CN117645579A - 作为ripk1抑制剂的氮杂䓬类稠环化合物及其应用 - Google Patents
作为ripk1抑制剂的氮杂䓬类稠环化合物及其应用 Download PDFInfo
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- CN117645579A CN117645579A CN202211077307.2A CN202211077307A CN117645579A CN 117645579 A CN117645579 A CN 117645579A CN 202211077307 A CN202211077307 A CN 202211077307A CN 117645579 A CN117645579 A CN 117645579A
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- cycloalkyl
- heterocyclyl
- oxo
- heteroaryl
- aryl
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Classifications
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- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本公开提供了式(I)化合物、其药物组合物及其在治疗和/或预防与RIPK1激酶活性相关的疾病或病症中的应用。
Description
技术领域
本申请涉及可用于抑制RIPK1激酶活性的化合物,和/或这些化合物在治疗和/或预防与RIPK1激酶活性相关的疾病或病症中的应用。
背景技术
蛋白激酶(Protein kinase)是广泛存在于细胞内和细胞表面的酶蛋白,至目前为止被发现和鉴定的蛋白激酶有将近600种,它们属于一个结构相关的蛋白家族,其已知成员与几乎所有细胞信号传导活动均有关。蛋白激酶的催化功能是将ATP分子中的γ-磷酸基团转移至靶蛋白特定的苏氨酸、丝氨酸或酪氨酸基团,使靶蛋白构象发生变化,导致靶蛋白功能由静止转变到活化状态。按照蛋白激酶的靶点氨基酸的特异性,蛋白激酶被分为两大类:丝氨酸/苏氨酸蛋白激酶和酪氨酸蛋白激酶。
蛋白激酶参与的信号传导和调节在细胞和器官的正常功能中起着极为重要的作用,包括细胞生长、分化、增殖、血管生成、细胞凋亡、细胞骨架排列、代谢反应的调节、膜转运和细胞运动等。除此之外,蛋白激酶的非催化功能也起着不可缺少的作用,包括别构效应、亚细胞靶向、蛋白质复合物支架、蛋白质竞争相互作用和DNA结合。但在另一方面,如发生基因突变或蛋白激酶过度表达时,失调的蛋白激酶会导致多种病理改变,包括癌症、炎症、自身免疫性病、心血管系统和神经系统疾病。因此,蛋白激酶已经成为当今药物开发中最重要靶点之一,而近年来蛋白激酶抑制剂在临床治疗上取得的成功进一步证明了这一策略的可行性,并揭示了以蛋白激酶作为治疗靶点的良好前景。
受体相互作用蛋白激酶1(Receptor-interacting protein kinase 1,RIPK1)属于TKL丝氨酸/苏氨酸蛋白激酶家族,包括N端激酶结构域、RHIM(Receptor-interactingprotein kinase homotypic interaction motif)结构域和C端死亡结构域。RIPK1的C端死亡结构域与其他含有死亡结构域的蛋白(如Fas、TNFR-1、TRAIL-R1、TRAIL-R2和TRADD等)结合并启动下游信号传递。RHIM结构域主要与其他含有RHIM结构域的蛋白(如TRIF和RIP3)结合起始下游信号。RIPK1主要由死亡受体(如TNFR-1、TRAILR和FasR)、Toll样受体(TLR3/4)、干扰素受体1(IFNAR1)、Z-DNA结合蛋白1(ZBP)、Dectin-1或RIPK3释放信号来起始活化。一旦被上游信号活化,RIPK1将自磷酸化并发挥激酶活性依赖的生物学功能,如Caspase 8(CASP8)依赖性凋亡、RIPK3/MLKL依赖性坏死和炎症。此外,RIPK1也可发挥激酶非依赖的支架功能,如促进细胞生存和炎症基因表达等。RIP激酶家族其他的成员参与不同的生理活动,RIPK2通常调节先天免疫和适应性免疫反应,RIPK3与RIPK1相互作用活化坏死和凋亡并调节一些代谢相关酶活性,RIPK4参与层状上皮组织的发展和NF-κB信号通路。其他RIP激酶家族成员的生物学功能尚未阐释清晰。RIP激酶家族中RIPK1对先天免疫反应至关重要,并参与TNF-α起始的下游信号。TNF-α刺激诱导TNF受体的聚集后,多种蛋白(如linear K63-linked polyubiquitinated RIPl、TRAF2/5、TRADD和cIAPs)被募集到TNF受体的胞质尾区并形成复合物I,复合物I将通过NF-κB和MAPK激酶信号通路参与细胞生存。此外,RIP1的去泛素化会促进复合物II或DISC(death-inducing signaling complex)复合物(RIPK1、TRADD、FADD和caspase 8)的形成。DISC复合物形成后,RIPK3表达,抑制细胞凋亡,RIPK3进入复合物II,被RIPK1磷酸化并在MLKL和PGAM5活化后启动细胞坏死性凋亡。坏死性凋亡是一种受调控的,不依赖于半胱天冬酶的细胞死亡途径,其形态学特征类似于坏死,可通过多种刺激诱发(如TNF-α和Fas配体),可发生在各种细胞类型,如单核细胞、成纤维细胞、淋巴细胞、巨噬细胞、上皮细胞和神经元等。在过度细胞应激、快速能量损失和大量氧化物种产生的病理条件下,坏死性凋亡可能是细胞死亡的重要途径,并且在某些高度依赖能量的过程不起作用的情况下是细胞死亡的主要模式。研究表明,RIPK1是坏死性凋亡通路中的关键分子,RIPK1失调后激活导致坏死性凋亡,成为多种疾病的重要发病因素,包括神经元退行性病变和炎症性疾病、中风、冠心病和心肌梗塞、视网膜退行性疾病、炎症性肠病、肾病、肝病以及COVID-19导致的病变。
有效的、选择性的RIPK1活性小分子抑制剂将阻断RIPK1依赖性促炎信号传导,从而为以RIPK1激酶活性失调为特征的炎性疾病提供治疗益处。现有技术中存在这样的RIPK1抑制剂的迫切需要。
发明内容
本发明人经过长期研究,意外发现一类具有显著的RIPK1活性抑制作用的化合物,其显示出高效的、高选择性的RIPK1激酶抑制作用,可用于治疗或预防与RIPK1活性相关的疾病。
特别地,本发明提供了可作为RIPK1激酶活性抑制剂的式(I)化合物或者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐:
其中,
X选自CH和N;
Y选自-CRaRb-、-O-、-NRa-和-S(O)m-;
Z选自-O和-S;
L选自单键、-(CRaRb)n-、-(CRaRb)nO-、-(CRaRb)nS-、-(CRaRb)nNRa-、-O-、-NRa-和-S(O)m-;
环A选自C5-C10芳基、杂芳基、环烷基和杂环基,其中所述芳基、杂芳基、环烷基和杂环基任选进一步被一个或多个R6取代;
R1独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基中的一个或多个基团取代;优选地,R1选自以下的炔基、烯基和联烯基:
R2和R3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基;
或者R1和R2与他们连接的原子一起形成C5-C10芳基、杂芳基、杂环基或环烷基,或者R2和R3与他们连接的原子一起形成C5-C10芳基、杂芳基、杂环基或环烷基,其中所述C5-C10芳基、杂芳基、杂环基或环烷基任选进一步被一个或多个R9取代;
R4和R5各自独立地选自选自氢、烷基、卤代烷基、环烷基和卤代环烷基;
R6、R7、R8和R9各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、羟基烷基、烯基、炔基、芳基、芳基氧基、杂芳基、环烷基和杂环基中的一个或多个基团取代;
Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基;
或者Ra和Rb与他们连接的原子一起形成环烷基或杂环基,所述环烷基或杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基中的一个或多个基团取代;
m为0、1或2;
n为0、1、2或3。
在一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐:
其中,
R’选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、羟基烷基、烯基、炔基、芳基、芳基氧基、杂芳基、环烷基和杂环基的一个或多个基团取代;
m为0、1或2;
L和环A如通式(I)所定义。
在另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐:
其中,
L和环A如通式(I)所定义;
R’如通式(II)所定义。
本发明的典型化合物,包括但不限于:
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。
本发明进一步提供一种根据本发明所述的通式(I)、(II)和(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法,其包括以下步骤:
将母核化合物A与草酰氯单乙酯反应得到中间体B,然后与化合物C经胺酯交换得到式(I)所示化合物。在式(I)所示化合物中的R1为溴或碘的情况下,再经Sonogashira偶联反应可得到式(II)或式(III)所示化合物。
其中,X、Y、Z、L、环A、R1、R2、R3、R4和R5如通式(I)所定义,R’如通式(II)所定义。
发明的术语说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
在本发明中,当提及具有特定结构式的“化合物”时,一般地还涵盖其可药用盐、立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。
本领域技术人员公知,除了化合物的盐外,溶剂合物、水合物是化合物的替代性存在形式,它们都可以在一定条件下转化为所述化合物,因此,当在本发明中当提到一种化合物时,一般地还包括它的溶剂合物和水合物。
本发明所述的“可药用盐”是指本发明化合物的盐,在合理的医学判断范围内,其适用于接触人和哺乳动物的组织,而没有不适当的毒性、刺激性、过敏反应等,且具有应有的生物活性,称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐,或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐。例如,游离碱可以与合适的酸反应。可药用的酸加成盐的示例是氨基(胺基)与无机酸(例如,盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如,醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用现有技术中的其他方法如离子交换形成的盐。本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如甲醇、乙醇、丙酮和乙腈),向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐。其他可药用盐包括海藻酸钠、抗坏血酸盐、苯磺酸盐、己二酸盐、樟脑磺酸盐、天门冬氨酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、柠檬酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、庚酸盐、己酸盐、氢碘酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。
在说明书和权利要求书中,给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C=C双键、C=N双键、环系统等的许多几何异构体,且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体,且其可分离成异构体的混合物或分开的异构体形式。
本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时,其可通过常规方法(例如通过色谱或分段结晶)进行分离。应当理解的是,可存在的所有互变异构体形式均包括在本发明内。本发明的化合物当作为现有技术已知化合物时可以通过商购获得。
术语“烷基”是指包括具有指定碳原子数的支链和直链饱和脂族烃基团。本发明中的烷基优选C1-C12烷基、C1-C10烷基、C1-C8烷基,更优选C1-C6烷基,特别优选C1-C4烷基,尤其是C1-C3烷基。例如,“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。对于本发明中的C1-C12烷基而言,其中的1至4个-CH2-单元任选地被O原子、S原子或-NH-所替代。
术语“烷氧基”是指-O-(烷基)或-O-(非取代的环烷基)。例如,“C1-C6烷氧基”是指包括C1、C2、C3、C4、C5、C6烷氧基。优选的烷氧基为C1-C10烷氧基、C1-C8烷氧基,更优选C1-C6烷氧基,特别优选C1-C4烷氧基,尤其是C1-C3烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)、叔丁氧基、环丙氧基、环丁氧基、环戊氧基和环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。类似地,“烷硫基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基;例如甲基-S-和乙基-S-。同样,优选的烷硫基为C1-C10烷硫基、C1-C8烷硫基,更优选C1-C6烷硫基,特别优选C1-C4烷硫基,尤其是C1-C3烷硫基。
术语“烯基”是指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。优选的是C2-C6烯基或C2-C4烯基。
术语“炔基”是指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基,例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。优选的是C2-C6炔基或C2-C4炔基。
术语“卤代”或“卤素”包括氟、氯、溴和碘。本发明中,一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
术语“卤代烷基”是指包括具有指定碳原子数且取代有一个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。优选的卤代烷基包括卤代(C1-C6烷基)或卤代(C1-C4烷基)。
术语“氧代基”或“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C=O或C(O))。
术语“苄基”指-CH2-苯基或“Bn”。
术语“羟基”指-OH基团。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”或“羧酸酯基”指-C(O)O-(烷基)或-C(O)O(环烷基),其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物,其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,本发明的环烷基优选C3-C8环烷基或C3-C6环烷基。单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基,多环环烷基包括但不限于螺环、稠环和桥环的环烷基,例如降莰烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上,其中与母体结构连接在一起的环为环烷基,其非限制性实施例包括但不限于:
