CN115710281A - 一种异噁唑并[5,4-b]吡啶类FLT3抑制剂及其制备方法与用途 - Google Patents
一种异噁唑并[5,4-b]吡啶类FLT3抑制剂及其制备方法与用途 Download PDFInfo
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- CN115710281A CN115710281A CN202211423729.0A CN202211423729A CN115710281A CN 115710281 A CN115710281 A CN 115710281A CN 202211423729 A CN202211423729 A CN 202211423729A CN 115710281 A CN115710281 A CN 115710281A
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Abstract
Description
技术领域
本发明涉及医药技术领域,具体涉及一类含有新型结构异噁唑并[5,4-b]吡啶的FLT3抑制剂,以及它的制备方法和在防治急性髓系白血病中的应用。
背景技术
急性髓性白血病(Acute myeloid leukemia,AML)急性非淋巴细胞白血病,是粒、红、单核、巨核细胞等髓系细胞恶性增生的疾病。在中国,大约有25万人每年被诊断为AML,约占急性白血病的70%,同时AML的发病率会随年龄的增长而增加(Prada-Arismendy J,Arroyave J C,Rothlisberger S.Molecular biomarkers in acute myeloid leukemia[J].Blood Rev,2017,31(1):63-76.)。
FLT3属于Ⅲ型受体酪氨酸,在造血细胞和淋巴细胞的增殖、分化和凋亡过程中发挥关键作用,FLT3的异常激活与多种肿瘤特别是AML的发生、发展密切相关。研究发现,70%以上的AML患者和急性淋巴白血病患者体内的FLT3高表达,超过1/3的AML患者伴随有FLT3基因突变(Daver N,Schlenk R F,Russell N H,et al.Targeting FLT3 mutations inAML:review of current knowledge and evidence[J].Leukemia,2019,33(2):299-312)。FLT3基因突变会导致其异常活化,不与配体结合也能发生自身磷酸化,激活下游JAK/STAT,RAS/MAPK和PI3K/AKT/mTOR信号通路,导致造血细胞和淋巴细胞异常增殖,由此引发了AML等多种恶性血液疾病(Zhong Y,Qiu R Z,Sun S L,et al.Small-Molecule Fms-likeTyrosine Kinase 3Inhibitors:An Attractive and Efficient Method for theTreatment of Acute Myeloid Leukemia[J].J Med Chem,2020,63(21):12403-12428.)。FLT3基因突变主要有两种类型:最常见的突变发生在近膜结构域(Juxtamembrane domain)的内部串联重复突变(Internal tandem duplication mutation,ITD),大约23%的AML患者会有此突变;其次是发生在激酶结构域(Tyrosine kinase domain)的点突变(Tyrosinekinase domain mutations,TKD),大约会有8%的AML患者中存在该突变。其中一次突变即ITD患者复发率高且不良反应多,与普通的AML患者相比,ITD突变患者的不良预后差;二次突变即ITD突变后二次发生的TKD是造成药物耐药的重要原因。因此,针对FLT3的靶向疗法已经成为治疗AML的重要手段之一,大量的FLT3抑制剂已进入临床研究。
AML的一线化疗药物一般为阿糖胞苷和柔红霉素,但是这类药物都具有明显的细胞毒性。有些年轻的患者通过传统化疗药物的干预病情能够改善,但是治愈率很低。65岁以上的将近70%的患者在常规治疗时,生存时间不会超过一年(Quintas-Cardama A,RavandiF,Liu-Dumlao T,et al.Epigenetic therapy is associated with similar survivalcompared with intensive chemotherapy in older patients with newly diagnosedacute myeloid leukemia[J].Blood,2012,120(24):4840-4845.)。早期的临床药物属于酪氨酸激酶多靶点抑制剂如Sunitinib、Sorafenib和Lestaurtinib,但是这类药物最初并不是以FLT3蛋白为靶点研发的,在AML病人的Ⅰ/Ⅱ期临床实验中均以失败而告终(PemmarajuN,Kantarjian H,Andreeff M,et al.Investigational FMS-like tyrosine kinase3inhibitors in treatment of acute myeloid leukemia[J].Expert Opin InvestigDrugs,2014,23(7):943-954.);近年来,针对FLT3靶蛋白研发的高活性,高选择性的第二代抑制剂包括Quizartinib、Crenolanib、Pexidartinib(PLX3397)、Tandutinib(MLN518)和Gilteritinib(ASP2215)进入临床研究。其中Gilteritinib于2018年11月由美国FDA批准上市,用于治疗携带FLT3基因突变的复发/难治性AML成人患者。但第二代抑制剂也面临许多问题,尤其是对FLT3二次突变的患者缓解率很低。这些小分子抑制剂虽然对野生型FLT3和一次突变FLT3-ITD型AML患者均有效,但对二次突变的FLT3-ITD-TKD患者疗效不佳,半数患者短期内仍会复发,这与FLT3二次点突变导致的耐药性有关。因此,AML患者的有效药物疗法需求十分迫切,研究并开发高效低毒的新型小分子靶向抑制剂对于AML治疗具有重要的现实意义和科学价值。
发明内容:
发明目的:本发明所要解决的技术问题是,克服现有技术的不足,致力于寻找治疗AML的小分子抑制剂。本发明获得了含有异噁唑并[5,4-b]吡啶结构的小分子(I),本发明另一个目的是提供FLT3抑制剂(I)的制备方法和其在制备防治AML药物中的应用。
技术方案:为了实现以上目的,本发明提供的FLT3抑制剂(I)的通式如下:
其中R1代表芳基、取代芳基、芳杂基、取代芳杂基,烷基,取代烷基,含有0~3个氮原子、硫原子或氧原子的环状烷基等。
n1为0~3的整数。
n2为0~3的整数。
X、Y、Z相同或不同,各自代表CH、N、O或S;
W代表H、CH2或NH。
M代表H、CH2或NH。
本申请所述化合物选自化合物F1-1~F2-8。
本申请所述化合物的的互变异构体、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的盐也在本申请的保护范围内。
本申请还公开了一种药物组合物,包括上述通式(I)所示的化合物和药学上可接受的载体。
本申请所述化合物在制备治疗或者预防急性髓系白血病的药物中的应用也在本发明的保护范围内。
除非另有说明,否则下列用在说明书和权利要求中的术语具有下述含义。
