO2002/096909;WO2010-009342)。
因此,本发明人发现了具有优异抑制活性的新型三唑吡啶衍生物作为激酶抑制剂,进而完成了本发明。
发明内容
[技术问题]
本发明的一个目的是提供具有激酶抑制活性的新型三唑吡啶衍生物以及包括其的药物组合物。
[技术方案]
为了实现上述目的,根据本发明,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]
在化学式1中,
R1为C6-10芳基,或含1至3个各自独立地选自由N、O和S组成的组的杂原子的C3-10杂芳基,
其中,R1未被取代,或取代有:C1-4烷基、取代有N(C1-4烷基)2的C1-4烷基、取代有吗啉基的C1-4烷基、C1-4卤代烷基、卤素、C1-4烷氧基、取代有N(C1-4烷基)2的C1-4烷氧基、N(C1-4烷基)2、吗啉基、吗啉羰基、苯氧基、哌啶基、-SO2-哌啶基、哌嗪基、取代有C1-4烷基的哌嗪基、苄基、取代有C1-4烷氧基的苄基、吡唑基、取代有1个或2个C1-4烷基的吡唑基、四唑基或取代有C1-4烷基的四唑基,
R2为C1-5烷基、C2-5烯基或C2-5炔基,
其中,R2未被取代,或取代有选自由卤素、氰基、C3-6环烷基和取代有氰基的C1-5烷基组成的组的一个或两个取代基,且
R3为氢、卤素、C1-4烷基、C1-4卤代烷基或C1-4烷氧基。
优选地,化学式1可以由以下化学式1-1表示:
[化学式1-1]
在化学式1-1中,
R1至R3如化学式1中所限定。
优选地,R1可以为苯并噻唑基、咪唑并[4,5-b]吡啶基、异恶唑[5,4-b]吡啶基、萘基、苯基、吡唑基、吡啶基或喹啉基。
优选地,R1为苯基,其中R1可以取代有:取代有N(C1-4烷基)2的C1-4烷基、取代有N(C1-4烷基)2的C1-4烷氧基、N(C1-4烷基)2、吗啉基、吗啉基羰基、苯氧基、-SO2-哌啶基、取代有C1-4烷基的哌嗪基、取代有2个C1-4烷基的吡唑基或取代有C1-4烷基的四唑基。
优选地,R1为吡唑基,其中R1可以取代有:C1-4烷基、取代有吗啉基的C1-4烷基、C1-4卤代烷基或取代有C1-4烷氧基的苄基。
优选地,R1未被取代,或可以为取代有卤素的苯并噻唑基;取代有C1-4烷基的咪唑并[4,5-b]吡啶基;取代有C1-4烷基的异噁唑并[5,4-b]吡啶基;未被取代的萘基;取代有吗啉基的吡啶基;或未被取代的喹啉基,且
更优选地,R1未被取代,或可以为取代有氯的苯并噻唑基;取代有甲基的咪唑并[4,5-b]吡啶基;取代有甲基的异噁唑并[5,4-b]吡啶基;未取代的萘基;取代有吗啉基的吡啶基;或未取代的喹啉基。
优选地,R2可以为选自由以下各项组成的组中的任何一种:
更优选地,R2可以为选自由以下各项组成的组中的任何一种:
优选地,R3可以为氢、氟、氯、甲基、三氟甲基或甲氧基。
更优选地,R3可以为氢或氟。
由化学式1表示的化合物的典型示例如下:
1)N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
2)N-(3-(2-(1-甲基-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
3)N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
4)N-(3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
5)N-(3-(2-(3-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
6)N-(3-(2-(4-(二甲氨基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
7)N-(3-(2-(3-(5-甲基-1H-四唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
8)N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
9)N-(3-(2-(3-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
10)N-(3-(2-(4-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
11)N-(3-(2-(2-氯苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
12)N-(3-(2-(苯并[d]噻唑-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
13)N-(3-(2-(4-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
14)N-(3-(2-(1-(3-甲氧苄基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
15)N-(3-(2-(4-(2-(二乙氨基)乙氧基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
16)N-(3-(2-(4-((二甲氨基)甲基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
17)N-(3-(2-(4-(吗啉-4-羰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
18)N-(3-(2-(4-(哌啶-1-基磺酰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
19)N-(3-(2-(1-(2-吗啉代乙基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
20)N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丁-2-炔酰胺,
21)N-(3-(2-(6-吗啉代吡啶-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
22)N-(3-(2-(6-氯苯并[d]噻唑-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
23)N-(3-(2-(萘-1-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
24)N-(3-(2-(喹啉-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
25)N-(3-(2-(3-甲基异噁唑并[5,4-b]吡啶-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
26)N-(3-(2-(1-甲基-1H-咪唑并[4,5-b]吡啶-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
27)N-(4-氟-3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
28)N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺,
29)N-(4-氟-3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
