CN114127063B - 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途 - Google Patents
嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途 Download PDFInfo
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- C07D473/32—Nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及一种嘧啶并五元杂环类化合物及其作为突变型IDH2抑制剂的用途,具体地,本发明公开了一种可作为突变型IDH2抑制剂的嘧啶并五元杂环类化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物。本发明还涉及包含上述化合物的药物组合物及其用于制备预防和/或治疗突变型IDH2介导的疾病的药物的用途。
Description
技术领域
本发明涉及医药化学领域,具体涉及一种嘧啶并五元杂环类化合物及其作为突变型IDH2抑制剂的用途。
背景技术
异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)是三羧酸循环中催化异柠檬酸生成alpha-酮戊二酸(α-KG)的关键限速酶。高等哺乳动物存在3种亚型,分别是IDH1、IDH2、IDH3。其中IDH1主要位于细胞质基质和过氧化物酶体,而IDH2和IDH3则主要定位在线粒体。IDH1,IDH2以同源二聚体的形式并以烟酰胺腺嘌呤二核苷酸磷酸(NADP+)作为辅酶行使酶催化功能。IDH3由2个α亚基、1个β亚基和1个γ亚基组成的异源四聚体,并以烟酰胺腺嘌呤二核苷酸(NAD+)为辅酶催化异柠檬酸生成α-KG,同时伴随产生NADH调控细胞内的氧化还原反应。
研究发现IDH1/2在许多不同类型的肿瘤中都存在突变。包括脑瘤、白血病、软骨肉瘤、胆管癌等。相比IDH1,IDH2在急性髓系白血病(acute myelocytic leukemia,AML)中的突变率率为8.7%-19%。其突变位点主要集中在R140Q和R172K。突变的IDH2(IDH2m)会导致其正常功能缺失,并将α-KG转化为致癌代谢物2-羟基戊二酸(2-HG),使2-HG在突变的肿瘤细胞中累积。研究表明α-KG与2-HG结构相似,2-HG会竞争性结合α-KG依赖的双加氧酶的活性(如DNA去甲基化酶和组蛋白去甲基化酶),导致一些基因组关键区域的核小体和/或DNA高度甲基化,这种表观遗传改变被认为干扰了正常的细胞分化,导致未成熟细胞过度增殖,从而引发癌症。
在含IDH2突变的肿瘤细胞中,突变型IDH2抑制剂可特异结合于突变酶蛋白,有效抑制突变蛋白酶活,使体内致癌代谢物2-HG减少,从而诱导组蛋白和/或DNA的去甲基化,达到促进肿瘤细胞分化,抑制肿瘤发展的效果。以IDH2突变体为靶点参与新药研发的公司主要以美国Agios制药公司为代表。其研发的靶向IDH2-R140Q突变的药物Enasidenib已于2017年8月1日获过FDA批准并成功上市,但IDH2抑制剂的研发化学型的多样化不足,因此急需开发新型的、高效低毒IDH2m抑制剂。
发明内容
本发明的目的是提供一类高选择性、高效低毒的突变型IDH2抑制剂。
本发明第一方面提供了一种式I所示的嘧啶并五元杂环类化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物,
其中,
R1选自无、氢、卤素、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C10环烷基;
R2选自氢、卤素、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C10环烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8羧基、取代或未取代的C2-C20酯基、取代或未取代的C6-C10芳基或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
X选自N、O、S或CR5;其中R5为氢、卤素、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、或取代或未取代的C3-C10环烷基;
m1为0、1、2、3、或4;各个L独立地选自无、O、S、-CO-、-NH-或-CH2-;
m2为0、1或2;各个Z独立地选自无、O、S、-CO-、-NH-或-CH2-;
R3选自氢、卤素、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的4-8元杂环基;
R4选自氢、卤素、CN、取代或未取代C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、苄基、C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基。
在另一优选例中,对于R3,所述取代是指被选自下组的一个或多个(例如2个、3个、4个等)取代基取代:卤素、CN、羟基、取代或未取代的C1-C6烷基、C1-C6卤代烷基或取代或未取代的C1-C6烷氧基。
在另一优选例中,对于R4,所述取代是指被选自下组的一个或多个(例如2个、3个、4个等)取代基取代:卤素、CN、羟基、取代或未取代C1-C6烷基或取代或未取代C1-C6卤代烷基。
在另一优选例中,所述的酯基包括-(取代或未取代的C1-C6亚烷基)-C(O)-O-(取代或未取代的C1-C6烷基)。
在另一优选例中,X为O或S,且R1为无。
在另一优选例中,所述化合物具有式Ia所示的结构:
式中,R1、R2、R3、R4、L、和m1的定义如上所述。
在另一优选例中,m1为2,且-(L)m1-为-NH-CH2或-CH2-NH-。
在另一优选例中,m2为2,且-(Z)m2-为-NH-CH2或-CH2-NH-。
在另一优选例中,L为NH,m1为1,并且Z为无,m2为0。
在另一优选例中,R3为C3-C6环烷基。
在另一优选例中,R2为甲基或三氟甲基。
在另一优选例中,R4为氟取代的苯基。
在另一优选例中,X为CR5。
在另一优选例中,R5为H、C1-C4烷基、或C3-C4环烷基。
在另一优选例中,所述的化合物为表1中的化合物#1、#2、#3、#4、#5、#6、#7、#8、#9、#10、#11、#12、#13、#14、#15、#16、#17、#18、#19、#20、#21、#22、#23、#24、#25、#26、#27、#28、#29、#30、#31、#32、#33、#34、#35、#36、#37、#38、#39、#40、#41、#42、#43、#44、#45、#46、#47、#48、#49、#50、或#51,或其药学上可接受的盐。
在另一优选例中,所述化合物为表1中的化合物#28、#48、#49或#51,或其药学上可接受的盐。
在另一优选例中,所述化合物选自:
本发明第二方面,提供了一种药物组合物,包含:(1)如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
本发明第三方面,提供了一种如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物或如本发明第二方面所述的药物组合物的用途,用于制备预防和/或治疗突变型IDH2介导的疾病的药物。
在另一优选例中,所述突变型IDH2介导的疾病为癌症;较佳地,所述癌症选自膀胱癌、乳腺癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);淋巴系的造血肿瘤,例如包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;间充质细胞来源的肿瘤,例如包括纤维肉瘤、横纹肌肉瘤;髓系的造血肿瘤,例如包括急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞白血病;中枢和周围神经系统肿瘤,例如包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;和其它肿瘤,例如包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、色性干皮病、角化棘皮瘤、甲状腺滤泡癌和卡波济氏肉瘤。
本发明第四方面,提供了一种式I化合物的制备方法,所述方法包括步骤:
(a)将式(1)化合物与H-(L)m1-R3反应,从而制得式(2)化合物,其中H-(L)m1-R3为R3取代的胺类化合物或者硼酸类化合物或者硼酸酯类化合物;和
(b)将式(2)化合物与H-(Z)m2-R4反应,从而制得式(I)化合物,其中H-(Z)m2-R4为R4取代的胺类化合物或者硼酸类化合物或者硼酸酯类化合物或者有机锡化合物;
式中,R1、R2、R3、R4、L、Z、m1、m2的定义如本发明第一方面所述。
本发明第五方面,提供了一种式Ia所示的化合物的制备方法,所述的方法包括步骤:
(a1)将式(1a)的化合物与N-溴代丁二酰亚胺或者S-(三氟甲基)二苯并噻吩嗡四氟硼酸盐(Umemoto′s reagents)反应,制得式(2a)化合物;和
(b1)将式(2a)化合物与硼酸类化合物R2-B(OH)2反应,从而制得式(Ia)所示的化合;
式中,R1、R2、R3、R4、L、m1的定义如本发明第一方面所述。
本发明的第六方面,提供了一种突变型IDH2抑制剂,所述抑制剂包含本发明第一方面化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物。
本发明的第七方面,提供了一种体外抑制含突变型IDH2的肿瘤细胞增殖的方法,包括步骤:将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物与突变型IDH2接触,从而抑制突变型IDH2的活性。
本发明的第八方面,提供了一种预防和/或治疗突变型IDH2介导的疾病的方法,包括步骤:向所需对象施用本发明第一方面所述的化合物、或其立体异构体或互变异构体、或药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物。
在另一优选例中,所述对象包括哺乳动物,如人。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究,首次开发了一类对突变型IDH2具有优异抑制活性的新型化合物。本发明的化合物对于突变型IDH2具有优异的选择性,对正常细胞的毒性极低,并且具有具有良好的成药性和药代活性。在此基础上,完成了本发明。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子(优选地,1-6个,更优选地,1-3个)的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C8烯基指具有2-8个碳原子(优选地,2-4个)的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C8炔基是指具有2-8个碳原子(优选地,2-4个)的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C10环烷基”指具有3-10个碳原子(优选地,3-6个)的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C1-C8烷氧基”是指具有1-8个碳原子(优选地,1-6个,更优选地,1-3个)的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环基”是指具有3-10个环原子的且其中1-3个环原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环或多环形式,例如桥环或螺环形式。代表性的实例包括但并不限于:氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个环原子的且其中1-3个环原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:选自下组的一个或多个(例如2个、3个、4个、5个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、苄基、C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
活性成分
如本文所用,“本发明化合物”指式I所示的化合物,并且还包括式I化合物的异构体、消旋体、晶型或无定形、药学上可接受的盐、水合物或溶剂合物。
如本文所用,“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于:氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱,氨水、三乙胺、二乙胺等有机碱。
本发明化合物可以是无定形的、晶型或其混合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水化形式。溶剂化形式通常与非溶剂化形式等价,应包括在本发明范围内。本发明的某些化合物可以多晶型或无定形形式存在。通常,就本发明所考虑的应用而言,所有物理形式是等价的,应包括在本发明范围内。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
在另一优选例中,所述的R1、R2、R3、R4、L、Z、m1、m2各自独立地为表1中各个化合物所对应的基团。
优选的本发明化合物如表1所示:
表1
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制备方法
一种式I化合物的制备方法,所述方法包括步骤:
(a)将式(1)化合物与H-(L)m1-R3反应,从而制得式(2)化合物,其中H-(L)m1-R3为R3取代的胺类化合物或者硼酸类化合物或者硼酸酯类化合物;和
(b)将式(2)化合物与H-(Z)m2-R4反应,从而制得式(I)化合物,其中H-(Z)m2-R4为R4取代的胺类化合物或者硼酸类化合物或者硼酸酯类化合物或者有机锡化合物;
式中,R1、R2、R3、R4、L、Z、m1、m2的定义如上所述。
一种式Ia所示的化合物的制备方法,所述的方法包括步骤:
(a1)将式(1a)的化合物与N-溴代丁二酰亚胺或者S-(三氟甲基)二苯并噻吩嗡四氟硼酸盐(Umemoto′s reagents)反应,制得式(2a)化合物;和
(b1)将式(2a)化合物与硼酸类化合物R2-B(OH)2反应,从而制得式(Ia)所示的化合;
式中,R1、R2、R3、R4、L、m1的定义如上所述。
药物组合物和施用方法
由于本发明化合物具有优异的突变型IDH2抑制活性和高选择性,因此本发明化合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)突变型IDH2介导的相关疾病。代表性的疾病包括但并不限于:膀胱癌、乳腺癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);淋巴系的造血肿瘤,例如包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;间充质细胞来源的肿瘤,例如包括纤维肉瘤、横纹肌肉瘤;髓系的造血肿瘤,例如包括急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞白血病;中枢和周围神经系统肿瘤,例如包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;和其它肿瘤,例如包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、色性干皮病、角化棘皮瘤、甲状腺滤泡癌和卡波济氏肉瘤。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如 )、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物(例如抗癌剂)联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物(例如抗癌剂)。该其他药学上可接受的化合物(例如抗癌剂)中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗突变型IDH2介导的疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(1)本发明的化合物结构新颖且具有优异的突变型IDH2抑制作用,且本发明的化合物对野生型的IDH2(IDH2/WT)几乎没有活性,具有很好的选择性。
(2)本发明的化合物对正常细胞的毒性非常低,因而可以在较大的剂量范围内应用于治疗对象。
(3)本发明化合物具有良好的成药性,极易制成药学上可接受的盐,因而有助于进一步形成制剂。
(4)本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗突变型IDH2介导的疾病。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。本发明实施例中所用原料或仪器,若非特别说明,均市售可得。
实施例中的对照化合物为Enasidenib(AG-221),CAS:1446502-11-9,结构式如下:
实施例1
Step 1:2-氯-9-异丙基-N-苯基-9H-嘌呤-6-胺(2)
在一个25毫升的圆底烧瓶中加入2,6-二氯-9-异丙基-9H-嘌呤(138mg,0.60mmol)和8毫升正丁醇。加入Et3N(96mg,0.96mmol)和苯胺(67mg,0.72mmol)。反应混合物在100℃下搅拌16h(过夜),并在真空中浓缩。采用自动闪柱柱色谱(硅胶,DCM∶MeOH=20∶1)对残留进行纯化,得到2-氯-9-异丙基-N-苯基-9H-嘌呤-6-胺(144mg,83%收率)为白色固体。
ESI m/z:415.2(M+H)+.