术语“烷基”是指饱和脂肪族烃基团,其为包含1至20个碳原子的直链、支链或环状基团,优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、仲丁基、环丁基、正戊基、环戊基、1,1-二甲基丙基、1,1-二甲基丙基、2,1-二甲基丙基、1-乙基丙基、1-甲基丁基、3-甲基丁基、正己基、1-乙基-1-甲基丙基、1,1,1-三甲基丙基、1,1-二甲基丁基、1,1-二甲基丁基、2,1-二甲基丁基、1,3-二甲基丁基、1-乙基丁基、1-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、1-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,1-二甲基戊基、3,3-二甲基戊基、1-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,1-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、1-乙基己基、3-乙基己基、4-乙基己基、1-甲基-1-乙基戊基、1-甲基-3-乙基戊基、正壬基、1-甲基-1-乙基己基、1-甲基-3-乙基己基、2,1-二乙基戊基、正癸基、3,3-二乙基己基、2,1-二乙基己基,及其各种支链异构体等。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,所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、羧基、酯基中的一个或多个取代基所取代。
术语“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,其为具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,优选为6至10元,例如苯基和萘基,所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
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,其独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,更优选为5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、吡唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。
杂芳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、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基中的一个或多个取代基所取代。
术语“羟基”指-OH。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
本发明提供的FLT3抑制剂(I)的制备方法,具体包括以下步骤:
(1)方案一,n1代表0,所述的方法包括以下步骤:
a、以对硝基苯甲醛为起始原料,以碳酸钾为碱,和丙酮在室温中发生羟醛缩合反应,生成甲基苯乙烯基酮类衍生物(1-1),备用;
b、取步骤a得到的甲基苯乙烯基酮衍生物(1-1)在碱性条件下,在二甲亚砜溶液中和氰基乙酰胺环合,生成氧代二氢吡啶类衍生物(1-2),备用;
c、取步骤b得到的氧代二氢吡啶类衍生物(1-2)为原料,在三氯氧磷回流条件下,得到氯代二氢吡啶类衍生物(1-3),备用;
d、取步骤c得到的氯代二氢吡啶类衍生物(1-3)在乙醇溶液中,经过铁粉还原生成取代芳基伯胺衍生物(1-4),备用;
e、取步骤d得到的取代芳基伯胺衍生物(1-4)在N,N-二甲基甲酰胺的水溶液中,在碳酸钾的作用下和乙酰氧肟酸成环,生成异噁唑并吡啶衍生物(1-5),备用;
f、伯胺衍生物和三光气在三乙胺的作用下,生成异氰酸酯盐(1-6),备用;
g、取步骤e得到的1-5和步骤f得到的1-6,在二氯甲烷溶液中和三乙胺催化作用下发生缩合反应,得到目标化合物(I-1);
(2)方案二,n1代表1,所述方法在于包括以下步骤:
i、以草酸二乙酯、和丙酮为起始原料,以乙醇钠为碱,和氰乙酰胺在室温中发生瓜列斯基-索普Guareschi–Thorpe缩合反应,生成氧代二氢吡啶羧酸酯类衍生物(2-1),备用;
j、取步骤i得到的氧代二氢吡啶羧酸酯类衍生物(2-1)在三氯氧磷回流条件下,发生氯代反应,生成异烟酸乙酯衍生物(2-2),备用;
k、取步骤j得到的异烟酸乙酯衍生物(2-2),以硼氢化钠还原剂,以四氢呋喃和水为溶剂,在室温下发生还原反应生成羟甲基烟腈衍生物(2-3),备用;
l、取步骤k得到的羟甲基烟衍生物(2-3)为原料,以碳酸钾为碱,在N,N-二甲基甲酰胺水溶液中,和乙酰氧肟酸发生环合反应生成异噁唑并吡啶衍生物(2-4),备用;
m、取步骤l得到的异噁唑并吡啶衍生物(2-4)在氯化亚砜的条件下,发生氯化反应生成异噁唑并吡啶氯代衍生物(2-5),备用;
n、取步骤m得到的异噁唑并吡啶氯代衍生物(2-5)为原料,以碳酸铯为碱,1,1'-双二苯基膦二茂铁二氯化钯为配体,以1,4-二氧六环和水为溶剂,和4-氨基苯硼酸频哪醇酯发生铃木-宫浦Suzuki-Miyaura反应,生成异噁唑并吡啶偶联衍生物(2-6),备用;
o、取步骤m得到的2-6和如方案一步骤f得到的1-6,在二氯甲烷溶液中和三乙胺催化作用下发生缩合反应,得到目标化合物(I-2);
优选的,步骤a中所用的对硝基苯甲醛和丙酮的用量比为1mol/2500ml~1mol/3750ml,碳酸钾摩尔比为1:0.5~0.8,反应温度为10℃~30℃,反应时间为36~40小时;
步骤b中所用的氰基乙酰胺摩尔比为1:1.5~3,叔丁醇钾摩尔比为1:1.5~4,反应溶剂为二甲基亚砜,1-1与二甲基亚砜的用量比为1mol/1500ml~1mol/2500ml,反应温度为40-70℃,反应时间为3~8小时;
步骤c中所用的氧代二氢吡啶衍生物(1-2)和三氯氧磷用量比为1mol/500ml~1mol/1000ml,反应温度为回流,反应时间为2~6小时;
步骤d中所用的氯代二氢吡啶衍生物(1-3)与铁粉摩尔比为1:3~6,与冰醋酸摩尔比为1:10~12,反应溶剂为乙醇,1-3与乙醇的用量比为1mol/1500ml~1mol/2000ml,反应温度为回流,反应时间为2~6小时;
步骤e中所用的取代芳基伯胺衍生物(1-4)与乙酰氧肟酸的摩尔比为1:1.5~3,碳酸钾的摩尔比为1:4~8,反应溶剂为N,N-二甲基甲酰胺与水体积比1:1~5,1-4与溶剂的用量比为1mol/500ml~1mol/1000ml反应温度为20℃~70℃,反应时间为12~24小时;
步骤f中所用胺类化合物与三光气摩尔比为1:3~6,反应催化剂为三乙胺,反应溶剂为无水乙酸乙酯,氮气保护,反应温度为室温至回流,反应时间为6~8小时;
步骤g中所用的吡啶并异噁唑衍生物(1-5)与异氰酸酯盐(1-6)的摩尔比为1:3~6,反应溶剂为二氯甲烷,1-5与溶剂的用量比为1mol/800ml~1mol/1000ml,反应温度为10℃~30℃,反应时间为12~24小时。
优选的,步骤i中所用的草酸二乙酯与丙酮的摩尔比为1:1~1.5,与乙醇钠的摩尔比1:1.2~2,与氰基乙酰胺的摩尔比为1:1~2,反应溶剂为无水乙醇,草酸二乙酯与溶剂的用量比为1mol/1000ml~1mol/1500ml,反应温度为20℃~90℃,反应时间为8~12小时;
步骤j中所用的氧代二氢吡啶羧酸酯类衍生物(2-1)与三氯氧磷的摩尔比为1:30~60,反应温度为回流,反应时间为8~16小时;
步骤k中所用的异烟酸乙酯衍生物(2-2)与硼氢化钠的摩尔比为1:4~10,反应溶剂为四氢呋喃和水的混合溶剂(体积比为1:1~1.5),2-2与溶剂的用量比为1mol/4000ml~1mol/8000ml,反应温度为10℃~30℃,反应时间为2~8小时;
步骤l中所用的羟甲基烟腈衍生物(2-3)与乙酰氧肟酸的摩尔比为1:3~9,与碳酸钾的摩尔比为1:8~16,反应溶剂为N,N-二甲基甲酰胺和水的混合溶剂(体积比为1:10~40),2-3与溶剂的用量比为1mol/800ml~1mol/1200ml,反应温度为50℃~90℃,反应时间为10~24小时;
步骤m中所用的异噁唑并吡啶衍生物(2-4)与二氯亚砜摩尔比为1:50~150,反应温度为回流,反应时间为4~8小时;
步骤n中所用的异噁唑并吡啶氯代衍生物(2-5)与取代硼酸频哪醇酯的摩尔比为1:1.2~4,与1,1'-双二苯基膦二茂铁二氯化钯的摩尔比为1:0.01~0.1;与碳酸铯的摩尔比为1:4~10,反应溶剂1,4-二氧六环和水的混合溶剂(体积比为1:0.1~0.4),2-5与溶剂的用量比为1mol/800ml~1mol/1500ml,反应温度为回流,反应时间为10~18小时;
步骤o中所用的异噁唑并吡啶偶联衍生物(2-6)与异氰酸酯盐(1-6)的摩尔比为1:3~6,反应溶剂为二氯甲烷,2-6与溶剂的用量比为1mol/800ml~1mol/1000ml,反应温度为10℃~30℃,反应时间为12~24小时。