30)N-(4-氟-3-(2-(1-甲基-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,和
31)N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺。
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,诸如由药学上可接受的游离酸形成的酸加成盐,但不限于此。本文使用的术语“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,其浓度对患者相对无毒和无害,并且有效地激活,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以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。替代性地,它可以通过在减压下从加酸的反应混合物中除去溶剂或过量的酸,然后干燥残余物,或通过加入不同的有机溶剂,然后过滤沉淀的盐来制备。此时,优选的盐可以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。
当制备化学式1的化合物或其药学上可接受的盐或溶剂化物时,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,还包括可由其制备的所有溶剂化物和水合物,且还包括所有可能的立体异构体。化学式1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,根据本发明的化学式1的化合物可以以结晶形式或非结晶形式制备,并且当化学式1的化合物以结晶形式制备时,可以可选地将该化合物水合化或溶剂化。在本发明中,化学式1的化合物不仅可以包括化学计量的水合物,还可以包括含有各种水含量的化合物。根据本发明的化学式1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图式1生产由化学式1表示的化合物。
[反应图式1]
(在反应图式1中,R1至R3如前所限定,且Z1和Z2各自独立地为卤素。
Y为卤素或OH)
步骤i是通过使由化学式1-1或化学式1-7表示的化合物与由化学式1-2或化学式1-8表示的化合物反应来制备由化学式1-3或化学式1-9表示的化合物的步骤。反应优选在碳酸铯的存在下于室温至高温下进行,溶剂优选为二甲基甲酰胺。
步骤ii是通过卤化由化学式1-3或化学式1-9表示的化合物来制备由化学式1-4或化学式1-10表示的化合物的步骤。反应优选在碘化钾、亚硝酸钠和对甲苯磺酸的条件下于室温下进行,且溶剂优选为乙腈和水的混合物。
步骤iii是通过使由化学式1-4或化学式1-10表示的化合物与R1-NH2反应来制备由化学式1-5或化学式1表示的化合物的步骤。反应优选在钯催化剂存在下,在碱性条件下于50℃至150℃下进行,所述钯催化剂为三(二亚苄基丙酮)二钯(Pd2(dba)3)、乙酸钯(Pd(OAc)2)、[1,1’-双(二苯基膦)二茂铁]二氯化钯((Pd(Dppf)Cl2),并且溶剂优选为二氧六环、甲苯或二甲基甲酰胺。反应中使用的碱优选为无机碱,诸如碳酸铯、碳酸钙、碳酸钠或磷酸钾。
步骤iv是通过使由化学式1-5表示的化合物进行还原反应来制备由化学式1-6表示的化合物的步骤。反应优选通过在10%钯/碳存在下,在甲醇和氯仿的混合溶液中氢化来进行。此外,化合物可以通过在盐酸或乙醇中使用金属(铁)或金属盐(氯化亚锡)来制备。
步骤v和v’是通过使由化学式1-6或1-11表示的化合物与由化学式1-12表示的化合物反应来制备由化学式1或1-8表示的化合物的步骤。在步骤v和v’中,优选地,Y可以为Cl或OH。当Y为Cl时,反应优选在三乙胺或碳酸氢钠的条件下的于-20℃至0℃下进行,且溶剂优选为二氯甲烷或四氢呋喃和水的混合物。当Y为OH时,反应优选在N,N-二异丙基乙胺、1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧化物六氟磷酸酯的条件下于室温下进行24小时,并且溶剂优选为四氢呋喃、二甲基甲酰胺或二甲基亚砜。
同时,在步骤v中,当R2具有氰基取代基时,反应可以通过如下步骤进行:通过使化学式1-6表示的化合物与化学式1-12表示的其中Y为OH的化合物反应,然后使醛在哌啶条件下反应来制备化学式1表示的化合物。优选地,反应可以在(1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧化物六氟磷酸酯)和N,N-二异丙基乙胺的条件下于25℃下进行,然后在哌啶条件下与醛反应。溶剂优选为二甲基甲酰胺或甲醇。
此外,根据本发明,提供了用于预防或治疗与激酶抑制作用相关的疾病的药物组合物,该药物组合物包括由化学式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、自身免疫性疾病、增殖性疾病、过度增殖性疾病和免疫介导的疾病。
如本文所用,术语“预防”是指通过施用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,而“治疗”是指通过施用本发明的组合物来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,根据本发明的药物组合物可以配制成用于口服或胃肠外给药的类型。除了活性成分之外,这些制剂可以含有添加剂,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、葡萄糖、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,可以将本发明的化合物溶解在油类、丙二醇或在制备注射溶液中通常使用的其他溶剂中。此外,可以将本发明的化合物配制成局部应用的软膏或乳膏。
本发明化合物的药物剂型可包括使用以其药学上可接受的盐或溶剂化物形式使用该化合物,以及单独或作为与其它药学活性化合物一起的组合和/或合适的混合物使用该化合物。
可以通过将化合物溶解、悬浮或乳化在水溶性溶剂如生理盐水、5%葡萄糖或非水溶剂如合成脂肪酸甘油酯、高级脂肪酸酯或丙二醇中而将本发明的化合物配制成注射溶液。本发明的制剂可以包括常规添加剂,诸如增溶剂、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以根据患者的病情和体重、疾病的严重程度、药物的类型以及给药的途径和持续时间而变化,但是可以由本领域技术人员适当选择。然而,为了达到期望的效果,本发明的化合物可以每天以0.0001mg/kg至100mg/kg(体重),优选0.001mg/kg至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每天分剂量给药。根据给药方法,组合物可以含有0.001重量%至99重量%,优选0.01重量%至60重量%的本发明化合物。
可以通过各种途径将根据本发明的药物组合物给药至哺乳动物,诸如大鼠、小鼠、家畜、人。可以通过所有可能的方法进行给药,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
[发明方式]
在下面,将更详细地描述本发明以帮助理解本发明。然而,以下实施例仅用于说明目的,并且不应被解释为将本发明的范围限制于这些实施例。
实施例1:N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
步骤1)5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺的制备