Step 2:9异丙基-N,2-二苯基-9H-嘌呤-6-胺(3)
以2-氯-9-异丙基-N-苯基-9H-嘌呤-6-胺(100mg,0.35mmol)、苯基硼酸(50mg,0.4mmol)、Pd(PPh3)4(40mg,0.03mmol)、K2CO3(140mg,1mmol)、甲苯(5mL)、水(1mL)充入10ml密封管。反应混合物在100℃惰性气体中搅拌3h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶1)对产物进行纯化,得到产物92mg,收率80%,为无色固体。
ESI m/z:330.2(M+H)+.1H NMR(DMSO-d6,400MHz)δ9.91(s,1H),8.41-8.44(m,3H),8.06(d,J=7.6Hz 2H),7.38-7.54(m,3H),7.36(m,2H),7.06(t,J=7.2Hz 1H),4.88-4.95(m,J=6.8Hz,1H),1.63(d,J=6.4Hz,6H)ppm.
实施例2
Step 1:2-氯-9-异丙基-N-(2-甲氧基苯基)-9H-嘌呤-6-胺(2)
用2,6-二氯-9-异丙基-9H-嘌呤(115mg,0.50mmol)和5mL正丁醇充入10mL密封管。加入Et3N(80mg,0.80mmol)和2-甲氧基苯胺(74mg,0.60mmol)。反应混合物在100℃下搅拌4h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=3∶2)对产物进行纯化,得到产物为白色固体(95mg,收率60%)。
分子式:C15H16ClN5O,分子量:317.78,ESI m/z:318.1(M+H)+.
Step 2:9-异丙基-N-(2-甲氧基苯基)-2-苯基-9H-嘌呤-6-胺(3EPT60049)
以2-氯-9-异丙基N-(2-甲氧基苯基)-9H-嘌呤-6-胺(95mg,0.3mmol)、苯基硼酸(50mg,0.4mmol)、Pd(PPh3)4(34mg,0.03mmol)、K2CO3(139mg,1mmol)、二氧六环(5mL)、水(1mL)充入10ml密封管。反应混合物在惰性气体中以100℃加热3h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶1)对产物进行纯化,得到产物(58mg,54%收率)为白色溶胶。
分子式:C21H21N5O,分子量:359.43,(ESI)m/z=360.2(M+H)+.1H NMR(400MHz,DMSO-d6)8.63-8.66(m,1H),8.41(m,4H),7.48-7.55(m,3H),7.10-7.17(m,3H),4.91(m,J=6.8Hz,1H)3.94(s,3H)1.63(d,J=6.8Hz,6H)ppm.
实施例3
Step 1:2-氯-9-异丙基-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(2)
用2,6-二氯-9-异丙基-9H-嘌呤(200mg,0.86mmol)和10mL DMSO充入10mL密封管。加入t-BuOK(150mg,1.33mmol)和2-(三氟甲基)吡啶-4-胺(180mg,1.11mmol)。反应混合物在100℃微波加热1h。反应后将混合物加水(50mL)。混合料用EA(20mL 3)萃取,有机层复合,在无水碳酸钠上干燥,过滤。然后用硅胶(100-200目)对有机层进行浓缩蒸发,得到粉状残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=7∶3)对残留进行纯化,得到标题化合物(225mg,收率73%)为黄色固体。
分子式:C14H12ClF3N6,分子量:356.74,(ESI)m/z=357.1(M+H)+.
Step 2:9-异丙基-2-苯基-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(3EPT60050)
用2-氯-9-异丙基N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(50mg,0.14mmol)、苯基硼酸(18mg,0.15mmol)、Pd(PPh3)4(15mg,0.014mmol)、K2CO3(56mg,0.4mmol)、二氧六环(5mL)、水(1mL)分别充入10-mL密封管。反应混合物在惰性气体中加热到100摄氏度,加热1.5h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=4∶1)对产物进行纯化,得到产物为白色固体(15mg,收率26.7%)。
分子式:C20H17F3N6,分子量:398.39,(ESI)m/z=399.2(M+H)+.1H NMR(400MHz,DMSO-d6)10.84(s,1H),8.93(d,J=2.0Hz,1H),8.61(d,J=5.6Hz,1H),8.55(s,1H),8.39-8.41(m,2H),8.19-8.21(m,1H),7.48-7.54(m,3H),4.92(m,J=6.8Hz,1H),1.61(d,J=6.8Hz,6H)ppm.
实施例4
Step 1(6-(三氟甲基)吡啶-2-基)硼酸(2)
用2-溴-6-(三氟甲基)吡啶(226mg,1.0mmol)、4、4、4′,4′,5、5、5′,5′,5′,5′,5′,5′,5′-八甲基-2,2′-bi(1,3,2-二噁硼烷)(280mg,1.1mmol)、Pd(dppf)Cl2(140mg,0.2mmol)、AcOK(400mg,4.0mmol)分别充入10mL密封管。反应混合物在惰性气体中以90c加热4h。采用LCMS对反应进行监测,(ESI)m/z=192.09,没有残留SM-1,下一步使用粗产物,未进一步纯化。
Step 2:9-异丙基-2-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(3EPT60061)
用2-氯-9-异丙基N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(50mg,0.14mmol),(6-(三氟甲基)吡啶-2-基)硼酸(2.5mL二氧六环原液),Pd(dppf)Cl2(10mg,0.014mmol),K2CO3(56mg,0.4mmol),加入水(0.5mL),密封管20ml。反应混合物在惰性气体中加热到90度,加热3h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。渣油通过蒸发浓缩而成黑色油渣。采用自动闪柱柱色谱法(硅胶,MeOH∶DCM=1∶24)对产物进行纯化,得到产物为白色固体(30mg,收率46%)。
分子式:C20H15F6N7,分子量:467.38,(ESI)m/z=468.2(M+H)+.1HNMR(400MHz,DMSO-d6)10.93(s,1H),9.01(d,J=2.0Hz,1H),8.70(d,J=8.0Hz,1H),8.66(s,1H),8.53-8.54(d,J=5.6Hz,1H),8.42-8.44(m,1H),8.26(t,J=8.0Hz 1H),8.00(d,J=7.6Hz,1H)4.95(m,J=6.8Hz,1H),1.60-1.62(d,J=6.8Hz,6H)ppm.
实施例5
Step 1:9-异丙基-2-(吡啶-3-基)-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(2EPT60062)
以2-氯-9-异丙基-N-(2-(三氟甲基)吡啶-4-酰基)-9H-嘌呤-6-胺(36mg,0.10mmol)、吡啶-3-基硼酸(37mg,0.30mmol)、Pd(dppf)Cl2(7mg,0.01mmol)、K3PO4(84mg,0.4mmol)、二氧六环(2.5mL)、水(0.5mL)分别充入10ml密封管。反应混合物在惰性气体中以100℃加热4h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,MeOH∶DCM=1∶10)对产物进行纯化,得到产物为白色固体(20mg,收率50%)。
分子式:C19H16F3N7,分子量:399.38,(ESI)m/z=400.2(M+H)+.1HNMR(400MHz,DMSO-d6)10.89(s,1H),9.52(d,J=1.6Hz,1H),8.82(d,J=2.0Hz,1H),8.58-8.68(m,4H),8.21-8.23(m,1H),7.53-7.56(m,1H),4.92(m,J=6.8Hz,1H),1.60-1.62(d,J=7.2Hz,6H)ppm.
实施例6
Step 1:2-氯-N-苯基-9H-嘌呤-6-胺(2)
一个25毫升的圆底烧瓶中装有2,6-二氯-9H-嘌呤(2,589mg,3.11mmol)和10毫升正丁醇。加入Et3N(944mg,9.35mmol)和苯胺(348mg,3.74mmol)。反应混合物在100℃下搅拌16h(过夜),LCMS分析确认反应完成。然后用MeOH对沉淀物进行过滤和洗涤,得到的产物产率为66%(505mg),为灰白色固体。ESI m/z:246.1(M+H)+.1H NMR(DMSO-d6,400MHz)δ7.08(d,J=7.2Hz,1H),7.36(t,J=7.6Hz,2H),7.84(d,J=7.6Hz,2H),8.30(s,1H),10.18(s,1H),13.29(s,1H)ppm.
Step 2:N,2-二苯基-9H-嘌呤-6-胺(3,EPT60063)
在一个10毫升的微波管中加入化合物2(65mg,0.26mmol)和二氧六环(2.5mL)和水(0.5mL)的混合物。加入K2CO3(108mg,0.78mmol)、苯基硼酸(39mg,0.32mmol)和Pd(dppf)Cl2(19mg,0.026mmol)。反应混合物在100℃氩气微波下搅拌4小时。通过LCMS分析证实了反应的完成。将混合物冷却至室温(20℃),形成沉淀,过滤收集。粗品经硅胶柱层析(DCM/MeOH=10/1)纯化得到所需的白色固体(38mg,产率54%)。ESI m/z:288.16(M+H)+.1H NMR(DMSO-d6,400MHz)δ7.07(d,J=7.2Hz,1H),7.40(t,J=7.6Hz,2H),7.53-7.43(m,3H),8.05(d,J=8.0Hz,2H),8.30(s,1H),8.39-8.37(m,2H),9.84(s,1H),13.20(s,1H)ppm.
实施例7
Step 1:2-氯-6-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(2)
将2,4-二氯-6-甲基-7H-吡啶(1)(150mg,0.743mmol)、苯基硼酸(145mg,1.19mmol)、碳酸钾(513mg,3.71mmol)、二(三苯基膦)氯化钯(II)(84mg,0.12mmol)在二氧六环/水(10/1,13mL)中,在80℃氮气气氛下搅拌过夜。冷却至室温后,用乙酸乙酯(30ml)和水(30ml)稀释。分离有机层,用乙酸乙酯(30ml)萃取水层。采用C18柱(乙腈/水浓度为55%~60%)对合成的有机层进行浓缩纯化,得到标题化合物2(110mg,产率61%)为灰白色固体。
LC-MS[流动相:在2.5min内,从95%水和5%CH3CN到5%水和95%CH3CN],Rt=1.64min;MS计算值:243.1;MS实测值:244.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.13-8.11(m,2H),7.61-7.56(m,3H),6.67(s,1H),2.45(s,3H).
Step 2:6-甲基-N,4-二苯基-7H-吡咯并[2,3-d]嘧啶-2-胺(3)
将2-氯-6-甲基-4-苯基-7H-吡咯[2,3-d]嘧啶(2)(90mg,0.37mmol)和苯胺(103mg,1.11mmol)溶于乙二醇(3mL)中,加一滴浓盐酸水溶液。混合物在150℃微波和氮气气氛下,在密封管中搅拌10小时。冷却至室温后,将混合物倒入水中(30ml),用乙酸乙酯萃取(15ml×2),用盐水(30ml)冲洗并浓缩。采用C18柱(乙腈/水从60%~70%)对残留进行纯化,得到标题化合物(90mg,收率82%)为灰白色固体。
LC-MS纯度:95.84%(214nm),98.12%(254nm);MS计算值:300.1;MS实测值:301.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),9.24(s,1H),8.13(d,J=7.2Hz,2H),7.90(d,J=7.6Hz,2H),7.59-7.50(m,3H),7.27(t,J=7.6Hz,2H),6.87(t,J=7.6Hz,1H),6.40(s,1H),2.37(s,3H).
实施例8
Step1:2-氯-6-甲基-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺
在乙二醇(4ml)中2,4-二氯-6-甲基-7H-吡咯[2,3-d]嘧啶(1)(100mg,0.495mmol)和苯胺(125mg,1.34mmol)溶液中加入4滴浓缩盐酸水溶液。混合物在100℃氮气气氛下搅拌过夜。冷却至室温后,将混合物倒入水中(30ml),用乙酸乙酯萃取(15ml×2),用盐水(30ml)冲洗并浓缩。用C18柱(乙腈/水从50%到60%)对残渣进行纯化,得到标题化合物2(80mg,收率63%)为灰白色固体。
LC-MS[流动相:在2.5min内,从70%水和30%CH3CN到5%水和95%CH3CN],Rt=1.30min;MS计算值:258.1;MS实测值:259.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),9.48(s,1H),7.76-7.74(dd,J=8.4,1.2Hz,2H),7.36(dd,J=8.4,3.2Hz,2H),7.06(t,J=7.6Hz,1H),6.40(s,1H),2.34(s,3H).
Step 2:6-甲基-N,2-二苯基-7H-吡咯并[2,3-d]嘧啶-4-胺
将2-氯-6-甲基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(2)(130mg,0.502mmol)、苯基硼酸(123mg,1.01mmol)、碳酸钾(347mg,2.51mmol)和四价(三苯基膦)钯(58mg,0.05mmol)在1,2-二甲氧基乙烷/水(5/1,3.6mL)中,在100℃微波氮气中搅拌3.5小时。冷却至室温后,将混合物倒入水中(25ml),用乙酸乙酯萃取(25ml×2),用盐水(30ml)冲洗并浓缩。用C18柱(乙腈/水从50%到60%)对残留进行纯化,得到标题化合物(70mg,收率47%)为灰白色固体。
LC-MS(ESI):RT=2.253min,MS计算值C19H16N4300.1,m/z实测值301.0[M+H]+.1HNMR(400MHz,DMSO-d6)δ11.69(s,1H),9.22(s,1H),8.37(d,J=7.2Hz,2H),7.98(d,J=7.6Hz,2H),7.50-7.37(m,5H),7.03(t,J=7.2Hz,1H),6.49(s,1H),2.39(s,3H).