本发明所述的中间体异氰酸酯盐(1-6)的制备方法如下::
取25ml圆底烧瓶,三光气(0.3mmol,89mg)溶于5mL乙酸乙酯中。搅拌并冰浴至0℃。将取代苯胺(0.6mmol)(其中R1代表芳基、取代芳基、芳杂基、取代芳杂基,烷基,取代烷基,含有0~3个氮原子、硫原子或氧原子的环状烷基)缓慢滴加入反应液。在N2保护下,冰浴搅拌0.5h后,撤去冰浴室温反应1h,再在82℃回流4h。反应完成后,减压除去溶剂,得中间体异氰酸酯盐(1-6)。只是R1取代基不同,按照这个方法可以合成多个符合1-6结构式的化合物。
有益效果:本发明提供了一种异噁唑并[5,4-b]吡啶类FLT3抑制剂,还提供了该抑制剂的制备方法,以及其用于制备由造血细胞和淋巴细胞恶性增殖而导致的急性髓系白血病等药物中的用途。本发明提供的化合物骨架还可用于衍生设计并合成共价抑制剂,PROTACs(proteolysis-targeting chimeras,蛋白降解靶向联合体)等FLT3抑制剂的用途。该类FLT3抑制剂结构新颖,制备条件温和,原料丰富易得,操作及后处理简单。
附图说明
图1为本发明的FLT3抑制剂通式(I)的结构图。
图2为化合物F1-2的核磁共振1H NMR图。
图3为化合物F1-2的核磁共振13C NMR图。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
在本申请中,除非特别定义,所采用的缩略语的含义如下所示:
min是指分钟;h是指小时;d是指天;℃是指摄氏度;V:V是指体积比。
DCM是指二氯甲烷;EA或EtOAc是指乙酸乙酯;PE是指石油醚;MeOH是指甲醇;THF是指四氢呋喃;DMF是指N,N-二甲基甲酰胺;DMSO是指二甲基亚砜;TEA是指三乙胺;Pd(OAc)2是指醋酸钯;Pd(dppf)Cl2是指1,1'-双二苯基膦二茂铁二氯化钯。
本发明已知的起始原料可以采用或者按照本领域已知的方法来合成,或者购买自安耐吉、阿拉丁等公司。
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂,纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括:A:二氯甲烷/甲醇体系,B:正己烷/乙酸乙酯体系,C:石油醚/乙酸乙酯体系,D:丙酮,E:二氯甲烷/丙酮体系,F:乙酸乙酯/二氯甲烷体系,G:乙酸乙酯/二氯甲烷/正己烷,H:乙酸乙酯/二氯甲烷/丙酮,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(乘以10-6(ppm)的单位给出。NMR的测定是用Ascend核磁共振仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用Agilent1100型液质联用。
柱层析一般使用烟台黄海硅胶300-400目硅胶为载体或100-200目酸性或碱性氧化铝。
实施例1 4-(4-硝基苯基)-丁-3-烯-1-酮(1-1)的制备
将对硝基苯甲醛(7.6g,50mmol)溶于125ml丙酮溶液中,加入K2CO3水溶液(10mL,0.02mol),室温搅拌24小时后加入浓盐酸(20mL),继续搅拌12小时至反应完成。加入大量的水后有固体析出,抽滤,滤饼干燥即为粗产品。以石油醚和乙酸乙酯(PE:EA=4:1)为流动相将粗产品进行柱层析分离纯化,得到黄色固体1-1(8.02g,84%)。1H NMR(500MHz,CDCl3)δ(ppm):8.27(d,J=8.7Hz,2H),7.72(d,J=8.8Hz,2H),7.55(d,J=16.3Hz,1H),6.84(d,J=16.3Hz,1H),2.44(s,3H)。
实施例2 6-甲基-4-(4-硝基苯基)-1-氧亚基-1,1-二氢吡啶-3-腈(1-2)的制备
取上述制备的1-1(3.825g,20mmol)和氰基乙酰胺(3.16g,30mmol)溶于DMSO(10mL)中,将叔丁醇钾(3.815g,34mmol)溶于DMSO(25mL)中并于0℃条件下缓慢滴入含有1-1和氰基乙酰胺的DMSO溶液中。加毕,将反应液转移至50~55℃反应4小时,同时进行氧气鼓泡。反应结束后,待其冷却至室温,加入水稀释,于0℃条件下缓慢滴加4N HCl调节反应液pH约为7,抽滤,并用水多次洗涤,滤饼干燥即为粗产品。以二氯甲烷和甲醇(DCM:MeOH=60:1)为流动相将粗产品进行柱层析分离纯化,得褐色油状液体1-2(1.07g,21%)。1H NMR(500MHz,DMSO-d6)δ(ppm):12.81(s,1H),8.38(d,J=8.7Hz,2H),7.88(d,J=8.7Hz,2H),6.40(s,1H),2.34(s,3H)。
实施例3 1-氯-6-甲基-4-(4-硝基苯基)烟腈(1-3)的制备
取中间体1-2(255mg,1mmol)溶于POCl3(10mL)中,110℃回流反应3小时。反应结束后,待其冷却至室温,转入大量冰中,并以乙酸乙酯萃取(20mL×3),合并有机层,无水Na2SO4干燥,抽滤,减压旋干,得粗品。以石油醚和乙酸乙酯(PE:EA=4:1)为流动相将粗产品进行柱层析分离纯化,得淡黄色固体1-3(216mg,79%)。1H NMR(500MHz,DMSO-d6)δ(ppm):8.43(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H),7.72(s,1H),2.63(s,3H)。
实施例4 1-氯-6-甲基-4-(4-硝基苯基)烟腈(1-4)的制备
取上述制备的1-3(216mg,0.79mmol),铁粉(177mg,3.16mmol),冰醋酸(356μL)溶于无水乙醇中(15mL),80℃回流反应2小时。反应结束后,待其冷却至室温,旋干反应液,并用热乙酸乙酯溶解残留固体,抽滤,滤液用饱和氯化钠溶液萃取(15mL×3),收集有机层,旋干即得粗品。以石油醚和乙酸乙酯(PE:EA=2:1)为流动相将粗产品进行柱层析分离纯化,得黄色固体1-4(175mg,91%)。1H-NMR(500MHz,DMSO-d6)δ7.48(s,1H),7.44(d,J=8.5Hz,2H),6.69(d,J=8.5Hz,2H),5.83(s,2H),2.53(s,3H)。
实施例5 4-(4-氨基苯基)-6-甲基异噁唑并[5,4-b]吡啶-3-胺(1-5)的制备
取上述制备的1-4(121mg,0.5mmol)溶于2mL DMF中,滴加溶有乙酰氧肟酸(75mg,1.0mmol)和碳酸钾(276mg,2.0mmol)的水溶液(3mL),在70℃下搅拌16h,反应完成后,用50mL水稀释体系,用乙酸乙酯萃取(100mL×3),合并有机层,无水Na2SO4干燥,以石油醚和乙酸乙酯(PE:EA=1:1)为流动相将粗产品进行柱层析分离纯化,得黄色固体1-5(63mg,53%)。1H NMR(500MHz,DMSO-d6)δ7.32(d,J=11.0Hz,2H),7.09(s,1H),6.72(d,J=8.5Hz,2H),5.65(s,2H),5.46(s,2H),2.55(s,3H)。
实施例6 3-氰基-6-甲基-2-氧基-1,2-二氢吡啶-4-羧酸乙酯(2-1)的制备
将乙醇钠(4.1g,60mmol)完全溶于50ml无水乙醇中,滴加草酸二乙酯(6.8ml,50mmol)和丙酮(3.7ml,50mmol),室温搅拌3h。搅拌完全后加入氰基乙酰胺(4.2g,50mmol),回流7h。反应完成后,减压除去乙醇,加入50ml沸水使固体完全溶解,冷却过程中加入3ml冰醋酸,固体完全析出,抽滤,真空干燥固体直接用于下步反应。
实施例7 2-氯-3-氰基-6-甲基异烟酸乙酯(2-2)的制备
取上述制备的2-1(4.1g,20mmol)加至150ml圆底烧瓶中,缓慢滴加POCl3(46ml,0.5mol),加毕,回流过夜。反应完成后,冷却至室温,减压除去POCl3,硅胶拌样,柱层析法纯化,以石油醚和乙酸乙酯(PE:EA=8:1)为流动相将粗产品进行柱层析分离纯化,得白色固体2-2(3.5g,77.9%)。1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),4.41(q,J=7.1Hz,2H),2.62(s,3H),1.37(t,J=7.1Hz,3H).