将5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺(800.0mg,3.8mmol)溶解在N,N-二甲基甲酰胺(5.0mL)中后,向其中加入碳酸铯(2447.0mg,7.5mmol)和3-硝基酚(784.0mg,5.6mmol)。将反应混合物在100℃加热60小时。向其中加入蒸馏水,并将溶液搅拌10分钟。分离有机层,用硫酸镁处理,过滤,并减压浓缩。向残留物中加入乙酸乙酯(2.0mL),然后搅拌10分钟。过滤固体,获得5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(766.0mg,产率:75.2%)。
1H NMR(500MHz,CD3OD)δ8.15(d,1H),8.03(s,1H),7.70(t,1H),7.57-7.52(m,2H),7.23(d,1H),6.50(d,1H)。
步骤2)2-碘代-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶的制备
将5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(500.0mg,1.8mmol)和甲苯磺酸(1052.0mg,5.5mmol)溶于乙腈(20.0mL)后,向其中滴加碘化钾(765.0mg,4.6mmol)和亚硝酸钠(254.0mg,3.7mmol)的蒸馏水(1.0mL)溶液。在室温下搅拌反应混合物20小时,然后向其中加入蒸馏水。分离有机层,用硫酸镁处理,过滤,然后减压浓缩。通过柱色谱分离残留物,得到2-碘代-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶(372.0mg,产率:52.8%)。
1H NMR(500MHz,CD3OD)δ8.21(dd,1H),8.15-8.14(m,1H),7.75-7.70(m,2H),7.65(dd,1H),7.57(d,1H),6.65(d,1H)。
步骤3)N-(4-(4-甲基哌嗪-1-基)苯基)-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺的制备
在将2-碘代-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶(100mg,0.3mmol)溶解在1,4-二氧六环(1.2mL)中之后,向其中加入4-(4-甲基哌嗪-1-基)苯胺(60.1mg,0.3mmol)、Pd2(dba)3(11.9mg,0.01mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)(15.0mg,0.03mmol)和碳酸铯(170.4mg,0.5mmol)。将反应混合物在100℃加热16小时,然后减压除去溶剂。通过柱色谱分离残留物,得到N-(4-(4-甲基哌嗪-1-基)苯基)-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(64.0mg,产率:54.9%)。
1H NMR(500MHz,CD3OD)δ8.10(d,1H),8.01(s,1H),7.57(t,1H),7.46-7.38(m,4H),7.30(d,1H),6.87(d,2H),6.37(d,1H),3.14-3.12(m,4H),2.62-2.60(m,4H),2.35(s,3H)。
步骤4)5-(3-氨基苯氧基)-N-(4-(4-甲基哌嗪-1-基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺的制备
将N-(4-(4-甲基哌嗪-1-基)苯基)-5-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(63.0mg,0.14mmol)溶解在甲醇(2.0mL)和氯仿(0.8mL)中后,向其中加入10%Pd/C(15.0mg,0.01mmol)。将反应混合物在氢气下搅拌4小时。反应完成后,通过硅藻土过滤混合物,并减压除去溶剂。通过柱色谱分离残留物,得到5-(3-氨基苯氧基)-N-(4-(4-甲基哌嗪-1-基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(30.0mg,产率:51.1%)。
1H NMR(500MHz,CD3OD)δ7.54-7.47(m,3H),7.15-7.11(m,2H),6.99-6.98(m,2H),6.62-6.25(m,3H),6.25-6.24(m,1H),3.40-3.20(m,8H)。
步骤5)N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧)苯基)丙烯酰胺的制备
将5-(3-氨基苯氧基)-N-(4-(4-甲基哌嗪-1-基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(30.0mg,0.07mmol)悬浮在二氯甲烷(0.5mL)中后,向其中滴加三乙胺(12.1μL,0.09mmol)和丙烯酰氯(6.5μL,0.08mmol)。在室温下搅拌反应混合物1小时,然后减压浓缩。通过柱色谱分离残留物,得到N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(7.0mg,产率:20.6%)。
1H NMR(500MHz,CD3OD)δ7.70(1H),7.53-7.50(m,2H),7.45(d,2H),7.40(t,1H),7.20(d,1H),6.95-6.90(m,3H),6.44-6.43(m,3H),5.77(dd,1H),3.11(t,4H),2.64(t,4H),2.36(s,1H)。
实施例2:N-(3-(2-(1-甲基-1H-吡唑-4-基氨)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例1中使用1-甲基-1H-吡唑-4-胺代替4-(4-甲基哌嗪-1-基)苯胺外,以与实施例1相同的方式获得标题化合物(9.6mg,产率20.0%)。
1H NMR(500MHz,CD3OD)δ7.69(d,2H),7.54-7.48(m,1H),7.44-7.40(m,1H),7.20(1,H),6.94(dd,1H),6.43-6.32(m,3H),5.76(dd,1H),3.81(s,1H)。
实施例3:N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
步骤1)N-(3-羟苯基)丙烯酰胺的制备
将3-氨基苯酚(500.0mg,4.6mmol)和碳酸氢钠(577.8mg,6.9mmol)溶于四氢呋喃(10mL)后,向其中加入丙烯酰氯(415.0mg,4.6mmol)。在室温下搅拌混合物12小时,然后向其中加入蒸馏水。分离有机层,用硫酸镁处理,过滤,然后减压浓缩。获得N-(3-羟苯基)丙烯酰胺(730.0mg,产率:97.6%)而未进一步纯化。
1H NMR(500MHz,CD3OD)δ7.24(s,1H),7.11(t,1H),7.00(d,1H),6.54(dd,1H),6.44-6.39(m,1H),6.33(dd,1H),5.74(dd,1H)。
步骤2)N-(3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