环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、羟基烷基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、芳基氧基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”是指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自N、O和S的杂原子(N和S杂原子可任选地被氧化),但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1至4个是杂原子;最优选包含3至8个环原子,其中1至3个是杂原子;最优选包含5至7个环原子,其中1至2或1至3个是杂原子。单环杂环基的实例包括但不限于四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基和四氢吡喃基,多环杂环基包括但不限于螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实施例包括但不限于:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、羟基烷基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、芳基氧基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”是指具有共轭π电子体系的总计6至14个环原子的单环、二环或三环的环系统,其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环原子。在本发明的某些实施方案中,“芳基”是指芳族环系统,其包括但不限于苯基、萘基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。本发明的芳基优选C6-C10芳基。芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、羟基烷基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、芳基氧基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”是指稳定的3元、4元、5元、6元、或7元芳香单环或7元、8元、9元、10元的芳香二环或芳香多环杂环,其为完全不饱和或部分不饱和的,且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子(N和S杂原子可任选地被氧化)。氮原子为取代的或未取代的(即N或NR,其中R为H或如果被定义,则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的,则本发明所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地,当杂环中S和O原子的总数超过1时,则这些杂原子彼此不相邻。优选地,杂环中S和O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。杂芳基的实施例包括但不限于吖啶基、咪唑基、呋喃基、噻吩基、噁唑基、噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、吲哚基、吲嗪基、吲唑基、嘧啶基、吩嗪基、哌嗪基、哌啶基、嘌呤基、吡喃基、吡嗪基、吡咯基和喹啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”、“杂环基”或“环烷基”与单环“杂芳基”所形成的联芳基结构,例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基-”、“-吡啶基联萘基-”、“-嘧啶基联萘基-”和“-吡啶基联嘧啶基-”,其中本发明还包括含有例如上述杂环的螺环、稠环和桥环化合物。
本发明所述的“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
本发明所述的“取代”或“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1至3个氢原子彼此独立地被相应数目的取代基取代,条件是维持正常化合价且所述取代得到稳定的化合物。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本发明所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
具体实施方式
为更好地阐述本发明所采取的技术手段及其效果,以下结合非限制性实施例来进一步说明本发明。本发明的实施例,包括实施例中提供的描述,旨在说明本发明的实施方式,其并非旨在限制任何权利要求的范围。根据本发明,本领域技术人员将理解,在不脱离本发明的精神和范围的情况下,可以对所公开的具体实施方案进行许多改变并仍然能获得相同或相似的结果。
除非另有说明,所有材料/试剂均从商业供应商处获得,无需进一步纯化即可使用。下述实施例的化合物结构是通过核磁共振(NMR)和/或质谱(MS)来表征和确定的。
1H NMR波谱通过Bruker Avance 400MHz波谱仪上在室温下记录,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD)或氘水(D2O)。化学位移值(δ)以ppm为单位,用四甲基硅烷(TMS)或残留溶剂峰作为内标,耦合常数(J)以赫兹(Hz)为单位,1H NMR谱图中峰型的多重性缩写如下:s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、qn(五重峰)、m(多重峰)、br(宽峰)。
液相色谱质谱联用(LC-MS)使用的仪器是Shimadzu LCMS-2020,制备型高效液相色谱(Prep-HPLC)使用的仪器是Bonna-Agela FLEXA FL-H100G。薄层色谱(TLC)所使用的薄层层析硅胶板型号是烟台黄海HSGF254薄层层析硅胶板,反应监测所用的规格为2.5×8cm,其涂层厚度为0.2±0.03mm,分离纯化所用的规格为20×20cm,其涂层厚度为0.4–0.5mm。硅胶柱层析色谱法使用的是青岛海洋硅胶100–200目或200–300目硅胶为载体。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
实施例1:(S)-N1-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(1)的合成
合成路线:
步骤1:O-(4-溴-2-硝基苯基)-N-(叔丁氧基羰基)-L-丝氨酸(1c)的合成
在0℃冰浴下向氢化钠(60%w/w分散于矿物油中,1.74g,47.39mmol)的DMF(N,N-二甲基甲酰胺,20mL)悬浮液中加入(叔丁氧基羰基)-L-丝氨酸(1b)(4.24g,20.66mmol)的DMF(5mL)溶液,反应液搅拌1小时后,在0℃冰浴下将4-溴-1-氟-2-硝基苯(1a)(5g,22.73mmol)的DMF(10mL)溶液慢慢滴加入反应液,然后升温至室温,再搅拌15小时。TLC和LC-MS显示反应完全,将反应混合物倒入冰水中(300mL),水相用稀盐酸(1N)酸化至pH=4,然后用乙酸乙酯(100mL×5)萃取。将合并的有机层依次用水(300mL×2)和饱和食盐水(100mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含1%甲醇的二氯甲烷为洗脱液)得到化合物1c(3.5g,产率38%)为黄色固体。
MS(ES+):m/z 347.9[M-tBu+H]+.
步骤2:O-(2-氨基-4-溴苯基)-N-(叔丁氧基羰基)-L-丝氨酸(1d)的合成
在0℃冰浴下向化合物1c(3.5g,8.6mmol)的乙酸(50mL)溶液加入锌粉(2.8g,43.2mmol),所得混合物在30℃下搅拌3小时。TLC和LC-MS显示反应完全,反应混合物经硅藻土过滤后,滤饼用二氯甲烷(300mL)润洗,将滤液减压浓缩。然后将浓缩后残余物溶于水(50mL),用饱和碳酸氢钠溶液中和至pH=7,然后用二氯甲烷(50mL)萃取。收集有机层,用饱和食盐水(20mL)洗涤,再用无水硫酸钠干燥并减压浓缩,得到化合物1d(3.4g)的粗产品为黑色固体,直接用于下一步而无需进一步纯化。
MS(ES+):m/z 374.9[M+H]+.
步骤3:(S)-(7-溴-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(1e)的合成
在室温下向化合物1d(3.4g,9.1mmol)的DMF(50mL)溶液中加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(EDCI,1.74g,9.1mmol),反应液在室温下搅拌2小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(300mL),用乙酸乙酯(100mL×3)萃取。合并有机层,用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥并减压浓缩,然后再经硅胶柱层析纯化(含15%乙酸乙酯的石油醚为洗脱液),得到化合物1e(880mg,两步产率28%)为浅黄色固体。
MS(ES+):m/z 300.7[M-tBu+H]+.
1H NMR(400MHz,DMSO-d6):δ10.03(s,1H),7.29–7.25(m,2H),7.14(d,J=7.6Hz,1H),7.07(d,J=8.4Hz,1H),4.35–4.26(m,3H),1.36(s,9H).
步骤4:(S)-(7-溴-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(1f)的合成
在室温和氮气保护下向化合物1e(2.1g,5.88mmol)和碳酸铯(2.5g,7.6mmol)的DMF(30mL)溶液混合物中加入碘甲烷(0.9g,6.5mmol),反应混合物在室温下搅拌15小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(400mL),用乙酸乙酯(100mL×3)萃取。合并的有机层依次用水(50mL×2)和盐水(100mL)洗涤,用无水硫酸钠干燥并减压浓缩,再经硅胶柱层析纯化(含15%乙酸乙酯的石油醚为洗脱液)得到化合物1f(1.3g,产率60%)为淡黄色固体。
MS(ES+):m/z 370.9[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.74(d,J=2.0Hz,1H),7.43(dd,J=8.6,2.2Hz,1H),7.19(d,J=8.4Hz,1H),7.15(d,J=8.8Hz,1H),4.40–4.25(m,3H),3.27(s,3H),1.34(s,9H).
步骤5:(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(1g)的合成
在室温下向化合物1f(1.6g,4.3mmol)的二氯甲烷(20mL)溶液中滴加氯化氢的1,4-二氧六环溶液(4N,25mL),反应液室温下搅拌3小时。TLC和LC-MS显示反应完全,减压浓缩除去溶剂等挥发物,得到化合物1g(1.3g,产率98%)为白色固体。
MS(ES+):m/z 272.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.66(s,3H),7.80(d,J=2.4Hz,1H),7.48(dd,J=8.6,2.2Hz,1H),7.23(d,J=8.8Hz,1H),4.60(dd,J=10.0,7.3Hz,1H),4.46(t,J=10.6Hz,1H),4.34(dd,J=11.2,7.6Hz,1H),3.34(s,3H).
步骤6:(S)-2-((7-溴-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基)-2-羰基乙酸乙酯(1h)的合成
在0℃冰浴下向化合物1g(1.3g,4.2mmol)和三乙胺(1.3g,12.8mmol)的二氯甲烷(30mL)溶液混合物中缓慢滴加草酰氯单乙酯(0.7g,5.1mmol)的二氯甲烷(5mL)溶液,反应液缓慢升温至室温,再搅拌3小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(200mL),用二氯甲烷(100mL×3)萃取。合并有机层,用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥并减压浓缩,然后再经硅胶柱层析纯化(含20%乙酸乙酯的石油醚为洗脱液),得到化合物1h(1.4g,产率90%)为白色固体。
MS(ES+):m/z 370.8[M+H]+.
1H NMR(400MHz,CDCl3):δ7.98(d,J=6.6Hz,1H),7.38–7.35(m,2H),7.09–7.07(m,1H),4.86(dt,J=11.1,7.2Hz,1H),4.67(dd,J=9.7,7.5Hz,1H),4.35(q,J=7.1Hz,2H),4.21(t,J=10.5Hz,1H),3.41(s,3H),1.37(t,J=7.1Hz,3H).
步骤7:(S)-N1-(7-溴-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(1)的合成
向化合物1h(1.4g,3.8mmol)的乙醇(20mL)溶液中加入2-苯乙胺1i(1.0g,8.3mmol),反应液升温至90℃,再搅拌4小时。TLC和LC-MS显示反应完全,且反应液中有较多白色固体析出。反应液冷却至室温后过滤,滤饼用含15%乙酸乙酯的石油醚(10mL)润洗,抽干滤饼后得到标题化合物1(1.3g,产率77%)为白色固体。
MS(ES+):m/z 446.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.22(d,J=7.5Hz,1H),7.35–7.28(m,5H),7.25–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.06(d,J=8.9Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.6,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).
实施例2:(S)-N1-(7-(环丙基乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(2)的合成
合成路线:
在室温下依次将化合物1(44.6mg,0.1mmol)、双(三苯基膦)二氯化钯(II)(7.0mg,0.01mmol)、碘化亚铜(1.9mg,0.01mmol)、三乙胺(1mL)、DMF(2mL)和环丙乙炔2a(0.2mL,2.4mmol)加入到密封管中,快速地用氮气置换管内空气三次后,反应液保持在80℃下搅拌15小时。TLC和LC-MS显示反应完全,反应液冷却至室温后,加水(20mL)淬灭,用乙酸乙酯(10mL×3)萃取。将合并的有机层用饱和食盐水(10mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含20%乙酸乙酯的石油醚为洗脱液)得到标题化合物2(38.8mg,产率90%)为浅黄色固体。
MS(ES+):m/z 432.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(d,J=7.2Hz,1H),7.37–7.27(m,4H),7.23–7.20(m,2H),7.17(d,J=7.4Hz,2H),7.05(d,J=8.7Hz,1H),4.79(dt,J=11.1,7.4Hz,1H),4.56(dd,J=9.5,7.5Hz,1H),4.22(t,J=10.5Hz,1H),3.57–3.52(m,2H),3.38(s,3H),2.83(t,J=7.0Hz,2H),1.48–4.41(m,1H),0.91–0.86(m,2H),0.83–0.80(m,2H).
实施例3:N1-(8-溴-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(3)的合成
合成路线:
与实施例1的合成路线和方法相同,除了将步骤1中的化合物4-溴-1-氟-2-硝基苯(1a)替换为等摩尔量的4-溴-2-氟-1-硝基苯(3a),制得标题化合物3。
MS(ES+):m/z 445.9[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.1Hz,1H),7.39–7.34(m,2H),7.32–7.28(m,3H),7.25–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.08(d,J=8.4Hz,1H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H).