实施例9
Step 1:9-异丙基-2-(吡啶-4-基)-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(2EPT60072)
向10mL密封管中加入2-氯-9-异丙基-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(50mg,0.14mmol),吡啶-4加入-硼酸(50mg,0.40mmol),Pd(dppf)Cl2(10mg,0.014mmol),K3PO4(84mg,0.4mmol),然后加入二氧六环(2.5mL)和水(0.5mL)。将混合物在惰性气氛下在100℃加热4小时。反应完成后,将反应混合物用硅胶(100-200mesh)浓缩,蒸发,得到粉末残余物。通过自动快速柱色谱法(硅胶,MeOH∶DCM=1∶10)纯化残余物,得到标题化合物(40mg,71%产率),为白色固体。
分子式:C19H16F3N7,分子量:399.38,(ESI)m/z=400.2(M+H)+.1HNMR(400MHz,DMSO-d6)10.97(s,1H),8.85(d,J=1.6Hz,1H),8.77-8.79(dd,J1=1.6Hz,J2=14.8Hz,2H),8.66-8.68(m,2H),8.27-8.30(m,3H),4.9(m,J=6.8Hz,1H),1.65(d,J=6.8Hz,6H)ppm.
实施例10
Step 1:9-异丙基-2-(吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-9H-嘌呤-6-胺(2EPT60073)
用2-氯-9-异丙基N-(2-(三氟甲基)吡啶-4-酰基)-9H-嘌呤-6-胺(107mg,0.30mmol),2-(三丁基锡基)吡啶(310mg,0.84mmol),Pd(PPh3)4(35mg,0.03mmol),加入二氧六环(5.0mL),密封管10-mL。反应混合物在100℃惰性气体中加热8h。反应完成后,用饱和KF水溶液(2mL)对反应混合物进行骤冷,用硅胶(100-200mesh)对有机相进行浓缩蒸发,得到粉体残渣。采用自动闪柱柱色谱法(硅胶,MeOH∶DCM=1∶19)对产物进行纯化,得到标题化合物(55mg,收率46%)为黄色固体。
分子式:C19H16F3N7,分子量:399.38,(ESI)m/z=400.2(M+H)+.1H NMR(500MHz,DMSO-d6)10.93(s,1H),9.22(d,J=2.5Hz,1H),8.78-8.80(m,1H),8.66(s,1H),8.62(d,J=5.5Hz,1H),8.44(d,J=8.0Hz,1H),8.35-8.36(m,1H),7.98-8.02(m,1H),7.51-7.55(m,1H),4.98(m,1H),1.63-1.65(d,J=7.0Hz,6H)ppm.
实施例11
Step 1:2-氯-7-甲基-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
用2,4-二氯-7-甲基-7H-吡啶[2,3-d]嘧啶(101mg,0.50mmol)、t-BuOK(85mg,0.75mmol)、苯胺(70mg,0.75mmol)分别充入20mL密封管,加入THF(5mL)。反应混合物在rt条件下搅拌1.5h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,PE∶EA=7∶3)对产物进行纯化,得到产物为白色固体(63mg,收率49%)。
分子式:C13H11ClN4,分子量:258.71,(ESI)m/z=259.1(M+H)+.
Step 2:7-甲基-N,2-二苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(3EPT60083)
用2-氯-7-甲基-N-苯基-7H-吡咯并[2,3-d]封闭管充入2-氯-7-甲基-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(63mg,0.25mmol)、苯基硼酸(45mg,0.37mmol)、Pd(dppf)Cl2(18mg,0.025mmol)、K3PO4(110mg,0.5mmol)、二氧六环(5mL)、水(1mL)。反应混合物在惰性气体中以100℃加热2h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析(硅胶,PE∶EA=7∶3)对产物进行纯化,得到产物为白色固体(20mg,收率27%)。
分子式:C19H16N4,分子量:300.37,(ESI)m/z=301.2(M+H)+.1H NMR(500MHz,DMSO-d6)9.43(s,1H),8.43-8.45(m,2H),7.99(d,J=7.5Hz,2H),7.39-7.51(m,5H),7.32(d,J=3.5Hz,1H),7.06(t,J=7.5Hz,1H),6.83(d,J=3.5Hz,1H),3.84(s,3H)ppm.
实施例12
Step 12-氯-9-异丙基-6-苯基-9H-嘌呤(3)
将2,6-二氯-9-异丙基-9H-嘌呤(1,100mg,0.43mmol)、苯基硼酸(2,63mg,0.52mmol)、Pd(dppf)Cl2(3mg,0.0043mmol)和K2CO3(120mg,0.86mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下搅拌2h。减压除去溶剂,用自动闪柱柱层析(硅胶,PE∶EA=5∶1)纯化得到2-氯-9-异丙基-6-苯基-9H-嘌呤(3,100mg,84.73%收率)为白色固体。
LCMS:(ESI)m/z=273.08(M+H)+;RT=1.75min.
Step 2:9-异丙基-N,6-二苯基-9H-嘌呤-2-胺(EPT60086)
一个25ml圆底烧瓶中加入2-氯-9-异丙基-6-苯基-9H-嘌呤(330毫克0.108mmol),苯胺(415.6毫克0.162mmol),Pd(OAc)2(0.24毫克,1.08μmol)BINAP(1.2毫克,2.16μmol)和Cs2CO3(108毫克,0.33mmol)。混合物悬浮在二氧六环(5ml)中。反应在100℃氮气气氛下搅拌2h。减压除去溶剂,采用自动闪柱柱层析(硅胶,PE∶EA=5∶1)纯化得到9-异丙基n,6-二苯基-9H-嘌呤-2-胺(EPT60086,20mg,55.2%收率)为黄色固体。
LCMS:(ESI)m/z=330.21(M+H)+;RT=1.84min.
1H NMR(500MHz,DMSO)δ9.59(s,1H),8.81(dd,J=8.1,1.5Hz,2H),8.43(s,1H),7.91(d,J=7.7Hz,2H),7.62-7.54(m,3H),7.35-7.30(m,2H),6.95(t,J=7.3Hz,1H),4.81(s,1H),1.61(d,J=6.8Hz,6H).
实施例13
Step 1:2-氯-N-异丙基-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
在一个25毫升的圆底烧瓶中加入2,4-二氯-6-甲基-7H-吡咯[2,3-d]嘧啶(1,202mg,1mmol)、propaN-2-amine(2,89mg,1.5mmol)和DIPEA(258mg,2mmol)。反应混合物是溶解在二氧六环在70℃(5毫升)和搅拌2h。与EA(10毫升x 3)提取后,用盐水洗净(10毫升x3),干燥无水硫酸钠和集中在真空,2-氯-N-异丙基-6-甲基-7H-吡咯并[2,3-d]嘧啶-N-4-胺(220毫克,收率98.9%)获得了作为一个棕色固体。
LCMS:(ESI)m/z=225.18(M+H)+;RT=1.44min.
Step 2:N-异丙基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60087)
将2-氯-N-异丙基-6-甲基-7H-吡啶醇[2,3-d]4-氨基吡啶(3,50mg,0.22mmol)、苯基硼酸(4,32mg,0.27mmol)、Pd(dppf)Cl2(2mg,0.0022mmol)和K3PO4(93mg,0.44mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下进行了2小时的搅拌。减压除去溶剂,用自动闪柱柱层析(硅胶,PE∶EA=1∶1)纯化得到N-异丙基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60087,10mg,16.87%收率)为黄色固体。
LCMS:(ESI)m/z=267.2(M+H)+;RT=1.30min.
1H NMR(500MHz,DMSO)δ11.35(s,1H),8.36-8.33(m,2H),7.45-7.35(m,3H),6.95(d,J=7.6Hz,1H),6.25(dd,J=1.9,1.0Hz,1H),4.51(d,J=6.9Hz,1H),2.32(d,J=0.7Hz,3H),1.28(d,J=6.5Hz,6H).
实施例14
Step 1:2-氯-8-甲基-N-苯基-9H-嘌呤-6-胺(2)
一个20毫升的密封管被充入2,6-二氯-8-甲基-9H-嘌呤(101毫克,0.50mmol)和5毫升正丁醇。加入DIPEA(129mg,1.0mmol)和苯胺(70mg,0.75mmol)。反应混合物在100℃下搅拌4h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,MeOH∶DCM=1∶10)对产物进行纯化,得到产物为白色固体(100mg,77.5%收率)。
分子式:C12H10ClN5,分子量:259.70,(ESI)m/z=260.1(M+H)+.
Step 2:8-甲基-N,2-二苯基-9H-嘌呤-6-胺(3EPT60088)
将2-氯-8-甲基-N-苯基-9H-嘌呤-6-胺(50mg,0.2mmol)、苯基硼酸(125mg,1.0mmol)、Pd(dppf)Cl2(30mg,0.04mmol)、K3PO4(212mg,1.0mmol)分别充入10-mL密封管,然后加入2,2,5ml的二氧六环和1mL的水。反应混合物在100℃惰性气体中加热22h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析(硅胶,DCM∶MeOH=19∶1)对产物进行纯化,得到标题化合物(40mg,收率66%)为黄色固体。
分子式:C18H15N5,分子量:301.35,(ESI)m/z=3020.2(M+H)+.1H NMR(400MHz,DMSO-d6)12.91(s,1H),9.67(s,1H),8.33(d,J=7.2Hz,2H),8.02(d,J=8.0Hz,2H),7.32-7.48(m,5H),7.01(m,1H),2.50(s,3H)ppm.
实施例15
Step 1:2,4-二氯-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(3)
到25ml圆底烧瓶中加入2-氯-N-异丙基-6-甲基-7H-吡咯并[2,3-d]嘧啶-N-4-胺(500毫克,2.47mmol),对甲苯磺酰氯(705毫克,3.71mmol)DIPEA(957毫克,7.42mmol)和深度贴图(30毫克,0.25mmol),反应混合物溶解在DCM(5毫升),搅拌2h RT。残渣集中在真空和净化自动闪光柱层析法(硅胶,PE∶EA=1∶1)将2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(3,800mg,产率91.24%)制成黄色固体。LCMS:(ESI)m/z=356.06(M+H)+;RT=1.88min.
Step 2:2-氯-N-环丙基-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(5)
在一个25毫升的圆底烧瓶中加入2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]3,100mg,0.28mmol,环丙胺(4,31mg,0.56mmol)和DIPEA(108mg,0.84mmol)。反应混合物溶解在二氧六环(5ml)中,70℃搅拌4h,残渣浓缩于真空中,用自动闪柱柱色谱(硅胶,PE∶EA=85∶15)纯化得到2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(5,100mg,94.98%收率)为白色固体。LCMS:(ESI)m/z=377.89(M+H)+;RT=1.76min.
Step 3:N-环丙基-6-甲基-2-(萘-2-基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(7)
在25ml圆底烧瓶中加入2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7-h-吡咯并[2,3-d]嘧啶-4-胺(5,100mg,0.26mmol),萘-1-基硼酸(6,134mg,0.78mmol),Pd(dppf)Cl2(19mg,0.026mmol)和K3PO4(165mg,0.78mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。该产品为黄色固体N-环丙基-6-甲基-2-(萘-2-基)-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(7,100mg,82.18%收率)。
LCMS:(ESI)m/z=469.29(M+H)+;RT=2.18min
Step 4:N-环丙基-6-甲基-2-(萘-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60187)
到25ml圆底烧瓶中加入N-环丙基-6-甲基-2-(萘-N-2-基)7-甲基磺酰基-7H-吡咯并[2,3-d]嘧啶-N-4-胺(100毫克,0.21mmol)溶解在MeONa(2毫升,5.4年的甲醇)和甲醇(10毫升)和搅拌60℃ 4h。残渣集中在真空和净化自动闪光柱层析法(硅胶、PE∶EA=5∶1)得到N-环丙基-6-甲基-2-(萘-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT6018750毫克,产率为75.82%)为白色固体。
LCMS:(ESI)m/z=315.21(M+H)+;RT=1.51min.
1H NMR(500MHz,DMSO)δ11.49(s,1H),8.89(s,1H),8.55(d,J=8.4Hz,1H),8.04-7.89(m,3H),7.57-7.48(m,2H),7.43(d,J=3.1Hz,1H),6.32(s,1H),3.08(s,1H),2.35(s,3H),0.88-0.83(m,2H),0.66-0.60(m,2H).
实施例16
Step 1:N-异丙基-6-甲基-2-(吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(2EPT60101)
用2-氯-N-异丙基-6-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(100mg,0.44mmol),2-(三丁基锡基)吡啶(300mg,0.81mmol),Pd(PPh3)4(50mg,0.04mmol),再加入二氧六环(5.0mL),充入10-mL密封管。反应混合物在100℃惰性气体中加热16h。反应完成后,用饱和KF水溶液(2mL)对反应混合物进行骤冷,用硅胶(100-200mesh)对有机相进行浓缩蒸发,得到粉体残渣。采用自动闪柱柱色谱法(硅胶,MeOH∶DCM=1∶19)对残留进行纯化,得到标题化合物(12mg,收率9%)为黄色固体。
分子式:C15H17N5,分子量:267.34,(ESI)m/z=268.2(M+H)+.1H NMR(400MHz,DMSO-d6)11.37(s,1H)8.60(m,1H),8.28(d,J=8.0Hz,1H),7.80-7.84(m,1H),7.31-7.34(m,1H),6.95(d,J=8.0Hz,1H),6.26(s,1H),4.46-4.52(m,1H),2.30(s,3H),1.29(m,6H)ppm.