将5-溴-[1,2,4三唑并[1,5-a]吡啶-2-胺(435.0mg,2.0mmol)和N-(3-羟苯基)丙烯酰胺(499.8mg,3.1mmol)溶解在N,N-二甲基甲酰胺(5.0mL)中后,向其中加入碳酸铯(1300.0mg,4.08mmol)。在100℃下搅拌混合物3小时,然后冷却。向其中加入蒸馏水,并将溶液搅拌10分钟。分离有机层,用硫酸镁处理,过滤,然后减压浓缩。通过柱色谱分离残留物,得到N-(3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(200.0mg,产率:33.2%)。
1H NMR(500MHz,CD3OD)δ7.69(s,1H),7.52-7.47(m,2H),7.42(t,1H),7.13(d,1H),6.97(dd,1H),6.43-6.33(m,2H),6.29(d,1H),5.77(dd,1H)。
步骤3)N-(3-(2-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
将N-(3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(180.0mg,0.6mmol)和甲苯磺酸(347.8mg,1.8mmol)溶于乙腈(6.0mL)后,向其中滴加碘化钾(252.8mg,1.5mmol)和亚硝酸钠(84.1mg,1.2mmol)的蒸馏水(0.5mL)溶液。在室温下搅拌混合物16小时,然后向其中加入蒸馏水。分离有机层,用硫酸镁处理,过滤,然后减压浓缩。通过柱色谱分离残留物,得到N-(3-(2-碘-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(110.0mg,产率:44.4%)。
1H NMR(500MHz,CD3OD)δ7.75(s,1H),7.67(t,1H),7.53(d,1H),7.48-7.45(m,2H),7.03(dd,1H),6.47(d,1H),6.44-6.33(m,2H),5.78(dd,1H)。
步骤4)N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
在将N-(3-(2-碘-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(30.0mg,0.07mmol)和苯并[d]噻唑-6-胺(11.1mg,0.07mmol)溶解在1,4-二氧六环(1.0mL)中后,向其中加入Pd2(dba)3(3.38mg,0.004mmol)、Xantphos(4.3mg,0.007mmol)和碳酸铯(48.1mg,0.15mmol),并且用微波(120℃,10分钟,正常)进行反应。向其中加入蒸馏水,并将溶液搅拌10分钟。分离有机层,用硫酸镁处理,过滤,然后减压浓缩。通过柱色谱分离残留物,得到N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺(5.0mg,产率15.8%)。
1H NMR(500MHz,CD3OD)δ8.46(m,1H),7.91(d,1H),7.73(s,1H),7.62-7.51(m,3H),7.46(t,1H),7.31(d,1H),6.99(dd,1H),6.52(d,1H),6.44-6.33(m,2H),5.77(dd,1H)。
实施例4:N-(3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中,使用4-吗啉代苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(6.2mg,产率:18.4%)。
1H NMR(500MHz,CD3OD)δ7.71(S,1H),7.54(t,2H),7.47-7.37(m,3H),7.22(d,1H),6.96-6.91(m,3H),6.44-6.34(m,3H),5.77(dd,1H),3.82(t,4H),3.05(t,4H)。
实施例5:N-(3-(2-(3-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用3-苯氧基苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(5.5mg,产率:16.7%)。
1H NMR(500MHz,CD3OD)δ7.68(s,1H),7.55(t,1H),7.50-7.48(m,1H),7.43-7.39(m,2H),7.33-7.29(m,3H),7.25-7.20(m,2H),7.05-7.00(m,3H),6.96(dd,1H),6.52(dd,1H),6.42-6.33(m,3H),5.77(dd,1H)。
实施例6:N-(3-(2-(4-(二甲氨基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用N1,N1-二甲苯-1,4-二胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(4.5mg,产率:14.7%)。
1H NMR(500MHz,CD3OD)δ7.70(s,1H),7.54-7.51(m,2H),7.44-7.40(m,3H),7.20(d,1H),6.99(dd,1H),6.81(d,1H),6.41-6.37(m,3H),5.78(dd,1H),2.85(s,6H)。
实施例7:N-(3-(2-(3-(5-甲基-1H-四唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用3-(5-甲基-1H-四唑-1-基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(4.0mg,产率:14.3%)。
1H NMR(500MHz,CD3OD)δ8.09(s,1H),7.65-7.63(m,2H),7.59(t,1H),7.50(t,1H),7.42(m,1H),7.34(q,2H),7.12(dd,1H),6.93(dd,1H),6.51(d,1H),6.42-6.31(m,2H),5.76(dd,1H),2.60(s,3H)。
实施例8:N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用1-(二氟甲基)-1H-吡唑-4-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(5.7mg,产率:22.5%)。
1H NMR(500MHz,CD3OD)δ8.09(s,1H),7.70(s,2H),7.56(t,1H),7.48-7.46(m,1H),7.41(t,1H),7.25(t,1H),6.95(dd,1H),6.48(d,1H),6.42-6.31(m,2H),5.76(dd,1H),2.00(s,1H)。
实施例9:N-(3-(2-(3-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用3-(3,5-二甲基-1H-吡唑-1-基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(0.8mg,产率:2.8%)。
1H NMR(500MHz,CD3OD)δ7.91-7.88(m,1H),7.68-7.63(m,1H),7.57(t,1H),7.52-7.51(m,1H),7.47-7.46(m,1H),7.39-7.34(m,2H),7.29(d,1H),6.97-6.92(m,2H),6.48(d,1H),6.42-6.32(m,2H),6.03(s,1H),5.77(dd,1H),2.28(s,3H),2.24(s,3H)。