实施例4:(S)-N1-(8-(环丙基乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(4)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将化合物1替换为等摩尔量的化合物3,制得标题化合物4。
MS(ES+):m/z 432.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.34–7.28(m,3H),7.24–7.20(m,2H),7.18–7.16(m,2H),7.09(d,J=8.3Hz,1H),4.79(dt,J=11.1,7.5Hz,1H),4.56(dd,J=9.7,7.5Hz,1H),4.21(t,J=10.5Hz,1H),3.58–3.52(m,2H),3.38(s,3H),2.83(t,J=7.1Hz,2H),1.47–4.42(m,1H),0.92–0.87(m,2H),0.83–0.79(m,2H).
实施例5:(S)-N1-(8-羟基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(5)的合成
合成路线:
步骤1:(S)-(8-羟基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(5a)的合成
在室温下向化合物3f(1.0g,2.7mmol)、联硼酸频那醇酯(863mg,3.4mmol)和乙酸钾(540mg,5.4mmol)的1,4-二氧六环溶液(20mL)溶液混合物中加入Pd(dppf)Cl2,(102mg,0.14mmol),快速地用氮气置换瓶内空气三次后,反应液保持在110℃下搅拌15小时。TLC和LC-MS显示反应完全,反应液冷却至室温后,加乙酸乙酯(10mL)稀释后过滤,将滤液减压浓缩。然后将浓缩后残余物溶于THF/H2O(2:1,30mL)的混合溶剂中,加入过硼酸钠四水合物(831mg,5.4mmol),反应液保持在30℃下搅拌2小时。TLC和LC-MS显示反应完全,加饱和氯化铵溶液(100mL)淬灭,用乙酸乙酯(100mL×3)萃取。将合并的有机层用饱和食盐水(100mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含25%乙酸乙酯的石油醚为洗脱液)得到化合物5a(591mg,产率71%)为灰色固体。
MS(ES+):m/z 309.0[M+H]+.
步骤2:(S)-3-氨基-8-羟基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮(5b)的合成
在室温下向化合物5a(339mg,1.1mmol)的二氯甲烷(5mL)溶液中滴加三氟乙酸(2mL),反应液室温下搅拌2小时。TLC和LC-MS显示反应完全,然后用饱和碳酸氢钠溶液中和至pH=7,直接减压浓缩,再经硅胶柱层析纯化(含6%甲醇的二氯甲烷为洗脱液)得到化合物5b(160mg,产率70%)为淡红色固体。
MS(ES+):m/z 209.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ9.68(s,1H),7.18(d,J=8.8Hz,1H),6.63(dd,J=8.4,2.8Hz,1H),6.52(d,J=2.4Hz,1H),4.20(dd,J=10.0,7.2Hz,1H),3.91(dd,J=11.6,10.0Hz,1H),3.58(dd,J=11.6,7.2Hz,1H),3.21(s,3H),1.75(br,2H).
步骤3:(S)-2-((8-((叔丁基二甲基硅基)氧基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基)-2-羰基乙酸乙酯(5c)的合成
在室温下向化合物5b(150mg,0.72mmol)、N,N-二甲基吡啶-4-胺(9mg,0.07mmol)和三乙胺(219mg,2.16mmol)的二氯甲烷(3mL)溶液混合物中缓慢滴加叔丁基二甲基氯硅烷(136mg,0.90mmol)的二氯甲烷(1mL)溶液,反应液室温下搅拌5小时,TLC和LC-MS显示反应完全。然后将反应液置于0℃冰浴下,缓慢滴加草酰氯单乙酯(196mg,1.44mmol)的二氯甲烷(1mL)溶液,反应液缓慢升温至室温,再搅拌3小时。TLC和LC-MS显示反应完全,向反应液中加入二氯甲烷(30mL)稀释,再依次用水(15mL)、饱和氯化铵溶液(20mL)和饱和食盐水(20mL)洗涤。将有机层用无水硫酸钠干燥,减压浓缩,然后再经硅胶柱层析纯化(含10–30%乙酸乙酯的石油醚为洗脱液),得到化合物5c(230mg,产率76%)为白色固体。
MS(ES+):m/z 423.1[M+H]+.
步骤4:(S)-N1-(8-羟基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(5)的合成
向化合物5c(200mg,0.47mmol)的乙醇(5mL)溶液中加入2-苯乙胺(190mg,1.56mmol),反应液升温至90℃,再搅拌15小时。TLC和LC-MS显示反应完全,将反应液减压浓缩,再经硅胶柱层析纯化(含含10–50%乙酸乙酯的石油醚为洗脱液)得到标题化合物5(150mg,产率83%)为白色固体。
MS(ES+):m/z 384.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.27(d,J=7.6Hz,1H),7.32–7.28(m,3H),7.24–7.21(m,1H),7.18(d,J=7.6Hz,2H),7.06(d,J=8.6Hz,1H),6.71–6.66(m,2H),4.83(dt,J=10.8,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.20(t,J=10.5Hz,1H),3.60–3.54(m,2H),3.37(s,3H),2.84(t,J=6.9Hz,2H).
实施例6:(S)-N1-(7-羟基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(6)的合成
合成路线:
与实施例5的合成路线和方法相同,除了将化合物3f替换为等摩尔量的化合物1f,制得标题化合物6。
MS(ES+):m/z 384.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.28(d,J=7.5Hz,1H),7.32–7.28(m,3H),7.24–7.21(m,1H),7.18(d,J=7.1Hz,2H),7.01(d,J=8.6Hz,1H),6.67–6.62(m,2H),5.59(br,1H),4.82(dt,J=11.1,7.6Hz,1H),4.56(dd,J=9.7,7.6Hz,1H),4.16(t,J=10.1Hz,1H),3.60–3.54(m,2H),3.38(s,3H),2.84(t,J=7.1Hz,2H).
实施例7:(S)-N1-(7-羟基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-甲基-N2-苯乙草酰胺(7)的合成
合成路线:
与实施例5步骤4的合成路线和方法相同,除了将化合物1i替换为等摩尔量的化合物7a,制得标题化合物7。
MS(ES+):m/z 398.1[M+H]+.
1H NMR(400MHz,CDCl3):δ7.92(minor),7.80(major)(d,J=7.5Hz,1H),7.32–7.27(m,1H),7.24–7.17(m,2H),7.13(d,J=7.1Hz,1H),7.03–6.99(m,1H),6.67–6.62(m,2H),5.97(s,1H),4.85(minor),4.74(major)(dt,J=11.0,7.4Hz,1H),4.59(minor),4.53(major)(dd,J=9.6,7.7Hz,1H),4.17(minor),4.06(major)(t,J=10.4Hz,1H),3.96–3.82(major),3.63–3.59(minor)(m,2H),3.37(minor),3.36(major)(s,3H),3.16(minor),2.99(major)(s,3H),2.91–2.86(m,2H).
实施例8:(S)-N1-(7-甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(8)的合成
合成路线:
在0℃冰浴下向化合物6(35mg,0.09mmol)和碳酸钾(25mg,0.18mmol)的DMF(0.5mL)溶液混合物中滴加碘甲烷8a(17mg,0.12mmol)的DMF(0.1mL)溶液,反应液在0℃冰浴下搅拌1.5小时,TLC和LC-MS显示反应完全。将反应液过滤,滤液经Prep-HPLC分离纯化(含30–95%乙腈的水为流动相),得到化合物8(27mg,产率75%)为白色固体。
MS(ES+):m/z 398.1[M+H]+.
1H NMR(400MHz,CDCl3):δ:8.24(d,J=7.4Hz,1H),7.31–7.28(m,3H),7.24–7.20(m,1H),7.17(d,J=7.2Hz,2H),7.09(d,J=8.6Hz,1H),6.76–6.72(m,2H),4.82(dt,J=11.1,7.6Hz,1H),4.56(dd,J=9.6,7.7Hz,1H),4.16(t,J=10.4Hz,1H),3.81(s,3H),3.59–3.53(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).
实施例9:(S)-N1-(7-(烯丙氧基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(9)的合成
合成路线:
与实施例8的合成路线和方法相同,除了将碘甲烷8a替换为等摩尔量的烯丙基溴9a,制得标题化合物9。
MS(ES+):m/z 424.0[M+H]+.
1H NMR(400MHz,CDCl3):δ:8.25(d,J=7.2Hz,1H),7.31–7.28(m,3H),7.25–7.22(m,1H),7.17(d,J=7.1Hz,2H),7.09–7.06(m,1H),6.76–6.74(m,2H),6.09–5.99(m,1H),5.42(d,J=17.3Hz,1H),5.32(d,J=10.5Hz,1H),4.82(dt,J=11.1,7.6Hz,1H),4.58–4.52(m,3H),4.16(t,J=10.4Hz,1H),3.58–3.53(m,2H),3.39(s,3H),2.83(t,J=7.0Hz,2H).
实施例10:(S)-N1-(5-甲基-4-氧代-7-(丙-2-炔-1-氧基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(10)的合成
合成路线:
与实施例8的合成路线和方法相同,除了将碘甲烷8a替换为等摩尔量的炔丙基溴10a,制得标题化合物10。
MS(ES+):m/z 422.0[M+H]+.
1H NMR(400MHz,CDCl3):δ:8.25(d,J=7.3Hz,1H),7.33–7.28(m,3H),7.25–7.22(m,1H),7.17(d,J=7.2Hz,2H),7.10(d,J=8.5Hz,1H),6.85–6.82(m,2H),4.83(dt,J=11.0,7.6Hz,1H),4.69(d,J=2.2Hz,2H),4.56(dd,J=9.7,7.6Hz,1H),4.18(t,J=10.5Hz,1H),3.58–3.53(m,2H),3.40(s,3H),2.83(t,J=7.0Hz,2H),2.56(t,J=2.2Hz,1H).
实施例11:(S)-N1-(5-甲基-4-氧代-7-(丙-2-炔-1-氧基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(11)的合成
合成路线:
在室温下依次将化合物1(44.6mg,0.1mmol)、醋酸钯(2.2mg,0.01mmol)、三(邻甲基苯基)磷(6.1mg,0.02mmol)、三乙胺(28mg,0.28mmol)、DMF(1mL)和1-甲基-3-乙烯基苯11a(13mg,0.11mmol)加入到密封管中,快速地用氮气置换管内空气三次后,反应液保持在80℃下搅拌15小时。TLC和LC-MS显示反应完全,反应液冷却至室温后,将反应液直接减压浓缩,先通过制备TLC分离纯化,再经Prep-HPLC分离纯化(含30–95%乙腈的水为流动相),得到化合物11(4mg,产率8%)为白色固体。
MS(ES-):m/z 482.1[M-H]-.
1H NMR(400MHz,CDCl3):δ:8.26(d,J=7.6Hz,1H),7.38–7.28(m,7H),7.24–6.93(m,8H),4.86(dt,J=11.4,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.51(m,2H),3.46(s,3H),2.84(t,J=7.0Hz,2H),2.39(s,3H).
实施例12:(S)-N1-(5-甲基-4-氧代-7-(吡啶-4-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(12)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-乙炔基吡啶12a(21mg,0.2mmol),制得标题化合物12。
MS(ES+):m/z 469.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.63(s,2H),8.26(d,J=7.3Hz,1H),7.43–7.28(m,7H),7.24–7.15(m,4H),4.84(dt,J=11.2,7.3Hz,1H),4.62(dd,J=9.5,7.4Hz,1H),4.28(t,J=10.5Hz,1H),3.59–3.52(m,2H),3.44(s,3H),2.84(t,J=6.9Hz,2H).
实施例13:(S)-N1-(5-甲基-4-氧代-7-(吡啶-3-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(13)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-乙炔基吡啶13a(21mg,0.2mmol),制得标题化合物13。
MS(ES+):m/z 469.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.56(s,1H),8.25(d,J=7.4Hz,1H),7.80(d,J=7.0Hz,1H),7.40–7.28(m,6H),7.22–7.13(m,4H),4.83(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9.6,7.4Hz,1H),4.26(t,J=10.5Hz,1H),3.57–3.52(m,2H),3.42(s,3H),2.82(t,J=6.9Hz,2H).