实施例17
Step 1:N-异丙基-6-甲基-2-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60102)
将2-氯-N-异丙基-6-甲基-7H-吡啶-4-胺(1,50mg,0.22mmol)、吡啶-3-基硼酸(2,81mg,0.66mmol)、Pd(dppf)Cl2(16mg,0.022mmol)和K3PO4(93mg,0.44mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下搅拌过夜。减压除去溶剂,采用自动闪柱柱层析(硅胶,DCM∶MeOH=95∶5)纯化得到N-异丙基-6-甲基-2-(吡啶-3-酰基)-7H-吡啶-4-胺(EPT60102,54mg,91.93%收率)为黄色固体。
LCMS:(ESI)m/z=268.28(M+H)+;RT=1.21min.
1H NMR(500MHz,DMSO)δ11.46(s,1H),9.47(d,J=1.4Hz,1H),8.60-8.54(m,2H),7.49-7.44(m,1H),7.08(d,J=7.6Hz,1H),6.28(d,J=0.8Hz,1H),4.51(dq,J=13.1,6.6Hz,1H),2.33(s,3H),1.28(d,J=6.5Hz,6H).
实施例18
Step 1:N-异丙基-6-甲基-2-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60103)
将2-氯-N-异丙基-6-甲基-7H-吡啶-4-胺(1,50mg,0.22mmol)、吡啶-4-乙基硼酸(2,81mg,0.66mmol)、Pd(dppf)Cl2(16mg,0.022mmol)和K3PO4(93mg,0.44mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下搅拌过夜。减压除去溶剂,采用自动闪柱柱色谱(硅胶,DCM∶MeOH=95∶5)进行纯化,得到N-异丙基-6-甲基-2-(吡啶-4-酰基)-7H-吡啶-4-胺(EPT60103,50mg,85.12%收率)为黄色固体。
LCMS:(ESI)m/z=268.28(M+H)+;RT=1.21min.
1H NMR(500MHz,DMSO)δ11.54(s,1H),8.64(dd,J=4.5,1.5Hz,2H),8.20(dd,J=4.5,1.6Hz,2H),7.13(d,J=7.6Hz,1H),6.31(d,J=0.8Hz,1H),4.52(dd,J=13.5,6.7Hz,1H),2.34(s,3H),1.28(d,J=6.5Hz,6H).
实施例19
Step 1:2-氯-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
将化合物1(100mg,0.54mmol)在正丁醇(5mL)溶液中加入Et3N(86.9mg,0.86mmol)和苯胺(60.5mg,0.65mmol)。反应混合物在100℃下搅拌16小时(过夜)。LCMS(EPN18040-002-1)显示反应完成,SM残留10%。溶剂在真空中被除去。未纯化的粗化合物直接用于下一步。(ESI)m/z=245.31(M+H)+
Step 2:N,2-二苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60098)
将化合物2(60mg,0.25mmol)在二氧六环(5mL)和H2O(1mL)溶液中分别加入Pd(dppf)Cl2(36.6mg,0.05mmol)、K3PO4(182.6mg,0.86mmol)和苯基硼酸(149.5mg,1.23mmol)。反应混合物在100℃下搅拌16h(过夜),Ar下LCMS(EPN18040-005-1)显示反应完成,SM残留10%。溶剂在真空中浓缩。采用自动闪柱柱色谱法(硅胶,PE/EA=8∶1)对残留进行纯化,得到粗品。用饱和K2CO3溶液(100mL)稀释残渣,用CH2Cl2(50mL×3)萃取混合物,再用饱和NaCl(100mL)洗涤。所得到的有机层用无水Na2SO4干燥,在真空中除去溶剂,得到所需的产物(40mg,57.1%收率)为白色固体。(ESI)m/z=287.12(M+H)+.1H NMR(500MHz,DMSO-d6)11.82(s,1H),9.40(s,1H),8.38-8.40(m,2H),7.99-8.01(m,2H),7.48-7.51(m,2H),7.40-7.45(m,3H),7.27-7.28(m,1H),7.04-7.07(m,1H),6.82-6.83(m,1H)ppm.
实施例20
Step 1:2,4-二氯-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(2)
取50ml圆底烧瓶,加入2,4-二氯-6-甲基-7H-吡啶[2,3-d]400mg,2.0mmol,4-甲基苯磺酰氯(570mg,3.0mmol),DMAP(24mg,0.2mmoL),DIPEA(1mL),再加入DCM(20mL)。反应混合物在室温下搅拌1h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶10)对产物进行纯化,得到标题化合物(565mg,收率80%)为白色固体。
分子式:C14H11Cl2N3O2S,分子量:356.22,(ESI)m/z=356.1(M+H)+.
Step 2:2-氯-6-甲基-7-甲苯磺酰基-N-(2-(三氟甲基)吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
取2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡咯啉[2,3-d]嘧啶(140mg,0.4mmol),Cs2CO3(156mg,0.48mmol),2-(三氟甲基)吡啶-4-胺(100mg,0.60mmol),加入DMSO(4ml),密封管20mL。反应混合物rt搅拌18h,70℃搅拌2h。反应由LCMS监测。反应完成后,加入水(20mL),用EA(20mL 2)萃取反应混合物。采用硅胶(100-200目)蒸发浓缩有机相,得到粉体残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=3∶2)对残留进行纯化,得到标题化合物(64mg,收率33%)为白色固体。分子式:C20H15ClF3N5O2S,分子量:481.88,(ESI)m/z=482.2(M+H)+.
Step 3:6-甲基-2-苯基-7-甲苯磺酰基-N-(2-(三氟甲基)吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(4)
用2-氯-6-甲基-7-甲苯磺酰-N-(2-(三氟甲基)吡啶-4-酰基)-7H-吡咯啉[2,3-d]苯基硼酸(12mg,0.1mmol),Pd(dppf)Cl2(5mg,0.008mmol),K3PO4(30mg,0.15mmol),然后加入二氧六环(2mL)和水(0.4mL),充入10-mL密封管。反应混合物在惰性气体中加热到100c,加热1.5h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶1)对产物进行纯化,得到标题化合物(20mg,收率77%)为白色固体。
分子式:C26H20F3N5O2S,分子量:523.53,(ESI)m/z=524.3(M+H)+.
Step 4:6-甲基-2-苯基-N-(2-(三氟甲基)吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(5EPT60121)
将6-甲基-2-苯基-7-甲苯磺酰-N-(2-(三氟甲基)吡啶-4-yl)-7H-吡咯[2,3-d]嘧啶-4-胺(20mg,0.04mmol)溶于CH3OH(3mL)中,加入CH3ONa(5.4mol/L,0.5mL)。反应混合物在55℃下搅拌2h。反应完成后,用饱和NH4Cl水溶液(1mL)对反应进行骤冷,蒸发浓缩反应得到油渣,反相柱层析(C18,H2O/MeCN=2/3)纯化得到标题化合物EPN18033-070-A(4mg,28%收率)为白色固体。分子式:C19H14F3N5,分子量:369.35,(ESI)m/z=370.2(M+H)+.1H NMR(400MHz,DMSO-d6)11.92(s,1H),10.05(s,1H),8.84(d,J=1.6Hz,1H),8.58(d,J=5.6Hz,1H),8.34(d,J=6.8Hz,2H),8.06(m,1H),7.41-7.49(m,3H),6.52(s,1H),2.29(d,J=3.6Hz,3H)ppm.
实施例21
Step 1:2-氯-N-(2-氟吡啶-4-基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
取2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(66mg,0.2mmol)、Cs2CO3(65mg,0.2mmol)、2-氟吡啶-4-胺(45mg,0.40mmol)分别充入20ml密封管,加入DMSO(2mL)。反应混合物rt搅拌18h,70℃搅拌2h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=3∶2)对产物进行纯化,得到标题化合物(26mg,产率32%)为白色固体。
分子式:C19H15ClFN5O2S,分子量:431.87(ESI)m/z=432.2(M+H)+.
Step 2:N-(2-氟吡啶-4-基)-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
用2-氯-N-(2-氟吡啶-4-酰基)-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]吡啶-4-胺(26mg,0.06mmol)、苯基硼酸(12mg,0.1mmol)、Pd(dppf)Cl2(5mg,0.008mmol)、K3PO4(30mg,0.15mmol)、二氧六环(3mL)、水(0.5mL)充入10-mL密封管。反应混合物在惰性气体中加热到100℃,加热5h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶4)对产物进行纯化,得到标题化合物(22mg,收率78%)为白色固体。
分子式:C25H20FN5O2S,分子量:473.53,(ESI)m/z=474.3(M+H)+.
Step 3:N-(2-氟吡啶-4-基)-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(4EPT60122)
将N-(2-氟吡啶-4-酰基)-6-甲基-2-苯基-7-甲苯磺酰-7H-吡咯啉[2,3-d]嘧啶-4-胺(22mg,0.046mmol)溶于CH3OH(3mL)中,加入CH3ONa(5.4mol/L,0.5mL)。反应混合物在60℃下搅拌2h。反应完成后,用饱和NH4Cl水溶液(1mL)对反应进行骤冷,蒸发浓缩反应得到油渣,反相柱层析(C18,H2O/MeCN=2/3)纯化产物为白色固体(5mg,产率32%)。分子式:C18H14FN5,分子量:319.34(ESI)m/z=320.2(M+H)+.1H NMR(400MHz,DMSO-d6)11.90(s,1H),9.92(s,1H),8.31(d,J=7.2Hz,2H),8.07(d,J=5.6Hz,1H),7.93(s,1H),7.74(d,J=4.8Hz,1H),7.42-7.51(m,3H),6.52(s,1H),2.38(s,3H)ppm.
实施例22
Step 1:6-甲基-N2,N4-二苯基-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(EPT60123)
一个25ml圆底烧瓶中加入2,4-二氯-6-甲基-7H-吡咯并[2,3-d]嘧啶(0.25150毫克mmol),苯胺(69毫克,0.74mmol),Pd(OAc)2(2.8毫克,12.5μmol)BINAP(15毫克,25μmol)和Cs2CO3(245毫克,0.75mmol)。混合物悬浮在二氧六环(2ml)中。反应在100℃氮气气氛下搅拌4h。减压除去溶剂,首先用自动闪柱柱层析(硅胶,DCM∶MeOH=95∶5)纯化得到粗品,然后用反相柱层析(NH4HCO3,a.q.,0.5%)得到白色固体6-甲基-n2,n4-二苯基-7H-吡啶-2,4-二胺(EPT60123,4mg,5.08%收率)得到n4-二苯基-2,4-二胺[2,3-d]。
LCMS:(ESI)m/z=316.25(M+H)+;RT=1.42min.
1H NMR(500MHz,DMSO)δ11.07(s,1H),8.94(s,1H),8.75(s,1H),7.91(d,J=7.7Hz,2H),7.81(d,J=7.7Hz,2H),7.31(t,J=7.9Hz,2H),7.21(t,J=7.9Hz,2H),6.99(t,J=7.3Hz,1H),6.84(t,J=7.3Hz,1H),6.31(s,1H),2.29(s,3H).
实施例23
Step 1:N-环丙基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
在25毫升的圆底烧瓶中加入2,4-二氯-6-甲基-7H-吡啶[2,3-d],100mg,0.5mmol,环丙胺(2,42mg,0.75mmol)和DIPEA(129mg,1mmol)。反应混合物溶解在二甲氧基(2ml)中,70℃搅拌2h,EA(10ml x 3)萃取后,用盐水(10ml x 3)冲洗,无水硫酸钠干燥,浓缩得到2-氯-N-环丙基-6-甲基-7H-吡啶-4-胺(3,110mg,产率99.1%)黄色固体。
LCMS:(ESI)m/z=223.22(M+H)+;RT=1.32min.
Step 2:N-环丙基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60124)
将2-氯-N-环丙基-6-甲基-7H-吡啶醇[2,3-d]4-氨基吡啶(3,50mg,0.22mmol)、苯基硼酸(4,80mg,0.66mmol)、Pd(dppf)Cl2(16mg,0.022mmol)和K3PO4(93mg,0.44mmol)分别装入25ml圆底烧瓶中。
混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,首先用自动闪柱柱层析(硅胶,DCM∶MeOH=95∶5)纯化得到粗品,然后用反相柱层析(NH4HCO3,a.q.0.5%):MeCN=70∶30得到白色固体N-环丙基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60124,20mg,34.3%收率)。LCMS:(ESI)m/z=265.24(M+H)+;RT=1.20min.
1H NMR(500MHz,DMSO)δ11.41(s,1H),8.37(d,J=7.1Hz,2H),7.46-7.30(m,4H),6.28(s,1H),3.02(dt,J=10.0,3.3Hz,1H),2.32(d,J=0.7Hz,3H),0.84-0.78(m,2H),0.65-0.55(m,2H).
实施例24
Step 1:2-氯-9-甲基-N-苯基-9H-嘌呤-6-胺(3)
在一个25毫升的圆底烧瓶中加入2,6-二氯-9-甲基-9H-嘌呤(1,100mg,0.49mmol),苯胺(2,69mg,0.74mmol)和DIPEA(191mg,1.48mmol)。反应混合物溶解在二氧六环(5ml)中,70℃搅拌4h,残渣浓缩于真空中,用自动闪柱柱色谱(硅胶,DCM∶MeOH=95∶5)纯化得到2-氯-9-甲基-N-苯基-9H-嘌呤-6-胺(3,120mg,94.55%收率)为off白色固体。
LCMS:(ESI)m/z=260.19(M+H)+;RT=1.52min.