实施例10:N-(3-(2-(4-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用4-(3,5-二甲基-1H-吡唑-1-基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(1.8mg,产率:6.3%)。
1H NMR(500MHz,CD3OD)δ7.73-7.71(m,3H),7.58(t,1H),7.50-7.48(m,1H),7.42(t,1H),7.29-7.27(m,3H),6.97(dd,1H),6.48(d,1H),6.42-6.31(m,2H),6.02(s,1H),5.75(dd,1H),2.22(s,3H),2.22(s,3H)。
实施例11:N-(3-(2-(2-氯苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用2-氯苯并[d]噻唑-6-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.9mg,产率:13.7%)。
1H NMR(500MHz,CD3OD)δ8.32-8.32(m,1H),7.57-7.74(m,1H),7.59(t,1H),7.51-7.30(m,5H),6.95(dd,1H),6.53(d,1H),6.42-6.33(m,2H),5.77(dd,1H)。
实施例12:N-(3-(2-(苯并[d]噻唑-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用苯并[d]噻唑-5-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(6.2mg,产率:23.5%)。
1H NMR(500MHz,CD3OD)δ9.17(s,1H),8.64(dd,1H),7.91(d,1H),7.74(s,1H),7.65(dd,1H),7.55(m,2H),7.45(t,1H),7.27(d,1H),7.03(dd,1H),6.44-6.33(m,3H),5.77(dd,1H)。
实施例13:N-(3-(2-(4-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用4-苯氧基苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(5.7mg,产率:20.0%)。
1H NMR(500MHz,CD3OD)δ7.72(s,1H),7.58-7.54(m,3H),7.50-7.48(m,1H),7.42(t,1H),7.29(t,2H),7.25(d,1H),7.03(t,1H),6.98-6.92(m,5H),6.44-6.34(m,3H),5.75(dd,1H)。
实施例14:N-(3-(2-(1-(3-甲氧苄基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用1-(3-甲氧苄基)-1H-吡唑-4-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.5mg,产率:11.8%)。
1H NMR(500MHz,CD3OD)δ7.72(s,1H),7.58-7.54(m,3H),7.50-7.48(m,1H),7.42(t,1H),7.29(t,2H),7.25(d,1H),7.03(t,1H),6.98-6.92(m,5H),6.44-6.34(m,3H),5.75(dd,1H)。
实施例15:N-(3-(2-(4-(2-(二乙氨基)乙氧基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用4-(2-(二乙氨基)乙氧基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(4.6mg,产率:15.4%)。
1H NMR(500MHz,CD3OD)δ7.71(s,1H),7.56-7.49(m,5H),7.43(t,1H),7.22(d,1H),6.97(dd,1H),6.90(d,2H),6.44-6.33(m,3H),5.78(dd,1H),4.15(t,2H),3.16-3.14(m,2H),2.92-2.91(m,4H),1.96(t,6H)。
实施例16:N-(3-(2-(4-((二甲氨基)甲基)苯胺基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用4-((二甲氨基)甲基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.9mg,产率:14.8%)。
1H NMR(500MHz,CD3OD)δ7.71(s,1H),7.57-7.50(m,4H),7.43(t,1H),7.26(d,1H),7.21(d,2H),6.98-6.97(m,1H),6.45-6.36(m,3H),5.77(dd,1H),3.47(s,2H),2.26(s,6H)。
实施例17:N-(3-(2-(4-(吗啉-4-羰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用(4-氨基苯基)(吗啉代)甲酮代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(7.7mg,产率:25.8%)。
1H NMR(500MHz,CD3OD)δ7.73(s,1H),7.68(d,2H),7.58(t,1H),7.54-7.53(m,1H),7.44-7.40(m,1H),7.37(d,2H),7.29(d,1H),6.97(dd,1H),6.47(d,1H),6.44-6.33(m,2H),5.78(dd,1H),3.68(m,8H)。
实施例18:N-(3-(2-(4-(哌啶-1-基磺酰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用4-(哌啶-1-基磺酰基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(6.4mg,产率:20.1%)。
1H NMR(500MHz,CD3OD)δ7.79-7.77(m,3H),7.63-7.59(m,3H),7.48(d,1H),7.42(t,1H),7.32(d,1H),6.96(dd,1H),6.52(d,1H),6.45-6.34(m,2H),5.78(dd,1H),2.95-2.92(m,4H),1.64-1.60(m,4H),1.42(m,2H)。
实施例19:N-(3-(2-(1-(2-吗啉代乙基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用1-(2-吗啉代乙基)-1H-吡唑-4-胺代替苯并[d]噻唑-6-胺之外,以与实施例3中相同的方式获得标题化合物(3.5mg,产率:12.0%)。
1H NMR(500MHz,CD3OD)δ7.86(s,1H),7.70(s,1H),7.56-7.43(m,4H),7.21(d,1H),6.94(d,1H),6.43-6.36(m,3H),7.77(dd,1H),4.25(t,2H),3.75-3.60(m,4H),2.90(m,2H),2.65-2.50(m,4H)。
