CN114014890A - 具有rip2激酶抑制活性的化合物,包含其的药物组合物,及其应用 - Google Patents
具有rip2激酶抑制活性的化合物,包含其的药物组合物,及其应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药技术领域,涉及一种具有NOD/RIP2通路抑制活性的氨基喹啉类化合物、包含其的组合物以及该氨基喹啉类化合物在医学中的用途,特别是用于预防和/或治疗应答于RIP2受体抑制的病症(包括肿瘤、自身免疫性疾病、神经退行性疾病、代谢性疾病以及遗传性疾病在内的多种疾病)的用途。
背景技术
NOD样受体NOD1和NOD2(即含核苷酸结合寡聚化域的蛋白质1和2)是模式识别受体(Pattern recognition receptors,PRRs),NOD1和NOD2任一发生活化都将引起细胞级联反应(Cell.Signal.18(2006)2223-2229)。例如,正常情况下,NOD2中的亮氨酸富集结构域(LPR)折叠进入中间结构域,处于自身抑制状态,但当LPR结构域被胞壁酰二肽(MDP)识别并结合时,NOD2的构象将发生变化从而自身发生活化(Science 300(2003)1584-1587;J.Biol.Chem.278(2003)5509-5512),继而通过CARD-CRAD相互作用的方式招募并活化下游的RIP2。RIP2经历自磷酸化,并在一系列E3泛素连接酶(如X染色体相关的凋亡抑制蛋白(XIAP)和细胞凋亡抑制蛋白1(cIAP1))的作用下发生泛素化。多聚泛素化的RIP2发生寡聚,促进NEMO/IKKγ的多聚泛素化和转录生长因子β激活激酶1(TAK1)的活化,TAK1的激活进一步调节TAB1和TAB2/3的招募,并导致MAPK激酶信号通路(ERK,p38,JNK)的激活和NF-κB的激活。例如,TAK1/TAB2/TAB3复合物的TAB蛋白结合k63泛素链,允许TAK1磷酸化并激活IKK复合物,IKK的激活促进IκBα的磷酸化引起IκB的解离以及NF-κB通路的激活,随后活性异二聚体p65/p50转移至细胞核,激活参与免疫反应、细胞死亡通路和生长控制的基因转录(Clinical Immunology(2021),223,108648)。
受体相互作用蛋白激酶2(RIP2,也称之为RICK、CARDIAK或CARD3)是受体相互作用丝氨酸/苏氨酸蛋白激酶家族中的一员,由位于人8号染色体上的RIP2基因编码。该61kDA的编码蛋白拥有一个碳末端的casepase招募结构域(CARD),氮末端的激酶结构域和一个中间结构域(Curr.Biol.8(1998)885-888)。RIP2在免疫***中扮演着重要作用,它可受细胞内肽聚糖传感器NOD1和NOD2调控(J.Immunol.178(2007)2380-2386),引起先天免疫应答抵御细菌和感染。起初的研究认为,RIP2的激酶活性对NF-kB通路活化和细胞因子的产生是非必要的,然而,缺乏RIP2蛋白的转基因小鼠对NOD1或NOD2激活配体均无反应,这凸显了RIP2激酶在NOD1和NOD2中的重要作用(J.Immunol.2007,178(4),2380-2386)。RIP2一经活化,丝氨酸176和酪氨酸474将发生自磷酸化,丝氨酸176的磷酸化对于RIP2的活性是必需的,酪氨酸474的磷酸化可提高RIP2活性,但对信号通路的传递来说不是必需的(Genes Dev.24(2010),2666-2677)。
NOD/RIP2依赖性的信号通路失调与诸多人类疾病相关,包括哮喘、早发性炎症性肠病、结节病、克罗恩病、多发性硬化和Blau综合征(一种超高度自体炎症性疾病)等。在脓毒症和阿尔兹海默症等病理条件下,RIP2处于上调状态。此外,RIP2在不同的癌症实体中发挥作用并作为预后标志,例如,在炎症性乳腺癌(一种罕见且攻击性很高的疾病,死亡率很高)的病人中,RIP2处于高表达状态(EMBO Mol.Med.5(2013)1278-1295;ArthritisRheum.43(2013)125-130;Pediatr.Rheumatol.Online J.12(2014)33;ScientificWorldJournal.2016(2016)2597376;J.Leukoc.Biol.94(2013)927-932;Biochem.Biophys.Res.Commun.281(2001)84-93;Cancers(Basel)10(2018))。
由于抑制RIP2激酶活性可以废除NOD1/2下游信号,因此,开发抑制RIP2激酶活性的小分子抑制剂有望减缓由NF-κB或MAPK通路活化引起的疾病或病理状态,从而产生预防和/或治疗效果,将具有广阔的临床应用前景。
发明内容
发明要解决的问题
本发明的目的是提出一种具有RIP2抑制活性的化合物,包含其的药物组合物,及其应用。
用于解决问题的方案
本发明的目的通过以下技术方案得以实现:
<第一方面>
本发明提供了一种具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,所述的化合物具有式(I)结构:
其中,
n选自0、1、2和3;
环A选自6至10元芳基和5至10元杂芳基;
R1各自独立地选自氢原子、氘原子、卤素、羟基、氨基、氰基、C1-6烷基、C3-6环烷基、O(C1-6烷基)、NH(C1-6烷基)、N(C1-6烷基)2、C2-6烯基和C2-6炔基,所述C1-6烷基、C3-6环烷基、C2-6烯基和C2-6炔基各自独立地任选被1、2或3个Ra取代;
R2选自氢原子、氘原子、C1-3烷基和C3-6环烷基,所述C1-3烷基和所述C3-6环烷基各自独立地任选被1、2或3个Rb取代;
R3选自氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基、5至10元芳基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基、5至10元芳基和5至10元杂芳基各自独立地任选被1、2或3个Rc取代;
R4选自C1-3烷基,所述C1-3烷基任选被1、2或3个Rd取代;
R5选自C1-3烷基,所述C1-3烷基任选被1、2或3个Re取代;
或者R4和R5与它们相连的磷原子一起形成5至6元杂环烷基或5至8元杂环烯基,所述5至6元杂环烷基和所述5至8元杂环烯基各自独立地任选地被1、2或3个Rd取代;
R6选自氢原子、C1-3烷基和C3-6环烷基,其中,所述C1-3烷基和所述C3-6环烷基各自独立地任选被1、2或3个Rf取代;
R7选自氢原子、氘原子、氟原子、氯原子、溴原子、羟基、氨基、氰基、C1-6烷基、C3-6环烷基、O(C1-6烷基)、NH(C1-6烷基)、N(C1-6烷基)2、C2-6烯基和C2-6炔基,所述C1-6烷基、C3-6环烷基、C2-6烯基和C2-6炔基各自独立地任选被1、2或3个Ra取代;
所述3至6元杂环烷基、所述5至6元杂环烷基、所述5至8元杂环烯基和所述5至10元杂芳基各自独立地包含1、2或3个成环杂原子或杂原子团,所述成环杂原子或原子团各自独立地选自O、S、NH、N和P(=O)。
优选地,所述的化合物,R2选自氢原子。
其中,R6的定义如上所定义。
优选地,所述的化合物,R3选自氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基和5至10元杂芳基各自独立地任选地被1、2或3个Rc取代,优选R3选自氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、3至6元杂环烷基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、3至6元杂环烷基和5至10元杂芳基各自独立地任选地被1、2或3个Rc取代;
其中,Rc的定义如上所定义。
优选地,所述的化合物,R4选自CH3,R5选自CH3。
优选地,所述的化合物,R6选自氢原子和C1-3烷基,优选氢原子。
优选地,所述的化合物,R7选自氢原子、氘原子、氟原子、氯原子和溴原子,优选氢原子和氟原子。
<第二方面>
本发明提供了下列具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体:
<第三方面>
本发明提供了一种药物组合物,该药物组合物包含根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体。
进一步地,上述药物组合物还包含至少一种药学上可接受的载体。
<第四方面>
本发明提供了一种药物制剂,该药物制剂包含根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体或者根据<第三方面>所述的药物组合物,所述药物制剂为片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂或干悬剂中的任一种。
<第五方面>
本发明提供一种药物联合形式,其包含根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据<第三方面>所述的药物组合物,或者根据<第四方面>所述的药物制剂,以及抗肿瘤药物、抗自身免疫性疾病药物、抗神经退行性疾病药物、抗代谢性疾病药物以及遗传性疾病药物中的一种或几种。
<第六方面>
本发明提供了根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据<第三方面>所述的药物组合物,或者根据<第四方面>所述的药物制剂,或者根据<第五方面>所述的药物联合形式在制备用于预防和/或治疗至少部分应答于RIP2受体的疾病和/或病症的药物中的应用。
所述疾病和/或病症包括:葡萄膜炎、皮炎、急性肺损伤、Ⅱ型糖尿病、关节炎、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、自身免疫性肝炎、哮喘、***性红斑狼疮、结节病、韦格纳肉芽肿和间质性肺病、肺纤维化、肾脏纤维化、肝纤维化、心肌梗塞、哮喘、过敏性肺炎、间质性肺病、强直性脊椎炎、多发性硬化症、全身性硬化症、多发性肌炎、类风湿性关节炎、重症肌无力、幼年发病糖尿病、肾小球肾炎、自身免疫性甲状腺炎、移植物排斥反应、Crohn病、Blau综合征、硬皮病、牛皮癣、口腔炎、视网膜色素变性、增殖性玻璃体视网膜病变、贝斯特氏卵黄状黄斑变性、湿疹、荨麻疹、脉管炎、嗜酸性筋膜炎、湿性和干性年龄相关性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、糖尿病性黄斑红肿、葡萄膜炎、视网膜静脉闭塞、囊样黄斑水肿、青光眼、帕金森、阿尔兹海默病、亨廷顿病、乳腺癌、肺癌、膀胱癌、胰腺癌、肝癌、头颈鳞状上皮癌、甲状腺癌、肉瘤、骨肉瘤、硬纤维瘤、黑色素瘤、***癌、结肠直肠癌、卵巢癌、***、食管癌、胃癌、骨髓瘤、淋巴瘤、套细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性和非进行性贫血、自发性或原发性血小板增多症、白血病、急性白血病、慢性白血病、淋巴性白血病、髓性白血病、骨髓增生异常综合征、骨髓增殖性病症、脑瘤、星形细胞瘤、髓母细胞瘤、许旺细胞瘤、原发性神经外胚瘤或者垂体瘤中的一种或几种。
<第七方面>
本发明提供了根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据<第三方面>所述的药物组合物,或者根据<第四方面>所述的药物制剂,或者根据<第五方面>所述的药物联合形式,其用于预防和/或治疗至少部分应答于RIP2受体的疾病和/或病症。
<第八方面>
本发明提供一种用于预防和/或治疗至少部分应答于RIP2受体的疾病和/或病症的方法,其包括下列步骤:将治疗有效量的根据<第一方面>、<第二方面>所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据<第三方面>所述的药物组合物,或者根据<第四方面>所述的药物制剂,或者根据<第五方面>所述的药物联合形式,施用于对其有需求的患者。
本发明的效果
本发明的具有RIP2激酶抑制活性的化合物,可用作RIP2的有效抑制剂,能够用于预防和/或治疗应答于RIP2受体的疾病和/或病症。
附图说明
图1是实施例19中化合物A6的测试结果曲线图。
图2是实施例27中化合物A6对MDP诱导的小鼠腹膜炎保护效果。
图3是实施例27中化合物A24对MDP诱导的小鼠腹膜炎保护效果。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解,现对本发明的技术方案进行以下详细说明,但不能理解为对本发明的可实施范围的限定。
为了更为清晰地描述本发明的内容,现将所涉及的术语定义如下:
术语“卤素”指单独或者以组合方式表示氟、氯、溴或碘,特别的是氟、氯或溴。
术语“C1-6烷基”指单独或者以组合方式表示包含1至6个(特别是1至3个碳原子)的饱和直链或支链的烷基,包括(但不限于)甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3,-二甲基-2-丁基等。优选地,“C1-6烷基”是甲基、乙基、正丙基、异丙基、叔丁基中的任一种。类似地,术语“C1-3烷基”单独或者以组合方式表示包含1至3个碳原子的饱和直链或支链的烷基,包括甲基、乙基、丙基、异丙基等。
术语“C2-6烯基”指单独或者以组合方式表示的包含2至6个碳原子(特别是2至4个碳原子)并且具有至少1个不饱和位点(>C=C<)的直链或支链烃基,包括(但不限于)乙烯基和烯丙基等。
术语“C2-6炔基”指单独或者以组合方式包含2至6个碳原子(特别是2至3个碳原子)并且具有至少1个炔属(-C≡C-)不饱和位点的直链或支链单价烃基,包括(但不限于)乙炔基(-C≡CH)和炔丙基(-CH2C≡CH)等。
术语“OC1-6烷基”单独或者以组合方式表示基团“C1-6烷基-O-”,其中,“C1-6烷基”表示如以上所定义。“O(C1-6烷基)”包括(但不限于)甲氧基(-OCH3)、乙氧基(-OCH2CH3)、正丙氧基(-OCH2CH2CH3)、异丙氧基(-OCH(CH3)2)、正丁氧基(-OCH2CH2CH2CH3)、仲丁氧基(-OCH(CH3)CH2CH3)、异丁氧基(-OCH2CH(CH3)2)、叔丁氧基(-OC(CH3)3)、正戊氧基(-OCH2CH2CH2CH2CH3)和新戊氧基(-OCH2C(CH3)3)等。
术语“3至8元环烷基”指单独或者以组合方式表示具有3至8个(特别是3至6个)碳原子的饱和或者部分不饱和单环或多环环烷基,包括(但不限于)环丙基、环丁基、环戊基、环己基、环庚基等。类似地,术语“C3-6环烷基”指单独或者以组合方式表示具有3至6个碳原子的饱和或者部分不饱和单环或多环环烷基。