实施例14:(S)-N1-(5-甲基-4-氧代-7-(吡啶-2-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(14)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的2-乙炔基吡啶14a(21mg,0.2mmol),制得标题化合物14。
MS(ES+):m/z 469.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.63(t,J=4.9Hz,1H),8.26(d,J=7.3Hz,1H),7.73–7.68(m,1H),7.55–7.45(m,2H),7.35–7.28(m,5H),7.22–7.15(m,4H),4.84(dt,J=11.2,7.3Hz,1H),4.62(dd,J=9.6,7.4Hz,1H),4.27(t,J=10.5Hz,1H),3.59–3.52(m,2H),3.43(s,3H),2.83(t,J=7.0Hz,2H).
实施例15:(S)-N1-(5-甲基-4-氧代-7-(嘧啶-5-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(15)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的5-乙炔基嘧啶15a(21mg,0.2mmol),制得标题化合物15。
MS(ES+):m/z 470.1[M+H]+.
1H NMR(400MHz,CDCl3):δ9.16(d,J=8.8Hz,1H),8.86(d,J=9.1Hz,2H),8.25(d,J=7.6Hz,1H),7.41(s,1H),7.32–7.28(m,3H),7.23–7.15(m,5H),4.85(dt,J=11.0,7.4Hz,1H),4.62(dd,J=9.7,7.2Hz,1H),4.28(t,J=10.5Hz,1H),3.59–3.48(m,2H),3.45(s,3H),2.86–2.80(m,2H).
实施例16:(S)-N1-(5-甲基-4-氧代-7-(噻吩-2-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(16)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的2-乙炔基噻吩16a(22mg,0.2mmol),制得标题化合物16。
MS(ES+):m/z 474.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.3Hz,1H),7.76–7.71(m,1H),7.37–7.28(m,6H),7.24–7.21(m,2H),7.18(d,J=7.1Hz,2H),7.06(d,J=8.6Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.57(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.6Hz,1H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).
实施例17:(S)-N1-(5-甲基-4-氧代-7-(噻吩-3-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(17)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-乙炔基噻吩17a(22mg,0.2mmol),制得标题化合物17。
MS(ES+):m/z 474.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.27(d,J=6.8Hz,1H),7.55(d,J=2.2Hz,1H),7.37–7.35(m,2H),7.33–7.28(m,4H),7.24–7.13(m,5H),4.84(dt,J=11.2,7.4Hz,1H),4.61(dd,J=9.6,7.4Hz,1H),4.26(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.43(s,3H),2.84(t,J=7.1Hz,2H).
实施例18:(S)-N1-(5-甲基-4-氧代-7-((三甲基硅基)乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(18)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为等摩尔量的(三甲基硅烷基)乙炔18a,制得标题化合物18。
MS(ES+):m/z 464.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.5Hz,1H),7.33–7.28(m,5H),7.24–7.24(m,1H),7.18(d,J=6.8Hz,2H),7.10(d,J=8.8Hz,1H),4.79(dt,J=11.3,7.3Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.23(t,J=10.6Hz,1H),3.59–3.52(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),0.26(s,9H).
实施例19:(S)-N1-(5-甲基-4-氧代-7-(丙-1-炔-1-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(19)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为等摩尔量的乙炔基三甲基硅烷19a(1M的DMF溶液),制得标题化合物19。
MS(ES+):m/z 406.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.5Hz,1H),7.34–7.28(m,4H),7.24–7.20(m,2H),7.18(d,J=7.3Hz,2H),7.08(d,J=8.7Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.6,7.5Hz,1H),4.22(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.05(s,3H).
实施例20:(S)-N1-(7-乙炔基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(20)的合成
合成路线:
在室温下向化合物18(18mg,0.04mmol)的四氢呋喃(1.0mL)溶液中加入四丁基氟化铵的四氢呋喃溶液(1M,0.3mL),反应液保持在室温下搅拌0.5小时。TLC和LC-MS显示反应完全,加水(5mL)淬灭,用乙酸乙酯(5mL×3)萃取。将合并的有机层用饱和食盐水(5mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含25–40%乙酸乙酯的石油醚为洗脱液)得到标题化合物20(8mg,产率51%)为白色固体。
MS(ES+):m/z 392.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.3Hz,1H),7.36–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.14–7.09(m,1H),4.81(dt,J=11.3,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.25(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.41(s,3H),3.11(s,1H),2.84(t,J=7.0Hz,2H).
实施例21:(S)-N1-(5-甲基-4-氧代-7-((四氢-2H-吡喃-4-基)乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(21)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-乙炔基-2H-吡喃21a(22mg,0.2mmol),制得标题化合物21。
MS(ES+):m/z 476.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.3Hz,1H),7.32–7.28(m,4H),7.25–7.21(m,2H),7.18(d,J=7.2Hz,2H),7.09(d,J=8.5Hz,1H),4.80(dt,J=11.1,7.4Hz,1H),4.58(dd,J=9.6,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.97–3.92(m,2H),3.59–3.52(m,4H),3.41(s,3H),2.85–2.79(m,3H),1.93–1.89(m,2H),1.80–1.71(m,2H).
实施例22:(S)-N1-(5-甲基-7-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(22)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-乙炔基-1-甲基-1H-吡唑22a(21mg,0.2mmol),制得标题化合物22。
MS(ES+):m/z 472.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(d,J=7.4Hz,1H),7.65(s,1H),7.56(s,1H),7.34–7.28(m,5H),7.24–7.20(m,1H),7.17(d,J=7.2Hz,2H),7.12(d,J=8.7Hz,1H),4.83(dt,J=11.2,7.4Hz,1H),4.60(dd,J=9.6,7.5Hz,1H),4.24(t,J=10.5Hz,1H),3.92(s,3H),3.58–3.54(m,2H),3.42(s,3H),2.84(t,J=7.1Hz,2H).
实施例23:(S)-N1-(5-甲基-4-氧代-7-(哌啶-4-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(23)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-乙炔基哌啶盐酸盐23a(29mg,0.2mmol),制得标题化合物23。
MS(ES+):m/z 475.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.81(t,J=5.9Hz,1H),8.77(d,J=7.4Hz,1H),7.54(s,1H),7.33–7.27(m,3H),7.22–7.18(m,4H),4.68–4.58(m,2H),4.40–4.32(m,1H),3.40–3.35(m,2H),3.30(s,3H),3.22–3.19(m,2H),2.98–2.93(m,3H),2.78(t,J=7.4Hz,2H),2.03–1.98(m,2H),1.79–1.69(m,2H).
实施例24:N1-((3S)-5-甲基-4-氧代-7-(哌啶-3-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(24)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-乙炔基哌啶盐酸盐24a(29mg,0.2mmol),制得标题化合物24。
MS(ES+):m/z 475.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.82(t,J=6.1Hz,1H),8.76(d,J=7.1Hz,1H),7.52(s,1H),7.30–7.27(m,3H),7.21–7.18(m,4H),4.68–4.57(m,2H),4.38–4.34(m,1H),3.40–3.36(m,2H),3.30(s,3H),3.14–3.09(m,1H),2.90–2.85(m,1H),2.78(t,J=7.4Hz,2H),2.70–2.67(m,2H),2.64–2.58(m,1H),2.01–1.97(m,1H),1.69–1.63(m,1H),1.60–1.52(m,1H),1.48–1.42(m,1H).
实施例25:(S)-N1-(7-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(25)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-乙炔基咪唑并[1,2-b]哒嗪25a(29mg,0.2mmol),制得标题化合物25。
MS(ES+):m/z 509.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.53(d,J=3.8Hz,1H),8.26(d,J=7.2Hz,1H),8.15–8.10(m,2H),7.52–7.48(m,2H),7.32–7.28(m,3H),7.24–7.17(m,5H),4.85(dt,J=11.2,7.3Hz,1H),4.63(dd,J=9.5,7.5Hz,1H),4.28(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.45(s,3H),2.84(t,J=7.0Hz,2H).
实施例26:(S)-N1-(7-(环己-1-烯-1-基乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(26)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-乙炔基-1-环己烯26a(21mg,0.2mmol),制得标题化合物26。
MS(ES+):m/z 472.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.5Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.09(d,J=8.8Hz,1H),6.25–6.22(m,1H),4.82(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9.9,7.7Hz,1H),4.23(t,J=10.5Hz,1H),3.58–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.24–2.13(m,4H),1.71–1.61(m,4H).
实施例27:(S)-N1-(7-((3,5-二氟苯基)乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(27)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-乙炔基-3,5-二氟苯27a(28mg,0.2mmol),制得标题化合物27。
MS(ES+):m/z 504.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.25(d,J=7.4Hz,1H),7.40–7.38(m,2H),7.32–7.28(m,3H),7.25–7.21(m,1H),7.19–7.16(m,3H),7.07–7.02(m,2H),6.83(tt,J=8.9,2.3Hz,1H),4.84(dt,J=11.3,7.3Hz,1H),4.62(dd,J=9.7,7.3Hz,1H),4.27(t,J=10.5Hz,1H),3.60–3.54(m,2H),3.44(s,3H),2.84(t,J=7.1Hz,2H).
实施例28:(S)-N1-(5-甲基-4-氧代-7-(3-苯氧基丙-1-炔-1-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(28)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的苯基炔丙基醚28a(26mg,0.2mmol),制得标题化合物28。
MS(ES+):m/z 498.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.0Hz,1H),7.35–7.28(m,7H),7.24–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.11(d,J=7.9Hz,1H),7.04–7.00(m,3H),4.92(s,2H),4.80(dt,J=11.4,7.5Hz,1H),4.58(dd,J=9.9,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H).
实施例29:(S)-N1-(7-(3-羟基-3-甲基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(29)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为等摩尔量的2-甲基-3-丁炔-2-醇29a,制得标题化合物29。
MS(ES+):m/z 450.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.3Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.10(d,J=8.7Hz,1H),4.80(dt,J=11.4,7.3Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),1.86(br,1H),1.62(s,6H).
实施例30:(S)-N1-(7-(3-羟基-3-甲基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(30)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为等摩尔量的(S)-3-丁炔-2-醇30a,制得标题化合物30。
MS(ES+):m/z 436.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.3Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),4.84–4.73(m,2H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),1.90(d,J=5.4Hz,1H),1.56(d,J=6.0Hz,3H).
实施例31:(S)-N1-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(31)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-丁炔-1-醇31a(14mg,0.2mmol),制得标题化合物31。
MS(ES+):m/z 436.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.09(d,J=8.8Hz,1H),4.81(dt,J=11.1,7.3Hz,1H),4.59(dd,J=9.8,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.83(t,J=6.2Hz,2H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.70(t,J=6.3Hz,2H).
实施例32:(S)-N1-苄基-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(32)的合成
合成路线:
步骤1:(S)-N1-苄基-N2-(7-溴-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(32b)的合成
向化合物1h(111mg,0.3mmol)的乙醇(5mL)溶液中加入苄胺32a(96mg,0.9mmol),反应液升温至90℃,再搅拌4小时。TLC和LC-MS显示反应完全,且反应液中有较多白色固体析出。反应液冷却至室温后过滤,滤饼用含15%乙酸乙酯的石油醚(5mL)润洗,抽干滤饼后得到化合物32b(118mg,产率91%)为白色固体。
MS(ES+):m/z 432.0[M+H]+.