实施例20:N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三并唑[1,5-a]吡啶-5-基氧基)苯基)丁-2-炔酰胺的制备
除了在实施例1中,步骤5按如下进行外,以与实施例1中相同的方式获得标题化合物(5.3mg,产率:17.9%)。
将5-(3-氨基苯氧基)-N-(4-(4-甲基哌嗪-1-基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(20.0mg,0.05mmol)和丁-2-烯酸(but-2-inoic acid)(4.86mg,0.06mmol)溶解在四氢呋喃(0.5mL)中后,向其中加入1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧化物六氟磷酸酯(22.0mg,0.06mmol)和N,N-二异丙基乙胺(25.0μL,0.15mmol)。在室温下搅拌反应混合物20小时,然后减压浓缩。通过柱色谱分离残余物,得到N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丁-2-炔酰胺。
1H NMR(500MHz,CD3OD)δ7.60(s,1H),7.51(t,1H),7.45-7.44(m,3H),7.38(t,1H),7.20(d,1H),6.92(d,3H),6.38(d,1H),3.20-3.10(m,4H),2.75-2.65(m,4H),2.42(s,3H),2.02(s,3H)。
实施例21:N-(3-(2-(6-吗啉代吡啶-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用6-吗啉代吡啶-3-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(7.7mg,产率:27.4%)。
1H NMR(500MHz,CD3OD)δ8.39(d,1H),7.92(dd,1H),7.70(s,1H),7.56-7.51(m,2H),7.42(t,1H),6.95(dd,1H),6.80(d,1H),6.44-6.33(m,3H),5.78(dd,1H),3.78(t,4H),3.36(t,4H)。
实施例22:N-(3-(2-(6-氯苯并[d]噻唑-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用6-氯苯并[d]噻唑-2-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(2.5mg,产率:11.0%)。
1H NMR(500MHz,CD3OD)δ7.75(s,1H),7.67(t,1H),7.62(d,1H),7.53-7.52(m,1H),7.48-7.45(m,2H),7.31(d,1H),7.24(dd,1H),7.03(dd,1H),6.47(d,1H),6.41-6.37(m,2H),5.78(dd,1H)。
实施例23:N-(3-(2-(萘-1-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用萘-1-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(6.2mg,产率:29.9%)。
1H NMR(500MHz,CD3OD)δ8.19-8.18(m,1H),7.96(d,1H),7.88-7.86(m,1H),7.71(s,1H),7.61(d,1H),7.56(t,1H),7.53-7.48(m,3H),7.44(td,2H),7.25(d,1H),7.49(dd,1H),6.44-6.33(m,3H),5.78(dd,1H)。
实施例24:N-(3-(2-(喹啉-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用喹啉-3-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(5.2mg,产率:25.0%)。
1H NMR(500MHz,CD3OD)δ8.90(d,1H),8.69(d,1H),7.91(d,1H),7.78-7.75(m,2H),7.64(t,1H),7.57-7.50(m,3H),7.45(t,1H),7.37(d,1H),6.97(dd,1H),6.58(d,1H),6.46-6.35(m,2H),5.78(dd,1H)。
实施例25:N-(3-(2-(3-甲基异噁唑并[5,4-b]吡啶-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用3-甲基异噁唑并[5,4-b]-吡啶-5-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.2mg,产率:15.2%)。
1H NMR(500MHz,CD3OD)δ8.66(dd,2H),7.73(s,1H),7.64-7.61(m,1H),7.48-7.40(m,2H),7.36-7.34(m,1H),6.96-6.94(m,1H),6.54(d,1H),6.43-6.33(m,2H),5.76(dd,1H),2.53(s,3H)。
实施例26:N-(3-(2-(1-甲基-1H-咪唑并[4,5-b]吡啶-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用1-甲基-1H-咪唑并[4,5-b]吡啶-6-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.0mg,产率:14.3%)。
1H NMR(500MHz,CD3OD)δ8.72(d,1H),8.68(d,1H),8.26(s,1H),7.53(t,2H),7.47-7.34(m,2H),7.21-7.12(m,2H),6.64(dd,1H),6.59-6.58(m,1H),6.52(dd,1H),6.29(d,1H),3.92(s,3H)。
实施例27:N-(4-氟-3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用5-氨基-2-氟苯酚代替3-氨基苯酚,并且使用4-吗啉代苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(8.3mg,产率:37.1%)。
1H NMR(500MHz,CD3OD)δ7.78(dd,1H),7.58-7.47(m,4H),7.32(t,1H),7.22(d,1H),6.93(d,2H),6.41-6.35(m,3H),5.77(dd,1H),3.82(t,4H),3.06(t,4H)。
实施例28:N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺的制备
除了在实施例3中使用5-氨基-2-氟苯酚代替3-氨基苯酚外,以与实施例3中相同的方式获得标题化合物(5.8mg,产率:27.6%)。
1H NMR(500MHz,CD3OD)δ8.51(s,1H),7.94(t,1H),7.81(dd,1H),7.64-7.52(m,4H),7.39-7.32(m,2H),6.52-6.50(m,1H),6.38-6.34(m,2H),5.76(dd,1H)。
实施例29:N-(4-氟-3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用5-氨基-2-氟苯酚代替3-氨基苯酚,并且使用4-(4-甲基哌嗪-1-基)苯胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(3.7mg,产率:16.1%)。