术语“3至8元杂环基”是指包含3至8个(特别是3至6个,更特别是5至6个)用于成环的碳原子和杂原子或杂原子基团的饱和或部分不饱和单环或多环杂环基,该杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2)。“3至8元杂环基”包括(但不限于)氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、丁内酰胺基、戊内酰胺基、己内酰胺基、丁内酯基、戊内酯基或己内酯基等。类似地,术语“3至6元杂环烷基”指包含3至6个用于成环的碳原子和杂原子或杂原子基团的饱和单环或多环杂环基,杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2);术语“5至6元杂环烷基”指包含5至6个用于成环的碳原子和杂原子或杂原子基团的饱和单环或多环杂环基,杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2)。类似地,术语“3至6元杂环烯基”指包含3至6个用于成环的碳原子和杂原子或杂原子基团以及至少一个碳碳双键的单环或多环杂环基,杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2);术语“5至8元杂环烯基”指包含5至8个用于成环的碳原子和杂原子或杂原子基团以及至少一个碳碳双键的单环或多环杂环基,杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2)。
术语“芳基”表示任何稳定的6至10元单环或双环芳香族基团,包括(但不限于)苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。“芳基”上的氢原子各自独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示环上的碳原子被至少一个选自硫、氧或氮的杂原子置换形成的芳香环基团,此芳香环基团可以是5至7元单环或7至12双环基团。在本发明中,杂芳基中杂原子个数优选1、2、3或4,例如噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡啶-2(1H)-酮基、吡啶-4(1H)-酮基、吡咯基、吡唑基、噻唑基、1,2,3-***基、1,2,4-***基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、萘基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、异喹啉基和喹唑啉基等。“杂芳基”上的氢原子各自独立任选地被一个或多个本发明所描述的取代基所取代。其中,术语“5至10元杂芳基”表述具有5至10个碳原子和杂原子的杂芳环,其中杂芳环表示如以上所定义。
术语“NH(C1-6烷基)”和术语“N(C1-6烷基)2”单独或者以组合方式表示如上所定义的氨基基团,其中,氨基基团的氢原子分别被一个和两个C1-6烷基所取代,其中“C1-6烷基”表示如以上所定义。
术语“药学上可接受的盐”表示本发明的化合物以它们的药用盐的形式存在,包括酸加成盐和碱加成盐。药学上可接受的盐在S.M.Berge在J.Pharmaceutical Sciences(66卷:1-19页,1977年)中描述的pharmaceutically salts中有所描述。在本发明中,药学上可接受的无毒的酸加成盐表示本发明中的化合物与有机或无机酸形成的盐,有机或无机酸包括(但不限于)盐酸、硫酸、氢溴酸、氢碘酸、磷酸、硝酸、高氯酸、乙酸、草酸、马来酸、富马酸、酒石酸、苯磺酸、甲磺酸、水杨酸、琥珀酸、柠檬酸、乳酸、丙酸、苯甲酸、对甲苯磺酸和苹果酸等。药学上可接受的无毒的碱加成盐表示本发明中的化合物与有机或无机碱所形成的盐,包括(但不限于)碱金属盐,例如锂、钠或钾盐;碱土金属盐,例如钙或镁盐;有机碱盐,例如通过与含N基团的有机碱形成的铵盐或N+(C1-6烷基)4盐,优选为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、碳酸钙、氨水、三乙胺或四丁基氢氧化铵等。“药学上可接受的盐”可通过一般的化学方法合成。
术语“酯”用于表示有机酯,包括单酯、二酯、三酯和更通常地多酯。
术语“溶剂化物”表示一个或多个溶剂分子与本发明中的化合物所形成的缔合物。形成溶剂化物的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等。
术语“前药”表示作为本发明的化合物的化学衍生物,该衍生物在体内通过发生化学反应转换成通式I所表示的化合物。
术语“同位素标记物”表示同位素包括(但不只限于)2H,3H,11C,13C,14C,15N,17O,18O,18F,32P,35S和36Cl等。
术语“异构体”包含所有的同分异构形式包括对映异构体、非对映异构体、互变异构体和几何异构体(包括顺反异构体)。因此,本发明中所设计的化合物的单个立体化学异构体或其对映异构体、非对映异构体、互变异构体或几何异构体(或顺反异构体)的混合物都属于本发明的范围。
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如,取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基,则当取代基X为氢时,取代基Y既可以为氢,也可以为卤素、羟基、氰基、烷基或芳基;同理,当取代基Y为氢时,取代基X既可以为氢,也可以为卤素、羟基、氰基、烷基或芳基。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“预防”是指例如当患者或受试者易患病状或者处于疾病或病状的风险中时,完全或几乎完全阻止疾病或病状(例如,感染、缺血或再灌注损伤)发生;预防还可以包括抑制,即阻止病状的发展。
术语“治疗”是指:1)抑制该疾病;例如,抑制正在经历或显示疾病、病状或病症的病理学或症状学的个体的该疾病、病状或病症(即,阻止病理学和/或症状学的进一步发展);或2)改善该疾病;例如,改善正在经历或显示疾病、病状或病症的病理学或症状学的个体的该疾病、病状或病症(即,逆转病理学和/或症状学)。
术语“治疗有效量”是指研究员、兽医、医师或其他临床医生寻找的在组织、***、动物、个人或人中引发生物学或医学反应的活性化合物或药剂的量。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
在下述的实施例中,所用溶剂和药品均为分析纯或化学纯;溶剂在使用前均经过重新蒸馏;无水溶剂均按照标准方法或文献方法进行处理。
柱层析硅胶(100-200目)和薄层层析硅胶(GF254)为青岛海洋化工厂和烟台化工厂产品;如未特别说明,均采用石油醚(60-90℃)/乙酸乙酯(v/v)作为洗脱剂。
显色剂用碘或磷钼酸的乙醇溶液。
所有萃取溶剂未经说明均用无水Na2SO4干燥。
1HNMR用varian-400型核磁共振仪记录,TMS为内标。
LC-MS用美国Agilent公司1100型高效液相色谱-离子阱质谱联用仪(LC-MSDTrap)记录,二极管阵列检测器(DAD),检测波长214nm和254nm,离子阱质谱(ESI源)。
HPLC柱为AgelaDurashellC18(4.6×50mm,3.5μm);流动相为0.1%NH4HCO3水溶液:乙腈(5分钟内从5:95到95:5);流速为1.8mL/min。
本发明可以使用以下缩写:MeOH(甲醇);Ph2O(二苯醚);dioxane(1,4-二氧六环);Xantphos(4,5-双(二苯基膦)-9,9-二甲基氧杂蒽);Pd2(dba)3(三(二亚苄基丙酮)二钯);Et3N(三乙胺);con.HCl/conc.HCl(浓盐酸);sol.HCl(稀盐酸);EtOH(乙醇);DCE(1,2-二氯乙烷);DMF(N,N-二甲基甲酰胺);i-PrOH(异丙醇);AcOH(醋酸);(AcO)2O(醋酸酐);DEAD(偶氮二甲酸二乙酯);NBS(N-溴代琥珀酰亚胺);DCM(二氯甲烷);CDI(N,N-碳酰二咪唑);THF(四氢呋喃);PMBNH2(对甲氧基苄胺)。
实施例1
化合物A1,其是由如下方法合成的:
1.中间体A1-1的合成
将对碘苯胺(1g,4.57mmol)溶于甲醇(15mL)中,随后缓慢加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(1.3g,6.85mmol),室温下搅拌30分钟,有大量固体析出,过滤,滤饼用乙醇(3mL)洗涤,烘干得淡白黄色固体中间体A1-1(1.2g,70%)。1H NMR(400MHz,DMSO-d6)δ11.21(d,J=14.4Hz,1H),8.54(d,J=14.4Hz,1H),7.76(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),1.67(s,6H)。
2.中间体A1-2的合成
将二苯醚(140mL)加入到圆底烧瓶中,加热至240℃并保持温度搅拌20分钟除去溶剂水分,随后加入A1-1(1.2g,3.2mmol)到反应液中,混合物在240℃下搅拌3分钟。冷却至室温,加入石油醚(80mL),固体析出,过滤,滤饼用乙酸乙酯(20mL)打浆,过滤烘干得到白色固体中间体A1-2(850mg,98%)。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.36(s,1H),7.97-7.87(m,2H),7.37(d,J=8.4Hz,1H),6.07(d,J=7.2Hz,1H).LC-MS(m/z):271.7[M+H]+。
3.中间体A1-3的合成
将A1-2(200mg,0.74mmol)溶于三氯氧磷(5mL)中,于110℃下搅拌15分钟。浓缩除去三氯氧磷,固体残渣溶于乙酸乙酯(10mL)中,将悬浮液滴入冰水(100mL)中,加入饱和碳酸氢钠水溶液调pH值至7,用乙酸乙酯(60mL*2)萃取,合并有机相,无水硫酸钠干燥,浓缩,硅胶柱纯化(石油醚/乙酸乙酯(v/v)=5/1)得中间体A1-3(200mg,94%)。1H NMR(400MHz,DMSO-d6)δ8.87(d,J=4.0Hz,1H),8.54(s,1H),8.15(d,J=8.8Hz,1H),7.88(d,J=8.8Hz,1H),7.81(d,J=4.0Hz,1H)。
4.中间体A1-4的合成
将A1-3(200mg,0.69mmol)溶于1,4-二氧六环(5mL)中,再依次加入二甲基氧化膦(81mg,1.04mmol)、三乙胺(118mg,1.17mmol)、三(二亚苄基丙酮)二钯(32mg,0.03mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(40mg,0.07mmol),在氮气保护下,于室温搅拌过夜。过滤,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得中间体A-4(100mg,60%)。1H NMR(400MHz,DMSO-d6)δ8.96(d,J=4.4Hz,1H),8.64(d,J=12.4Hz,1H),8.27-8.13(m,2H),7.89(d,J=4.4Hz,1H),1.79(s,3H),1.76(s,3H)。
5.终产物A1的合成
将A1-4(100mg,0.42mmol)和5-氨基苯并噻唑(69mg,0.46mmol)溶于乙醇(3mL)中,滴入一滴浓盐酸,混合物在85℃下搅拌30分钟,有黄色固体析出,冷却至室温,过滤,烘干得黄色固体终产物A1(50mg,收率34%),为盐酸盐。
参照实施例1的方法合成化合物A2-A5,其区别在于,将步骤5中的5-氨基苯并噻唑分别替换为3-氨基-4-甲基苯酚、5-氟-1H-吲唑-3-胺、4,5-二甲基-1H-吡唑-3-胺和3-氨基-4-氟苯酚。
实施例2
化合物A6,其是由如下方法合成的:
1.中间体A6-1的合成
将4-溴-3-甲氧基苯胺(10g,49.49mmol)溶于乙醇(30mL)中,随后缓慢加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(13.8g,72.24mmol),室温下搅拌30分钟,有大量固体析出,过滤,滤饼用乙醇(20mL)洗涤,烘干得淡黄色固体中间体A6-1(17.3g,98%)。1H NMR(400MHz,DMSO-d6)δ11.23(d,J=14.4Hz,1H),8.64(d,J=14.8Hz,1H),7.59(d,J=8.8Hz,1H),7.43(d,J=2.4Hz,1H),7.10(dd,J=2.8Hz,J=8.8Hz,1H),3.90(s,3H),1.67(s,6H).LC-MS(m/z):353.9[M-H]-。
2.中间体A6-2的合成
将二苯醚(500mL)加入到圆底烧瓶中,加热至240℃并保持温度搅拌20分钟除去溶剂水分,随后加入A6-1(14.8g,41.55mmol)到反应液中,混合物在240℃下搅拌5分钟。冷却至室温,加入石油醚(200mL),固体析出,过滤,烘干得到白色固体中间体A6-2(9.7g,92%)。1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.17(s,1H),7.86(d,J=7.6Hz,1H),7.05(s,1H),5.99(d,J=7.2Hz,1H),3.93(s,3H).LC-MS(m/z):254.0[M+H]+。
3.中间体A6-3的合成
将A6-2(9.7g,38.18mmol)溶于三氯氧磷(40mL)中,110℃下搅拌30分钟。浓缩除去三氯氧磷,固体残渣溶于乙酸乙酯(20mL)中,将悬浮液滴入冰水(800mL)中,加入饱和碳酸氢钠水溶液调pH值至7,用乙酸乙酯(800mL)萃取,有机相用无水硫酸钠干燥,浓缩。用乙酸乙酯(50mL)打浆,过滤,烘干得白色固体中间体A6-3(6.8g,65%)。1H NMR(400MHz,DMSO-d6)δ8.81(d,J=4.8Hz,1H),8.37(s,1H),7.65(d,J=4.8Hz,1H),7.60(s,1H),4.04(s,3H).LC-MS(m/z):271.9[M+H]+。
4.中间体A6-4的合成
将A6-3(6.8g,24.95mmol)和5-氨基苯并噻唑(7.5g,49.90mmol)溶于异丙醇(200mL)中,加入浓盐酸(1mL),混合物在95℃下搅拌3小时,有固体析出,冷却至室温,过滤。滤饼用乙醇(50mL)打浆,过滤烘干得淡青色固体中间体A6-4盐酸盐(7.0g,73%)。1H NMR(400MHz,DMSO-d6)δ14.25(s,1H),11.02(s,1H),9.53(s,1H),9.16(s,1H),8.46(d,J=6.8Hz,1H),8.37(d,J=8.4Hz,1H),8.20(s,1H),7.59(d,J=8.4Hz,1H),7.53(s,1H),6.82(d,J=6.8Hz,1H),4.07(s,3H).LC-MS(m/z):386.0[M+H]+。