步骤2:(S)-N1-苄基-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(32)的合成
在室温下依次将化合物32b(43.2mg,0.1mmol)、双(三苯基膦)二氯化钯(II)(7.0mg,0.01mmol)、碘化亚铜(1.9mg,0.01mmol)、三乙胺(1mL)、DMF(2mL)和3-丁炔-1-醇31a(14.0mg,0.2mmol)加入到密封管中,快速地用氮气置换管内空气三次后,反应液保持在80℃下搅拌15小时。TLC和LC-MS显示反应完全,反应液冷却至室温后,加水(20mL)淬灭,用乙酸乙酯(10mL×3)萃取。将合并的有机层用饱和食盐水(10mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含25–50%乙酸乙酯的石油醚为洗脱液)得到标题化合物32(35.8mg,产率85%)为白色固体。
MS(ES+):m/z 422.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.29(d,J=7.4Hz,1H),7.56(t,J=5.7Hz,1H),7.36–7.29(m,3H),7.28–7.25(m,4H),7.10(d,J=8.7Hz,1H),4.82(dt,J=11.2,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.48(d,J=6.2Hz,2H),4.24(t,J=10.5Hz,1H),3.83(t,J=6.3Hz,2H),3.41(s,3H),2.70(t,J=6.3Hz,2H).
实施例33:(S)-N1-(2-氟苯乙基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(33)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的2-氟苯乙胺33a,制得标题化合物33。
MS(ES+):m/z 453.9[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.34(t,J=6.0Hz,1H),7.28–7.26(m,2H),7.24–7.15(m,2H),7.10–7.00(m,3H),4.81(dt,J=11.4,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.1Hz,2H),3.59–3.52(m,2H),3.40(s,3H),2.89(t,J=6.9Hz,2H),2.70(t,J=6.2Hz,2H),1.82(t,J=6.2Hz,1H)..
实施例34:(S)-N1-(3-氟苯乙基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(34)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的3-氟苯乙胺34a,制得标题化合物34。
MS(ES+):m/z 454.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.3Hz,1H),7.31–7.23(m,4H),7.10(d,J=8.8Hz,1H),6.96–6.87(m,3H),4.80(dt,J=11.1,7.5Hz,1H),4.59(dd,J=9.6,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.2Hz,2H),3.58–3.53(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.70(t,J=6.2Hz,2H),1.80(t,J=6.2Hz,1H).
实施例35:(S)-N1-(4-氟苯乙基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(35)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的4-氟苯乙胺35a,制得标题化合物35。
MS(ES+):m/z 454.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.30–7.26(m,3H),7.15–7.08(m,3H),6.98(t,J=8.6Hz,2H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.0Hz,2H),3.58–3.49(m,2H),3.40(s,3H),2.81(t,J=7.1Hz,2H),2.70(t,J=6.2Hz,2H),1.80(t,J=6.1Hz,1H).
实施例36:(S)-N1-(3,5-二氟苯乙基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(36)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的3,5-二氟苯乙胺36a,制得标题化合物36。
MS(ES+):m/z 472.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.5Hz,1H),7.33–7.27(m,3H),7.10(d,J=8.7Hz,1H),6.72–6.66(m,3H),4.80(dt,J=11.1,7.4Hz,1H),4.59(dd,J=9.6,7.5Hz,1H),4.23(t,J=10.6Hz,1H),3.83(q,J=6.2Hz,2H),3.58–3.53(m,2H),3.41(s,3H),2.83(t,J=7.1Hz,2H),2.70(t,J=6.1Hz,2H),1.78(t,J=6.3Hz,1H).
实施例37:N1-((S)-7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-(1-苯基丙烷-2-基)草酰胺(37)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的1-苯基丙烷-2-胺37a,制得标题化合物37。
MS(ES+):m/z 450.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26–8.20(m,1H),7.31–7.21(m,5H),7.17–7.13(m,3H),7.10(d,J=8.8Hz,1H),4.80(dt,J=11.1,7.5Hz,1H),4.60–4.55(m,1H),4.25–4.19(m,2H),3.86–3.81(m,2H),3.40(s,3H),2.89–2.82(m,1H),2.76–2.69(m,3H),1.81(t,J=6.0Hz,1H),1.17–1.14(m,3H).
实施例38:(S)-N1-(2-氟苄基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(38)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的2-氟苄胺38a,制得标题化合物38。
MS(ES+):m/z 440.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(d,J=7.3Hz,1H),7.58(t,J=6.0Hz,1H),7.33–7.27(m,4H),7.12–7.03(m,3H),4.81(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.53(dd,J=6.1,2.8Hz,2H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.0Hz,2H),3.40(s,3H),2.70(t,J=6.2Hz,2H),1.77(t,J=6.0Hz,1H)..
实施例39:(S)-N1-(3-氟苄基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(39)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的3-氟苄胺39a,制得标题化合物39。
MS(ES+):m/z 440.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.28(d,J=7.3Hz,1H),7.58(t,J=6.3Hz,1H),7.31–7.25(m,3H),7.12–6.96(m,4H),4.82(dt,J=11.3,7.4Hz,1H),4.61(dd,J=9.7,7.3Hz,1H),4.48(dd,J=6.2,1.4Hz,2H),4.23(dd,J=11.1,9.9Hz,1H),3.83(q,J=6.1Hz,2H),3.41(s,3H),2.70(t,J=6.3Hz,2H),1.78(t,J=6.2Hz,1H).
实施例40:(S)-N1-(4-氟苄基)-N2-(7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(40)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的4-氟苄胺40a,制得标题化合物40。
MS(ES+):m/z 440.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.28(d,J=7.4Hz,1H),7.55(t,J=5.8Hz,1H),7.28–7.22(m,4H),7.10(d,J=8.8Hz,1H),7.01(t,J=8.6Hz,2H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.44(d,J=6.2Hz,2H),4.24(t,J=10.5Hz,1H),3.83(q,J=6.2Hz,2H),3.41(s,3H),2.70(t,J=6.2Hz,2H),1.80(t,J=6.2Hz,1H).
实施例41:N1-((S)-7-(4-羟基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-(1-苯乙基)草酰胺(41)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a替换为等当量的1-苯乙胺41a,制得标题化合物41(dr=1:1)。
MS(ES+):m/z 436.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(br,1H),7.49(d,J=8.4Hz,1H),7.36–7.26(m,7H),7.12–7.09(m,1H),5.10–5.03(m,1H),4.84–4.76(m,1H),4.62–4.54(m,1H),4.27–4.18(m,1H),3.83(t,J=5.9Hz,2H),3.40(s,3H),2.70(t,J=6.2Hz,2H),1.82(br,1H),1.53(t,J=6.0Hz,3H).
实施例42:(S)-N1-(3-氟苯乙基)-N2-(7-(3-羟基-3-甲基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(42)的合成
合成路线:
与实施例32的合成路线和方法相同,除了将步骤1中的苄胺32a和步骤2中的3-丁炔-1-醇31a分别替换为等当量的3-氟苯乙胺34a和2-甲基-3-丁炔-2-醇29a,制得标题化合物42。
MS(ES+):m/z 468.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=8.0Hz,1H),7.31–7.23(m,4H),7.11(d,J=8.8Hz,1H),6.96–6.88(m,3H),4.80(dt,J=11.4,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.58–3.53(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),2.00(s,1H),1.63(s,6H).
实施例43:(S)-N1-(7-((3-羟基噁丁环-3-基)乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(43)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-丁炔-1-醇43a(20mg,0.2mmol),制得标题化合物43。
MS(ES+):m/z 464.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.0Hz,1H),7.32–7.27(m,5H),7.25–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.14(d,J=8.8Hz,1H),4.94(d,J=6.6Hz,2H),4.85–4.78(m,3H),4.60(dd,J=9.7,7.2Hz,1H),4.26(t,J=10.5Hz,1H),3.60–3.54(m,2H),3.42(s,3H),2.84(t,J=7.0Hz,2H),2.60(br,1H).
实施例44:(S)-N1-(7-((1-羟基环己基)乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(44)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-乙炔基-1-环己醇44a(25mg,0.2mmol),制得标题化合物44。
MS(ES-):m/z 488.1[M-H]-.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.11(d,J=8.6Hz,1H),4.80(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.02–1.99(m,2H),1.77–1.55(m,8H).
实施例45:(S,Z)-N1-(7-(5-羟基-3-甲基戊-3-烯-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(45)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的(Z)-3-甲基戊-2-烯-4-炔-1-醇45a(19mg,0.2mmol),制得标题化合物45。
MS(ES-):m/z 460.1[M-H]-.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.2Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.13(d,J=8.0Hz,1H),5.97(td,J=6.8,1.4Hz,1H),4.82(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9.7,7.3Hz,1H),4.41(d,J=6.2Hz,2H),4.25(t,J=10.5Hz,1H),3.59–3.52(m,2H),3.42(s,3H),2.84(t,J=7.0Hz,2H),1.99(s,3H).
实施例46:N1-((3S)-7-(3-(3-羟基吡咯烷-1-基)丙-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(46)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-(丙-2-炔-1-基)吡咯烷-3-醇46a(25mg,0.2mmol),制得标题化合物46。
MS(ES+):m/z 491.3[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.4Hz,1H),7.36–7.28(m,5H),7.24–7.20(m,1H),7.17(d,J=7.1Hz,2H),7.10(d,J=8.8Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.57(dd,J=9.6,7.4Hz,1H),4.47–4.45(m,1H),4.24(t,J=10.5Hz,1H),3.76(s,2H),3.58–3.53(m,2H),3.40(s,3H),3.17–3.11(m,1H),2.94(s,2H),2.84(t,J=7.1Hz,2H),2.78–2.72(m,1H),2.32–2.24(m,1H),1.93–1.86(m,1H).
实施例47:(S)-N1-(5-甲基-4-氧代-7-(3-(4-羰基哌啶-1-基)丙-1-炔-1-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(47)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-(丙-2-炔-1-基)哌啶-4-酮47a(27mg,0.2mmol),制得标题化合物47。
MS(ES+):m/z 503.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.23(d,J=7.4Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.17(d,J=7.1Hz,2H),7.10(d,J=8.9Hz,1H),4.81(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.70(s,2H),3.59–3.53(m,2H),3.41(s,3H),2.99(t,J=5.4Hz,4H),2.84(t,J=7.1Hz,2H),2.58(t,J=5.5Hz,4H).
实施例48:(S)-N1-(5-甲基-7-(3-吗啉基丙-1-炔-1-基)-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(48)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-(丙-2-炔-1-基)吗啉48a(25mg,0.2mmol),制得标题化合物48。
MS(ES+):m/z 491.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.4Hz,1H),7.32–7.28(m,5H),7.24–7.20(m,1H),7.17(d,J=7.1Hz,2H),7.11(d,J=8.8Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.85(t,J=4.6Hz,4H),3.62(s,2H),3.59–3.53(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.77(t,J=4.4Hz,4H).
实施例49:(S)-N1-(5-甲基-4-氧代-7-(3-(哌嗪-1-基)丙-1-炔-1-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(49)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的1-(丙-2-炔-1-基)哌嗪49a(25mg,0.2mmol),制得标题化合物49。
MS(ES+):m/z 490.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(d,J=6.8Hz,1H),7.39–7.35(m,2H),7.31–7.27(m,3H),7.23–7.19(m,1H),7.17(d,J=7.2Hz,2H),7.11(d,J=8.3Hz,1H),4.79(dt,J=11.2,6.8Hz,1H),4.57(dd,J=9.6,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.52(m,4H),3.40(s,3H),3.30–3.23(m,4H),2.95–2.87(m,4H),2.83(t,J=7.1Hz,2H).
实施例50:(S)-N1-(7-(4-氨基丁-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(50)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的丁-3-炔-1-胺50a(14mg,0.2mmol),制得标题化合物50。
MS(ES+):m/z 435.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.3Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.10(d,J=8.8Hz,1H),4.81(dt,J=11.5,7.4Hz,1H),4.58(dd,J=9.8,7.2Hz,1H),4.24(t,J=10.5Hz,1H),3.60–3.53(m,4H),3.40(s,3H),2.84(t,J=7.0Hz,2H),2.67(t,J=6.6Hz,2H).
实施例51:(S)-N1-(5-甲基-7-(4-(甲基磺酰氨基)丁-1-炔-1-基)-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(51)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的N-(丁-3-炔-1-基)甲磺酰胺51a(29mg,0.2mmol),制得标题化合物51。
MS(ES+):m/z 513.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.4Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),4.81(dt,J=11.1,7.4Hz,1H),4.63–4.57(m,2H),4.24(t,J=10.6Hz,1H),3.59–3.51(m,2H),3.41–3.35(m,5H),3.02(s,3H),2.84(t,J=7.0Hz,2H),2.73(t,J=6.4Hz,2H).