1H NMR(500MHz,CD3OD)δ7.79(dd,1H),7.58-7.52(m,2H),7.48(d,2H),7.32(t,1H),7.23(d,1H),6.95(d,2H),6.41-6.33(m,3H),5.77(s,1H),3.16(m,4H),2.75(m,4H),2.44(s,3H)。
实施例30:N-(4-氟-3-(2-(1-甲基-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺的制备
除了在实施例3中使用5-氨基-2-氟苯酚代替3-氨基苯酚,并且使用1-甲基-1H-吡唑-4-胺代替苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(0.9mg,产率:3.9%)。
1H NMR(500MHz,CD3OD)δ7.80-7.78(m,1H),7.76-7.75(m,1H),7.68-7.66(m,1H),7.55-7.52(m,2H),7.47-7.46(m,1H),7.36-7.32(m,1H),7.23-7.21(m,1H),6.41-6.39(m,1H),6.37-6.35(m,1H),5.78-5.76(m,1H),3.84(s,3H)。
实施例31:N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺的制备
除了在实施例3中使用5-氨基-2-氟苯酚代替3-氨基苯酚,并且使用1-(二氟甲基)-1H-吡唑-4-胺代苯并[d]噻唑-6-胺外,以与实施例3中相同的方式获得标题化合物(1.4mg,产率:5.5%)。
1H NMR(500MHz,CD3OD)δ8.14-8.13(m,1H),7.79-7.77(m,1H),7.59(s,1H),7.58-7.56(m,1H),7.52-7.49(m,1H),7.35-7.25(m,2H),6.48-6.46(m,1H),6.36-6.31(m,2H),5.77-5.75(m,1H)。
实验实施例1:JAK 3抑制活性测试
通过在ADP Glow(Glo)平台上的体外分析,测量了上述实施例中制备的化合物对JAK3的抑制活性。
具体而言,使用购自Promega的JAK3激酶测定试剂盒(Promega,V9441)测量对JAK3的抑制活性。用1x激酶反应缓冲液(JAK3:40mM Tris-Cl,pH 7.5,20mM MgCl2,0.1mg/mLBSA和50μM DTT)稀释重组纯化的人JAK3并将其加入到96孔板中(JAK3:终浓度为每个反应4ng)。将前述实施例中制备的化合物处理成最终为1%DMSO水性溶液,并将在总共25μL反应物中含有ATP(JAK3:最终浓度为5μM)和0.2μg/μL多(Glu4,Tyr1)肽(JAK3最终浓度)的底物混合物加入到96孔板中以引发酶促反应。温育(30℃)1小时后,加入等体积(每个反应25μL)的ADP Glo,并在室温(30℃)下温育40分钟。然后,加入激酶检测试剂(每个反应50μL)并在室温(30℃)下温育30分钟。根据ADP Glo激酶测定试剂盒的说明书,通过化学发光法测量激酶活性,并计算本发明化合物的抑制活性。为了分析每种化合物的结果,使用MicrosoftExcel,并通过SigmaPlot软件计算IC50值。结果如下表1所示。
[表1]
实施例编号 | JAK3 IC<sub>50</sub>(nM) | 实施例编号 | JAK3 IC<sub>50</sub>(nM) |
1 | 0.47 | 17 | 0.7 |
2 | 1.1 | 18 | 3 |
3 | 2.4 | 19 | 5.1 |
4 | 0.6 | 20 | 0.6 |
5 | 35.8 | 21 | 0.7 |
6 | 2.1 | 22 | >400 |
7 | 1.2 | 23 | >400 |
8 | 1.3 | 24 | 15.5 |
9 | 10.4 | 25 | 105.2 |
10 | 3.6 | 26 | >80 |
11 | 10.3 | 27 | 1.3 |
12 | 2.6 | 28 | 1.2 |
13 | 9.8 | 29 | 0.7 |
14 | 11.1 | 30 | 13.1 |
15 | 6.2 | 31 | 18.2 |
16 | 0.7 | - | - |
Claims (10)
1.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]
在化学式1中,
R1为C6-10芳基,或含1至3个各自独立地选自由N、O和S组成的组的杂原子的的C3-10杂芳基,其中,R1未被取代,或取代有:C1-4烷基、取代有N(C1-4烷基)2的C1-4烷基、取代有吗啉基的C1-4烷基、C1-4卤代烷基、卤素、C1-4烷氧基、取代有N(C1-4烷基)2的C1-4烷氧基、N(C1-4烷基)2、吗啉基、吗啉基羰基、苯氧基、哌啶基、-SO2-哌啶基、哌嗪基、取代有C1-4烷基的哌嗪基、苄基、取代有C1-4烷氧基的苄基、吡唑基、取代有一个或两个C1-4烷基的吡唑基、四唑基或取代有C1-4烷基的四唑基,
R2为C1-5烷基、C2-5烯基或C2-5炔基,
其中,R2未被取代,或取代有选自由卤素、氰基、C3-6环烷基和取代有氰基的C1-5烷基组成的组的一个或两个取代基,且
R3为氢、卤素、C1-4烷基、C1-4卤代烷基或C1-4烷氧基。
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:
R1为苯并噻唑基、咪唑并[4,5-b]吡啶基、异噁唑[5,4-b]吡啶基、萘基、苯基、吡唑基、吡啶基或喹啉基。
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:
R1为苯基,
其中,R1取代有:取代有N(C1-4烷基)2的C1-4烷基、取代有N(C1-4烷基)2的C1-4烷氧基、N(C1-4烷基)2、吗啉基、吗啉基羰基、苯氧基、-SO2-哌啶基、取代有C1-4烷基的哌嗪基、取代有两个C1-4烷基的吡唑基或取代有C1-4烷基的四唑基。
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:
R1为吡唑基,
其中,R1取代有:C1-4烷基、取代有吗啉基的C1-4烷基、C1-4卤代烷基或取代有C1-4烷氧基的苄基。
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:
R1未被取代,或为取代有卤素的苯并噻唑基;
取代有C1-4烷基的咪唑并[4,5-b]吡啶基;
取代有C1-4烷基的异噁唑并[5,4-b]吡啶基;
未被取代的萘基;
取代有吗啉基的吡啶基;或
未被取代的喹啉基。
8.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为氢、氟、氯、甲基、三氟甲基或甲氧基。
9.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表示的化合物为选自由以下各项组成的组中的任何一个:
1)N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
2)N-(3-(2-(1-甲基-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
3)N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