实施例8 2-氯-4-(羟甲基)-6-甲基烟腈(2-3)的制备
取上述制备的2-2(4.5g,0.02mol)溶于THF/H2O(V/V=1:1)混合溶剂120ml中,在冰浴下分批将硼氢化钠(3.9g,0.10mol)加入体系中,在室温搅拌3h。反应完成后,在冰浴下用4mol/L盐酸调节体系pH至2,减压除去部分溶剂,用乙酸乙酯萃取(300mL×2),合并有机层,有机层依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,无水Na2SO4干燥,减压旋干,得粗品。以石油醚和乙酸乙酯(PE:EA=4:1)为流动相将粗产品进行柱层析分离纯化,得白色固体2-3(1.2g,32.8%)。1H NMR(500MHz,DMSO-d6)δ7.55(s,1H),5.90(t,J=5.6Hz,1H),4.68(d,J=5.4Hz,2H),2.57(s,3H).
实施例9(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲醇(2-4)的制备
取上述制备的2-3(913mg,5mmol)溶于2ml DMF中,加入溶有碳酸钾(5.5g,40mmol)和乙酰氧肟酸(1.5g,20mmol)的水溶液,在70℃下搅拌过夜。反应完成后沉淀析出,抽滤,用100ml水洗涤滤饼,烘干即得产物2-4(610mg,68.1%)。1H-NMR(500MHz,DMSO-d6)δ7.55(s,1H),5.90(t,J=5.6Hz,1H),4.68(d,J=5.4Hz,2H),2.57(s,3H)。
实施例10 4-(氯甲基)-6-甲基异恶唑并[5,4-b]吡啶-3-胺(2-5)的制备
取上述制备的2-4(448mg,2.5mmol)置50ml圆底烧瓶中,加入SOCl2(7.3ml,0.1mol),回流4h。反应完成后将体系用150ml冰水淬灭,用乙酸乙酯萃取(300mL×3),合并有机层,有机层依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,无水Na2SO4干燥,减压除去溶剂得粗品,硅胶拌样,以石油醚和乙酸乙酯(PE:EA=2:1)为流动相将粗产品进行柱层析分离纯化,得黄色固体2-5(230mg,46.6%)。1H-NMR(500MHz,DMSO-d6)δ7.15(s,1H),6.31(s,2H),6.13(s,1H),4.84(d,J=5.1Hz,2H),2.53(s,3H)。
实施例11 4-(4-氨基苄基)-6-甲基异恶唑并[5,4-b]吡啶-3-胺(2-6)的制备
取上述制备的2-5(197mg,1.0mmol)置50ml圆底烧瓶中,加入4-氨基苯硼酸频哪醇酯(241mg,1.1mmol,碳酸铯(1.6g,5mmol)和Pd(dppf)Cl2(14mg,0.05mmol),加毕,加入1,4-二氧六环和水的混合溶剂(V:V=4:1)10ml,在氮气保护下回流过夜。反应完成后,用乙酸乙酯萃取(400mL×5),合并有机层,无水Na2SO4干燥,减压除去溶剂得粗品,硅胶拌样,以石油醚和乙酸乙酯(PE:EA=2:1)为流动相将粗产品进行柱层析分离纯化,得黄色固体2-6(120mg,47.2%)。1H-NMR(500MHz,DMSO-d6)δ6.92(d,J=8.3Hz,2H),6.82(s,1H),6.52(d,J=8.3Hz,2H),6.08(s,2H),5.13(s,2H),4.15(s,2H),2.46(s,3H)。
实施例12异氰酸酯盐(1-6)的制备
取25ml圆底烧瓶,三光气(0.3mmol,89mg)溶于5mL乙酸乙酯中。搅拌并冰浴至0℃。取代苯胺(0.6mmol)(R1代表芳基、取代芳基、芳杂基、取代芳杂基,烷基,取代烷基,含有0~3个氮原子、硫原子或氧原子的环状烷基等)缓慢滴加入反应液。在N2保护下,冰浴搅拌0.5h后,撤去冰浴室温反应1h,再在82℃回流4h。反应完成后,减压除去溶剂,得白色固体1-6(该合成步骤只是R1取代基不同,按照这个方法可以合成多个符合1-6结构式的化合物),无需进一步处理直接用于下一步反应。
实施例13 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(4-氟苯基)脲(F1-1)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-氟-4-异氰酸苯(1-6)(51mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-1(19mg,40%)。1H NMR(500MHz,DMSO-d6)δ8.99(s,1H),8.83(s,1H),7.67(d,J=8.6Hz,2H),7.56(d,J=8.6Hz,2H),7.51–7.47(m,2H),7.19(s,1H),7.14(t,J=8.9Hz,2H),5.47(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.88,160.68,158.42,152.98,147.51,141.56,136.29,136.27,129.78,128.82,120.63,120.57,119.44,118.82,115.88,115.70,102.51,24.52.19F NMR(471MHz,DMSO)δ-121.21。
实施例14 1-(4-(3-氨基-6-甲基异噁唑并[5,4-b]吡啶-4-基)苯基)-3-(4-(叔丁基)苯基)脲(F1-2)的制备
取25ml圆底烧瓶,三光气(0.3mmol,89mg)溶于5mL乙酸乙酯中。搅拌并冰浴至0℃。将4-叔丁基苯胺(0.6mmol,89mg)缓慢滴加入反应液,加入10μL三乙胺。在N2保护下,冰浴搅拌0.5h后,撤去冰浴后转移至室温反应1h,再在82℃回流4h。反应完成后,减压除去溶剂,得1-叔丁基-4-异氰酸苯(1-6),备用。
取上述实施例5制备的1-5(30mg,0.125mmol)溶于无水DCM中,加至上述制备的1-叔丁基-4-异氰酸苯(1-6)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,反应完后减压除去溶剂,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-2(23mg,44%)。如图2所示,1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.71(s,1H),7.67(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),7.39(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),7.19(s,1H),5.48(s,2H),2.60(s,3H),1.27(s,9H)。如图3所示,13C NMR(126MHz,DMSO-d6)δ169.89,160.66,158.43,152.91,147.54,144.83,141.69,137.30,129.79(2C),128.67,125.89(2C),119.42,118.68(2C),118.64(2C),102.50,34.38,31.72(3C),24.53。
实施例15 1-(4-(3-氨基-6-甲基噁唑并[5,4-b]吡啶-4-基)苯基)-3-(4-丁基苯基)脲(F1-3)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-正丁基-4-异氰酸苯(1-6)(66mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-3(31mg,59.7%)。1H NMR(500MHz,DMSO-d6)δ8.94(s,1H),8.69(s,1H),7.66(d,J=8.7Hz,2H),7.56(d,J=8.7Hz,2H),7.38(d,J=8.5Hz,2H),7.19(s,1H),7.11(d,J=8.5Hz,2H),5.49(s,2H),2.54(t,2H),1.59–1.48(m,2H),1.35–1.26(m,2H),0.90(t,J=7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.89,160.65,158.43,152.90,147.54,141.69,137.55,136.43,129.80,129.02,128.67,119.43,118.89,118.67,102.50,99.99,34.63,33.77,24.53,22.17。
实施例16 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(4-(三氟甲基)苯基)脲(F1-4)的制备