实施例52:(S)-N1-(7-(3-甲氧基丙-1-炔-1-基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(52)的合成
合成路线:
与实施例2的合成路线和方法相同,除了将环丙乙炔2a替换为等摩尔量的甲基炔丙基醚52a,制得标题化合物52。
MS(ES+):m/z 436.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.0Hz,1H),7.32–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.7Hz,1H),4.81(dt,J=11.4,7.1Hz,1H),4.59(dd,J=9.6,7.4Hz,1H),4.32(s,2H),4.24(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.46(s,3H),3.40(s,3H),2.84(t,J=7.1Hz,2H).
实施例53:(S)-2-(2-(2-(4-((5-甲基-4-氧代-3-(2-氧代-2-(苯乙胺基)乙酰氨基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-7-基)乙炔基)哌啶-1-基)乙氧基)乙氧基)乙酸叔丁酯(53)的合成
合成路线:
在室温下将化合物23(60mg,0.13mmol),碳酸钾(54mg,0.39mmol)与2-(2-(2-(甲苯磺酰氧代)乙氧基)乙氧基)乙酸叔丁酯53a(57mg,0.15mmol)的混合物溶于DMF(1.0mL)中,反应液加热至80℃,搅拌2小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(10mL),用乙酸乙酯(10mL×3)萃取。将合并的有机层用饱和食盐水(10mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经制备TLC分离纯化(含5%甲醇的二氯甲烷为洗脱液)得到标题化合物53(55mg,产率65%)为无色油状。
MS(ES+):m/z 677.1[M+H]+.
实施例54:(S)-1-(2-(2-(羧基甲氧基)乙氧基)乙基)-4-((5-甲基-4-氧代-3-(2-氧代-2-(苯乙胺基)乙酰氨基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-7-基)乙炔基)哌啶-1-正离子2,2,2-三氟乙酸盐(54)的合成
合成路线:
在室温下向化合物53(34mg,0.05mmol)的二氯甲烷(0.6mL)溶液中加入三氟乙酸(0.6mL),反应液室温下搅拌2小时。TLC和LC-MS显示反应完全,将反应液减压浓缩和真空干燥后得到标题化合物54(36mg,产率98%)为浅黄色油状。
MS(ES+):m/z 621.2[M+H]+.
实施例55:N1-((S)-7-((1-(2-(2-(2-(((R)-1-((2R,4S)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰)吡咯烷-1-基)-3,3-二甲基-1-羰基丁烷-2-基)氨基)-2-羰基乙氧基)乙氧基)乙基)哌啶-4-基)乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(55)的合成
合成路线:
在室温下将化合物54(35mg,0.05mmol)、(2R,4S)-1-((R)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-甲酰胺盐酸盐55a(25mg,0.05mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,19mg,0.1mmol)、1-羟基苯并三唑(HOBt,14mg,0.1mmol)和N,N-二异丙基乙胺(DIPEA,39mg,0.3mmol)溶解于二氯甲烷(1.0mL),反应液室温下搅拌15h。TLC和LC-MS显示反应完全,将反应液减压浓缩后,经Prep-HPLC分离纯化(含30–80%乙腈的水为流动相),得到化合物55(11mg,产率23%)为白色固体。
MS(ES+):m/z 1033.2[M+H]+
1H NMR(400MHz,CDCl3):δ8.67(s,1H),8.24(d,J=7.5Hz,1H),7.80(s,1H),7.39–7.28(m,9H),7.24–7.21(m,2H),7.17(d,J=6.9Hz,2H),7.09(d,J=8.2Hz,1H),4.83–4.77(m,2H),4.63(d,J=8.9Hz,1H),4.59–4.52(m,3H),4.42–4.38(m,1H),4.24(t,J=10.5Hz,1H),4.13–4.09(m,1H),3.97(d,J=11.0Hz,1H),3.93–3.85(m,3H),3.76–3.62(m,6H),3.58–3.48(m,3H),3.39(s,3H),3.33–3.12(m,6H),2.85–2.78(m,3H),2.51(s,3H),2.35–2.29(m,2H),2.05–2.01(m,2H),1.83(br,1H),0.99(s,9H).
实施例56:N1-((3S)-7-((1-(2-(2-(2-((2-(2,6-二羰基哌啶-3-基)-1-羰基异二氢吲哚-4-基)氨基)-2-羰基乙氧基)乙氧基)乙基)哌啶-4-基)乙炔基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(56)的合成
合成路线:
与实施例55的合成路线和方法相同,除了将(2R,4S)-1-((R)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-甲酰胺盐酸盐55a替换为等当量的3-(4-氨基-1-羰基异二氢吲哚-2-基)哌啶-2,6-二酮56a(Lenalidomide),制得标题化合物56。
MS(ES+):m/z 862.2[M+H]+
1H NMR(400MHz,DMSO-d6):δ11.01(s,1H),9.68(s,1H),8.81(t,J=5.9Hz,1H),8.74(d,J=7.3Hz,1H),7.74(d,J=7.7Hz,1H),7.57–7.47(m,3H),7.29–7.25(m,3H),7.20–7.17(m,4H),5.14(dd,J=13.2,4.8Hz,1H),4.67–4.55(m,2H),4.44–4.32(m,3H),4.14(s,2H),3.70–3.68(m,2H),3.61–3.59(m,2H),3.54(t,J=5.4Hz,2H),3.43–3.35(m,2H),3.29(s,3H),2.90–2.86(m,1H),2.77(t,J=7.5Hz,2H),2.73–2.67(m,2H),2.61–2.57(m,2H),2.39–2.33(m,2H),2.18–2.09(m,2H),2.03–1.97(m,2H),1.81–1.75(m,2H),1.56–1.48(m,2H).
实施例57:(S)-N1-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯乙草酰胺(57)的合成
合成路线:
与实施例1的合成路线和方法相同,除了将步骤1中的化合物4-溴-1-氟-2-硝基苯(1a)替换为等摩尔量的1-氟-2-硝基苯(57a),制得标题化合物57。
MS(ES+):m/z 368.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.26(d,J=7.2Hz,1H),7.32–7.28(m,3H),7.25–7.21(m,4H),7.19–7.17(m,3H),4.83(dt,J=11.2,7.5Hz,1H),4.61(dd,J=9.6,7.6Hz,1H),4.23(t,J=10.4Hz,1H),3.58–3.55(m,2H),3.42(s,3H),2.84(t,J=7.2Hz,2H).
实施例58:(S)-N1-苄基--N2-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)草酰胺(58)的合成
合成路线:
与实施例1步骤7的合成路线和方法相同,除了将化合物1h和1i分别替换为等当量的化合物57g和32a,制得标题化合物58。
MS(ES+):m/z 354.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.31(d,J=7.6Hz,1H),7.55(t,J=4.8Hz,1H),7.35–7.27(m,4H),7.24–7.17(m,5H),4.84(dt,J=11.1,7.6Hz,1H),4.62(dd,J=9.8,7.6Hz,1H),4.48(d,J=6.0Hz,2H),4.24(t,J=10.0Hz,1H),3.43(s,3H).
实施例59:(S)-N1-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-(3-苯基丙基)草酰胺(59)的合成
合成路线:
与实施例1步骤7的合成路线和方法相同,除了将化合物1h和1i分别替换为等当量的化合物47g和59a,制得标题化合物59。
MS(ES+):m/z 382.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.27(d,J=4.4Hz,1H),7.30–7.28(m,2H),7.25–7.15(m,8H),4.83(dt,J=10.9,6.8Hz,1H),4.62(dd,J=9.8,7.4Hz,1H),4.24(dd,J=11.1,9.8Hz,1H),3.42(s,3H),3.33(q,J=6.9Hz,2H),2.65(t,J=7.6Hz,2H),1.88(qn,J=7.4Hz,2H).
实施例60:(S)-N1-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯草酰胺(60)的合成
合成路线:
步骤1:(S)-2-((5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基)-2-羰基乙酸(60a)的合成
在室温下向化合物57g(60mg,0.2mmol)的四氢呋喃:甲醇:水(1:1:1,6mL)的混合溶液中加入氢氧化锂一水合物(26mg,0.6mmol),反应液室温下搅拌1小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(10mL),用稀盐酸(1N)酸化至pH=6左右,然后用乙酸乙酯(20mL×5)萃取。将合并的有机层用饱和食盐水(50mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到化合物60a(46mg)的粗产品,直接用于下一步而无需进一步纯化。
MS(ES+):m/z 263.1[M+H]+.
步骤2:(S)-N1-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-N2-苯草酰胺(60)的合成
在0℃冰浴下向化合物60a(46mg,0.17mmol)和苯胺(20mg,0.2mmol)的吡啶(0.5mL)溶液缓慢滴加三氯氧磷(72mg,0.47mmol),所得混合物在0℃下搅拌0.5小时。TLC和LC-MS显示反应完全,将反应混合物倒入冰水中(10mL),用乙酸乙酯(10mL×3)萃取。将合并的有机层用饱和食盐水(10mL)洗涤,用无水硫酸钠干燥并减压浓缩,再经Prep-HPLC分离纯化(含30–90%乙腈的水为流动相),得到化合物60(5mg,两步产率7%)为白色固体。
MS(ES+):m/z 340.1[M+H]+.
1H NMR(400MHz,CDCl3):δ9.01(s,1H),8.42(d,J=7.1Hz,1H),7.69–7.60(m,3H),7.43–7.35(m,3H),7.24–7.16(m,3H),4.88(dt,J=11.1,7.4Hz,1H),4.68(dd,J=9.7,7.5Hz,1H),4.27(dd,J=11.0,9.9Hz,1H),3.44(s,3H).
实施例61:N1-(8-溴-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(61)的合成
合成路线:
步骤1:(E)-7-溴-3,4-二氢萘-1(2H)-酮肟(61b)的合成
向7-溴-3,4-二氢萘-1(2H)-酮61a(5.0g,22mmol)的乙醇(50mL)溶液中加入盐酸羟胺(3.1g,44mmol)和乙酸钠(3.6g,44mmol),反应液在70℃下搅拌2小时。TLC和LC-MS显示反应完全,反应液冷却至室温后减压浓缩除去大部分溶剂,再将残余物倒入水中(50mL),用乙酸乙酯(50mL×3)萃取。将合并的有机层用无水硫酸钠干燥,减压浓缩后得到化合物61b(5.3g)的粗产品为黄色固体,直接用于下一步而无需进一步纯化。
MS(ES+):m/z 283.0[M+CH3CN+H]+.
1H NMR(400MHz,CDCl3):δ8.24(br,1H),8.03(d,J=2.0Hz,1H),7.37(dd,J=8.2,2.4Hz,1H),7.03(d,J=8.0Hz,1H),2.80(t,J=6.8Hz,2H),2.71(t,J=6.4Hz,2H),1.86(qn,J=6.4Hz,2H).
步骤2:8-溴-1,3,4,5-四氢-2H-苯并[b]氮杂-2-酮(61c)的合成
将五氧化二磷(5.4g,38mmol)和甲磺酸(54mL)的混合物在90℃下搅拌1小时,冷却至50℃后分五批加入化合物61b,所得混合物再在80℃下搅拌16小时。TLC和LC-MS显示反应完全,将反应混合物缓慢地倒入冰水中(100mL),用乙酸乙酯(100mL×3)萃取。将合并的有机层用无水硫酸钠干燥并减压浓缩,再经硅胶柱层析纯化(含30%乙酸乙酯的石油醚为洗脱液)得到化合物61c(3.8g,产率70%)为浅黄色固体。
MS(ES+):m/z 282.9[M+CH3CN+H]+.
1H NMR(400MHz,DMSO-d6):δ9.61(s,1H),7.27–7.24(m,1H),7.22–7.19(m,1H),7.13(d,J=2.0Hz,1H),2.65(t,J=7.2Hz,2H),2.16–2.06(m,4H).