Step 2:9-甲基-N,2-二苯基-9H-嘌呤-6-胺(EPT60125)
将2-氯-9-甲基-N-苯基-9H-嘌呤-6-胺(3,50mg,0.19mmol)、苯基硼酸(4,69mg,0.57mmol)、Pd(dppf)Cl2(14mg,0.019mmol)和K3PO4(80mg,0.38mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下搅拌过夜。减压除去溶剂,用自动闪柱柱层析(硅胶,PE∶EA=1∶1)纯化得到9-甲基-n,2-二苯基-9H-嘌呤-6-胺(EPT60125,40mg,69.94%收率)为黄色固体。
LCMS:(ESI)m/z=302.25(M+H)+;RT=1.76min.
1H NMR(500MHz,DMSO)δ9.90(s,1H),8.43(d,J=7.5Hz,2H),8.30(s,1H),8.05(d,J=7.9Hz,2H),7.55-7.46(m,3H),7.40(t,J=7.7Hz,2H),7.07(t,J=7.1Hz,1H),3.87(s,3H).
实施例25
Step 1:2-(2-氟苯基)-N-异丙基-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60126)
将化合物1(50mg,0.22mmol)加入到2,5mL二氧六环(5ml)和H2O(1ml)溶液中,加入K3PO4(163.4mg,0.77mmol),Pd(dppf)Cl2(32.7mg,0.04mmol)和2-氟苯硼酸(154.0mg,1.1mmol)。反应混合物在100℃条件下搅拌16h(过夜)。LCMS(EPN18040-009-1)显示反应已经完成,SM残留20%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)进行纯化,得到标题化合物(8.5mg,13.4%收率)为白色固体。(ESI)m/z=285.24(M+H)+.1H NMR(500MHz,DMSO-d6)11.42(s,1H),9.94-9.98(m,1H),7.38-7.43(m,1H),7.20-7.26(m,2H),6.98-6.99(d,J=7.5Hz,1H),6.26(s,1H),4.38-4.42(m,1H),3.32(s,3H),1.23-1.25(d,J=6.5Hz,6H)ppm.
实施例26
Step 1:6-甲基-2,4-二苯基-7H-吡咯并[2,3-d]嘧啶(EPT60132)
在一个25毫升的圆底烧瓶中加入2,4-二氯-6-甲基-7H-吡啶[2,50mg,0.25mmol],苯基硼酸(2,90mg,0.75mmol),Pd(dppf)Cl2(18mg,0.025mmol)和K3PO4(159mg,0.75mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。采用自动闪柱柱色谱法(硅胶,PE∶EA=1∶1)将残渣浓缩在真空中纯化,得到6-甲基-2,4-二苯基-7H-吡咯啉[2,3-d]嘧啶(EPT60132,40mg,56.14%得率)为白色固体。LCMS:(ESI)m/z=286.20(M+H)+;RT=1.83min.
1H NMR(500MHz,DMSO)δ12.17(s,1H),8.56-8.50(m,2H),8.31-8.26(m,2H),7.65-7.44(m,6H),6.65(s,1H),2.48(s,3H).
实施例27
Step 1:N-(叔丁基)-2-氯-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺
将2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(100mg,0.28mmol),2-甲基丙基-2-胺(31mg,0.42mmol)和DIPEA(108mg,0.84mmol)分别装入25ml圆底烧瓶中。反应混合物溶解于二氧六环(5ml)中,70℃搅拌4h,残渣浓缩于真空中,用自动闪柱柱色谱(硅胶,PE∶EA=85∶15)纯化得到N-(叔丁基)-2-氯-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(80mg,72.89%收率)为白色固体。LCMS:(ESI)m/z=393.27(M+H)+;RT=1.93min.
Step 2:N-(叔丁基)-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺
在一个25毫升的圆底烧瓶中加入N-(叔丁基)-2-氯-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(80mg,0.2mmol),苯基硼酸(6,73mg,0.6mmol),Pd(dppf)Cl2(17mg,0.02mmol)和K3PO4(127mg,0.6mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃氮气气氛下搅拌过夜。减压除去溶剂,采用自动闪柱柱层析(硅胶,PE∶EA=5∶1)纯化得到N-(叔丁基)-6-甲基-2-苯基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-4-胺(7,60mg,69.12%)。
LCMS:(ESI)m/z=435.32(M+H)+;RT=2.02min.
Step 3:N-(叔丁基)-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60133)
将装有N-(叔丁基)-6-甲基-2-苯基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-4-胺(60mg,0.14mmol)溶于MeONa(0.5ml,5.4M in MeOH)和MeOH(5ml)中,在50c下搅拌过夜。减压除去溶剂,用自动闪柱柱层析(硅胶,PE∶EA=5∶1)纯化得到N-(叔丁基)-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60133,20mg,51.02%收率)为白色固体。
LCMS:(ESI)m/z=281.20(M+H)+;RT=1.49min.
1H NMR(500MHz,DMSO)δ11.33(s,1H),8.36-8.33(m,2H),7.45(dd,J=10.3,4.6Hz,2H),7.40-7.36(m,1H),6.53(s,1H),6.35(dd,J=1.9,1.0Hz,1H),2.31(d,J=0.6Hz,3H),1.58(s,9H).
实施例28
Step 1:N-环丙基-2-(2-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60134)
将2-氯-N-环丙基-6-甲基-7H-吡啶醇[2,3-d]4-氨基吡啶(1,50mg,0.22mmol),(2-氟苯基)硼酸(2,92mg,0.66mmol),Pd(dppf)Cl2(16mg,0.022mmol)和K3PO4(93mg,0.44mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,首先用自动闪柱柱层析(硅胶,PE∶EA=1∶1)纯化得到粗品,然后用反相柱层析(NH4HCO3,a.q.0.5%)得到白色固体N-环丙基-2-(2-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60134,6mg,9.67%收率):MeCN=55∶45。
LCMS:(ESI)m/z=283.16(M+H)+;RT=1.13min.
1H NMR(500MHz,DMSO)δ11.44(d,J=35.0Hz,1H),8.02-7.89(m,1H),7.44-7.34(m,2H),7.28-7.19(m,2H),6.27(d,J=34.6Hz,1H),2.98-2.94(m,1H),2.33(s,3H),0.80-0.73(m,2H),0.62-0.55(m,2H).
实施例29
Step 1:2-氯-N-(环丙基甲基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
向EtOH(3ml)中化合物1(100mg,0.50mmol)溶液中加入Et3N(202.2mg,2.0mmol)、氨基甲基环丙烷(142.1mg,2.0mmol)。反应混合物在80℃下搅拌2小时。LCMS(EPN18040-010-1)显示反应完成,无SM残留。溶剂在真空中浓缩。未纯化的粗化合物直接用于下一步。(ESI)m/z=237.21(m+H)+。
步骤2:N-(环丙基甲基)-6-甲基-2-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(EPT60135)将化合物2(68.5mg,0.29mmol)在二氧六环(5mL)和H2O(1mL)溶液中分别加入K3PO4(216.5mg,1.02mmol)、Pd(dppf)Cl2(47.4mg,0.058mmol)和苯硼酸(176.9mg,1.45mmol)。反应混合物在100℃下搅拌16h(过夜),Ar条件下LCMS(EPN18040-012-1)显示反应完成,SM残留30%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)进行纯化,得到标题化合物(7.5mg,9.3%收率)为淡黄色固体。(ESI)m/z=279.26(M+H)+.1H NMR(500MHz,DMSO-d6)11.37(s,1H),8.34-8.36(m,2H),7.42-7.45(m,2H),7.31-7.39(m,2H),6.24(s,1H),3.44-3.50(m,2H),2.33(s,3H),1.18-1.21(m,1H),0.46-0.48(m,2H),0.33-0.36(m,2H)ppm.
实施例30
Step 1:N-苄基-2-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
在EtOH(5mL)中加入化合物1(100mg,0.50mmol)的溶液中加入Et3N(101.16mg,1.0mmol)和苄胺(107.1mg,1.0mmol)。反应混合物在80℃下搅拌2小时。LCMS(EPN18040-014-1)显示反应完成,无SM残留。溶剂在真空中浓缩。未纯化的粗化合物直接用于下一步。(ESI)m/z=273.28(M+H)+.
Step 2:N-苄基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60136)
将化合物2(55mg,0.2mmol)在二噁烃(5mL)和H2O(1mL)溶液中分别加入K3PO4(150.2mg,0.71mmol)、Pd(dppf)Cl2(32.7mg,0.04mmol)和苯硼酸(122.1mg,1.0mmol)。反应混合物在100℃下搅拌16h(过夜),Ar下LCMS(EPN18040-017-1)显示反应完成,SM残留20%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)纯化残渣,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)纯化得到标题化合物(4.4mg,7%产率)。(ESI)m/z=315.15(M+H)+.1H NMR(500MHz,DMSO-d6)11.43(s,1H),8.31-8.33(m,2H),7.82-7.84(m,1H),7.39-7.43(m,4H),7.35-7.37(m,1H),7.29-7.32(m,2H),7.20-7.23(m,1H),6.25(s,1H),4.81-4.82(d,J=6.0Hz,2H),2.33(s,3H)ppm.
实施例31
Step 1:2-氯-N-(3-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
将化合物1(100mg,0.50mmol)在二氧六环(3ml)溶液中加入tBuOK(101.0mg,1.0mmol),pd(OAc)2(11.3mg,0.05mmol),BINAP(62.3mg,0.1mmol)和3-氟苯胺(134.2mg,1.1mmol)。反应混合物在100℃下搅拌16h(过夜),Ar下LCMS(EPN18040-015-1)显示反应完成,SM残留20%。溶剂在真空中浓缩。采用自动闪柱柱色谱法(硅胶,PE/EA=8∶1)对残留进行纯化,得到标题化合物(60mg,44.2%收率)为淡黄色固体。(ESI)m/z=277.21(M+H)+.
Step 2N-(3-氟苯基)-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60137)
将化合物2(66.0mg,0.22mmol)在二噁烃(5mL)和H2O(1mL)溶液中分别加入Pd(dppf)Cl2(32.7mg,0.04mmol)、K3PO4(163.4mg,0.77mmol)和苯基硼酸(134.2mg,1.1mmol)。反应混合物在100℃下搅拌16h(过夜),Ar下LCMS(EPN18040-023-1)显示反应完成,SM残留5%。反应混合物集中在真空中。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残渣进行纯化,得到粗品,用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=60/40)对固体进行进一步纯化,得到标题化合物(2.6mg,4.1%收率)为白色固体。
(ESI)m/z=319.21(M+H)+.1H NMR(500MHz,DMSO-d6)11.75(s,1H),9.44(s,1H),8.35-8.37(m,2H),8.09-8.13(m,1H),7.70(m,1H),7.49-7.52(m,2H),7.38-7.45(m,2H),6.81-6.85(m,1H),6.52(s,1H),2.4(s,3H)ppm.
实施例32
Step 1:2-氯-N-异丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
取2,4-二氯-7H-吡咯并[2,3-d]嘧啶(1.0g,5.31mmol),丙二胺(3.0mL),DIPEA(1.0mL)分别充入20mL密封管,再加入二氧六环(10ml)。反应混合物在70℃下搅拌16h。反应完成后,混合物在常压真空蒸馏下浓缩。将残渣溶解于(EtOH)5mL,加入水(20mL),RT搅拌10min。对混合料进行过滤,收集固体,真空干燥,得到目标化合物(940mg,收率83%)为白色固体。
分子式:C9H11ClN4,分子量:210.67,(ESI)m/z=211.2(M+H)+.
Step 2:N-异丙基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(3EPT60138)
以2-氯-N-异丙基-7H-吡咯[2,3-d]吡啶-4-胺(440mg,4.0mmol)、苯基硼酸(1.22g,10.0mmol)、Pd(dppf)Cl2(140mg,0.2mmol)、K3PO4(2.12g,10.0mmol)充入10-mL密封管,然后加入二氧六环(15mL)和水(3.0mL)。反应混合物在惰性气体中以100℃加热22h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶3)对产物进行纯化,得到标题化合物224mg,收率44%)为白色固体,为白色固体。
分子式:C15H16N4,分子量:252.32,(ESI)m/z=253.2(M+H)+.1HNMR(500MHz,DMSO-d6)11.50(s,1H),8.37(m,2H),7.37-7.46(m,3H),7.19(d,J=7.5Hz,1H),7.08(m,1H),6.60(m,1H)4.56(m,1H),1.30(d,J=6.5Hz,6H)ppm.
实施例33
Step 1:6-溴-N-异丙基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(2EPT60139)
将N-异丙基-2-苯基-7H-吡啶醇[2,3-d]嘧啶-4-胺(200mg,0.8mmol)溶于DCM(30mL)中,然后将NBS(144mg溶于DCM(10mL)溶液中)于0-10℃缓慢滴入30min。反应混合物在rt下搅拌20min。反应由LCMS监测。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶8)对产物进行纯化,得到标题化合物(152mg,收率57.5%)为白色固体。
分子式:C15H15BrN4,分子量:331.22,(ESI)m/z=331.1(M+H)+.1HNMR(500MHz,DMSO-d6)12.03(s,1H),8.35-8.37(m,2H),7.42-7.49(m,3H),7.36(d,J=2.5Hz,1H),5.99(d,J=7.5Hz,1H),4.55(m,1H),1.34(d,J=6.5Hz,6H)ppm.