取1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(70mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-4(25mg,46.8%)。1H NMR(500MHz,DMSO-d6)δ9.22(s,1H),9.12(s,1H),7.65-7.71(m,6H),7.58(d,J=8.5Hz,2H),7.20(s,1H),5.48(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.88,160.69,158.42,152.66,147.44,141.17,138.23,132.86,129.83,129.22,126.63,126.61,123.35,119.48,119.04,118.46(2C),102.53,24.53.19F NMR(471MHz,DMSO-d6))δ-60.06。
实施例17 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(对甲苯基)脲(F1-5)的制备
取1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(70mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-5(19mg,40.7%)。1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),8.67(s,1H),7.66(d,J=8.6Hz,2H),7.56(d,J=8.6Hz,2H),7.36(d,J=8.4Hz,2H),7.19(s,1H),7.11(d,J=8.3Hz,2H),5.48(s,2H),2.60(s,3H),2.26(s,3H).13C NMR(126MHz,DMSO-d6)δ169.89,160.65,158.43,152.90,147.53,141.69,137.37,131.36,129.79,129.68,128.69,119.43,118.88,118.69,102.50,24.52,20.83。
实施例18 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(3-(三氟甲基)苯基)脲(F1-6)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(70mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-6(25mg,46.8%)。1H NMR(500MHz,DMSO-d6)δ9.19(s,1H),9.13(s,1H),8.05(s,1H),7.69(d,J=8.5Hz,1H),7.62(d,J=8.2Hz,1H),7.59–7.54(m,1H),7.52(d,J=8.0Hz,1H),7.36–7.30(m,1H),7.18(s,1H),5.47(s,2H),2.59(s,3H).13C NMR(126MHz,DMSO-d6)δ169.89,160.67,158.41,152.88,147.44,141.24,140.88,130.39,130.16,129.78,129.16,122.42,119.43,119.07,118.71,114.73,114.44,102.53,24.50。
实施例19 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-硝基苯基)脲(F1-7)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(62mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-7(50mg,98.9%)。1H NMR(500MHz,DMSO-d6)δ10.12(s,1H),9.68(s,1H),8.29(d,J=8.3Hz,1H),8.11(dd,J=8.4,1.3Hz,1H),7.76–7.73(m,1H),7.70(d,J=8.6Hz,2H),7.57(dd,J=19.5,8.6Hz,2H),7.25(dd,J=11.5,4.1Hz,1H),7.20(s,1H),5.50(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.88,160.68,158.42,152.27,147.40,141.08,138.44,135.45,135.03,129.87,129.49,125.90,123.18,123.02,119.49,119.14,102.54,24.52。
实施例20 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(3-硝基苯基)脲(F1-8)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(62mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-8(45mg,89%)。1H NMR(500MHz,DMSO-d6)δ9.33(s,1H),9.16(s,1H),8.60(s,1H),7.86(dd,J=8.1,2.1Hz,1H),7.79–7.74(m,1H),7.70(d,J=8.6Hz,2H),7.60(t,J=8.9Hz,3H),7.21(s,1H),5.49(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.88,160.68,158.43,154.50,152.83,148.62,147.42,141.35,141.12,130.60,129.83,129.12,126.67,119.48,119.12,112.69,102.53,24.53。
实施例21 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-甲基-3-硝基苯基)脲(F1-9)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(66mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-9(25mg,41.3%)。1H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.45(s,1H),8.07(d,J=8.1Hz,1H),7.69(d,J=8.3Hz,2H),7.59(t,J=9.2Hz,3H),7.43(t,J=8.1Hz,1H),7.19(s,1H),5.46(s,2H),2.60(s,3H),2.32(s,3H).13C NMR(126MHz,DMSO-d6)δ169.89,160.69,158.42,153.01,151.49,147.47,141.39,139.41,129.86,129.07,127.20,126.89,123.35,119.45,118.98,118.85,102.53,24.52,13.92。
实施例22 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-氯-4-硝基苯基)脲(F1-10)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(74mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-10(28mg,51.1%)。1H NMR(500MHz,DMSO-d6)δ10.05(d,J=5.3Hz,1H),8.94(d,J=3.1Hz,1H),8.57(d,J=9.3Hz,1H),8.37(d,J=2.6Hz,1H),8.24(dd,J=9.3,2.6Hz,1H),7.70(d,J=8.6Hz,2H),7.61(d,J=8.5Hz,2H),7.20(s,1H),5.50(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ174.94,169.87,160.71,158.41,151.86,147.29,142.74,141.65,140.55,129.98,129.80,125.35,124.15,121.40,119.60,119.50,119.11,102.54,24.52。
实施例23 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-氯-5-硝基苯基)脲(F1-11)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(74mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-11(24mg,43.8%)。1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),9.19(d,J=2.6Hz,1H),8.83(s,1H),7.89(dd,J=8.8,2.6Hz,1H),7.79(d,J=8.8Hz,1H),7.71(d,J=8.5Hz,2H),7.60(d,J=8.5Hz,2H),7.20(s,1H),5.49(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.87,160.74,158.41,152.34,147.34,147.04,140.71,137.43,130.86,129.95,129.62,128.40,119.50,119.07,117.96,115.05,102.53,24.52.。