5.终产物A6的合成
将A6-4(5.6g,14.50mmol)溶于1,4-二氧六环(25mL)中,再依次加入二甲基氧化膦(1.7g,21.75mmol)、三乙胺(2.49g,24.65mmol)、三(二亚苄基丙酮)二钯(1.3g,1.45mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.8g,1.45mmol),在氮气保护下,于125℃微波反应4小时。过滤,滤液用碳酸氢钠饱和溶液调pH值至7,用二氯甲烷(300mL)和甲醇(50mL)混合溶剂萃取,无水硫酸钠干燥,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=15/1)得终产物A6(2.4g,收率43%)。
实施例3
化合物A7,其是由如下方法合成的:
1.中间体A7-1的合成
将A6-3(2.8g,10.27mmol)溶于1,2-二氯乙烷(10mL),于常温下滴加三溴化硼(10.3mL,31mmol),于110℃微波反应1小时。待反应体系冷却至室温,加入饱和无水亚硫酸钠溶液(20mL)淬灭反应,再加入水(50mL),用二氯甲烷(50mL*2)萃取,无水硫酸钠干燥,浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得中间体A7-1(1.7g,64%)。1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.87(d,J=5.2Hz,1H),8.42(s,1H),7.75(d,J=5.2Hz,1H),7.55(s,1H).LC-MS(m/z):257.7[M+H]+。
2.中间体A7-2的合成
将A7-1(200mg,0.77mmol)、碳酸钾(215mg,1.55mmol)溶于N,N-二甲基甲酰胺(3mL),于80℃搅拌30分钟,再加入2-溴乙醇(193mg,1.55mmol),继续搅拌过夜。反应完成后,直接浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得中间体A7-2(150mg,64%)。LC-MS(m/z):301.7[M+H]+。
3.中间体A7-3的合成
将A7-2(150mg,0.50mmol)和5-氨基苯并噻唑(93mg,0.62mmol)溶于异丙醇(3mL)中,滴入一滴浓盐酸,混合物在85℃下搅拌30分钟,有黄色固体析出,冷却至室温,过滤,烘干得黄色固体中间体A7-3盐酸盐(120mg,58%)。1H NMR(400MHz,DMSO-d6)δ14.27(s,1H),11.03(s,1H),9.53(s,1H),9.17(s,1H),8.45(d,J=6.4Hz,1H),8.37(d,J=8.4Hz,1H),8.20(s,1H),7.60(d,J=8.4Hz,1H),7.56(s,1H),6.81(d,J=6.8Hz,1H),4.28(s,2H),3.88(s,2H).LC-MS(m/z):415.6[M+H]+。
4.终产物A7的合成
将A7-3盐酸盐(120mg,0.29mmol)溶于1,4-二氧六环(3mL)中,再依次加入二甲基氧化膦(34mg,0.43mmol)、三乙胺(50mg,0.49mmol)、三(二亚苄基丙酮)二钯(26mg,0.03mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(18mg,0.03mmol),在氮气保护下,于125℃微波反应1小时。反应液中加入饱和碳酸氢钠水溶液,室温搅拌30分钟,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=20/1)得终产物A7(30mg,收率25%)。
实施例4
化合物A8,其是由如下方法合成的:
1.中间体A8-1的合成
将A7-1(200mg,0.78mmol)、碳酸钾(218mg,1.56mmol)溶于N,N-二甲基甲酰胺(3mL),于80℃搅拌30分钟,再加入1-溴-2-甲氧基乙烷(216mg,1.56mmol),继续搅拌过夜。反应完成后,直接浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得中间体A8-1(160mg,65%)。LC-MS(m/z):315.7[M+H]+。
2.中间体A8-2的合成
将A8-1(140mg,0.44mmol)和5-氨基苯并噻唑(80mg,0.53mmol)溶于异丙醇(2mL)中,滴入一滴浓盐酸,混合物在95℃下搅拌30分钟,有黄色固体析出,冷却至室温,过滤,烘干得黄色固体中间体A8-2盐酸盐(150mg,79%)。1H NMR(400MHz,DMSO-d6)δ14.30(s,1H),11.04(s,1H),9.53(s,1H),9.17(s,1H),8.45(d,J=6.0Hz,1H),8.37(d,J=8.4Hz,1H),8.20(s,1H),7.60(d,J=8.4Hz,1H),7.55(s,1H),6.81(d,J=6.4Hz,1H),4.45-4.34(m,2H),3.89-3.75(m,2H),3.39(s,3H).LC-MS(m/z):427.6[M-H]-。
3.终产物A8的合成
将A8-2(160mg,0.37mmol)溶于1,4-二氧六环(2mL)中,再依次加入二甲基氧化膦(44mg,0.56mmol)、三乙胺(64mg,0.63mmol)、三(二亚苄基丙酮)二钯(34mg,0.04mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(22mg,0.04mmol),在氮气保护下,于125℃微波反应1小时。反应液中加入饱和碳酸氢钠水溶液,室温搅拌30分钟,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=15/1)得终产物A8(16mg,收率10%)。
实施例5
化合物A9,其是由如下方法合成的:
1.中间体A9-1的合成
将A7-1(200mg,0.77mmol)、碳酸钾(215mg,1.55mmol)溶于N,N-二甲基甲酰胺(3mL),于80℃搅拌30分钟,再加入3-溴甲基-3-甲基-1-氧杂环丁烷(257mg,1.55mmol),继续搅拌过夜。反应完成后,直接浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得中间体A9-1(180mg,68%)。
2.中间体A9-2的合成
将A9-1(180mg,0.52mmol)和5-氨基苯并噻唑(94mg,0.63mmol)溶于异丙醇(3mL)中,滴入一滴浓盐酸,混合物在95℃下搅拌30分钟,有黄色固体析出,冷却至室温,过滤,烘干得黄色固体中间体A9-2盐酸盐(150mg,63%)。1H NMR(400MHz,DMSO-d6)δ14.18(s,1H),11.00(s,1H),9.53(s,1H),9.15(s,1H),8.46(d,J=6.8Hz,1H),8.38(d,J=8.4Hz,1H),8.20(s,1H),7.60(d,J=8.4Hz,1H),7.55(s,1H),6.83(d,J=6.4Hz,1H),4.65-4.55(m,2H),4.42-4.32(m,4H),1.48(s,3H).LC-MS(m/z):455.6[M+H]+。
3.终产物A9的合成
将A9-2(150mg,0.33mmol)溶于1,4-二氧六环(3mL)中,再依次加入二甲基氧化膦(38mg,0.49mmol)、三乙胺(56mg,0.56mmol)、三(二亚苄基丙酮)二钯(30mg,0.03mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(19mg,0.03mmol),在氮气保护下,于125℃微波反应1小时。反应液中加入饱和碳酸氢钠水溶液,室温搅拌30分钟,浓缩,硅胶柱纯化(二氯甲烷/甲醇=20/1)得终产物A9(26mg,收率17%)。
实施例6
化合物A10,其是由如下方法合成的:
1.中间体A10-1的合成
将4-溴-3-甲氧基苯胺(1g,4.95mmol)溶于1,2-二氯乙烷(7mL),于常温下滴加三溴化硼(4.95mL,14.85mmol),于100℃微波反应1小时。待反应体系冷却至室温,加入饱和亚硫酸钠溶液(10mL)淬灭反应,再加入水(30mL),用二氯甲烷(30mL*2)萃取,无水硫酸钠干燥,浓缩。残余物经硅胶柱纯化(石油醚/乙酸乙酯(v/v)=5/1)得中间体A10-1(660mg,71%)。LC-MS(m/z):187.8[M+H]+。
2.中间体A10-2的合成
将A10-1(660mg,3.5mmol)溶于醋酸(5mL)中,于室温将醋酸酐(396mg,3.9mmol)滴加入反应体系中,继续搅拌10分钟,有白色固体析出,加入水(200mL),过滤,得白色固体中间体A10-2(600mg,74%)。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.93(s,1H),7.47(s,1H),7.33(d,J=8.8Hz,1H),6.86(d,J=8.4Hz,1H),2.01(s,3H).LC-MS(m/z):229.8[M+H]+。
3.中间体A10-3的合成
将A10-2(600mg,2.61mmol)、三苯基膦(1.37g,5.22mmol)、偶氮二甲酸二乙酯(909mg,5.22mmol)溶于干燥的四氢呋喃(5mL)中,在氮气保护下,室温搅拌30分钟后,再加入3-羟基四氢呋喃(275mg,3.13mmol),继续搅拌2小时。反应完全后,浓缩,硅胶柱纯化(石油醚/乙酸乙酯(v/v)=5/1)得白色固体中间体A10-3粗品(960mg)。LC-MS(m/z):299.7[M+H]+。
4.中间体A10-4的合成
将中间体A10-3粗品(960mg)溶于乙醇(15mL)中,向反应体系中滴入浓盐酸(4mL),于85℃下搅拌3小时。反应完成后,浓缩得无色油状中间体A10-4粗品(620mg)。LC-MS(m/z):257.8[M+H]+。
5.中间体A10-5的合成
将A10-4(620mg,2.4mmol)溶于乙醇(15mL)中,随后缓慢加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(490mg,2.6mmol),室温下搅拌10分钟,有固体析出,过滤,滤饼用乙醇(3mL)洗涤,烘干得淡白黄色固体中间体A10-5(430mg,43%)。1H NMR(400MHz,DMSO-d6)δ11.22(d,J=14.4Hz,1H),8.61(d,J=14.4Hz,1H),7.60(d,J=8.4Hz,1H),7.44(s,1H),7.12(d,J=8.4Hz,1H),5.20(s,1H),3.98-3.74(m,4H),2.32-2.20(m,1H),2.04-1.95(m,1H),1.68(s,6H).LC-MS(m/z):409.6[M-H]-。
6.中间体A10-6的合成
将二苯醚(60mL)加入到圆底烧瓶中,加热至240℃并保持温度搅拌20分钟除去溶剂水分,随后加入A10-5(430mg,1.04mmol)到反应液中,混合物在240℃下搅拌5分钟。冷却至室温,加入石油醚(30mL),固体析出,过滤,烘干得到白色固体中间体A10-6(250mg,77%)。1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.17(s,1H),7.87(d,J=7.6Hz,1H),7.04(s,1H),5.99(d,J=7.6Hz,1H),5.14(s,1H),3.99-3.77(m,4H),2.35-2.26(m,1H),2.11-2.02(m,1H).LC-MS(m/z):310.0[M+H]+。
7.中间体A10-7的合成
将A10-6(250mg,0.81mmol)溶于三氯氧磷(5mL)中,110℃下搅拌30分钟。反应完成后,浓缩得中间体A10-7粗品(280mg)。
8.中间体A10-8的合成
将A10-7粗品(220mg,0.67mmol)和5-氨基苯并噻唑(111mg,0.74mmol)溶于异丙醇(5mL)中,滴入一滴浓盐酸,在95℃下搅拌30分钟,有黄色固体析出,冷却至室温,过滤,烘干得中间体A10-8盐酸盐(190mg,64%)。1H NMR(400MHz,DMSO-d6)δ14.48(s,1H),11.12(s,1H),9.53(s,1H),9.22(s,1H),8.46(d,J=7.2Hz,1H),8.37(d,J=8.8Hz,1H),8.20(s,1H),7.65(s,1H),7.59(d,J=8.4Hz,1H),6.81(d,J=7.2Hz,1H),5.27(s,1H),4.03-3.93(m,4H),2.45-2.37(m,1H),2.16-2.07(m,1H).LC-MS(m/z):442.0[M+H]+。
9.终产物A10的合成
将A10-8(190mg,0.43mmol)溶于1,4-二氧六环(3mL)中,再依次加入二甲基氧化膦(40mg,0.52mmol)、三乙胺(65mg,0.65mmol)、三(二亚苄基丙酮)二钯(37mg,0.04mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(23mg,0.04mmol),在氮气保护下,于125℃微波反应1小时。过滤,用饱和碳酸氢钠溶液调pH值至7,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得终产物A10(45mg,收率24%)。
参照实施例6的方法合成化合物A14-A15,其区别在于,将步骤3中的3-羟基四氢呋喃分别替换为(R)-3-羟基四氢呋喃和(S)-3-羟基四氢呋喃。
实施例7
化合物A11,其是由如下方法合成的:
1.中间体A11-1的合成
将4-硝基苯胺(10g,72.5mmol)溶于二氯甲烷(60mL)中,加入NBS(13g,72.5mmol),常温搅拌过夜。向反应液中加入饱和碳酸氢钠水溶液(50mL)搅拌5分钟,有机相用无水硫酸钠干燥,过滤,滤液浓缩干得黄色固体产物A11-1(15g,96%)。LC-MS(m/z):216.7[M+H]+。
2.中间体A11-2的合成
将A11-1(7.0g,32.3mmol)溶于醋酸(80mL),冰浴下逐滴加到含有亚硝酸钠(2.4g,34.8mmol)的浓硫酸溶液(16mL)中,搅拌4小时后,加入含有碘化钾(16g,96.9mmol)和碘(3.5g,32.3mmol)的水溶液(60mL),常温搅拌过夜。向反应中加入质量浓度为15%NaOH水溶液(200mL),水相用乙酸乙酯(300mL)萃取,有机相用无水硫酸钠干燥,过滤并减压浓缩干得粗品A11-2(10.0g,95%)。