步骤3:8-溴-1-甲基-1,3,4,5-四氢-2H-苯并[b]氮杂-2-酮(61d)的合成
在室温下向化合物61c(3.8g,16mmol)和碳酸钾(6.6g,47mmol)的DMF(30mL)溶液混合物中加入碘甲烷(4.5g,32mmol),反应混合物在室温下搅拌15小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(200mL),用乙酸乙酯(100mL×3)萃取。合并的有机层用盐水(100mL)洗涤,用无水硫酸钠干燥并减压浓缩,再经硅胶柱层析纯化(含20%乙酸乙酯的石油醚为洗脱液)得到化合物61d(3.4g,产率84%)为白色固体。
MS(ES+):m/z 255.9[M+H]+.
1H NMR(400MHz,CDCl3):δ7.31(d,J=2.0Hz,1H),7.28(dd,J=8.0,2.0Hz,1H),7.06(d,J=8.0Hz,1H),3.33(s,3H),2.67(t,J=6.8Hz,2H),2.30(t,J=6.8Hz,2H),2.17–2.14(m,2H).
步骤4:8-溴-3-碘-1-甲基-1,3,4,5-四氢-2H-苯并[b]氮杂-2-酮(61e)的合成
在0℃冰浴下向化合物61d(1.5g,5.9mmol)和N,N,N',N'-四甲基乙二胺(2.1g,17.8mmol)的二氯甲烷(15mL)溶液中逐滴加入碘代三甲基硅烷(3.6g,17.8mmol),反应混合物在0℃下搅拌1小时后,向反应液中加入碘(2.3g,8.9mmol),然后反应液在0℃下再搅拌2小时。TLC和LC-MS显示反应完全,用5%硫代硫酸钠水溶液(40mL)淬灭反应,再用二氯甲烷(40mL×3)萃取水相。合并的有机层用无水硫酸钠干燥并减压浓缩,再经硅胶柱层析纯化(含5%乙酸乙酯的石油醚为洗脱液)得到化合物61e(1.5g,产率66%)为浅黄色固体。
MS(ES+):m/z 381.7[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.61(d,J=2.0Hz,1H),7.41(dd,J=8.0,2.0Hz,1H),7.24(d,J=8.0Hz,1H),4.61(t,J=8.4Hz,1H),3.28(s,3H),2.72–2.54(m,4H),.
步骤5:3-叠氮-8-溴-1-甲基-1,3,4,5-四氢-2H-苯并[b]氮杂-2-酮(61f)的合成
在0℃冰浴下向化合物61e(1.5g,3.9mmol)的DMF(15mL)溶液中加入叠氮化钠(309mg,4.7mmol),反应混合物升温至室温后搅拌3小时。TLC和LC-MS显示反应完全,用冰水(20mL)淬灭反应后过滤,滤饼用冰水(5mL)润洗,抽干滤饼后得到化合物61f(1.1g,产率96%)为白色固体,直接用于下一步而无需进一步纯化。
MS(ES+):m/z 296.8[M+H]+.
步骤6:3-氨基-8-溴-1-甲基-1,3,4,5-四氢-2H-苯并[b]氮杂-2-酮(61g)的合成
在室温下向化合物61e(1.1g,3.7mmol)和三苯基膦(1.1g,4.0mmol)的四氢呋喃(20mL)溶液中加入水(132mg,7.3mmol),反应混合物在室温下搅拌15小时。TLC和LC-MS显示反应完全,反应液直接减压浓缩,再经硅胶柱层析纯化(含1–5%甲醇的二氯甲烷为洗脱液)得到化合物61g(790mg,产率79%)为白色固体。
MS(ES+):m/z 270.9[M+H]+.
1H NMR(400MHz,CDCl3):δ7.30–7.27(m,2H),7.08(d,J=7.6Hz,1H),3.37(s,3H),3.35–3.33(m,1H),2.77–2.68(m,1H),2.59–2.53(m,1H),2.42–2.32(m,1H),1.91–1.83(m,1H).
步骤7:2-((8-溴-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)氨基)-2-羰基乙酸乙酯(61h)的合成
在0℃冰浴下向化合物61g(790mg,2.9mmol)和三乙胺(587mg,5.8mmol)的二氯甲烷(15mL)溶液混合物中缓慢滴加草酰氯单乙酯(478mg,3.5mmol)的二氯甲烷(2mL)溶液,反应液缓慢升温至室温,再搅拌3小时。TLC和LC-MS显示反应完全,将反应混合物倒入水中(100mL),用二氯甲烷(60mL×3)萃取。合并有机层,用饱和食盐水(60mL)洗涤,用无水硫酸钠干燥并减压浓缩,然后再经硅胶柱层析纯化(含20%乙酸乙酯的石油醚为洗脱液),得到化合物61h(985mg,产率92%)为白色固体。
MS(ES+):m/z 368.9[M+H]+.
1H NMR(400MHz,CDCl3):δ8.02(d,J=6.7Hz,1H),7.37–7.33(m,2H),7.13(d,J=8.0Hz,1H),4.43(dt,J=11.0,7.4Hz,1H),4.34(q,J=7.1Hz,2H),3.41(s,3H),2.85–2.60(m,3H),2.00–1.92(m,1H),1.37(t,J=7.1Hz,3H).
步骤8:N1-(8-溴-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(61)的合成
向化合物61h(985mg,2.7mmol)的乙醇(20mL)溶液中加入2-苯乙胺1i(787mg,6.0mmol),反应液升温至90℃,再搅拌4小时。TLC和LC-MS显示反应完全,且反应液中有较多白色固体析出。反应液冷却至室温后过滤,滤饼用含15%乙酸乙酯的石油醚(10mL)润洗,抽干滤饼后得到标题化合物61(971mg,产率81%)为白色固体。
MS(ES+):m/z 446.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.5Hz,1H),7.35–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.0Hz,2H),7.11(d,J=8.6Hz,1H),4.39(dt,J=11.2,7.5Hz,1H),3.62–3.49(m,2H),3.40(s,3H),2.87–2.76(m,3H),2.64–2.53(m,2H),2.05–1.97(m,1H).
实施例62:N1-(8-(环丙基乙炔基)-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(62)的合成
合成路线:
在室温下依次将化合物61(44.4mg,0.1mmol)、双(三苯基膦)二氯化钯(II)(7.0mg,0.01mmol)、碘化亚铜(1.9mg,0.01mmol)、三乙胺(1mL)、DMF(2mL)和环丙乙炔2a(0.2mL,2.4mmol)加入到密封管中,快速地用氮气置换管内空气三次后,反应液保持在80℃下搅拌15小时。TLC和LC-MS显示反应完全,反应液冷却至室温后,加水(20mL)淬灭,用乙酸乙酯(10mL×3)萃取。将合并的有机层用饱和食盐水(10mL)洗涤,再用无水硫酸钠干燥,减压浓缩后得到粗产品,再经硅胶柱层析纯化(含20%乙酸乙酯的石油醚为洗脱液)得到标题化合物62(37.4mg,产率87%)为白色固体。
MS(ES+):m/z 430.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.25(d,J=7.6Hz,1H),7.35–7.28(m,3H),7.24–7.17(m,5H),7.12(d,J=7.7Hz,1H),4.37(dt,J=11.3,7.5Hz,1H),3.61–3.50(m,2H),3.38(s,3H),2.89–2.79(m,3H),2.63–2.52(m,2H),2.05–1.95(m,1H),1.51–1.42(m,1H),0.91–0.85(m,2H),0.83–0.79(m,2H).
实施例63:N1-(7-溴-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(63)的合成
合成路线:
与实施例61的合成路线和方法相同,除了将步骤1中的化合物7-溴-3,4-二氢萘-1(2H)-酮61a替换为等摩尔量的6-溴-3,4-二氢萘-1(2H)-酮63a,制得标题化合物63。
MS(ES+):m/z 446.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.25(d,J=7.5Hz,1H),7.45(dd,J=8.5,2.1Hz,1H),7.38(d,J=2.1Hz,1H),7.34–7.28(m,3H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.05(d,J=8.5Hz,1H),4.38(dt,J=11.2,7.5Hz,1H),3.62–3.49(m,2H),3.38(s,3H),2.89–2.80(m,3H),2.64–2.54(m,2H),2.05–1.97(m,1H).
实施例64:N1-(7-(环丙基乙炔基)-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(64)的合成
合成路线:
与实施例62的合成路线和方法相同,除了将化合物61替换为等摩尔量的化合物63,制得标题化合物64。
MS(ES+):m/z 430.2[M+H]+.
1H NMR(400MHz,CDCl3):δ8.24(d,J=7.6Hz,1H),7.36–7.27(m,4H),7.25–7.20(m,2H),7.17(d,J=7.3Hz,2H),7.07(d,J=8.2Hz,1H),4.37(dt,J=11.2,7.4Hz,1H),3.61–3.48(m,2H),3.38(s,3H),2.88–2.77(m,3H),2.62–2.52(m,2H),2.04–1.95(m,1H),1.49–1.42(m,1H),0.91–0.85(m,2H),0.83–0.79(m,2H).
实施例65:N1-(8-(4-羟基丁-1-炔-1-基)-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(65)的合成
合成路线:
与实施例62的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的3-丁炔-1-醇31a(14mg,0.2mmol),制得标题化合物65。
MS(ES+):m/z 434.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.25(d,J=7.4Hz,1H),7.35–7.28(m,3H),7.23–7.15(m,6H),4.38(dt,J=11.2,7.6Hz,1H),3.83(t,J=6.2Hz,2H),3.60–3.50(m,2H),3.39(s,3H),2.89–2.80(m,3H),2.70(t,J=6.2Hz,2H),2.65–2.53(m,2H),2.04–1.96(m,1H).
实施例66:N1-(1-甲基-2-氧代-8-(哌啶-4-基乙炔基)-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(66)的合成
合成路线:
与实施例62的合成路线和方法相同,除了将环丙乙炔2a替换为两当量的4-乙炔基哌啶盐酸盐23a(29mg,0.2mmol),制得标题化合物66。
MS(ES+):m/z 473.3[M+H]+.
1H NMR(400MHz,CDCl3):δ8.25(d,J=7.3Hz,1H),7.34–7.28(m,3H),7.23–7.16(m,6H),4.38(dt,J=11.2,7.6Hz,1H),3.58–3.52(m,2H),3.45–3.40(m,5H),3.29–3.23(m,2H),3.10–3.06(m,1H),2.88–2.81(m,3H),2.66–2.54(m,2H),2.32–2.24(m,2H),2.11–1.96(m,3H).
实施例67:N1-(1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)-N2-苯乙草酰胺(67)的合成
合成路线:
与实施例61的合成路线和方法相同,除了将步骤1中的化合物7-溴-3,4-二氢萘-1(2H)-酮61a替换为等摩尔量的3,4-二氢萘-1(2H)-酮67a,制得标题化合物67。
MS(ES+):m/z 366.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.27(d,J=7.7Hz,1H),7.34–7.27(m,4H),7.24–7.16(m,6H),4.41(dt,J=11.3,7.6Hz,1H),3.62–3.49(m,2H),3.41(s,3H),2.93–2.81(m,3H),2.66–2.56(m,2H),2.04–1.97(m,1H).
实施例68:N1-苄基-N2-(1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-3-基)草酰胺(68)的合成
合成路线:
与实施61步骤8的合成路线和方法相同,除了将化合物61h和1i分别替换为等当量的化合物67h和32a,制得标题化合物68。
MS(ES+):m/z 352.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.33(d,J=7.1Hz,1H),7.57(t,J=5.4Hz,1H),7.35–7.27(m,6H),7.23–7.17(m,3H),4.48(d,J=6.2Hz,2H),4.43(dt,J=11.3,7.5Hz,1H),3.42(s,3H),2.93–2.84(m,1H),2.68–2.58(m,2H),2.06–1.98(m,1H).