实施例24 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-氟-4-硝基苯基)脲(F1-12)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(68mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-12(25mg,47.3%)。1H NMR(500MHz,DMSO-d6)δ9.60(s,1H),9.30(d,J=2.8Hz,1H),8.53(t,J=8.6Hz,1H),8.25–8.04(m,2H),7.69(d,J=8.5Hz,2H),7.60(d,J=8.5Hz,2H),7.20(s,1H),5.50(s,2H),2.60(s,3H).13C NMR(126MHz,DMSO-d6)δ169.87,160.71,158.42,151.91,151.51,149.56,147.29,141.06,140.51,129.98,129.76,121.61,119.50,119.02,111.71,102.54,24.52。
实施例25 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-甲基-4-硝基苯基)脲(F1-13)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(66mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-13(24mg,45.9%)。1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.49(s,1H),8.36(d,J=9.1Hz,1H),8.13–8.04(m,2H),7.69(d,J=8.5Hz,2H),7.58(d,J=8.5Hz,2H),7.18(s,1H),5.48(s,2H),2.59(s,3H),2.38(s,3H).13C NMR(126MHz,DMSO-d6)δ169.86,160.71,158.39,152.29,147.38,144.74,141.52,140.91,129.91,129.42,127.37,125.91,122.97,119.45,118.95,118.71–118.68,102.51,24.50,18.29。
实施例26 1-(4-(3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)苯基)-3-(2-甲氧基-4-硝基苯基)脲(F1-14)的制备
取上述制备的1-5(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(72mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F1-14(35mg,67.1%)。1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.90(s,1H),8.45(d,J=9.0Hz,1H),7.92(d,J=8.7Hz,1H),7.81(s,1H),7.68(d,J=8.0Hz,2H),7.58(d,J=7.9Hz,2H),7.18(s,1H),5.49(s,2H),4.05(s,3H),2.59(s,3H).13C NMR(126MHz,DMSO-d6)δ169.87,160.69,158.41,152.18,147.50,147.36,141.49,140.89,136.09,129.93,129.45,119.46,118.85,118.01,116.75,106.05,102.51,57.05,24.51。
实施例27 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(4-(叔丁基)苯基)脲(F2-1)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(66mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-1(32mg,59.6%)。1H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.56(s,1H),7.41(d,J=8.5Hz,2H),7.36(d,J=8.7Hz,2H),7.29(d,J=8.7Hz,2H),7.19(d,J=8.4Hz,2H),6.86(s,1H),6.17(s,2H),4.29(s,2H),2.47(s,3H),1.25(s,9H).13C NMR(126MHz,DMSO-d6)δ169.64,160.57,158.93,153.03,149.32,144.56,138.79,137.50,131.91,129.89,125.83,119.51,118.89,118.48,104.61,36.31,34.33,31.71,24.51。
实施例28 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(对甲苯基)脲(F2-2)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(50mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-2(28mg,57.8%)。1H NMR(500MHz,DMSO-d6)δ8.59(s,1H),8.52(s,1H),7.39(d,J=8.5Hz,2H),7.32(d,J=8.4Hz,2H),7.18(d,J=8.5Hz,2H),7.08(d,J=8.3Hz,2H),6.86(s,1H),6.13(s,2H),4.29(s,2H),2.47(s,3H),2.24(s,3H).13C NMR(126MHz,DMSO-d6)δ169.64,160.58,158.92,153.02,149.30,138.78,137.57,131.93,131.06,129.87,129.62,119.53,118.92,118.71,104.61,36.30,24.51,20.80。
实施例29 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(4-(三氟甲基)苯基)脲(F2-3)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(70mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-3(30mg,54.3%)。1H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.78(s,1H),7.66(d,J=8.9Hz,2H),7.62(d,J=9.0Hz,2H),7.42(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),6.87(s,1H),6.14(s,2H),4.30(s,2H),2.47(s,3H).13C NMR(126MHz,DMSO-d6)δ169.65,160.59,158.92,152.73,149.20,143.94,138.27,132.53,129.92,126.53,126.10,123.94,122.18,119.55,119.27,118.27,104.63,36.30,24.50.19F NMR(471MHz,DMSO-d6)δ-60.06。
实施例30 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(间甲苯基)脲(F2-4)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(50mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-4(27mg,55.8%)。1H NMR(500MHz,DMSO-d6)δ8.64(s,1H),8.57(s,1H),7.41(d,J=8.5Hz,2H),7.29(s,1H),7.22(d,J=8.4Hz,1H),7.19(d,J=8.5Hz,2H),7.15(t,J=7.8Hz,1H),6.86(s,1H),6.78(d,J=7.4Hz,1H),6.16(s,2H),4.29(s,2H),2.47(s,3H),2.27(s,3H).13C NMR(126MHz,DMSO-d6)δ169.64,160.58,158.93,152.96,149.29,140.07,138.72,138.40,132.02,129.89,129.07,123.00,119.54,119.11,118.93,115.80,104.62,36.30,24.51,21.69。