3.中间体A11-3的合成
将粗品A11-2(10.0g,30.7mmol)溶于乙醇(60mL),加入氯化铵(8.2g,153mmol)和铁粉(8.5g,153mmol),于85℃下搅拌2h。过滤,滤液浓缩,剩余物经硅胶柱层析得黄色固体A11-3(6.0g,65%)。1H NMR(400MHz,CDCl3)δ8.45(s,1H),8.08(d,J=8.8Hz,1H),7.85(d,J=8.4Hz,1H),LC-MS(m/z):297.6[M+H]+。
3.中间体A11-4的合成
将A11-3(6g,20mmol)加到乙醇(30mL)中,再加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(7.4g mg,40mmol),常温搅拌2h。过滤,滤饼加到二苯醚(30mL)中,于220℃下搅拌3min。冷却至室温,过滤,得滤饼A11-4(4g)。LC-MS(m/z):349.5[M+H]+。
4.中间体A11-5的合成
将A11-4(2g,5.75mmol)加到三氯氧磷(20mL)中,在110℃下反应2小时。将反应液减压浓缩干,加入乙酸乙酯(20mL*2)后旋干,向剩余物中加入5-氨基苯并噻唑(950mg,6.33mmol)和异丙醇(15mL),升温至95℃,搅拌过夜。将反应液浓缩,加入饱和碳酸氢钠水溶液(50mL)调节pH值至7-8,水相用乙酸乙酯(100mL)萃取,有机相浓缩后,剩余物经硅胶柱层析(二氯甲烷:甲醇(v/v)=50:1)纯化得黄色固体产物A11-5(950mg,35%)。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.09(s,1H),8.48(d,J=5.6Hz,1H),8.24-8.21(m,2H),8.04(d,J=2.0Hz,1H),7.53(dd,J=4.2,2.0Hz,1H),7.01(d,J=5.6Hz,1H).LC-MS(m/z):481.4[M+H]+。
5.中间体A11-6的合成
将A11-5(800mg,1.60mmol)、Pd2(dba)3(73mg,0.08mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(93mg,0.16mmol)、二甲基氧化膦(187mg,2.40mmol)和三乙胺(323mg,3.20mmol)加到1,4-二氧六环(10mL)中,氮气保护下于70℃搅拌过夜。将反应液浓缩,剩余物经硅胶柱层析(二氯甲烷:甲醇(v/v)=50:1)纯化得黄色固体产物A11-6(240mg,33%)。1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),9.53(s,1H),9.18(d,J=12.8Hz,1H),8.55(d,J=6.8Hz,1H),8.42-8.31(m,2H),8.19(s,1H),7.59(d,J=8.4Hz,1H),6.92(d,J=6.4Hz,1H),2.00(s,3H),1.96(s,3H).LC-MS(m/z):432.0[M+H]+。
6.终产物A11的合成
将A11-6(60mg,0.14mmol)、Pd(dppf)Cl2(10mg,0.014mmol)、1-甲基-1H-吡唑-4-基硼酸(35mg,0.28mmol)和碳酸钾(40mg,0.28mmol)混悬于1,4-二氧六环/水(10mL/0.5mL)中,氮气保护下于100℃搅拌过夜。将反应液浓缩,剩余物经硅胶柱层析(二氯甲烷/甲醇(v/v)=10/1)纯化得青色固体产物A11(10mg,收率17%)。
参照实施例7的方法合成化合物A12、A27,区别在于,将实施例7中的1-甲基-1H-吡唑-4-基硼酸分别替换为1H-吡唑-3-基硼酸和(3,5-二甲基异噁唑-4-基)硼酸。
实施例8
化合物A13,其是由如下方法合成的:
1.终产物A13的合成
将A11-6(50mg,0.12mmol)、Pd(dppf)Cl2(10mg,0.014mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(90mg,0.24mmol)和碳酸钾(40mg,0.28mmol)混悬于1,4-二氧六环/水(10mL/0.5mL)中,氮气保护下于100℃搅拌过夜。将反应液浓缩,剩余物经硅胶柱层析(二氯甲烷:甲醇(v/v)=10:1)纯化得黄色固体粗品(50mg)。加入EtOH(2mL),滴加HCl/EA(1.5M,2mL)。常温搅拌2h,有固体析出。滤饼溶入MeOH(3mL)后,加入无水***(15mL),有固体析出,过滤得黄色固体产物A13(20mg,17%),为盐酸盐。
实施例9
化合物A16,其是由如下方法合成的:
1.中间体A16-1的合成
将A7-1(200mg,0.77mmol)、碳酸钾(211mg,1.54mmol)溶于N,N-二甲基甲酰胺(3mL),于80℃搅拌30分钟,再加入3-溴氧杂环丁烷(213mg,1.54mmol),继续搅拌过夜。反应完成后,直接浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=60/1)得中间体A16-1(150mg,62%)。1H NMR(400MHz,DMSO-d6)δ8.81(d,J=4.0Hz,1H),8.43(s,1H),7.68(d,J=4.4Hz,1H),7.25(s,1H),5.66-5.56(m,1H),5.11-5.03(m,2H),4.68-4.61(m,2H).LC-MS(m/z):314.0[M+H]+。
2.中间体A16-2的合成
将A16-1(150mg,0.48mmol)和5-氨基苯并噻唑(78mg,0.52mmol)溶于乙醇(2mL)中,滴入一滴浓盐酸,混合物在80℃下搅拌5小时,有黄色固体析出,冷却至室温,过滤,烘干得黄色固体中间体A16-2盐酸盐(170mg,83%)。1H NMR(400MHz,DMSO-d6)δ14.34(s,1H),11.08(s,1H),9.53(s,1H),9.22(s,1H),8.47(d,J=6.4Hz,1H),8.37(d,J=8.4Hz,1H),8.19(s,1H),7.59(d,J=8.4Hz,1H),7.27(s,1H),6.82(d,J=6.4Hz,1H),5.62-5.52(m,1H),5.10-5.01(m,2H),4.76-4.65(m,2H).LC-MS(m/z):428.0[M+H]+。
3.终产物A16的合成
将A16-2(170mg,0.40mmol)溶于1,4-二氧六环(2mL)中,再依次加入二甲基氧化膦(46mg,0.60mmol)、三乙胺(60mg,0.60mmol)、三(二亚苄基丙酮)二钯(36mg,0.04mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(23mg,0.04mmol),在氮气保护下,于125℃微波反应2小时。过滤,用饱和碳酸氢钠溶液调pH值至7,浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=15/1)得终产物A16(30mg,收率18%)。
参照实施例9的方法合成化合物A21,区别在于,将实施例9步骤1中的3-溴氧杂环丁烷替换为溴代环丁烷。
实施例10
化合物A18,其是由如下方法合成的:
1.中间体A18-1的合成
将(R)-(-)-甘油醇缩丙酮(1.0g,7.6mmol)、四溴化碳(3.2g,10.0mmol)依次溶于二氯甲烷(50mL),在常温下将三苯基膦(2.0g,7.6mmol)的二氯甲烷溶液(30mL)用恒压滴液漏斗滴入,并于常温下搅拌过夜。浓缩,加入石油醚(50mL)和5%碳酸氢钠水溶液(50mL),搅拌,有白色固体析出。过滤,滤液用乙酸乙酯(50mL)萃取,有机相再用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥,浓缩。残余物经硅胶柱纯化(石油醚/乙酸乙酯(v/v)=10/1)得无色油状中间体A18-1(340mg,23%)。
2.中间体A18-2的合成
将A7-1(150mg,0.58mmol)、碳酸钾(160mg,1.16mmol)溶于N,N-二甲基甲酰胺(3mL),于80℃搅拌30分钟后,再加入A18-1(340mg,1.75mmol),继续搅拌过夜。直接浓缩,残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得黄色固体中间体A18-2(130mg,20%)。1H NMR(400MHz,DMSO-d6)δ8.81(d,J=4.8Hz,1H),8.39(s,1H),7.67–7.64(m,2H),4.54–4.48(m,1H),4.39–4.34(m,1H),4.32–4.27(m,1H),4.17–4.13(m,1H),3.93–3.88(m,1H),1.40(s,3H),1.34(s,3H).LC-MS(m/z):371.9[M+H]+.
3.中间体A18-3的合成
将A18-2(130mg,0.35mmol)和5-氨基苯并噻唑(58mg,0.38mmol)溶于乙醇(3mL)中,滴入一滴0.5N盐酸,混合物在85℃下搅拌1.5小时,浓缩。残余物用二氯甲烷(20mL)和甲醇(10mL)混合溶剂溶解澄清,加入饱和碳酸氢钠水溶液(1mL),搅拌后直接浓缩。残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=50/1)得黄色固体中间体A18-3(130mg,77%)。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.24(s,1H),8.75(s,1H),8.43(d,J=5.2Hz,1H),8.19(d,J=8.8Hz,1H),8.01(d,J=1.6Hz,1H),7.52(dd,J=8.8Hz,J=2.0Hz,1H),7.43(s,1H),6.92(d,J=5.6Hz,1H),4.54–4.48(m,1H),4.33–4.28(m,1H),4.27–4.22(m,1H),4.18–4.13(m,1H),3.94–3.89(m,1H),1.41(s,3H),1.35(s,3H).LC-MS(m/z):486.0[M+H]+.
4.中间体A18-4的合成
将中间体A18-3(130mg,0.27mmol)溶于1,4-二氧六环(2mL)中,再依次加入二甲基氧化磷(31mg,0.40mmol)、三乙胺(46mg,0.46mmol)、三二亚苄基丙酮二钯(25mg,0.03mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(15mg,0.03mmol),在氮气保护下,于125℃微波反应2小时。浓缩,残余物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=10/1)得黄色固体中间体A18-4(120mg,93%)。1H NMR(300MHz,DMSO-d6)δ10.23(s,1H),9.45(s,1H),8.92(d,J=13.8Hz,1H),8.46(d,J=5.7Hz,1H),8.23(d,J=5.7Hz,1H),8.07(s,1H),7.54(dd,J=8.1Hz,J=1.2Hz,1H),7.41(d,J=3.9Hz,1H),6.90(d,J=5.7Hz,1H),4.62–4.55(m,1H),4.38–4.36(m,1H),4.26–4.21(m,1H),4.18–4.12(m,1H),3.88–3.82(m,1H),1.79(dd,J=13.8,4.2Hz,6H),1.40(s,3H),1.34(s,3H).LC-MS(m/z):484.1[M+H]+.
5.终产物A18的合成
将中间体A18-4(120mg,0.25mmol)溶于乙醇(5mL),加入3N盐酸乙酸乙酯(2mL),于室温搅拌2小时。有固体析出,浓缩,残余物用二氯甲烷(20mL)和甲醇(10mL)混合溶剂溶解澄清,用饱和碳酸氢钠水溶液调pH至7,直接浓缩。残余物用18C柱纯化(水/甲醇(v/v)=60/40)得黄色固体终产物A18(90mg,收率82%)。
参照实施例10的方法合成化合物A19,区别在于,将实施例10步骤1中的(R)-2,2-二甲基-1,3-二氧杂环戊烷-4-基甲醇替换为(S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基甲醇。
实施例11
化合物A20,其是由如下方法合成的:
1.中间体A20-1的合成
将4-溴-3-氟苯胺(500mg,2.63mmol)溶于乙醇(10mL)中,随后缓慢加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(587mg,3.16mmol),室温下搅拌2小时,有大量固体析出,过滤,滤饼用甲醇(10mL)洗涤,烘干得白色固体中间体A20-1(820mg,91%)。1HNMR(300MHz,DMSO-d6)δ11.24(d,J=14.1Hz,1H),8.58(d,J=14.4Hz,1H),7.84–7.68(m,2H),7.42(dd,J=8.7,1.5Hz,1H),1.67(s,6H).LC-MS(m/z):342.0[M-H]-.
2.中间体A20-2的合成
将二苯醚(50mL)加入到圆底烧瓶中,加热至240℃并保持温度搅拌30分钟除去溶剂水分,随后加入A20-1(800mg,2.32mmol)到反应液中,混合物在240℃下搅拌3分钟。冷却至室温,加入石油醚(50mL),白色固体析出,过滤,滤饼烘干得到白色固体中间体A20-2粗品(450mg,80%)。1H NMR(300MHz,DMSO-d6)δ11.92(s,1H),8.28(d,J=7.8Hz,1H),7.96(d,J=7.2Hz,1H),7.47(d,J=9.6Hz,1H),6.08(d,J=7.8Hz,1H).LC-MS(m/z):242.0[M+H]+.
3.中间体A20-3的合成
将A20-2(450mg,1.86mmol)溶于三氯氧磷(3mL)中,110℃下搅拌2小时。浓缩除去三氯氧磷,固体残渣溶于乙酸乙酯(20mL)中,将悬浮液滴入冰水(60mL)中,加入饱和碳酸氢钠水溶液调pH至7,用乙酸乙酯(20mL)萃取,有机相用无水硫酸钠干燥,浓缩。残余物经硅胶柱纯化(石油醚/乙酸乙酯(v/v)=50/1)得白色固体中间体A20-3(274mg,57%)。1H NMR(300MHz,DMSO-d6)δ8.90(d,J=4.8Hz,1H),8.52(d,J=7.2Hz,1H),7.08(d,J=9.6Hz,1H),7.82(d,J=4.8Hz,1H).LC-MS(m/z):260.0[M+H]+.