4)N-(3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
5)N-(3-(2-(3-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
6)N-(3-(2-(4-(二甲氨基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
7)N-(3-(2-(3-(5-甲基-1H-四唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
8)N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
9)N-(3-(2-(3-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
10)N-(3-(2-(4-(3,5-二甲基-1H-吡唑-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
11)N-(3-(2-(2-氯苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
12)N-(3-(2-(苯并[d]噻唑-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
13)N-(3-(2-(4-苯氧基苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
14)N-(3-(2-(1-(3-甲氧苄基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
15)N-(3-(2-(4-(2-(二乙氨基)乙氧基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
16)N-(3-(2-(4-((二甲氨基)甲基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
17)N-(3-(2-(4-(吗啉-4-羰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
18)N-(3-(2-(4-(哌啶-1-基磺酰基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
19)N-(3-(2-(1-(2-吗啉代乙基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
20)N-(3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丁-2-炔酰胺,
21)N-(3-(2-(6-吗啉代吡啶-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
22)N-(3-(2-(6-氯苯并[d]噻唑-2-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
23)N-(3-(2-(萘-1-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
24)N-(3-(2-(喹啉-3-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
25)N-(3-(2-(3-甲基异噁唑并[5,4-b]吡啶-5-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
26)N-(3-(2-(1-甲基-1H-咪唑并[4,5-b]吡啶-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
27)N-(4-氟-3-(2-(4-吗啉代苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
28)N-(3-(2-(苯并[d]噻唑-6-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺,
29)N-(4-氟-3-(2-(4-(4-甲基哌嗪-1-基)苯氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,
30)N-(4-氟-3-(2-(1-甲基-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)苯基)丙烯酰胺,和
31)N-(3-(2-(1-(二氟甲基)-1H-吡唑-4-基氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基氧基)-4-氟苯基)丙烯酰胺。
10.一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,所述药物组合物包括根据权利要求1至9中任一项所述的化合物或其药学上可接受的盐。
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CN102665718A (zh) * | 2009-10-06 | 2012-09-12 | 米伦纽姆医药公司 | 可用作pdk1抑制剂的杂环化合物 |
CN104093719A (zh) * | 2012-02-08 | 2014-10-08 | 韩美药品株式会社 | 作为酪氨酸激酶抑制剂的三唑并吡啶衍生物 |
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CN102131389A (zh) * | 2008-06-20 | 2011-07-20 | 健泰科生物技术公司 | 三唑并吡啶jak抑制剂化合物和方法 |
WO2010010184A1 (en) * | 2008-07-25 | 2010-01-28 | Galapagos Nv | [1, 2, 4] triazolo [1, 5-a] pyridines as jak inhibitors |
WO2010010188A1 (en) * | 2008-07-25 | 2010-01-28 | Galapagos Nv | Novel compounds useful for the treatment of degenerative and inflammatory diseases. |
CN102665718A (zh) * | 2009-10-06 | 2012-09-12 | 米伦纽姆医药公司 | 可用作pdk1抑制剂的杂环化合物 |
CN104093719A (zh) * | 2012-02-08 | 2014-10-08 | 韩美药品株式会社 | 作为酪氨酸激酶抑制剂的三唑并吡啶衍生物 |
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JP7371253B2 (ja) | 2023-10-30 |
EP4067354A1 (en) | 2022-10-05 |
JP2023503875A (ja) | 2023-02-01 |
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CN114728963B (zh) | 2023-10-31 |
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