实施例31 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(间甲苯基)脲(F2-5)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(70mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-5(25mg,45.3%)。1H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.78(s,1H),8.01(s,1H),7.56(d,J=8.4Hz,1H),7.51(t,J=7.9Hz,1H),7.42(d,J=8.5Hz,2H),7.30(d,J=7.6Hz,1H),7.21(d,J=8.5Hz,2H),6.87(s,1H),6.17(s,2H),4.30(s,2H),2.47(s,3H).13C NMR(126MHz,DMSO-d6)δ169.63,160.59,158.93,152.96,149.24,141.06,138.31,132.47,130.36,129.91,125.76,123.59,122.24,119.54,119.30,118.48,114.50,104.61,36.29,24.51.19F NMR(471MHz,DMSO-d6)δ-61.31。
实施例32 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(3-(叔丁基)苯基)脲(F2-6)的制备
取上述制备的2-6(30mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(66mg,0.375mmol)中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-6(31mg,57.7%)。1H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.60(s,1H),7.45(t,J=1.7Hz,1H),7.41(d,J=8.5Hz,2H),7.28(d,J=8.0Hz,1H),7.22–7.17(m,3H),7.00(d,J=7.8Hz,1H),6.86(s,1H),6.16(s,2H),4.30(s,2H),2.47(s,3H),1.27(s,9H).13C NMR(126MHz,DMSO-d6)δ169.64,160.58,158.94,153.05,151.72,149.32,139.87,138.73,131.99,129.89,128.87,119.51,119.29,119.01,115.92,115.62,104.62,36.31,34.84,31.58,24.51。
实施例33 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(4-乙基苯基)脲(F2-7)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(55mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-7(21mg,41.9%)。1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.54(s,1H),7.39(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),6.86(s,1H),6.16(s,2H),4.29(s,2H),2.54(q,J=7.6Hz,2H),2.47(s,3H),1.15(t,J=7.6Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.62,160.58,158.93,153.02,149.32,138.78,137.77,137.61,131.93,129.88,128.44,119.53,118.90,118.77,104.60,36.29,27.97,24.51,16.28。
实施例34 1-(4-((3-氨基-6-甲基异恶唑并[5,4-b]吡啶-4-基)甲基)苯基)-3-(4-异丙基苯基)脲(F2-8)的制备
取2-6(32mg,0.125mmol)溶于无水DCM中,加入至上述制备的1-6(55mg,0.375mmol中,加入10μL三乙胺,在N2保护下室温搅拌过夜,以二氯甲烷和甲醇(DCM:MeOH=80:1)为流动相将粗产品进行柱层析分离纯化,得白色固体F2-8(29mg,55.8%)。1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.54(s,1H),7.40(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.14(d,J=8.5Hz,2H),6.86(s,1H),6.16(s,2H),4.29(s,2H),2.82(m,J=6.9Hz,1H),2.47(s,3H),1.18(d,J=6.9Hz,6H).13C NMR(126MHz,DMSO-d6)δ169.62,160.58,158.93,153.03,149.33,142.30,138.78,137.83,131.91,129.88,126.94,119.52,118.88,118.79,104.60,36.29,33.23,24.51,24.50。
实施例35 FLT3抑制剂(I)对FLT3激酶的药效实验
(1)实验方法:
使用ADP-GloTM激酶测定法(Promega,Madison,WI)进行FLT3抑制活性的测试。最佳浓度选择如下:FLT3和FLT3-ITD 10ng/μL,底物0.1mg/mL,ATP用量分别为50μM(FLT3)和100μM(FLT3-ITD)。具体操作如下:按照试剂盒说明书操作流程,预先配置5×DMSO待测化合物(以上制备得到的F1-1~F1-14,F2-1~F2-8)药液,2.5×ATP/底物混合溶液,2.5×激酶溶液,以及1×激酶缓冲液。于384孔板中依次加入2μl的2.5×激酶溶液,1μl的5×DMSO药液,2μl的2.5×ATP/底物混合液,同时设置复孔(2个),空白组(不加酶和药)和对照组(加酶但不加药)。在室温下混合10分钟,然后加入2μL ATP/底物混合物,在37℃下孵育1小时。反应完成后分两步进行ADP-GloTM激酶测定。随后,将5μL ADP-Glo试剂添加到每个孔中以停止激酶反应并耗尽未消耗的ATP。然后将混合物在室温下孵育40分钟,加入10μL激酶检测试剂将ADP转化为ATP并引入荧光素酶和荧光素以检测ATP。最后,将混合物在室温下孵育30~60分钟,测量化学发光。发光信号与反应体系中ATP的含量有关,与激酶活性成反比。以Quizartinib(奎扎替尼)为阳性对照药物进行测定。根据公式:抑制率%=(RLU对照-RLU实验)/(RLU对照-RLU空白)×100%(RLU,指相对发光强度),计算在1μM浓度下化合物对FLT3和FLT3-ITD激酶的抑制率。
选择对FLT3和FLT3-ITD两种激酶抑制率都较高(>65%)的化合物药液浓度从10μM起按3倍梯度进行稀释,共9个浓度。用上述实验方法计算各浓度下化合物对酶的抑制率,拟合出其对FLT3和FLT3-ITD激酶的IC50值,所用计算软件为Graphpad Prism 7.0。
(2)测定的实验结果如下表1:
表1
由表1的实验结果表明,化合物F1-1、F1-2、F1-6、F1-8等对FLT3激酶和FLT3-ITD均具有显著的抑制活性。特别是F1-2化合物活性最强。
实施例36 FLT3抑制剂(I)对表达FLT3相关细胞的药效实验
(1)实验方法:
人白血病细胞系(MV4-11/MOLM-13)购自美国典型培养物保藏中心(ATCC,USA)。MV4-11细胞在含有10%胎牛血清(FBS)和1%青霉素/链霉素的Dulbecco培养基(Gibco)中培养。MOLM-13细胞在含有10%FBS和1%青霉素/链霉素的RPMI 1640培养基(BI)中培养。所有细胞均在37℃、5%CO2条件下培养。将细胞接种到96孔板(2000-5000个细胞/孔)中。将化合物以溶剂DMSO成10mM浓度,并稀释9个浓度。以0.5%DMSO作为空白对照,第二天开始用药物处理细胞72h,其中测定中使用的最终浓度为10、3.3、1.1、0.37、0.122、0.041、0.0136、0.0045和0.0015μM,每个浓度设三孔测定。使用CCK8测定法(Apexbio)测量细胞活力,并使用iMark酶标仪(Bio-Rad)在450nm处测量吸光度。将数据标准化为对照组(DMSO),并表示为三个独立测量值的平均值,标准误差为<20%。使用GraphPad Prism 8.0.1(GraphPadSoftware,San Diego,CA,USA)计算IC50值。
(2)实验结果如下表2所示:
表2(表中的SD值表示标准差值)
由表2的实验结果表明,化合物F1-2、F1-4、F1-5、F1-6、F1-8等对表达FLT3的人白血病细胞系MOLM-13和MV4-11均具有显著的抑制活性。特别是F1-2化合物活性最强。