4.中间体A20-4的合成
将A20-3(250mg,0.96mmol)和5-氨基苯并噻唑(157mg,1.06mmol)溶于异丙醇(2mL)中,加入一滴浓盐酸,混合物在95℃下搅拌1小时,有黄色固体析出,浓缩。残余物溶于甲醇(15mL)和二氯甲烷(30mL)混合溶剂,加入饱和碳酸氢钠水溶液调pH至7,直接浓缩得白色固体中间体A20-4(320mg,89%)。1H NMR(300MHz,DMSO-d6)δ9.47–9.39(m,2H),8.92(d,J=7.8Hz,1H),8.49(d,J=5.1Hz,1H),8.21(d,J=8.7Hz,1H),8.04(s,1H),7.78(d,J=10.2Hz,1H),7.54(d,J=7.8Hz,1H),6.99(d,J=4.8Hz,1H).LC-MS(m/z):373.9[M+H]+.
5.终产物A20的合成
将A20-4(320mg,0.86mmol)溶于1,4-二氧六环(2mL)中,再依次加入二甲基氧化磷(100mg,1.28mmol)、三乙胺(130mg,1.28mmol)、三二亚苄基丙酮二钯(78mg,0.09mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(49mg,0.09mmol),在氮气保护下,于125℃微波反应2小时。直接浓缩,硅胶柱纯化(二氯甲烷/甲醇(v/v)=15/1)得黄色固体终产物A20(117mg,收率37%)。
实施例12
化合物A23,其是由如下方法合成的:
1.中间体A23-1的合成
将2-氨基-4-甲氧基苯甲酸(15.0g,89.7mmol)溶于N,N-二甲基甲酰胺(50mL)中,于0℃下分批加入N-溴代丁二酰亚胺(16.0g,89.7mmol)后,移至常温搅拌1小时。TLC检测反应完成后,反应液浓缩,加入乙酸乙酯(200mL),石油醚(200mL)混合溶解打浆,过滤固体得灰色固体中间体A23-1(18.0g,82%)。1H NMR(400MHz,DMSO-d6)δ7.76(s,1H),6.41(s,1H),3.79(s,3H).LC-MS(m/z):246.0[M+H]+.
2.中间体A23-2的合成
在室温下将硝基甲烷(21.9g,359.2mmol)滴加到氢氧化钠(53.9g,1347.5mmol)的水溶液(50mL)中。随后在搅拌下将混合物在45℃下加热5分钟,然后将反应溶液冷却至室温再次加入硝基甲烷(21.9g,359.2mmol)。随后将反应混合物搅拌10分钟后,移至50℃再加热5分钟,将混合物冷却至室温,并倒入冰(500g)中,用浓盐酸将水溶液酸化至pH<2,立即加入到A23-1(22.0g,89.8mmol)的水悬浮溶液(300mL)中,再加入浓盐酸(161.5mL)。将获得的悬浮液搅拌过夜后,过滤得黄色固体中间体A23-2(24.0g,85%)。1H NMR(300MHz,DMSO-d6)δ13.07(d,J=13.5Hz,1H),8.19(dd,J=13.2,6.3Hz,1H),8.09(s,1H),7.35(s,1H),6.82(d,J=6.3Hz,1H),3.99(s,3H).LC-MS(m/z):314.9[M-H]-.
3.中间体A23-3的合成
将A23-2(2.0g,6.3mmol)溶于N,N-二甲基甲酰胺(300mL)中,加入N,N-羰基二咪唑(1.5g,9.45mmol),于60℃下加热过夜。TLC监测反应完成后,反应液浓缩,加入乙腈(300mL),析出固体后,过滤得棕色固体中间体A23-3(1.4g,74.2%)。1H NMR(300MHz,DMSO-d6)δ8.58(s,1H),7.76(s,1H),6.67(s,1H),6.64(s,1H),3.42(s,3H).LC-MS(m/z):299.0[M+H]+.
4.中间体A23-4的合成
将A23-3(14.0g,46.9mmol)溶于三氯氧磷(100mL)中,加入N,N-二甲基甲酰胺(2mL),于110℃加热过夜。反应完成后,旋蒸除去三氯氧磷,加入乙酸乙酯(20mL×2)再次旋蒸除去。向残余物加入二氯甲烷(100mL),水(100mL)搅拌半小时后,分液。用二氯甲烷(200mL×2)萃取水相,收集有机相,无水硫酸钠干燥,硅胶柱层析(二氯甲烷)得白色固体中间体A23-4(3.36g,23%)。1H NMR(300MHz,CDCl3)δ9.25(s,1H),8.64(s,1H),7.51(s,1H),4.11(s,3H).
5.中间体A23-5的合成
将A23-4(3.4g,10.6mmol)溶于异丙醇(100mL)与水(25mL)的混合溶剂中,加入铁粉(3.0g,53.2mmol),氯化铵(2.8g,53.2mmol),于75℃下反应2小时。反应完成后,通过硅藻土过滤,加入二氯甲烷(100mL×3)萃取,加入水(200mL),收集有机相,无水硫酸钠干燥,硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)得棕色固体中间体A23-5(2.5g,86%)。1H NMR(300MHz,DMSO-d6)δ8.54(s,1H),8.04(s,1H),7.41(s,1H),5.96(s,2H),3.94(s,3H).LC-MS(m/z):287.0[M+H]+.
6.中间体A23-6的合成
将A23-5(2.5g,8.74mmol)溶于无水四氢呋喃(20mL)中,冷却至-10℃下,加入四氟硼酸亚硝(1.1g,9.42mmol),将混合物在0℃搅拌50分钟后过滤,得黄色固体。将固体在红外下烘干后,加到170℃的十氢萘中,反应5分钟后,停止加热。将十氢萘旋蒸去除,溶于二氯甲烷,硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)得白色固体中间体A23-6(435mg,17%)。1HNMR(300MHz,CDCl3)δ8.76(s,1H),8.39(s,1H),7.46(s,1H),4.05(s,3H).LC-MS(m/z):289.9[M+H]+.
7.中间体A23-7的合成
将A23-6(435mg,1.5mmol)溶于乙醇(30mL)中,加入1,3-苯并噻唑胺(225mg,1.5mmol),加入1滴浓盐酸于85℃下反应2小时,反应完成后,硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)得白色固体中间体A23-7(85mg,14%)。1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),9.24(s,1H),8.77(d,J=3.3Hz,1H),8.63(s,1H),8.04(d,J=8.7Hz,1H),7.59(s,1H),7.50(s,1H),7.23(d,J=7.5Hz,1H),4.01(s,3H).LC-MS(m/z):403.9[M+H]+.
8.终产物A23的合成
将A23-7(90mg,0.22mmol)溶于1,4-二氧六环(3mL),加入二甲基氧化膦(19mg,0.24mmol),Pd2(dba)3(20mg,0.02mmol),Xantphos(13mg,0.02mmol),三乙胺(45mg,0.12mmol),氮气保护,微波125℃下反应2小时。反应完成,硅胶柱层析(二氯甲烷/甲醇(v/v)=20/1)。向所得粗产物中加入混合溶剂乙酸乙酯/***(1mL/4mL)打浆,过滤得黄色固体终产物A23(14mg,收率16%)。
实施例13
化合物A24,其是由如下方法合成的:
1.中间体A24-1的合成
将3-三氟甲氧基苯胺(1.0g,5.6mmol)溶于N,N-二甲基甲酰胺(3mL)中,之后将N-溴代琥珀酰亚胺(1.0g,5.6mmol)溶于N,N-二甲基甲酰胺(2mL)中,用恒压滴液漏斗逐滴加入反应体系。混合物在常温下反应1小时,之后向混合物中加入水(10mL),用乙酸乙酯(15mL×3)萃取,浓缩有机相,硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化得黑色油状物中间体A24-1(1.3g,91%)。1H NMR(300MHz,DMSO-d6)δ7.31(d,J=8.4Hz,1H),6.66(s,1H),6.51(d,J=6.9Hz,1H).LC-MS(m/z):255.9[M+H]+.
2.中间体A24-2的合成
将中间体A24-1(0.99g,3.9mmol)溶于乙醇(6mL)中,加入5-(甲氧基亚甲基)-2,2-二甲基-1,3-二恶烷-4,6-二酮(1.08g,5.8mmol),室温下搅拌10分钟。固体析出,过滤固体,滤饼烘干得白色固体中间体A24-2(1.5g,94%)。1H NMR(300MHz,CDCl3)δ11.26(d,J=13.8Hz,1H),8.57(d,J=13.8Hz,1H),7.71(d,J=8.4Hz,1H),7.19(s,1H),7.10(d,J=8.1Hz,1H),1.77(s,6H).LC-MS(m/z):407.9[M-H]-.
3.中间体A24-3的合成
将二苯醚(20mL)在240℃下加热约10分钟,之后加入中间体A24-2(1.5g,3.7mol)反应1分钟,反应体系中无气泡产生。将混合物冷却至室温,加入石油醚(20mL)搅拌,10分钟后过滤,用石油醚(10mL)洗涤滤饼,得淡黄色固体中间体A24-3(0.98g,86%)。1H NMR(300MHz,DMSO-d6)δ11.97(s,1H),8.35(s,1H),8.02(d,J=7.5Hz,1H),7.70(s,1H),6.13(d,J=7.5Hz,1H).LC-MS(m/z):307.9[M+H]+.
4.中间体A24-4的合成
将中间体A24-3(0.98g,3.2mmol)溶于三氯氧磷(10mL)中,混合物在110℃下搅拌3小时。之后将反应体系浓缩,加入乙酸乙酯(10mL)将其溶解,之后滴加进冰水(20mL)中,用饱和碳酸氢钠调节pH至7,再用乙酸乙酯(20mL×3)萃取,合并有机相,浓缩,硅胶柱层析(二氯甲烷/甲醇(v/v)=50/1)纯化得黄色固体中间体A24-4(1.01g,96%)。1H NMR(300MHz,DMSO-d6)δ8.96(d,J=4.8Hz,1H),8.60(s,1H),8.19(s,1H),7.90(d,J=4.8Hz,1H).LC-MS(m/z):325.9[M+H]+.
5.中间体A24-5的合成
将中间体A24-4(1.01g,3.09mmol)溶于乙醇(10mL)中,加入5-氨基苯并噻唑(0.47g,3.09mmol),向反应体系中加入一滴浓盐酸催化反应,混合物在85℃下反应3小时。之后将混合物冷却至室温,固体析出,过滤固体并用乙醇洗涤,滤饼烘干得灰色固体中间体A24-5(0.96g,70%),为盐酸盐。1H NMR(300MHz,DMSO-d6)δ14.95(s,1H),11.49(s,1H),9.54(s,1H),9.50(s,1H),8.59(d,J=6.9Hz,1H),8.38(d,J=8.4Hz,1H),8.29(s,1H),8.21(s,1H),7.61(d,J=8.4Hz,1H),6.94(d,J=6.9Hz,1H).LC-MS(m/z):439.9[M+H]+.
6.终产物A24的合成
将中间体A24-5(956mg,2.00mmol)溶于1,4-二氧六环(10mL)中,再依次加入二甲基氧化磷(254mg,3.26mmol)、三乙胺(373mg,3.69mmol)、三二亚苄基丙酮二钯(199mg,0.2mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(126mg,0.2mmol),在氮气保护下,于125℃微波反应1小时。固体析出,过滤固体,用甲醇(20mL)溶解滤饼,加入水(20mL)中,用饱和碳酸氢钠调节pH至7,用二氯甲烷(20mL×2)萃取,浓缩有机相,硅胶柱纯化(二氯甲烷/甲醇(v/v)=40/1)得淡青色粗产物,之后再用乙醇(10mL)打浆过夜,过滤得白色固体终产物A24(71mg,收率8%)。
参照实施例13的方法合成化合物A25,区别在于,将实施例13步骤1中的3-(三氟甲氧基)苯胺替换为3-(二氟甲氧基)苯胺。
实施例14
化合物A26,其是由如下方法合成的:
1.中间体A26-1的合成
将3-频哪醇硼酸酯苯胺(4.0g,18.3mmol),二碘化镍(562mg,1.8mmol),反式-2-氨基环己醇乙酸盐(274mg,1.8mmol)加入到微波管中,随后加入2mmol/mL二(三甲基硅基)氨基钠(9.15mL,18.3mmol),干燥的异丙醇(20mL),氮气保护,混合物在室温条件下搅拌10分钟,加入3-碘氧杂环丁烷(3.4g,18.3mmol),混合物在微波照射下120℃搅拌2小时,加水淬灭反应,二氯甲烷(50mL*2)提取有机相,有机相合并,干燥浓缩,残留物经硅胶柱纯化(石油醚/乙酸乙酯(v/v)=4/1)得黄色油状中间体A26-1(1.01g,37%)。1H NMR(300MHz,CDCl3)δ7.21–7.09(m,1H),6.81–6.71(m,2H),6.60(d,J=8.7Hz,1H),5.04(dd,J=8.4,6.0Hz,2H),4.76(t,J=6.3Hz,2H),4.21–4.06(m,1H),3.70(s,2H).LC-MS(m/z):150.1[M+H]+.
2.中间体A26-2的合成
将中间体A26-1(1.01g,6.7mmol)溶于乙腈(15mL)中,冰浴条件下逐滴加入N-溴代丁二酰亚胺(961mg,5.4mmol)的乙腈溶液(5mL),混合物在此温度下搅拌30分钟。反应液浓缩,残留物经硅胶柱纯化(石油醚/乙酸乙酯(v/v)=4/1)得白色固体中间体A26-2(913mg,60%)。1H NMR(300MHz,CDCl3)δ7.31–7.24(m,1H),6.78(d,J=2.4Hz,1H),6.47(dd,J=8.7,2.7Hz,1H),5.05(dd,J=7.8,6.0Hz,2H),4.77(t,J=6.6Hz,2H),4.59–4.45(m,1H),3.77(s,2H).LC-MS(m/z):228.0[M+H]+.