实施例34
Step 1:N-环丙基-2-(3-氟苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(7)
在一个25毫升的圆底烧瓶中加入2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(100mg,0.26mmol),(3-氟苯基)硼酸(109mg,0.78mmol),Pd(dppf)Cl2(19mg,0.026mmol)和K3PO4(93mg,0.78mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,采用自动闪柱柱层析(硅胶,PE∶EA=1∶1)纯化得到白色固体N-环丙基-2-(3-氟苯基)-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(7,100mg,88.21%收率)。LCMS:(ESI)m/z=437.32(M+H)+;RT=1.13min.
Step 2:N-环丙基-2-(3-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60152)
向25mL圆底烧瓶中加入N-环丙基-2-(3-氟苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(100mg)将0.23mmol(0.23mmol)溶于MeONa(1ml,5.4M的MeOH溶液)和MeOH(5ml)中,并在50℃下搅拌2小时。将残余物真空浓缩,并通过自动快速柱色谱法(硅胶,PE∶EA=4∶1)纯化,得到灰白色固体N-环丙基-2-(3-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60152,50mg,产率77.09%)。
LCMS:(ESI)m/z=283.16(M+H)+;RT=1.31min.
1H NMR(500MHz,DMSO)δ11.48(s,1H),8.21(d,J=7.8Hz,1H),8.07(d,J=10.0Hz,1H),7.48(td,J=8.0,6.2Hz,1H),7.42(d,J=3.1Hz,1H),7.21(d,J=2.7Hz,1H),6.30(s,1H),3.02(dd,J=6.6,3.4Hz,1H),2.33(s,3H),0.84-0.79(m,2H),0.63-0.57(m,2H).
实施例35
Step 1:1-((2-氯-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基丙-2-醇(2)在EtOH(5mL)中加入化合物1(100mg,0.28mmol)的溶液中加入Et3N(56.6mg,0.56mmol)和1-氨基-2-甲基propaN-2-ol(49.8mg,0.56mmol)。反应混合物在80℃下搅拌2小时。LCMS(EPN18040-019-1)显示反应完成,无SM残留。溶剂在真空中浓缩。未纯化的粗化合物直接用于下一步(ESI)m/z=409.28(M+H)+.
Step 2:2-甲基-1-((6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)丙-2-醇(3)
将化合物2(90mg,0.22mmol)在二氧六环(5mL)和H2O(1mL)溶液中分别加入K3PO4(163.4mg,0.77mmol)、Pd(dppf)Cl2(35.9mg,0.04mmol)和苯基硼酸(134.2mg,1.1mmol)。反应混合物在100℃下搅拌16h(过夜),Ar下LCMS(EPN18040-021-1)显示反应完成,SM残留35%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)进行纯化,得到标题化合物(43.5mg,43.8%收率)为淡黄色固体。(ESI)m/z=451.36(M+H)+.
Step 3:2-甲基-1-((6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)丙-2-醇(EPT60153)在MeOH(5mL)中加入化合物3(43.5mg,0.10mmol)溶液中加入MeONa(0.5mL,2.7mmol,)。反应混合物在60℃下搅拌4小时。LCMS(EPN18040-025-1)显示反应完成,无SM残留。溶剂在真空中浓缩。用饱和NH4Cl溶液(30ml)稀释残渣,用CH2Cl2(30ml×3)萃取混合物,再用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。用Flash(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=40/60)对残留进行纯化,得到标题化合物(5.8mg,20.3%收率)为白色固体。
(ESI)m/z=297.23(M+H)+.1H NMR(500MHz,DMSO-d6)11.43(s,1H),8.32-8.34(m,2H),7.42-7.45(m,2H),7.36-7.39(m,1H),7.14(s,1H),6.31(s,1H),5.01(s,1H),3.58-3.59(d,J=5.5Hz,2H),2.33(s,3H),1.17(s,6H)ppm.
实施例36
Step 1:2-氯-N-环戊基-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
取2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(100mg,0.28mmol)、环戊胺(0.5mL)、DIPEA(0.5mL)分别充入20ml密封管,加入2,4-二氯-6-甲基-7-甲苯磺酰-7H-pyrrolo[2,3-d]嘧啶(100mg,0.28mmol)、环戊胺(0.5mL)、二氧环(5ml)。反应混合物在70℃下搅拌16h。反应由LCMS监测。分子式:C19H21ClN4O2S,分子量:404.91,(ESI)m/z=405.3(M+H)+.No SM-1 was remained,the crude product was used in the next step withoutfurther purification.
Step 2:N-环戊基-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
以2-氯-N-环戊基-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]2,3-d-嘧啶-4-胺(5mL二氧六环中粗品)、苯基硼酸(110mg,0.9mmol)、Pd(dppf)Cl2(20mg,0.03mmol)、K3PO4(210mg,1.0mmol)充入10ml密封管,再加水(1.0mL)。反应混合物在100℃惰性气体中加热16h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶7)对产物进行纯化,得到产物为白色固体(100mg,收率80%)。
分子式:C25H26N4O2S,分子量:446.57,(ESI)m/z=447.3(M+H)+.
Step 3:N-环戊基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(4EPT60155)
将N-环戊基-6-甲基-2-苯基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-4-胺(100mg,0.22mmol)溶于CH3OH(5mL)中,加入CH3ONa(5.4M,0.5mL)。反应混合物在55℃下搅拌20h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶3)对产物进行纯化,得到产物为白色固体(55mg,收率84%)。
分子式:C18H20N4,分子量:292.39,(ESI)m/z=293.2(M+H)+.1HNMR(500MHz,DMSO-d6)11.37(s,1H),8.34-8.36(m,2H),7.35-7.44(m,3H),7.08(d,J=7.0Hz,1H),6.27(s,1H),4.57(m,1H),2.31(s,3H),2.03-2.08(m,2H),1.73-1.74(m,2H),1.57-1.63(m,4H)ppm.
实施例37
Step 1:2-氯-N-环己基-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
取2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(100mg,0.28mmol)、环己胺(0.5mL)、DIPEA(0.5mL)分别充入20ml密封管,加入5mL的二氧六环。反应混合物在70℃下搅拌16h。反应由LCMS监测。分子式:C20H23ClN4O2S,分子量:418.94(ESI)m/z=419.3(M+H)+.没有残留SM-1,下一步使用粗品,没有进一步纯化。
Step 2:N-环己基-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
以2-氯-N-环己基-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]2,3-d-嘧啶-4-胺(5mL二氧六环中粗品)、苯基硼酸(110mg,0.9mmol)、Pd(dppf)Cl2(20mg,0.03mmol)、K3PO4(210mg,1.0mmol)充入10ml密封管,再加水(1.0mL)。反应混合物在100℃惰性气体中加热14h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶9)对产物进行纯化,得到标题化合物(105mg,收率81%)为白色固体。
分子式:C26H28N4O2S,分子量:460.60(ESI)m/z=461.3(M+H)+.
Step 3:N-环己基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(4EPT60156)
将N-环己基-6-甲基-2-苯基-7-甲苯磺酰-7H-吡咯[2,3-d]吡啶-4-胺(105mg,0.22mmol)溶于CH3OH(5mL)中,加入CH3ONa(5.4M,0.5mL)。反应混合物在55℃下搅拌20h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析(硅胶,EA∶PE=3∶7)对产物进行纯化,得到产物为白色固体(60mg,85%收率)。
分子式:C19H22N4,分子量:306.41,(ESI)m/z=307.2(M+H)+.1HNMR(500MHz,DMSO-d6)11.34(s,1H),8.33-8.35(m,2H),7.41-7.44(m,2H),7.35-7.38(m,1H),6.95(d,J=7.5Hz,1H),6.21(s,1H),4.15(m,1H),2.31(s,3H),2.03(m,2H),1.17-1.80(m,8H)ppm.
实施例38
Step 1:N-环丙基-2-(4-氟苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
以2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7H-吡咯烷[2,3-d]嘧啶-4-胺(75mg,0.2mmol)、2-(4-氟苯基)-4、4、5-四甲基-1,3,2-二噁硼烷(100mg,0.45mmol)、Pd(dppf)Cl2(14mg,0.02mmol)、K3PO4(120mg,0.6mmol)、水(1.0mL)、二氧六环(5mL)充入10-mL密封管。反应混合物在90℃惰性气体中加热16h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶4)对产物进行纯化,得到标题化合物(71mg,收率81%)为白色固体。
分子式:C23H21FN4O2S,分子量:436.51(ESI)m/z=437.3(M+H)+.
Step 3:N-环丙基-2-(4-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60157)
将N-环丙基-2-(4-氟苯基)-6-甲基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-4-胺(71mg,0.16mmol)溶于THF(5mL)中,加入TBAF(1M,0.5mL)。反应混合物在55℃下搅拌1h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶4)对产物进行纯化,得到标题化合物(32mg,收率69.5%)为白色固体。分子式:C16H15FN4,分子量:282.32(ESI)m/z=283.3(M+H)+.1HNMR(400MHz,DMSO-d6)11.36(s,1H),8.34-8.37(m,2H),7.32(d,J=3.2Hz,1H),7.18-7.22(m,2H),6.23(s,1H),2.97(m,1H),2.28(s,3H),0.74-0.83(m,2H),0.53-0.576(m,2H)ppm.
实施例39
Step 1:2-氯-N-异丁基-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
在EtOH(3ml)中加入化合物1(100mg,0.28mmol)的溶液中加入Et3N(56.6mg,0.56mmol)和2-甲基丙基-1-胺(40.9mg,0.56mmol)。反应混合物在80℃下搅拌4h,LCMS(EPN18040-040-1)表明反应已经完成,没有SM残留。溶剂在真空中浓缩。未纯化的粗化合物直接用于下一步。(ESI)m/z=393.22(M+H)+.
Step 2:N-异丁基-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
将化合物2(90mg,0.23mmol)在二噁烃(5mL)和H2O(1mL)溶液中分别加入K3PO4(163.5mg,0.81mmol)、Pd(dppf)Cl2(35.9mg,0.046mmol)和苯基硼酸(134.2mg,1.15mmol)。反应混合物在100℃下搅拌16h(过夜)。LCMS(EPN18040-041-1)显示反应完成,SM残留10%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)进行纯化,得到标题化合物(15mg,15.1%收率)为淡黄色固体。
(ESI)m/z=435.32(M+H)+.
Step 3:N-异丁基-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60163)
在MeOH(3ml)中加入化合物1(15mg,0.03mmol)溶液中加入MeONa(0.5mL,2.7mmol)。反应混合物在60℃下搅拌6h,LCMS(EPN18040-043-1)显示反应已经完成,没有SM残留。溶剂在真空中浓缩。反应混合物用饱和NH4Cl溶液(30ml)稀释,用CH2Cl2(30ml×3)萃取,再用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。采用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)纯化得到标题化合物(8.0mg,87%收率)为白色固体。(ESI)m/z=281.21(M+H)+.1H NMR(500MHz,DMSO-d6)11.36(s,1H),8.34-8.35(d,J=8.5Hz,2H),7.41-7.44(m,2H),7.37(m,1H),7.24-7.26(m,1H),6.25(s,1H),3.50(m,2H),2.30(s,3H),2.02-2.04(m,1H),0.78-0.95(m,6H)ppm.
实施例40
Step 1:2-氯-6-甲基-4-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(2)
将化合物1(150mg,0.43mmol)在二氧六环(5mL)和H2O(1mL)溶液中分别加入K3PO4(320.5mg,1.51mmol)、Pd(dppf)Cl2(73.4mg,0.09mmol)和苯硼酸(52.5mg,1.0mmol)。反应混合物在80℃条件下搅拌16h(过夜),Ar条件下LCMS(EPN18040-028-1)显示反应已经完成,没有SM残留。溶剂在真空中浓缩。采用自动闪柱柱色谱法(硅胶,PE/EA=8∶1)对残留进行纯化,得到标题化合物(90mg,54%收率)为淡黄色固体。(ESI)m/z=398.20(M+H)+.
Step 2:N-异丙基-6-甲基-4-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-2-胺(3)
在化合物2(85mg,0.21mmol)的二氧六环(3mL)溶液中加入tBuOK(47.1mg,0.42mmol)、pd(OAc)2(4.5mg,0.02mmol)、BINAP(24.9mg,0.2mmol)和propaN-2-amine(25mg,0.42mmol)。反应混合物在Ar下60℃搅拌16h(过夜),LCMS(EPN18040-034-1)显示反应已经完成,没有SM残留。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=40/60)进行纯化,得到标题化合物(30mg,34%收率)为淡黄色固体。(ESI)m/z=421.88(M+H)+.
Step 3:N-异丙基-6-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-2-胺(EPT60164)
在MeOH(3ml)中加入化合物3(30mg,0.07mmol)溶液中加入MeONa(0.5mL,2.7mmol)。反应混合物在60℃下搅拌4h,LCMS(EPN18040-036-1)表明反应已经完成,没有SM残留。溶剂在真空中浓缩。反应混合物用饱和NH4Cl溶液(30ml)稀释,用CH2Cl2(30ml×3)萃取,然后用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。经C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30纯化,得到标题化合物(3.1mg,16.4%收率)为白色固体。(ESI)m/z=267.24(M+H)+.1H NMR(400MHz,DMSO-d6)11.12(s,1H),8.00-8.02(d,J=8.4Hz,2H),7.43-7.50(m,3H),6.22-6.26(m,2H),4.02(m,1H),2.26(s,3H),1.45-1.13(m,6H)ppm.