实施例37化合物F1-2对人类激酶组的选择性评价实验
(1)实验方法:
将化合物F1-2溶于DMSO中制备成10mM储备液,连续稀释,使化合物浓度为0.2mM。
均相时间分辨荧光技术HTRF激酶分析:
用分析缓冲液制备2×ATP/底物溶液和2×激酶/金属离子溶液,备用。使用Echo655将25nL化合物转移至384孔板,离心,加入2.5μL 2×激酶/金属离子溶液,混匀,在25℃下孵育10分钟;再添加2.5μL 2×ATP/底物溶液,并在25℃下孵育60分钟。用检测缓冲液配制2×XL665抗体溶液。向微孔中添加5μL激酶检测试剂,并在25℃下孵育60分钟。用微量滴定板阅读器读取在620nm(Cryptate)和665nm(XL665)下的荧光信号。
ADP蛋白激酶检测:
用分析缓冲液制备2×ATP/底物溶液和2×激酶/金属离子溶液,备用。使用Echo655将20nL化合物转移至384孔板中,加入2μL 2×激酶/金属离子溶液,混匀,在25℃下孵育10分钟;完成后加入2μL 2×底物和ATP溶液,并在25℃下孵育60分钟;完成后加入4μL ADP-Glo试剂,在25℃下孵育40分钟;最后加入8μL激酶检测试剂,并在25℃下孵育40分钟。用微量滴定板阅读器记录发光信号。以0.5%DMSO的读数设为阴性对照(0%抑制),化合物F1-2浓度为10μM时的读数设为阳性对照(100%抑制)。
(2)实验结果如下表3:
表3
由以上表3的筛选实验结果表明,本发明筛选得到的化合物F1-2对多种肿瘤疾病的靶点具有较高的选择性。可开发成为新的抗肿瘤药物。
Claims (11)
3.权利要求1或2所述异噁唑并[5,4-b]吡啶类FLT3抑制剂的互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐。
4.一种如权利要求2所述异噁唑并[5,4-b]吡啶类FLT3抑制剂的制备方法,其特征在于,所述的方法选自下述方案一或方案二:
(1)方案一,n1代表0,所述的方法包括以下步骤:
a、以对硝基苯甲醛为起始原料,以碳酸钾为碱,和丙酮在室温中发生羟醛缩合反应,生成甲基苯乙烯基酮类衍生物(1--1),备用;
b、取步骤a得到的甲基苯乙烯基酮衍生物(1--1)在碱性条件下,在二甲亚砜溶液中和氰基乙酰胺环合,生成氧代二氢吡啶类衍生物(1--2),备用;
c、取步骤b得到的氧代二氢吡啶类衍生物(1--2)为原料,在三氯氧磷回流条件下,得到氯代二氢吡啶类衍生物(1--3),备用;
d、取步骤c得到的氯代二氢吡啶类衍生物(1--3)在乙醇溶液中,经过铁粉还原生成取代芳基伯胺衍生物(1--4),备用;
e、取步骤d得到的取代芳基伯胺衍生物(1--4)在N,N-二甲基甲酰胺的水溶液中,在碳酸钾的作用下和乙酰氧肟酸成环,生成异噁唑并吡啶衍生物(1--5),备用;
f、伯胺衍生物和三光气在三乙胺的作用下,生成异氰酸酯盐(1--6),备用;
g、取步骤e得到的1--5和步骤f得到的1--6,在二氯甲烷溶液中和三乙胺催化作用下发生缩合反应,得到目标化合物(Ⅰ--1);
(2)方案二,n1代表1,所述方法在于包括以下步骤:
i、以草酸二乙酯和丙酮为起始原料,以乙醇钠为碱,和氰乙酰胺在室温中发生瓜列斯基-索普Guareschi–Thorpe缩合反应,生成氧代二氢吡啶羧酸酯类衍生物(2--1),备用;
j、取步骤i得到的氧代二氢吡啶羧酸酯类衍生物(2--1)在三氯氧磷回流条件下,发生氯代反应,生成异烟酸乙酯衍生物(2--2),备用;
k、取步骤j得到的异烟酸乙酯衍生物(2--2),以硼氢化钠还原剂,以四氢呋喃和水为溶剂,在室温下发生还原反应生成羟甲基烟腈衍生物(2--3),备用;
l、取步骤k得到的羟甲基烟衍生物(2--3)为原料,以碳酸钾为碱,在N,N-二甲基甲酰胺水溶液中,和乙酰氧肟酸发生环合反应生成异噁唑并吡啶衍生物(2--4),备用;
m、取步骤l得到的异噁唑并吡啶衍生物(2--4)在氯化亚砜的条件下,发生氯化反应生成异噁唑并吡啶氯代衍生物(2--5),备用;
n、取步骤m得到的异噁唑并吡啶氯代衍生物(2--5)为原料,以碳酸铯为碱,1,1'-双二苯基膦二茂铁二氯化钯为配体,以1,4-二氧六环和水为溶剂,和4-氨基苯硼酸频哪醇酯发生铃木-宫浦Suzuki-Miyaura反应,生成异噁唑并吡啶偶联衍生物(2--6),备用;
o、取步骤m得到的2--6和方案一步骤f得到的1--6,在二氯甲烷溶液中和三乙胺催化作用下发生缩合反应,得到目标化合物(Ⅰ--2)。
5.根据权利要求4所述的制备方法,其特征在于,步骤a中所用的对硝基苯甲醛和丙酮的用量比为1mol/2500ml~1mol/3750ml,碳酸钾摩尔比为1:0.5~0.8,反应温度为10℃~30℃,反应时间为36~40小时;
步骤b中所用的氰基乙酰胺摩尔比为1:1.5~3,叔丁醇钾摩尔比为1:1.5~4,反应溶剂为二甲基亚砜,1--1与二甲基亚砜的用量比为1mol/1500ml~1mol/2500ml,反应温度为40-70℃,反应时间为3~8小时;
步骤c中所用的氧代二氢吡啶衍生物(1--2)和三氯氧磷用量比为1mol/500ml~1mol/1000ml,反应温度为回流,反应时间为2~6小时;
步骤d中所用的氯代二氢吡啶衍生物(1--3)与铁粉摩尔比为1:3~6,与冰醋酸摩尔比为1:10~12,反应溶剂为乙醇,1--3与乙醇的用量比为1mol/1500ml~1mol/2000ml,反应温度为回流,反应时间为2~6小时;
步骤e中所用的取代芳基伯胺衍生物(1--4)与乙酰氧肟酸的摩尔比为1:1.5~3,碳酸钾的摩尔比为1:4~8,反应溶剂为N,N-二甲基甲酰胺与水体积比1:1~5,1--4与溶剂的用量比为1mol/500ml~1mol/1000ml反应温度为20℃~70℃,反应时间为12~24小时;
步骤f中所用胺类化合物与三光气摩尔比为1:3~6,反应催化剂为三乙胺,反应溶剂为无水乙酸乙酯,氮气保护,反应温度为室温至回流,反应时间为6~8小时;
步骤g中所用的吡啶并异噁唑衍生物(1--5)与异氰酸酯盐(1--6)的摩尔比为1:3~6,反应溶剂为二氯甲烷,1--5与溶剂的用量比为1mol/800ml~1mol/1000ml,反应温度为10℃~30℃,反应时间为12~24小时。
6.根据权利要求4所述的制备方法,其特征在于,步骤i中所用的草酸二乙酯与丙酮的摩尔比为1:1~1.5,与乙醇钠的摩尔比1:1.2~2,与氰基乙酰胺的摩尔比为1:1~2,反应溶剂为无水乙醇,草酸二乙酯与溶剂的用量比为1mol/1000ml~1mol/1500ml,反应温度为20℃~90℃,反应时间为8~12小时;
步骤j中所用的氧代二氢吡啶羧酸酯类衍生物(2--1)与三氯氧磷的摩尔比为1:30~60,反应温度为回流,反应时间为8~16小时;
步骤k中所用的异烟酸乙酯衍生物(2--2)与硼氢化钠的摩尔比为1:4~10,反应溶剂为四氢呋喃和水的混合溶剂(体积比为1:1~1.5),2--2与溶剂的用量比为1mol/4000ml~1mol/8000ml,反应温度为10℃~30℃,反应时间为2~8小时;
步骤l中所用的羟甲基烟腈衍生物(2--3)与乙酰氧肟酸的摩尔比为1:3~9,与碳酸钾的摩尔比为1:8~16,反应溶剂为N,N-二甲基甲酰胺和水的混合溶剂(体积比为1:10~40),2--3与溶剂的用量比为1mol/800ml~1mol/1200ml,反应温度为50℃~90℃,反应时间为10~24小时;
步骤m中所用的异噁唑并吡啶衍生物(2--4)与二氯亚砜摩尔比为1:50~150,反应温度为回流,反应时间为4~8小时;
步骤n中所用的异噁唑并吡啶氯代衍生物(2--5)与取代硼酸频哪醇酯的摩尔比为1:1.2~4,与1,1'-双二苯基膦二茂铁二氯化钯的摩尔比为1:0.01~0.1;与碳酸铯的摩尔比为1:4~10,反应溶剂1,4-二氧六环和水的混合溶剂(体积比为1:0.1~0.4),2--5与溶剂的用量比为1mol/800ml~1mol/1500ml,反应温度为回流,反应时间为10~18小时;
步骤o中所用的异噁唑并吡啶偶联衍生物(2--6)与异氰酸酯盐(1--6)的摩尔比为1:3~6,反应溶剂为二氯甲烷,异噁唑并吡啶偶联衍生物(2--6)与溶剂的用量比为1mol/800ml~1mol/1000ml,反应温度为10℃~30℃,反应时间为12~24小时。
7.一种药物组合物,其特征在于,包括权利要求1或2所述的化合物和药学上可接受的盐及其药学上可接受的载体。
8.权利要求1或2所述的异噁唑并[5,4-b]吡啶类FLT3抑制剂在制备防治肿瘤的药物中的应用。
9.权利要求1或2所述异噁唑并[5,4-b]吡啶类FLT3抑制剂的互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐在制备防治肿瘤的药物中的应用。
10.权利要求1或2所述的异噁唑并[5,4-b]吡啶类FLT3抑制剂在制备防治急性髓系白血病的药物中的应用。
11.权利要求1或2所述异噁唑并[5,4-b]吡啶类FLT3抑制剂的互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐在制备防治急性髓系白血病的药物中的应用。
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