3.中间体A26-3的合成
将中间体A26-2(913mg,4.0mmol)溶于乙醇(8mL)中,加入5-(甲氧基亚甲基)-2,2-二甲基-1,3-二恶烷-4,6-二酮(893mg,4.8mmol),混合物在室温条件下搅拌30分钟。固体析出,过滤固体并用乙醇洗涤,滤饼烘干得淡黄色固体中间体A26-3(1.18g,77%)。1H NMR(300MHz,CDCl3)δ11.28(d,J=14.4Hz,1H),8.63(d,J=14.0Hz,1H),7.61(d,J=8.3Hz,1H),7.31–7.27(m,1H),7.12–7.02(m,1H),5.17–5.07(m,2H),4.84–4.74(m,2H),4.67–4.52(m,1H),1.60(s,6H).
4.中间体A26-4的合成
将二苯醚(30mL)加入圆底烧瓶中,升温至240℃搅拌20分钟除去溶剂水分,缓慢加入A26-3(1.18g,3.1mmol),混合物在此温度下搅拌2分钟。冷却至室温,固体析出,过滤固体并用***洗涤,滤饼烘干得黄色固体中间体A26-4(490mg,56%)。1H NMR(300MHz,DMSO-d6)δ11.80(s,1H),8.19(s,1H),7.96(d,J=6.9Hz,1H),7.64(s,1H),6.07(d,J=7.5Hz,1H),5.11–4.93(m,2H),4.68(t,J=6.3Hz,2H),4.63–4.47(m,1H).LC-MS(m/z):280.0[M+H]+.
5.中间体A26-5的合成
将中间体A26-4(250mg,0.89mmol)溶于二氯甲烷(4mL)中,加入吡啶(703mg,8.9mmol),0℃下逐滴加入三氟甲磺酸酐(1.25g,4.45mmol),混合物在此温度下继续搅拌30分钟。反应液浓缩,残留物中加入分子筛干燥的1,4-二氧六环(4mL)溶解后转移至二颈瓶中,加入5-氨基苯并噻唑(161mg,1.07mmol),Pd2dba3(82mg,0.09mmol),Xantphos(52mg,0.09mmol),碳酸铯(870mg,2.67mmol),氮气保护,混合物在100℃搅拌10分钟。反应液浓缩,残留物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=20/1)得灰色固体中间体A26-5(130mg,35%)。1H NMR(300MHz,DMSO-d6)δ9.43(s,1H),9.30(s,1H),8.77(s,1H),8.51(s,1H),8.20(d,J=8.1Hz,1H),8.02(s,1H),7.94(s,1H),7.53(d,J=7.5Hz,1H),7.02(s,1H),5.11–4.96(m,2H),4.90–4.73(m,2H),4.71–4.53(m,1H).LC-MS(m/z):412.0[M+H]+
6.终产物A26的合成
将中间体A26-5(120mg,0.29mmol)溶于1,4-二氧六环(4mL)中,加入二甲基氧化磷(45mg,0.58mmol),Pd2dba3(27mg,0.03mmol),Xantphos(17mg,0.03mmol),碳酸铯(284mg,0.87mmol),混合物在微波照射130℃下搅拌2.5小时。反应液浓缩,残留物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=100/9)得粗品,随后经混合溶剂乙醇/***(0.5mL/5mL)打浆得淡黄色固体终产物A26(20mg,收率17%)。
实施例15
化合物A28,其是由如下方法合成的:
1.中间体A28-1的合成
将5-氨基苯并噻唑(3.0g,20mmol)溶于乙腈(80mL)中,0℃下缓慢加入1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(7.0g,20mmol)的乙腈溶液(20mL),在该温度下搅拌1小时。反应液中加入水(200mL),二氯甲烷(100mL*3)提取有机相,合并有机相,无水硫酸钠干燥,浓缩,残留物经硅胶柱纯化(石油醚/乙酸乙酯=4/1)得黄色固体中间体A28-1(310mg,9.2%)。1H NMR(300MHz,CDCl3)δ8.92(s,1H),7.48(d,J=8.4Hz,1H),6.97(t,J=8.1Hz,1H),3.87(s,2H).LC-MS(m/z):169.0[M+H]+.
2.中间体A28-2的合成
将中间体A28-1(37mg,0.22mmol)溶于乙醇(2mL)中,加入A6-3(60mg,0.22mmol),随后加入一滴浓盐酸,混合物在85℃下搅拌4小时。冷却至室温,固体析出,过滤固体并用乙醇洗涤,滤饼烘干的白色固体中间体A28-2(68mg,73%)。1H NMR(300MHz,DMSO-d6)δ14.01(s,1H),10.77(s,1H),9.55(s,1H),9.11(s,1H),8.55–8.43(m,1H),8.25–8.14(m,1H),7.72–7.57(m,1H),7.48(s,1H),6.69–6.47(m,1H),4.08(s,3H).LC-MS(m/z):404.0[M+H]+.
3.终产物A28的合成
将中间体A28-2(68mg,0.18mmol)溶于1,4-二氧六环(2mL)中,加入二甲基氧化磷(21mg,0.27mmol),Pd2dba3(18mg,0.02mmol),Xantphos(12mg,0.02mmol),三乙胺(36mg,0.36mmol),氮气保护,混合物在微波照射130℃下搅拌2小时。饱和碳酸氢钠水溶液中和盐酸,二氯甲烷(10mL*3)提取有机相,合并有机相,无水硫酸钠干燥,浓缩,残留物经硅胶柱(二氯甲烷/甲醇(v/v)=20/1)纯化得白色固体终产物(9mg,收率13%)。
实施例16
化合物A29,其是由如下方法合成的:
1.中间体A29-1的合成
将A16-1(160mg,0.51mmol),A28-1(86mg,0.51mmol)溶于乙醇(4mL)中,将1滴浓盐酸加入到乙醇(1mL),随后取其中1滴加入到反应液中,混合物在85℃下搅拌过夜,加入饱和碳酸氢钠水溶液调节pH至7,二氯甲烷(20mL*2)提取有机相,合并有机相,无水硫酸钠干燥,反应液浓缩,残留物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=20/1)得淡黄色固体中间体A29-1(220mg,97%)。1H NMR(300MHz,DMSO-d6)δ9.48(s,1H),9.15(s,1H),8.83(s,1H),8.48–8.28(m,1H),8.16–7.98(m,1H),7.68–7.44(m,1H),7.01(s,1H),6.35(s,1H),5.69–5.45(m,1H),5.19–4.96(m,2H),4.77–4.53(m,2H).LC-MS(m/z):445.9[M+H]+.
2.终产物A29的合成
将中间体A29-1(220mg,0.49mmol)溶于1,4-二氧六环(4mL)中,加入二甲基氧化磷(76mg,0.98mmol),Pd2dba3(46mg,0.05mmol),Xantphos(29mg,0.05mmol)和碳酸铯(319mg,0.98mmol),混合物在110℃下搅拌过夜。反应液浓缩,残留物经硅胶柱纯化(二氯甲烷/甲醇(v/v)=15/1)得粗品,经***(10mL)打浆得白色固体终产物A29(109mg,收率50%)。
表1.化合物A1-A29的解析结构和波谱数据
实施例17
化合物B1,其是由如下方法合成的:
1.中间体B1-1的合成
将2-氯-5-溴烟酸(3g,12.7mmol)和CDI(3.1g,19.1mmol)溶于N,N-二甲基甲酰胺(30mL)中,室温搅拌1小时后,再加入N,O-二甲基羟胺盐酸盐(1.5g,15.3mmol)和三乙胺(1.9g,19.1mmol),继续室温搅拌5小时。反应完成,加入乙酸乙酯(100mL),用饱和碳酸氢钠溶液(400mL*3)水洗。有机相用无水硫酸钠干燥,浓缩。经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化得黄色固体中间体B1-1(3.0g,85%)。1H NMR(400MHz,CDCl3):δ8.50(s,1H),7.80(s,1H),3.52(s,3H),3.39(s,3H).LC-MS(m/z):279.0[M+H]+。
2.中间体B1-2的合成
将中间体B1-1(2.6g,9.3mmol)溶于四氢呋喃(30mL)中,于0℃下将3M甲基溴化镁四氢呋喃溶液(3.4mL,10.2mmol)逐滴加入,室温反应2小时。加入饱和氯化铵溶液(10mL)淬灭反应,加入水(200mL),用乙酸乙酯(200mL)萃取。有机相用无水硫酸钠干燥,浓缩。经硅胶柱层析(石油醚/乙酸乙酯(v/v)=15/1)纯化得无色油状中间体B1-2(2.0g,92%)。1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.02(s,1H),2.70(s,3H).LC-MS(m/z):234.0[M+H]+。
3.中间体B1-3的合成
将中间体B1-2(2.00g,8.55mmol)溶于N,N-二甲基甲酰胺-二甲基缩醛(10mL)中,于110℃搅拌3小时。将反应液旋干,再溶于N,N-二甲基乙酰胺(10mL)中,加入对甲氧基苄胺(1.76g,12.82mmol)和碳酸铯(5.57g,17.09mmol),于100℃反应过夜。加入乙酸乙酯(100mL),用饱和氯化钠溶液(400mL*3)水洗。有机相用无水硫酸钠干燥,浓缩。经硅胶柱层析(二氯甲烷/甲醇(v/v)=120/1)纯化得黄色固体中间体B1-3(700mg,24%)。1H NMR(400MHz,CDCl3)δ8.81(d,J=2.4Hz,1H),8.75(d,J=2.4Hz,1H),7.72(d,J=8.0Hz,1H),7.23-7.20(m,2H),6.87-6.85(m,2H),6.33(d,J=7.6Hz,1H),5.48(s,2H),3.78(s,3H).LC-MS(m/z):345.1[M+H]+。
4.中间体B1-4的合成
将中间体B1-3(700mg,2.03mmol)溶于三氟乙酸(2mL)中,于微波110℃反应2小时。将反应液旋干,加入饱和碳酸氢钠水溶液调pH值至7,加入水(100mL),用二氯甲烷(50mL)和甲醇(10mL)萃取。有机相用无水硫酸钠干燥,浓缩。经柱层析(二氯甲烷/甲醇(v/v)=50/1)得黄色固体中间体B1-4(320mg,70%)。1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.85(s,1H),8.53(s,1H),8.02-7.96(m,1H),6.15(d,J=6.8Hz,1H).LC-MS(m/z):224.9[M+H]+。
5.中间体B1-5的合成
将B1-4(300mg,1.33mmol)溶于三氯氧磷(4mL)中,于110℃下搅拌1小时。浓缩得棕色固体中间体B1-5粗品(350mg)。
6.中间体B1-6的合成
将B1-5(350mg,1.44mmol)和5-氨基苯并噻唑(237mg,1.58mmol)溶于乙醇(3mL)中,滴入一滴浓盐酸,在85℃下搅拌3小时,有黄色固体析出。加入水(30mL),用碳酸氢钠饱和溶液调pH值至7,用二氯甲烷和甲醇(30mL/10mL*2)萃取。有机相用无水硫酸钠干燥,浓缩。经柱层析得(二氯甲烷/甲醇(v/v)=30/1)黄色固体中间体B1-6(105mg,收率20%)。1HNMR(400MHz,DMSO-d6)δ11.78(s,1H),9.81(s,1H),9.55(s,1H),9.28(s,1H),8.55(d,J=5.6Hz,1H),8.40(d,J=8.0Hz,1H),8.22(s,1H),7.62(d,J=8.4Hz,1H),6.96(d,J=6.4Hz,1H).LC-MS(m/z):357.0[M+H]+。
7.终产物B1的合成
将B1-6(105mg,0.29mmol)溶于1,4-二氧六环(2mL)中,再依次加入二甲基氧化膦(34mg,0.44mmol)、三乙胺(45mg,0.44mmol)、三(二亚苄基丙酮)二钯(27mg,0.03mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(17mg,0.03mmol),在氮气保护下,于125℃微波反应2小时。反应液中加入饱和碳酸氢钠水溶液,室温搅拌30分钟,浓缩,经硅胶柱纯化(二氯甲烷/甲醇(v/v)=20/1)得终产物B1(10mg,收率10%)。
实施例18
化合物B2,其是由如下方法合成的:
1.中间体B2-1的合成
将2-氨基-4-甲氧基苯甲腈(2.0g,13.5mmol)溶于乙腈(30mL)中,N-溴代丁二酰亚胺(2.7g,14.9mmol)溶于乙腈(10mL)中形成悬浮液,于0℃下逐滴加入到反应液中,恢复至室温,继续搅拌30分钟,浓缩,硅胶柱纯化(石油醚/乙酸乙酯(v/v)=10/1)得淡黄色中间体B2-1(2.5g,82%)。1H NMR(400MHz,CDCl3)δ7.52(s,1H),6.23(s,1H),4.48(s,2H),3.89(s,3H).LC-MS(m/z):228.0[M+H]+。
2.中间体B2-2的合成
于一个氮气保护的二颈瓶中加入3M甲基溴化镁(20.5mL,61.5mmol)和B2-1(2.0g,8.8mmol)溶于四氢呋喃(100mL)冰浴条件下逐滴加入到反应液中。恢复至室温搅拌5分钟,随后55℃下搅拌16小时,冷却至室温,6N盐酸水溶液(20mL)缓慢加入到反应液中,混合物继续搅拌30分钟,饱和碳酸氢钠水溶液加入中和盐酸,二氯甲烷(50mL*3)提取有机相,合并干燥,残留物经过硅胶柱纯化(石油醚/乙酸乙酯(v/v)=5/1)的淡灰色中间体B2-2(700mg,33%)。1H NMR(400MHz,CDCl3)δ7.83(s,1H),6.45(s,2H),6.08(s,1H),3.87(s,3H),2.51(s,3H).LC-MS(m/z):244.0[M+H]+。