实施例41
Step 1:2-氯-N-(3-氯苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
在DMSO(3ml)中加入化合物1(100mg,0.50mmol),加入Cs2CO3(182.5mg,0.56mmol)和3-氯苯胺(71.1mg,0.56mmol)溶液。反应混合物在40℃下搅拌16小时(过夜)。LCMS(EPN18040-027-1)显示反应完成,SM残留5%。反应混合物用H2O(30mL)稀释,用CH2Cl2(50mL×3)萃取,然后用饱和NaCl(30mL)洗涤。所得的有机层用无水Na2SO4干燥,在真空中除去溶剂,得到所需的产物(90mg,71.6%收率)为淡黄色固体。(ESI)m/z=447.20(M+H)+.
Step 2:N-(3-氯苯基)-6-甲基-2-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
将化合物2(90mg,0.20mmol)在二噁烃(5mL)和H2O(1mL)溶液中分别加入K3PO4(148.6mg,0.70mmol)、Pd(dppf)Cl2(29.3mg,0.04mmol)和苯硼酸(122.0mg,1.0mmol)。反应混合物在100℃条件下搅拌16h(过夜)。LCMS(EPN18040-031-1)显示反应完成,SM残留20%。溶剂在真空中浓缩。采用自动闪柱柱层析(硅胶,PE/EA=8∶1)对残留进行纯化,再用闪柱(C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30)进行纯化,得到标题化合物(20mg,20.3%收率)为白色固体。
(ESI)m/z=489.25(M+H)+.
Step 3:N-(3-氯苯基)-6-甲基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60165)
在MeOH(3ml)中加入化合物3(20mg,0.04mmol)溶液中加入MeONa(0.5mL,2.7mmol)。反应混合物在60℃下搅拌5小时。LCMS(EPN18040-037-1)显示反应完成,无SM残留。溶剂在真空中浓缩。反应混合物用H2O(30ml)稀释,用CH2Cl2(30ml×3)萃取,然后用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。反应混合物用H2O(30ml)稀释,用CH2Cl2(30ml×3)萃取,然后用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。采用预薄层色谱法(PE/EA=2/1)对残留进行纯化,得到所需产物(1.9mg,8.5%yiled)为白色固体。
(ESI)m/z=335.22(M+H)+ 1H NMR(400MHz,DMSO-d6)11.73(s,1H),9.39(s,1H),8.32-8.34(m,3H),7.80-7.82(m,1H),7.35-7.47(m,4H),7.01-7.04(m,1H),6.47(m,1H),2.36(m,3H)ppm.
实施例42
Step 1:N-环丙基-6-甲基-2-(间甲苯基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
用N-环丙基-6-甲基-2-(间甲苯基)-7-甲苯磺酰-7H-吡咯并[2,3-d],间甲苯硼酸(40mg,0.3mmol),Pd(dppf)Cl2(14mg,0.02mmol),K3PO4(63mg,0.3mmol),加入水(0.5mL)和二氧六环(3mL),充入10-mL密封管。反应混合物在90℃惰性气体中加热16h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=1∶3)对产物进行纯化,得到产物为白色固体(84mg,97%收率)。
分子式:C24H24N4O2S,分子量:432.54,(ESI)m/z=433.3(M+H)+.
Step 2:N-环丙基-6-甲基-2-(间甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(3EPT60166)
将N-环丙基-6-甲基-2-(间甲苯基)-7-甲苯磺酰-7H-吡咯啉[2,3-d]嘧啶-4-胺(84mg,0.20mmol)溶于THF(5mL)中,加入TBAF(2M,2.0mL)。反应混合物在55℃下搅拌24h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=1∶3)对产物进行纯化,得到标题化合物(26mg,收率46%)为白色固体。
分子式:C17H18N4,分子量:278.36,(ESI)m/z=279.2(M+H)+.1HNMR(500MHz,DMSO-d6)11.39(s,1H),8.16-8.19(m,2H),7.29-7.32(m,2H),7.18(d,J=7.5Hz,1H),6.28(s,1H),3.01(s,1H),2.38(s,3H),2.32(s,3H),0.78-0.85(m,2H),0.58-0.61(m,2H)ppm.
实施例43
Step 1:N-环丙基-6-甲基-2-(邻甲苯基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
在一个25毫升的圆底烧瓶中加入2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7H-吡咯啉[2,3-d]嘧啶-4-胺(50mg,0.13mmol),邻甲苯硼酸(53mg,0.39mmol),Pd(dppf)Cl2(9mg,0.013mmol)和K3PO4(83mg,0.39mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,首先用自动闪柱柱层析(硅胶,PE∶EA=90∶10)纯化得到N-环丙基-6-甲基-2-(o-tolyl)-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(7,20mg,35.53%收率)为黄色固体。
LCMS:(ESI)m/z=433.12(M+H)+;RT=1.91min.
Step 2:N-环丙基-6-甲基-2-(邻甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60167)
到25ml圆底烧瓶中加入N-cyclopropyl-6-methyl-2——(o-tolyl)7-甲苯磺酰-7H-pyrrolo[2,3-d]pyrimidiN-4-amine(0.057,20毫克,mmol)溶解在TBAF(1毫升,1.0年的四氢呋喃)和四氢呋喃(2毫升)和搅拌在50℃ 4h。残渣被自动闪光集中在真空和纯化柱层析法(硅胶,DCM∶甲醇=97∶3)给黄色固体N-cyclopropyl-6-methyl-2-(o-tolyl)7H-pyrrolo[2,3-d]pyrimidiN-4-amine(EPT601676毫克,43.16%的收率)。
LCMS:(ESI)m/z=279.24(M+H)+;RT=1.23min.
1H NMR(500MHz,DMSO)δ11.35(s,1H),7.73(d,J=6.4Hz,1H),7.31(d,J=2.5Hz,1H),7.24(d,J=5.8Hz,3H),6.27(s,1H),2.91(s,1H),2.55(s,3H),2.33(s,3H),0.75(d,J=5.2Hz,2H),0.57(s,2H).
实施例44
Step 1:2-(2,4-二羟基-7H-吡咯并[2,3-d]嘧啶-6-基)-乙酸乙酯(3)
在6-氨基嘧啶-2,4(1H,3H)-二酮(1)(15.0g,118mmol)水溶液(300mL)悬浮液中加入乙酸钠(10.7g,130mmol)。将混合物加热到95℃。滴加4-氯-3-草酸乙酯(2)(21.4g,130mmol),静置30min,95℃搅拌过夜,冷却过滤。蛋糕用水(30ml×3)和丙酮(30ml×2)洗涤,真空干燥,得到标题化合物(5.0g,收率18%)为黄色固体。
1H NMR(400MHz,DMSO-d6):δ11.49(s,1H),11.15(s,1H),10.46(s,1H),6.05(s,1H),4.08(q,J=7.2Hz,2H),3.60(s,2H),1.20(t,J=7.2Hz,3H).
Step 2:2-(2,4-二氯-7H-吡咯并[2,3-d]嘧啶-6-基)乙酸乙酯(4)
在甲苯(12ml)中加入2-(2-苯基-4-(苯基氨基)-7H-吡咯[2,3-d]嘧啶-6-基)乙酸乙酯(3)(5.00g,2.11mmol),POCl3(12.9g,8.44mmol)。将反应升温至70℃,滴加N、N-二异丙基乙胺(7.08g,5.49mmol)10min,110℃搅拌过夜。将混合物冷却至室温,倒入水中(50毫升)。加入DIEA(10mL),搅拌30min,加入乙酸乙酯(50mL),过滤。滤液用乙酸乙酯(50mL×2)萃取,混合有机物层用盐水(20mL)冲洗,Na2SO4烘干,过滤。滤液浓缩后,用硅胶柱层析法(石油醚∶乙酸乙酯,5∶1~3∶1)纯化残渣,得到粗品1.1g。将原油与(石油醚∶乙酸乙酯=10∶1,5mL)三聚氰胺(880mg,收率15%)反应得到黄色固体。
1H NMR(400MHz,DMSO-d6):δ12.74(s,1H),6.54(s,1H),4.14(q,J=6.8Hz,2H),3.95(s,2H),1.21(t,J=6.8Hz,3H).
Step 3:2-(2-氯-4-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶-6-基)乙酸乙酯(5)
在乙二醇(15ml)中乙酸乙酯(4)(880mg,3.21mmol)和苯胺(806mg,8.67mmol)溶液中加入2滴浓缩盐酸水溶液。将混合物加热到95摄氏度,搅拌5小时。冷却至室温后,倒入80毫升水搅拌10分钟,过滤。滤饼用水(10mL×5)和石油醚(10mL×5)洗涤,真空干燥,得到标题化合物(950mg,收率90%)为粉红色固体。
1H NMR(400MHz,DMSO-d6):δ11.86(s,1H),9.61(s,1H),7.76(d,J=7.6Hz,2H),7.36(t,J=8.0Hz,2H),7.07(t,J=7.6Hz,1H),6.61(s,1H),4.13(q,J=7.2Hz,2H),3.81(s,2H),1.22(t,J=7.2Hz,3H).
Step 4:2-(2-苯基-4-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶-6-基)乙酸乙酯(6,EPT60168)
将2-乙基2-(2-氯-4-(苯基氨基)-7H-吡啶醇[2,3-d]]乙酸乙酯(5)(500mg,1.51mmol),苯基硼酸(553mg,4.53mmol),DIEA(974mg,7.55mmol)和HPd(PPh3)4(349mg,0.30mmol)在DMA/水(5mL/1mL)中密封管中,在140℃微波下搅拌3小时。冷却到室温后,混合物注入水(30毫升),用乙酸乙酯提取(20毫升2)。合并后的有机层集中和残渣被C18柱纯化(乙腈∶水15分钟期间从60%到80%)给原油产品(160毫克)。用预薄层色谱法(石油醚∶乙酸乙酯=3∶1)纯化粗品60mg,得到标题化合物(30mg,收率14%)为黄色固体。
1H NMR(400MHz,DMSO-d6):δ11.79(s,1H),9.35(s,1H),8.37(d,J=9.2Hz,2H),7.98(d,J=10.4Hz,2H),7.51-7.40(m,5H),7.04(t,J=10.0Hz,1H),6.69(s,1H),4.14(q,J=9.6Hz,2H),3.85(s,2H),1.23(t,J=9.6Hz,3H).
LC-MS[流动相:从80%水(0.02%NH4OAc)和20%CH3CN变为5%水(0.02%NH4OAc)和95%CH3CN,在6.5min内],Rt=3.981min;纯度:94.35%(214nm),96.03%(254nm);MS计算值:372.2;MS实测值:373.0[M+H]+.
实施例45
Step 2:N-环丙基-6-甲基-2-(对甲苯基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
将化合物1(100mg,0.27mmol)在二氧六环(5mL)和H2O(1mL)溶液中分别加入K3PO4(201.7mg,0.95mmol)、Pd(dppf)Cl2(36.6mg,0.05mmol)和4-甲基苯硼酸(183.6mg,1.35mmol)。反应混合物在100℃下搅拌16h(过夜),Ar条件下LCMS(EPN18040-044-1)显示反应完成,SM残留30%。溶剂在真空中浓缩。采用自动闪柱柱色谱法(硅胶,PE/EA=20/1)对残留进行纯化,得到标题化合物(60mg,43.8%收率)为淡黄色固体。(ESI)m/z=433.36(M+H)+.
Step 2:N-环丙基-6-甲基-2-(对甲苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60180)
在MeOH(3ml)中加入化合物2(60mg,0.14mmol)溶液中加入MeONa(0.5mL,2.7mmol)。反应混合物在60℃下搅拌4h,LCMS(EPN18040-046-1)表明反应已经完成,没有SM残留。溶剂在真空中浓缩。反应混合物用饱和NH4Cl溶液(30ml)稀释,用CH2Cl2(30ml×3)萃取,然后用饱和NaCl(30ml)洗涤。用无水Na2SO4干燥所得到的有机层,在真空中除去溶剂。经C-18柱层析,H2O(NH4HCO3,0.8g/L)/CH3CN=70/30纯化,得到标题化合物(3.1mg,16.4%产率)白色固体。(ESI)m/z=279.24(M+H)+.1H NMR(500MHz,DMSO-d6)11.26(s,1H),8.25-8.26(d,J=8.0Hz,2H),7.31-7.32(m,1H),7.22-7.24(m,2H),6.23(s,1H),2.99(s,1H),2.35(s,3H),2.31(s,3H),0.79-0.81(s,2H),0.58-0.59(s,2H)ppm.
实施例46
Step 1:N-异丙基2,6-二苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(5EPT60181)
取6-溴-N-异丙基-2-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(50mg,0.15mmol)、苯基硼酸(61mg,0.5mmol)、Pd(dppf)Cl2(10mg,0.015mmol)、K3PO4(110mg,0.5mmol)、水(1.0mL)、二氧六环(5mL)充入10ml密封管。反应混合物在90℃惰性气体中加热16h。反应由LCMS监测。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=35∶65)对产物进行纯化,得到产物为白色固体(30mg,收率60%)。
分子式:C21H20N4,分子量:328.42,(ESI)m/z=329.3(M+H)+.1H NMR(400MHz,DMSO-d6)11.86(s,1H),8.36-8.38(m,2H),7.33-7.50(m,8H),7.24(d,J=2.4Hz,1H),5.06(d,J=7.2Hz,1H),4.41-4.46(m,1H),1.17(d,J=6.4Hz,6H)ppm.