实施例69:N1-(9-甲基-8-氧代-6,7,8,9-四氢-5H-吡啶并[2,3-b]氮杂-7-基)-N2-苯乙草酰胺(69)的合成
合成路线:
与实施例61的合成路线和方法相同,除了将步骤1中的化合物7-溴-3,4-二氢萘-1(2H)-酮61a替换为等摩尔量的6,7-二氢喹啉-8(5H)-酮69a,制得标题化合物69。
MS(ES+):m/z 367.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.41(dd,J=4.8,1.5Hz,1H),8.34(d,J=7.2Hz,1H),7.58(dd,J=7.5,1.4Hz,1H),7.32–7.28(m,3H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.13(dd,J=7.5,4.8Hz,1H),4.40(dt,J=11.3,7.4Hz,1H),3.61–3.52(m,2H),3.51(s,3H),2.87–2.82(m,3H),2.74–2.62(m,2H),2.10–2.00(m,1H).
实施例70:N1-(8-氧代-6,7,8,9-四氢-5H-吡啶并[2,3-b]氮杂-7-基)-N2-苯乙草酰胺(70)的合成
合成路线:
与实施例61的步骤4–8的合成路线和方法相同,除了将步骤4中的化合物61d替换为等摩尔量的化合物69c,制得标题化合物70。
MS(ES+):m/z 353.1[M+H]+.
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),8.81(t,J=6.0Hz,1H),8.66(d,J=7.8Hz,1H),8.30(dd,J=4.8,1.2Hz,1H),7.76(d,J=7.4Hz,1H),7.30–7.26(m,2H),7.21–7.16(m,4H),4.13(dt,J=11.3,8.1Hz,1H),2.79–2.64(m,5H),2.43–2.31(m,3H).
体外激酶活性检测
RIPK1激酶活性通过ADP-Glo检测方法和RIPK1激酶反应体系(Promega,目录号:VA7593)进行检测,RIPK1激酶活性检测参考Promega试剂盒说明书。
化合物(1μM)对RIPK1激酶活性的抑制率
实验方法简述如下:RIPK1激酶反应体系中RIPK1激酶浓度通过激酶滴定和S/B10确定。化合物用1×激酶缓冲液D稀释(1%DMSO),1μL的100μM化合物DMSO储存液加入19μL 1×激酶缓冲液D。RIPK1激酶用1×激酶缓冲液D稀释。2.5×三磷酸腺苷/底物用1×激酶缓冲液D稀释,激酶反应体系中ATP终浓度为10μM,MBP底物终浓度为100μg/mL。1μL稀释的化合物和2μL稀释的RIPK1激酶混合,室温孵育15分钟,加入2μL 2.5×三磷酸腺苷/底物,混合,室温孵育1小时。每孔加入5μL ADP-Glo试剂,室温孵育1小时。每孔加入10μL ADP检测试剂,室温孵育0.5-1小时。通过酶标仪读化学发光信号,计算激酶活性抑制率。
下表1中提供了一些化合物在1μM对RIPK1激酶活性的抑制率区间:A:≥75%;B:50-74%;C:25-49%。
表1化合物(1μM)对RIPK1激酶活性的抑制率区间
体外激酶活性IC50检测
实验方法简述如下:RIPK1激酶反应体系中RIPK1激酶浓度通过激酶滴定和S/B10确定。化合物用1×激酶缓冲液D稀释(1%DMSO),1μL的1mM化合物DMSO储存液加入19μL 1×激酶缓冲液D,用1×激酶缓冲液D按1:5比例对化合物进行梯度连续稀释,共计8个浓度点,同时设相同DMSO体积的对照。RIPK1激酶用1×激酶缓冲液D稀释。2.5×三磷酸腺苷/底物用1×激酶缓冲液D稀释,激酶反应体系中ATP终浓度为10μM,MBP底物终浓度为100μg/mL。1μL稀释的化合物和2μL稀释的RIPK1激酶混合,室温孵育15分钟,加入2μL 2.5×三磷酸腺苷/底物,混合,室温孵育1小时。每孔加入5μL ADP-Glo试剂,室温孵育1小时。每孔加入10μLADP检测试剂,室温孵育0.5-1小时。通过酶标仪读化学发光信号,计算激酶活性抑制率。IC50通过GraphPad Prism中nonlinear regression curve log[inhibitor]vs.response—Variable slope(four parameters)拟合得到。
下表2中提供了一些化合物对RIPK1激酶活性的IC50区间:A<100nM;B:100-500nM;C:500-2000nM。
表2化合物对RIPK1激酶活性的IC50区间
U937中对细胞坏死凋亡的抑制活性的测定
RIPK1抑制剂的生物学活性通过对U937细胞坏死凋亡的抑制进行测定。U937细胞购于华拓生物并储存于液氮中,在实验前复苏。U937细胞使用RPMI-1640培养基(附加10%胎牛血清,100U/mL的青霉素和100μg/mL链霉素)在37℃,5%CO2条件下进行培养。通过Promega公司的CellTiter-Glo 2.0Assay细胞活力检测试剂盒试剂盒(目录号:G9242)对细胞ATP水平进行检测,以此评定化合物的活性。
化合物(1μM)对U937细胞坏死性凋亡的抑制率
实验方法简述如下:离心收集对数生长期的U937细胞,用RPMI1640培养基(附加10%胎牛血清,100U/mL的青霉素和100μg/mL链霉素)将细胞稀释成5×105个/毫升浓度的细胞悬液,以15μL/孔将细胞悬液加入白色无菌384孔细胞培养板中。测试化合物溶解于DMSO中配置成10mM储存液,并用培养基稀释成10μM,同时设相同DMSO体积的对照,每个浓度两个复孔。稀释后的化合物以2.5μL/孔加入含有细胞的384孔细胞培养板中,并于37℃,5%CO2中培养15分钟。Z-VAD-FMK(碧云天,目录号:C1202-5mg)溶解于DMSO中配置成20mM储存液,SM-164(碧云天,目录号:SC0114-10mM)溶解于DMSO中配置成10mM储存液并稀释成0.1mM,hTNF-α(义翘神州,目录号:10602-HNAE)用无菌水溶解成10μg/mL。用RPMI1640培养基(附加10%胎牛血清,100U/mL的青霉素和100μg/mL链霉素)配置TSZ混合液,混合液中Z-VAD-FMK 133.3μM,hTNF-α33.3ng/mL和SM-164 0.3μM。化合物和细胞共培养15分钟后,每孔加入7.5μL TSZ混合液,混匀,置于37℃,5%CO2中培养20小时。20小时后,取出培养板放置于室温平衡30分钟,之后每孔加入10μL室温预平衡的CellTiter-Glo试剂,震荡混匀。避光放置10分钟后用酶标仪测定各孔的化学发光读数,计算抑制率%=(1-(无TSZ-TSZ&化合物)/(无TSZ-TSZ))×100。
下表3中提供了一些化合物在1μM对U937细胞坏死性凋亡的抑制率区间:A:≥90%;B:50-89%。
表3化合物(1μM)对U937细胞坏死性凋亡的抑制率区间
化合物抑制U937细胞坏死性凋亡的EC50
实验方法简述如下:离心收集对数生长期的U937细胞,用RPMI1640培养基(附加10%胎牛血清,100U/mL的青霉素和100μg/mL链霉素)将细胞稀释成5×105个/毫升浓度的细胞悬液,以15μL/孔将细胞悬液加入白色无菌384孔细胞培养板中。测试化合物溶解于DMSO中配置成10mM储存液,并用培养基按1:3比例对化合物进行梯度连续稀释,共计10个浓度点,同时设相同DMSO体积的对照,每个浓度两个复孔。稀释后的化合物以2.5μL/孔加入含有细胞的384孔细胞培养板中,并于37℃,5%CO2中培养15分钟。Z-VAD-FMK(碧云天,目录号:C1202-5mg)溶解于DMSO中配置成20mM储存液,SM-164(碧云天,目录号:SC0114-10mM)溶解于DMSO中配置成10mM储存液并稀释成0.1mM,hTNF-α(义翘神州,目录号:10602-HNAE)用无菌水溶解成10μg/mL。用RPMI1640培养基(附加10%胎牛血清,100U/mL的青霉素和100μg/mL链霉素)配置TSZ混合液,混合液中Z-VAD-FMK 133.3μM,hTNF-α33.3ng/mL和SM-164 0.3μM。化合物和细胞共培养15分钟后,每孔加入7.5μL TSZ混合液,混匀,置于37℃,5%CO2中培养20小时。20小时后,取出培养板放置于室温平衡30分钟,之后每孔加入10μL室温预平衡的CellTiter-Glo试剂,震荡混匀。避光放置10分钟后用酶标仪测定各孔的化学发光读数,计算抑制率%=(1-(无TSZ-TSZ&化合物)/(无TSZ-TSZ))×100,EC50通过GraphPad Prism中nonlinear regression curve log[inhibitor]vs.response—Variable slope(fourparameters)拟合得到。
下表4中提供了一些化合物抑制U937细胞坏死性凋亡的EC50区间:A<100nM;B:100-500nM;C:500-2000nM。
表4化合物抑制U937细胞坏死性凋亡的EC50区间
Claims (7)
1.式(I)化合物:
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,
其中,
X选自CH和N;
Y选自-CRaRb-、-O-、-NRa-和-S(O)m-;
Z选自-O和-S;
L选自单键、-(CRaRb)n-、-(CRaRb)nO-、-(CRaRb)nS-、-(CRaRb)nNRa-、-O-、-NRa-和-S(O)m-;
环A选自C5-C10芳基、杂芳基、环烷基和杂环基,其中所述芳基、杂芳基、环烷基和杂环基任选进一步被一个或多个R6取代;
R1独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基,杂环基,和R7中的一个或多个基团取代;优选地,R1选自以下的炔基、烯基和联烯基:
R2和R3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基;
或者R1和R2与他们连接的原子一起形成C5-C10芳基、杂芳基、杂环基或环烷基,或者R2和R3与他们连接的原子一起形成C5-C10芳基、杂芳基、杂环基或环烷基,其中所述C5-C10芳基、杂芳基、杂环基或环烷基任选进一步被一个或多个R9取代;
R4和R5各自独立地选自选自氢、烷基、卤代烷基、环烷基和卤代环烷基;
R6、R7、R8和R9各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、羟基烷基、烯基、炔基、芳基、芳基氧基、杂芳基、环烷基和杂环基中的一个或多个基团取代;
Ra和Rb各自独立地选自氢、氘原子、卤素、氨基、、氰基、氧代基、羟基、巯基、烷基、烷氧基、、芳基、杂芳基、环烷基和杂环基;
或者Ra和Rb与他们连接的原子一起形成环烷基或杂环基,所述环烷基或杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基和杂环基中的一个或多个基团取代;
m为0、1或2;
n为0、1、2或3。
2.根据权利要求1所述的式I化合物或者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其中式I化合物具有以下式(II)结构:
其中,
R’选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基、-NRaRb、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、-NHC(O)Ra、-S(O)mRa、-S(O)mNRaRb和-NHS(O)mRa,其中所述烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、羟基烷基、烯基、炔基、芳基、芳基氧基、杂芳基、环烷基和杂环基中的一个或多个基团取代;
m为0、1或2;
L和环A如权利要求1中所定义。
3.根据权利要求1所述的式I化合物或者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其中式I化合物具有以下式(III)结构:
其中,
L和环A如权利要求1中所定义;
R’如权利要求2中所定义。
4.根据权利要求1-3中任一项所述的化合物或者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其中所述化合物选自下述化合物:
5.药物组合物,其包含根据权利要求1-4中任一项所述的化合物或者者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,以及任选的可药用载体。
6.如权利要求1至4中任一项所述的化合物或者者其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐在制备用于治疗或预防与RIPK1激酶活性相关的疾病或病症中的应用。
7.如权利要求6所述的应用,其中所述与RIPK1激酶活性相关的疾病或病症选自神经退行性病变和炎症性疾病、中风、冠心病和心肌梗塞、视网膜退行性疾病、炎症性肠病、肾病、肝病以及COVID-19导致的病变。
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