3.中间体B2-3的合成
冰浴条件下,将B2-2(700mg)溶于浓盐酸(10mL)中,混合物在此温度下搅拌15分钟,形成悬浊液,亚硝酸钠(221mg,3.2mmol)溶于水(1mL)逐滴加入到反应液中,继续在冰浴下搅拌1.5小时,随后室温搅拌过夜,接着回流搅拌6小时,冷却至室温,饱和碳酸氢钠水溶液中和盐酸,二氯甲烷/甲醇(5/1,40mL*5)提取有机相,合并干燥,残余物经过硅胶柱纯化(二氯甲烷/甲醇=50/1)得白色固体中间体B2-3(350mg,69%)。1H NMR(400MHz,DMSO-d6)δ13.43(s,1H),8.15(s,1H),7.73(s,1H),7.01(s,1H),3.98(s,3H).LC-MS(m/z):255.0[M+H]+。
3.中间体B2-4的合成
将中间体B2-3(350mg,1.4mmol)溶于三氯氧磷(4mL)中,混合物在110℃下搅拌2小时,浓缩,加入乙酸乙酯形成悬浮液,继续浓缩,残余物溶于乙醇(5mL)中,加入5-氨基苯并噻唑(225mg,1.5mmol),混合物在80℃下搅拌2小时,冷却至室温,固体析出,过滤固体并用乙醇洗涤,烘干得黄色固体中间体B2-4(290mg,54%),为盐酸盐。1H NMR(400MHz,DMSO-d6)δ15.79(s,1H),12.18(s,1H),9.54(s,1H),9.37(d,J=10.4Hz,1H),8.54(s,1H),8.39(d,J=8.0Hz,1H),8.30(s,1H),7.68(d,J=8.4Hz,1H),7.54(d,J=6.4Hz,1H),4.11(s,3H).LC-MS(m/z):386.9[M+H]+。
4.终产物B2的合成
将中间体B2-4(130mg,0.34mmol)、二甲基氧化膦(52mg,0.68mmol),Pd2(dba)3(31mg,0.03),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(17mg),三乙胺(103mg,1.02mmol)溶于1,4-二氧六环(4mL)中,氮气保护,在微波照射下120℃搅拌4小时,冷却至室温,反应液中加入饱和碳酸氢钠水溶液(20mL),室温搅拌30分钟,二氯甲烷(10mL*3)提取有机相,合并干燥,浓缩,残余物经过硅胶柱纯化(二氯甲烷/甲醇(v/v)=20/1)得淡黄色固体,经乙醇/***(1/5,5mL)打浆,固体溶于水(4mL)经过冷冻干燥得黄色固体终产物B2(25mg,收率19%)。
表2.化合物B1、B2的解析结构和波谱数据
实施例19:竞争性结合实验
本实施例对实施例1-18制备得到的化合物A1-A16、A20-A21、A24-A26和B1分别和RIP2激酶进行结合能力测试。
在试验中,激酶标记的T7噬菌体菌株是在来自BL21菌株的大肠杆菌宿主中制备的。将大肠杆菌培养至对数期,用T7噬菌体感染,32℃振荡培养至裂解。裂解液离心并过滤以去除细胞碎片,其余激酶在HEK-293细胞中产生,随后用DNA标记进行qPCR检测。链霉亲和素包被的磁珠用生物素化的小分子配体在室温下处理30分钟,以生成亲和力树脂用于激酶分析。用过量的生物素阻断配体珠,用阻断缓冲液(SeaBlock(Pierce),1%BSA,0.05%Tween 20和1mM DTT)清洗,去除未结合的配体,减少非特异性结合。通过结合激酶、配体亲和珠,并在1x Binding buffer(20%SeaBlock,0.17xPBS,0.05%Tween 20,6mM DTT)中测试化合物来组装结合反应。试验化合物以111×原液准备在100%DMSO中。使用11浓度点3倍化合物稀释系列和3个DMSO控制点确定Kds。所有用于Kd测量的化合物均通过声学转移(非接触式分布)分布在100%DMSO中。然后将化合物直接稀释到测定物中,最终浓度为0.9%。所有反应均在384聚丙烯孔板上进行,体积均为0.02mL。实验板在室温下振荡孵育1小时,用洗涤液(1倍PBS,0.05%Tween 20)清洗亲和珠。随后亲和珠重新悬浮在洗脱缓冲液中(1xPBS,0.05%渐变20日0.5μM non-biotinylated亲和配体)和在室温下摇动孵育30分钟。用qPCR法测定洗脱液中的激酶浓度。
结合常数(Kds)用希尔方程计算标准剂量-响应曲线,化合物A1-A16、A20-A21、A24-A26和B1对RIP2的结合能力测试结果如表3所示,其中,化合物A6的测试曲线图如图1所示。
表3.化合物对RIP2的结合能力测试结果
编号 | RIP2 Kd(nM) | 编号 | RIP2 Kd(nM) |
A1 | 28 | A2 | 89 |
A3 | 430 | A4 | 89 |
A5 | 120 | A6 | 3.1 |
A7 | 5.8 | A8 | 2.0 |
A9 | 2.1 | A10 | 1.8 |
A11 | 3 | A12 | 2.3 |
A13 | 1.4 | A14 | 3.0 |
A15 | 3.0 | A16 | 3.8 |
A20 | 8.7 | A21 | 1.5 |
A24 | 5.2 | A25 | 6.4 |
A26 | 12 | B1 | 3200 |
通过表3可以得知,化合物A1-A16、A20-A21、A24-A26对RIP2激酶有较强的亲和力,而化合物B1对RIP2激酶亲和力较弱。
实施例20:THP-1细胞实验
实验步骤:
使用的细胞为急性单核细胞白血病细胞系THP-1(ATCC,货号TIB-202TM),无菌培养箱温度37~38℃,渗透压260~320mmol/L,pH范围7.2~7.4,5%的二氧化碳气体比例。
THP-1细胞(1x105个/孔)首先铺在96孔板中。1小时后,THP-1细胞使用化合物预孵育2小时(化合物原始浓度为20mM,使用DMSO进行梯度稀释,稀释后浓度为0,1,3,10μM,取1.1μL化合物加入100μL的PBS中,涡旋混匀,按10μL/孔加入96孔板中)。2小时后,各孔加入MDP 10μL(终浓度3μg/μL)。6小时后,3000rmp/min离心5分钟,吸取上清,使用IL-8ELISA试剂盒(联科生物,货号EK108-96)检测上清IL-8含量。
表4化合物对白介素8的抑制效果
编号 | 白介素8抑制率% | 编号 | 白介素8抑制率% |
A6 | 50 | A7 | 25 |
A8 | 51 | A9 | 55 |
A10 | 51 | A11 | 37 |
A17 | 11 | A18 | 12 |
A19 | 13 | A22 | 60 |
A27 | 37 | A28 | 63 |
A29 | 85 | B2 | 0 |
通过表4得知,化合物A6-A11、A17-A19、A22、A27-29在THP-1细胞中可以抑制由MDP诱导产生的白介素8的释放,B2没有明显抑制效果。
实施例21:热力学溶解度测试
实验步骤:
1.将化合物加入到FaSSIF(pH 6.5)缓冲液中形成4mg/mL的溶液。
2.样品管摇动1小时,随后室温平衡过夜。
3.将样品离心(10min/12000rpm)以沉淀未溶解的部分。
4.上清液转移到新试管中。
5.离心后上清液通过LC/MS/MS确定峰面积。
6.测量化合物在20nM,200nM,800nM,4000nM,10000nM,20000nM浓度时峰面积,绘制标准曲线,根据上面所得峰面积线性回归得溶解度。
表5.化合物热力学溶解度测试结果
化合物 | 热力学溶解度FaSSIF(pH 6.5) |
A6 | 6115μM |
A7 | 5310μM |
A8 | 1038μM |
A9 | 283μM |
A13 | 4325μM |
通过表5可以得知,化合物A6-A9、A13具有较好的热力学溶解度,溶解度均超过200μM。
实施例22:化合物CYP酶抑制测试
实验步骤:
1.预热0.1M磷酸钾缓冲液(K缓冲液),pH 7.4。
2.在96孔板中准备待测化合物和参考抑制剂(400×):
2.1.将8μL 10mM的待测化合物转移到12μL乙腈中;
2.2.配制CYP1A2、CYP2C9、CYP2D6鸡尾酒抑制剂加标准样品溶液:12μL 1mMα-萘黄酮+10μL 40mM磺胺苯唑+10μL 10mM奎尼丁+8μL DMSO。
2.3.配制CYP3A4、CYP2C19单个抑制剂加标准样品溶液:8μL DMSO样品原液加到12μL乙腈中;准备4×NADPH辅助因子溶液(66.7mg NADPH加到0.1M钾离子缓冲液中,pH7.4)。
4.准备4×底物(每个异构体2mL)。
5.在冰上准备0.2mg/mL人的肝微粒体溶液(将10μL肝微粒体溶液(20mg/mL)加入至990μL K-buffer(0.1M)中)。
6.将400μL 0.2mg/kg人微粒体溶液加入到检测孔中然后将2μL 400×待测化合物加入至相应的孔中。
7.将200μL 0.2mg/kg人微粒体溶液加入到96孔板然后加入1μL参考抑制剂溶液。
8.下列溶液(一式两份)加入到96孔板中。
8.1.将30μL 2×待测化合物和参考化合物到0.2mg/mL的人肝微粒体溶液中;
8.2.加入15μL基底溶液。
9.将96孔实验板与NADPH溶液37℃预孵育5分钟。
10.添加15μL预热的8mM NADPH溶液启动反应。
11.37℃孵育实验板:3A4 5分钟;1A2、2B6、2C8、2C9、2D6 10分钟;2C19 45分钟。
12.通过加入120μL含有IS的乙腈溶液终止反应。
13.冷却后,在振动器(IKA,MTS 2/4)上振动10分钟(600rpm/min),然后5594g离心15分钟(热复液×3R)。
14.将每个孔中的50μL上清液转移到包含50μL超纯水(Millipore,ZMQS50F01)的96孔样品板上,以进行LC/MS/MS分析。
表6.CYP450抑制实验
表7.化合物CYP测试结果
通过表7可以得知,本发明化合物A6、A14-A16没有明显的CYP抑制活性,对所测的CYP同工酶1A2、2C9、2C19、2D6、CYP3A4抑制率均低于20%,体现较弱的药物-药物相互作用。
实施例23:化合物Caco-2测试
实验步骤
1.37℃预热HBSS缓冲液。
2.从-20℃取化合物,超声几分钟(不少于1分钟)。
3.溶剂准备
3.1.供体缓冲液溶液:
A-B方向:
配制HBSS缓冲液与0.3%DMSO和5μM LY(Lucifer Yellow,荧光黄):将150μL DMSO和50μL LY(5mM)加入到50mL HBSS缓冲液中(pH7.4)。
HBSS缓冲液与0.1%DMSO和5μM LY:将50μL DMSO和50μL LY(5mM)加入到50mLHBSS缓冲液中(pH7.4)。
B-A方向:
HBSS缓冲液与0.3%DMSO:将150μL DMSO加入到50mL HBSS缓冲液中(pH7.4)。
HBSS缓冲液与0.1%DMSO:将50μL DMSO加入到50mL HBSS缓冲液中(pH7.4)
3.2.受体缓冲液溶液:
A-B方向:准备HBSS缓冲0.4%DMSO:200μL DMSO溶液添加到50毫升HBS缓冲液中(pH7.4)。
B-A方向:准备HBSS缓冲液与0.4%DMSO和5uM LY:将200uL DMSO和50uL LY(5mM)加入到50mL HBSS缓冲液。
表8.准备供体溶液
4.计算TEER:将细胞培养板从培养箱中取出,用HBSS缓冲液清洗细胞单层,然后在Rm(室温)温度下测量TEER值。
5.离心:在将化合物溶液加入供体室之前离心(4000rpm)5min。
6.给药:按下表所列体积添加溶液(确保能够额外取100uL供体样品作为T0备用)。
表9.添加溶液体积
7.顶端LYT0样品:确定在顶端室LY浓度,从顶端取100μL样品室到不透明板上作为LYT0。
8.预热:将顶端和基侧板在37℃下预热约5分钟,然后将顶端板放置到基侧板上开始转运。
9.孵育:保持板在37℃下孵育90分钟。
10.准备标准曲线:准备300μM(20×)化合物溶液:将6μL样品原液加入到194μL的甲醇/水(1:1)溶液中。
表10.用甲醇:水(1:1)配置实验溶液
化合物溶液(μM) | 溶液(μL) | MeOH/H<sub>2</sub>O(μL) | 最终溶液(μM) | |
300 | 100 | 400 | → | 60 |
60 | 100 | 200 | → | 20 |
20 | 100 | 400 | → | 4 |
4 | 100 | 400 | → | 0.8 |
0.8 | 100 | 300 | → | 0.2 |
0.2 | 100 | 100 | → | 0.1 |
准备1×溶液:3μL(20×)+57μL的0.4%DMSO HBSS+60μL乙腈与IS(欧沙美或丙咪嗪)---120μL(1×)。
11.转运终止:孵育90分钟后将顶端板与基侧板分离。
12.测量LY:从基侧板上取出100μL样品到不透明板中。
13.通过荧光计测量LYT0-LYT90的浓度。
14.用0.4%DMSO HBSS稀释供体或接受者样品,然后与具有IS的乙腈(欧沙美或丙咪嗪)混合。
表11.化合物Caco-2测试结果
a:测试浓度为2μM
通过表11可以得知,化合物A24具有较好的渗透性,无明显外排,化合物A6、A8、A9、A14、A15的渗透性也较好,但有一些外排作用,化合物A7、A13、A16的渗透性较弱,可见,化合物取代基微小变化,渗透性就有明显的改变,甚至会引起外排现象。
实施例24:化合物血浆蛋白结合率测试
实验步骤:
大鼠/狗/人的血浆蛋白结合率通过在Chemparter使用平衡透析法评估。在实验中,将待测加入血浆中,使其浓度达到1μM。化合物加标血浆放置在供体侧,空白PBS缓冲液放置在接收侧。透析块盖上塑料盖,置于摇床(60rpm)中,37℃孵育5小时。孵育后收集供体和受体。血浆蛋白结合率的计算公式如下:
表12.化合物血浆蛋白结合率测试结果
通过表12可以得知,化合物A6、A14-A16、A25在人和狗中血浆蛋白结合率适中,A24在人、大鼠和狗中血浆蛋白结合率较高,A25在大鼠中血浆蛋白结合率较高。
实施例25:化合物代谢稳定性测试
实验步骤:
1.缓冲液制备
缓冲液A:1.0L含1.0mM EDTA的0.1M一元磷酸钾缓冲液。
缓冲液B:1.0L含1.0mM EDTA的0.1M磷酸氢二钾缓冲液。
缓冲液C:通过用缓冲液A滴定700mL缓冲液B,同时用pH计进行监测,从而获得0.1M磷酸钾缓冲液,1.0mM EDTA,pH 7.4。
2.配置参考化合物(Ketanserin)和待测化合物的加标溶液
500μM加标溶液:将10μL的10mM DMSO储备溶液添加到190μL的乙腈中。
微粒体中的1.5μM加标溶液(0.75mg/mL):将479.75μL缓冲液C中加入1.5μL 500μM加标溶液和18.75μL 20mg/mL肝微粒体中。
3.将NADPH溶解在缓冲液C中来制备NADPH储备溶液(6mM)。
4.将30μL含0.75mg/mL微粒体溶液的1.5μM加标溶液分配到指定用于不同时间点(0、5、15、30、45分钟)的测定板上。
5.对于0分钟,将135μL含IS的ACN加入到0分钟板的孔中,然后添加15μL NADPH储备溶液(6mM)。
6.将所有其他平板在37℃下预孵育5分钟。
7.向板中加入15μL NADPH储备溶液(6mM)以开始反应和计时。
8.在5分钟、15分钟、30分钟和45分钟时,分别向相应板的孔中加入135μL含IS的ACN,以终止反应。
9.淬灭后,在振动器(IKA,MTS 2/4)上摇动平板10分钟(600rpm/min),然后以5594g离心15分钟(Thermo Multifuge×3R)。
10.将每个孔中的50μL上清液转移到包含50μL超纯水(Millipore,ZMQS50F01)的96孔样品板上,以进行LC/MS/MS分析。
表13.化合物代谢稳定性测试结果
通过表13可以得知,本发明化合物A6-A9、A13-A16在人、大鼠和狗肝微粒体中具有良好的代谢稳定性,在人、大鼠和狗半衰期均大于38分钟。
实施例26:化合物药代动力学评价
实验目的1:测试化合物在ICR小鼠药代动力学
实验步骤:
以标准方案测试化合物静脉注射和口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射和悬浮液用于口服给药。静脉溶媒为5%DMSO+95%盐水,口服溶媒为0.5%CMCNa。该项目使用48只雄性ICR小鼠,24只小鼠进行静脉注射给药,给药剂量为2mg/kg,收集0h(给药前)和给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h的血浆样品.24只小鼠鼠口服灌胃给药,给药剂量为10mg/kg,收集0h(给药前)和给药后0.25h,0.5h,1h,2h,4h,6h,8h和24h的血浆样品。然后对收集的样品进行LC/MS/MS分析并采集数据。AUC代表从零时间点到24小时时血浆浓度-时间曲线下面积。Cmax代表峰浓度;Tmax代表达峰时间;T1/2代表半衰期;Cl代表清除率;Vd代表表观分布容积;F代表生物利用度;p.o.代表口服;i.v.代表静脉注射。
表14.化合物小鼠药代动力学测试结果
通过表14可以得知,化合物A6、A24、A25在小鼠体内具有优异的血浆暴露量和生物利用度。
实验目的2:测试化合物在SD大鼠药代动力学
实验步骤:
以标准方案测试化合物静脉注射和口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予大鼠单次静脉注射和悬浮液用于口服给药。静脉溶媒为5%DMSO+95%盐水,口服溶媒为0.5%CMCNa。该项目使用9只雄性SD大鼠,3只大鼠进行静脉注射给药,给药剂量为2mg/kg,收集0h(给药前)和给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h的血浆样品。3只大鼠口服灌胃给药,给药剂量为10mg/kg,3只大鼠口服灌胃给药,给药剂量为100mg/kg,收集0h(给药前)和给药后0.25h,0.5h,1h,2h,4h,6h,8h和24h的血浆样品。然后对收集的样品进行LC/MS/MS分析并采集数据。AUC代表从零时间点到24小时时血浆浓度-时间曲线下面积。Cmax代表峰浓度;Tmax代表达峰时间;T1/2代表半衰期;Cl代表清除率;Vd代表表观分布容积;F代表生物利用度;p.o.代表口服;i.v.代表静脉注射。
表15.化合物大鼠药代动力学测试结果
通过表15可以得知,化合物A6、A24在大鼠体内具有优异的血浆暴露量和生物利用度。
实验目的3:测试化合物在比格犬(Beagle)药代动力学
实验步骤:
以标准方案测试化合物静脉注射和口服给药后的哺乳类动物药代特征,实验中候选化合物配成澄清溶液给予比格犬单次静脉注射和悬浮液用于口服给药。静脉溶媒为5%DMSO+95%盐水,口服溶媒为0.5%CMCNa。该项目使用9只雄性比格犬,3只比格犬进行静脉注射给药,给药剂量为1mg/kg,收集0h(给药前)和给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h的血浆样品.3只比格犬口服灌胃给药,给药剂量为5mg/kg,3只比格犬口服灌胃给药,给药剂量为30mg/kg,收集0h(给药前)和给药后0.25h,0.5h,1h,2h,4h,6h,8h和24h的血浆样品。然后对收集的样品进行LC/MS/MS分析并采集数据。AUC代表从零时间点到24小时时血浆浓度-时间曲线下面积。Cmax代表峰浓度;Tmax代表达峰时间;T1/2代表半衰期;Cl代表清除率;Vd代表表观分布容积;F代表生物利用度;p.o.代表口服;i.v.代表静脉注射。
表16.化合物A6比格犬药代动力学测试结果
表17.化合物A24比格犬药代动力学测试结果
通过表16、17可以得知,化合物A6、A24在犬体内具有优异的血浆暴露量和生物利用度。
实施例27:MDP(胞壁酰二肽)诱导的小鼠腹膜炎模型体内药效研究
实验目的:考察RIPK2激酶抑制剂在MDP诱导腹膜炎模型中的活性,通过检测下游炎症因子IL-6的表达水平,明确化合物对NOD-RIPK2信号通路的阻断作用。为RIPK2参与的相关疾病的治疗提供药效学依据。
实验步骤:小鼠共分为四组,分别为正常组、DMSO组、阳性对照组(GSK2983559)与化合物组,正常组不做任何处理。GSK2983559采用灌胃给药方式给予的剂量为10mg/kg,化合物组为3mg/kg或者10mg/kg。动物给药30分钟后,给予动物腹腔注射MDP(100μg/只)。3小时后,小鼠麻醉后行眼静脉采血。ELISA检测血清中IL-6的含量。
实验结果:如图2、图3所示。
实验结论:与正常组比较,MDP建模后IL-6水平明显升高,提示下游炎症通路被激活,模型诱导成功;各给药组IL-6水平与模型组相比均有所下滑,其中A6、A24在相同给药剂量下比阳性对照GSK2983559下滑的更明显,提示这两个化合物更有效的抑制RIP2激酶的活性,阻断了下游炎症信号的激活,进而影响细胞因子IL-6的合成和释放。
Claims (14)
1.一种具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,所述的化合物具有式(I)结构:
其中,
n选自0、1、2和3;
环A选自6至10元芳基和5至10元杂芳基;
R1各自独立地选自氢原子、氘原子、卤素、羟基、氨基、氰基、C1-6烷基、C3-6环烷基、O(C1-6烷基)、NH(C1-6烷基)、N(C1-6烷基)2、C2-6烯基和C2-6炔基,所述C1-6烷基、C3-6环烷基、C2-6烯基和C2-6炔基各自独立地任选被1、2或3个Ra取代;
R2选自氢原子、氘原子、C1-3烷基和C3-6环烷基,所述C1-3烷基和所述C3-6环烷基各自独立地任选被1、2或3个Rb取代;
R3选自氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基、5至10元芳基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基、5至10元芳基和5至10元杂芳基各自独立地任选被1、2或3个Rc取代;
R4选自C1-3烷基,所述C1-3烷基任选被1、2或3个Rd取代;
R5选自C1-3烷基,所述C1-3烷基任选被1、2或3个Re取代;
或者R4和R5与它们相连的磷原子一起形成5至6元杂环烷基或5至8元杂环烯基,所述5至6元杂环烷基和所述5至8元杂环烯基各自独立地任选地被1、2或3个Rd取代;
R6选自氢原子、C1-3烷基和C3-6环烷基,其中,所述C1-3烷基和所述C3-6环烷基各自独立地任选被1、2或3个Rf取代;
R7选自氢原子、氘原子、氟原子、氯原子、溴原子、羟基、氨基、氰基、C1-6烷基、C3-6环烷基、O(C1-6烷基)、NH(C1-6烷基)、N(C1-6烷基)2、C2-6烯基和C2-6炔基,所述C1-6烷基、C3-6环烷基、C2-6烯基和C2-6炔基各自独立地任选被1、2或3个Ra取代;
所述3至6元杂环烷基、所述5至6元杂环烷基、所述5至8元杂环烯基和所述5至10元杂芳基各自独立地包含1、2或3个成环杂原子或杂原子团,所述成环杂原子或原子团各自独立地选自O、S、NH、N和P(=O)。
2.根据权利要求1所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,其特征在于:
R2选自氢原子。
6.根据权利要求1-5中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,其特征在于:
R3选自氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、C3-6环烷基、3至6元杂环烷基和5至10元杂芳基各自独立地任选地被1、2或3个Rc取代,优选氢原子、卤素、羟基、氨基、C1-6烷基、O(C1-6烷基)、3至6元杂环烷基和5至10元杂芳基,所述C1-6烷基、O(C1-6烷基)、3至6元杂环烷基和5至10元杂芳基各自独立地任选地被1、2或3个Rc取代;
其中,Rc的定义如权利要求1中所定义。
9.根据权利要求1-8中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,其特征在于:
R4选自CH3;
R5选自CH3;
R6选自氢原子和C1-3烷基,优选氢原子。
10.根据权利要求1-9中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,其特征在于:
R7选自氢原子、氘原子、氟原子、氯原子和溴原子,优选氢原子和氟原子。
12.一种药物组合物,其包含根据权利要求1-11中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体。
13.一种药物联合形式,其包括根据权利要求1-11中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据权利要求12所述的药物组合物,以及抗肿瘤药物、抗自身免疫性疾病药物、抗神经退行性疾病药物、抗代谢性疾病药物以及遗传性疾病药物中的一种或几种。
14.根据权利要求1-11中任一项所述的具有RIP2激酶抑制活性的化合物或其药学上可接受的盐、酯、溶剂化物、前药、同位素标记物或异构体,或者根据权利要求12所述的药物组合物,或者根据权利要求13所述的药物联合形式在制备用于预防和/或治疗至少部分应答于RIP2受体的疾病和/或病症的药物中的应用;
优选地,所述疾病和/或病症包括:葡萄膜炎、皮炎、急性肺损伤、Ⅱ型糖尿病、关节炎、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、自身免疫性肝炎、哮喘、***性红斑狼疮、结节病、韦格纳肉芽肿和间质性肺病、肺纤维化、肾脏纤维化、肝纤维化、心肌梗塞、哮喘、过敏性肺炎、间质性肺病、强直性脊椎炎、多发性硬化症、全身性硬化症、多发性肌炎、类风湿性关节炎、重症肌无力、幼年发病糖尿病、肾小球肾炎、自身免疫性甲状腺炎、移植物排斥反应、Crohn病、Blau综合征、硬皮病、牛皮癣、口腔炎、视网膜色素变性、增殖性玻璃体视网膜病变、贝斯特氏卵黄状黄斑变性、湿疹、荨麻疹、脉管炎、嗜酸性筋膜炎、湿性和干性年龄相关性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、糖尿病性黄斑红肿、葡萄膜炎、视网膜静脉闭塞、囊样黄斑水肿、青光眼、帕金森、阿尔兹海默病、亨廷顿病、乳腺癌、肺癌、膀胱癌、胰腺癌、肝癌、头颈鳞状上皮癌、甲状腺癌、肉瘤、骨肉瘤、硬纤维瘤、黑色素瘤、***癌、结肠直肠癌、卵巢癌、***、食管癌、胃癌、骨髓瘤、淋巴瘤、套细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性和非进行性贫血、自发性或原发性血小板增多症、白血病、急性白血病、慢性白血病、淋巴性白血病、髓性白血病、骨髓增生异常综合征、骨髓增殖性病症、脑瘤、星形细胞瘤、髓母细胞瘤、许旺细胞瘤、原发性神经外胚瘤或者垂体瘤中的一种或几种。
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