实施例47
Step 1:4-(4-(环丙基氨基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-2-基)苯酚(2)
10mL封管中加入2-氯-N-环丙基-6-甲基-7-甲苯磺酰-7-h-吡咯并[2,3-d]嘧啶-4-氨基(110mg,0.3mmol)、(4-羟基苯基)硼酸(84mg,0.6mmol)、Pd(dppf)Cl2(20mg,0.03mmol)、K3PO4(124mg,0.6mmol)、水(1.0mL)、二氧六环(5mL)。反应混合物在90℃惰性气体中加热16h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=3∶7)对产物进行纯化,得到标题化合物(88.8mg,收率73.6%)为白色固体。
分子式:C23H22N4O3S,分子量:434.51,(ESI)m/z=435.3(M+H)+.
Step 2:4-(4-(环丙基氨基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-2-基)苯酚(3EPT60182)
将4-(4-(环丙基氨基)-6-甲基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-2-基)苯酚(50mg,0.115mmol)溶于CH3OH(2mL)中,加入CH3ONa(1.0mL)。反应混合物在55℃下搅拌16h。反应完成后,用饱和NH4Cl水溶液(1mL)对反应进行骤冷,再用硅胶(100-200mesh)对反应混合物进行蒸发浓缩,得到粉体残渣。采用自动闪柱柱层析法(硅胶,EA∶PE=2∶3)对产物进行纯化,得到标题化合物(8mg,收率25%)为白色固体。
分子式:C16H16N4O,分子量:280.33(ESI)m/z=281.2(M+H)+.1H NMR(400MHz,DMSO-d6)11.23(s,1H),9.54(s,1H),8.15(d,J=8.4Hz,2H),7.18(d,J=2.8Hz,1H),6.75(d,J=8.8Hz,2H),6.20(s,1H),2.94-2.98(m,1H),2.26(s,3H),0.73-0.77(m,2H),0.52-0.56(m,2H)ppm.
实施例48
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Step 1:2-氯-N-环丁基-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
用2,4-二氯-6-甲基-7-甲苯磺酰-7-h-吡咯并[2,3-d]嘧啶(107mg,0.3mmol)、环丁胺(185mg,2.6mmol)分别充入20ml密封管,然后加入二氧六环(5mL)。反应混合物在70℃下搅拌3h。反应由LCMS监测。
分子式:C18H19ClN4O2S,分子量:390.89,(ESI)m/z=391.2(M+H)+,下一步直接使用。
Step 2:N-环丁基-2-(2-氟苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
用2-氯-N-环丁基-6-甲基-7-甲苯磺酰-7-H-吡咯并[2,3-d]吡啶-4-胺(5mL二氧六环中粗品)、(2-氟苯基)硼酸(140mg,1.0mmol)、Pd(dppf)Cl2(20mg,0.03mmol)、K3PO4(210mg,1.0mmol)充入10ml密封管,再加水(1.0mL)。反应混合物在90℃惰性气体中加热16h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=15∶85)对产物进行纯化,得到标题化合物112mg,收率83%)为白色固体。
分子式:C24H23FN4O2S,分子量:450.53,(ESI)m/z=451.3(M+H)+.
Step 4:N-环丁基-2-(2-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(4EPT60183)
将N-环丁基-2-(2-氟苯基)-6-甲基-7-甲苯磺酰-7H-吡咯[2,3-d]嘧啶-4-胺(112mg,0.25mmol)溶于THF(5mL)中,加入TBAF(2M,2.0mL)。反应混合物在55℃下搅拌1h。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,EA∶PE=35∶65)对产物进行纯化,得到产物为白色固体(35mg,收率47.3%)。
分子式:C17H17FN4,分子量:296.35,(ESI)m/z=297.2(M+H)+.1H NMR(400MHz,DMSO-d6)11.41(s,1H),7.91-7.95(m,1H),7.34-7.39(m,2H),7.16-7.23(m,2H),6.21(s,1H),4.61-4.67(m,1H),2.24-2.32(m,5H),1.96-2.06(m,2H),1.64-1.70(m,2H)ppm.
实施例49
Step 1:N-异丙基-2-苯基-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺(2EPT60184)
以N-异丙基-2-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(50mg,0.2mmol)、梅莫托试剂(Umemoto′s reagents)(136mg,0.4mmol)、4-甲基吗啉(41mg,0.4mmol)充入10ml密封管,加入DMF(1mL)。反应混合物在室温下搅拌3h。反应由LCMS监测。反应完成后,将反应混合物与硅胶(100-200目)通过蒸发浓缩,得到粉末残渣。采用自动闪柱柱色谱法(硅胶,DCM)对产物进行纯化,得到产物为黄色固体(18mg,收率28%)。分子式分子式:C16H15F3N4,分子量:320.32,(ESI)m/z=321.2(M+H)+.1HNMR(500MHz,DMSO-d6)12.78(s,1H),8.37-8.40(m,2H),7.67(d,J=7.5Hz,1H),7.43-7.50(m,3H),7.22(s,1H),4.54-4.58(m,1H),1.31(m,6H)ppm.
实施例50
Step 1:2-氯-6-甲基-N-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(2)
在一个25毫升的圆底烧瓶中加入2,4-二氯-6-甲基-7-甲苯磺酰-7H-吡啶[2,3-d]嘧啶(50mg,0.14mmol),苯胺(26mg,0.28mmol)和Cs2CO3(138mg,0.42mmol)。将混合物悬浮于DMSO(3ml)中,50℃搅拌1h,残渣在真空中浓缩,得到2-氯-6-甲基-N-苯基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(50mg,收率86.67%)为黄色固体。粗产物用于下一步没有进一步提纯。
LCMS:(ESI)m/z=413.24(M+H)+;RT=1.88min.
Step 2:2-(2-氟苯基)-6-甲基-N-苯基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
将2-氯-6-甲基-N-苯基-7-甲苯磺酰-7H-吡啶醇[2,3-d]4-氨基嘧啶(50mg,0.12mmol),(2-氟苯基)硼酸(50mg,0.36mmol),Pd(dppf)Cl2(9mg,0.012mmol)和K3PO4(51mg,0.24mmol)分别装入25ml圆底烧瓶中。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,采用自动闪柱柱层析(硅胶,PE∶EA=1∶1)纯化得到产物为黄色固体2-(2-氟苯基)-6-甲基-N-苯基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(7,40mg,70.62%收率)。LCMS:(ESI)m/z=473.33(M+H)+;RT=1.96min.
Step 3:2-(2-氟苯基)-6-甲基-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60185)
到25ml圆底烧瓶中加入2-(2-氟苯基)6-甲基-N-苯基-7-甲基磺酰基-7H-吡咯并[2,3-d]嘧啶-N-4-胺(40毫克,0.08mmol)溶解在TBAF(1毫升,1.0年的四氢呋喃)和四氢呋喃(2毫升)和搅拌在8小时50℃。残留物被自动闪光集中在真空和纯化柱层析法(硅胶,DCM∶甲醇=97∶3)给了白色固体2-(2-氟苯基)-6-甲基-N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺(10毫克,EPT6018539.31%收率)。
LCMS:(ESI)m/z=319.21(M+H)+;RT=1.52min.
1H NMR(400MHz,dmso)δ11.76(s,1H),9.23(s,1H),8.05-7.95(m,3H),7.46(dd,J=12.5,5.9Hz,1H),7.30(dt,J=8.2,6.7Hz,4H),6.98(t,J=7.3Hz,1H),6.51(s,1H),2.39(s,3H).
实施例51
Step 1:N-环戊基-2-(2-氟苯基)-6-甲基-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(3)
在一个25毫升的圆底烧瓶中加入2-氯-N-环戊基-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(100mg,0.25mmol),(2-氟苯基)硼酸(105mg,0.75mmol),Pd(dppf)Cl2(18mg,0.025mmol)和K3PO4(106mg,0.5mmol)。混合物悬浮在二氧六环(5ml)和H2O(1ml)中。反应在100℃的氮气气氛下进行了一夜。减压除去溶剂,用自动闪柱柱层析(硅胶,PE∶EA=60∶40)纯化得到淡黄色固体N-环戊基-2-(2-氟苯基)-6-甲基-7-甲苯磺酰-7H-吡咯并[2,3-d]嘧啶-4-胺(7,110mg,94.83%)。LCMS:(ESI)m/z=465.37(M+H)+;RT=1.99min.
Step 2:N-环戊基-2-(2-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60186)
到25ml圆底烧瓶中加入N-环戊基-2-(2-氟苯基)-6-甲基-7-甲基磺酰基-7H-吡咯并[2,3-d]嘧啶-N-4-胺(40毫克,0.09mmol)溶解在TBAF(1毫升,1.0年的四氢呋喃)和四氢呋喃(2毫升)和搅拌在8小时50℃。残留物被自动闪光集中在真空和纯化柱层析法(硅胶,DCM∶甲醇=97∶3)给了白色固体N-环戊基-2-(2-氟苯基)-6-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(EPT60186,25毫克,38.4%收率)。
LCMS:(ESI)m/z=311.21(M+H)+;RT=1.34min.
1H NMR(500MHz,DMSO)δ11.42(s,1H),7.97(td,J=7.8,1.7Hz,1H),7.44-7.37(m,1H),7.28-7.19(m,2H),7.09(d,J=6.9Hz,1H),6.28(d,J=0.9Hz,1H),4.48(dd,J=13.8,6.9Hz,1H),2.32(s,3H),2.01(dd,J=9.3,5.4Hz,2H),1.72(s,2H),1.56(d,J=4.6Hz,4H).
生物学实施例
实施例52化合物对IDH2/R140Q抑制活性的测定
本实施例通过测定辅助因子NADPH的消减来测定化合物对IDH2/R140Q的抑制活性。将化合物与IDH2/R140Q和NADPH进行孵育,然后通过添加α-KG启动反应,线性条件下反应一定时间后添加硫辛酰胺脱氢酶和相应的底物刃天青进行检测。硫辛酰胺脱氢酶通过消减可供使用的辅助因子NADPH而终止IDH2/R140Q反应,它将NADPH氧化成NADP,并且将刃天青还原成高荧光的试卤灵,通过检测试卤灵的生成来量化特定反应时间之后剩余的辅助因子NADPH的量。
具体操作方式为:在96孔板中,反应总体积是50μL,1.2nM IDH2/R140Q、梯度稀释的抑制剂和5μM NADPH的混合液在包含Tris-HCl 50mM(pH 7.5)、150mM NaCl、10mM MgCl2、BSA 0.05%、10%Glycerol和2.5mMβ-巯基乙醇的反应缓冲液中,在25℃预孵育16小时。加入α-KG至1mM,在25℃反应40分钟。后加入25μL上述反应缓冲液配置的终止混合液(硫辛酰胺脱氢酶36μg/mL,刃天青30μM),使刃天青转化为试卤灵来测量剩余的NADPH。25℃孵育10分钟后通过Tecan INFINITE F FLEX在Ex544/Em590下进行荧光值测定。每个化合物分别在10个浓度下测定酶的活性,反应中设置多个不加酶的背景孔和不含化合物的全酶活性孔。体系中二甲亚砜浓度小于等于百分之二。IC50的值使用XLFit5软件(IDBS Software)通过公式:Y=100/(1+10^((LogIC50-X)*HillSlope))获得。本实施例的多孔板购自Thermo FisherScientific公司,NADPH、α-KG、硫辛酰胺脱氢酶和刃天青购自生工生物工程有限公司,IDH2/R140Q购自Abcam公司(ab198153)。
根据本实施例所述的生物学方法对本发明所选的化合物进行分析,其结果如表2所示。其中,表2的“A”指对IDH2/R140Q的IC50≤100nM的抑制活性;“B”指对IDH2/R140Q的100nM<IC50≤1μM的抑制活性;“C”指对IDH2/R140Q的1μM<IC50≤10μM的抑制活性;“D”指对IDH2/R140Q的IC50>10μM的抑制活性。
表2优选化合物的IDH2/R140Q抑制活性
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结果显示,本专利所列化合物具有很好的IDH2/R140Q抑制活性,其中,活性水平为A和B的化合物的抑制作用极为明显。
实施例53化合物对野生型IDH2(IDH2/WT)选择性的测定
将化合物与IDH2/WT和NADP进行孵育,然后通过添加异柠檬酸启动反应,线性条件下反应一段时间后加入硫辛酰胺脱氢酶和刃天青检测荧光物质的量。本实验将NADP还原成NADPH,后者在硫辛酰胺脱氢酶的作用下将刃天青还原成高荧光的试卤灵,通过检测试卤灵的生成来量化特定反应时间之后生成的辅助因子NADPH的量,从而来计算化合物对IDH2/WT的抑制作用。
具体操作方式为:在96孔板中,反应总体积是50μL,0.6nM IDH2/WT、梯度稀释的抑制剂和50μM NADP的混合液在包含Tris-HCl 20mM(pH 7.5)、150mM NaCl、10mM MgCl2、10%Glycerol、0.03%BSA和2.5mMβ-巯基乙醇的反应缓冲液中,在25℃预孵育16小时。加入isocitrate至50μM,25℃反应30分钟。后加入25μL上述反应缓冲液配置的混合液(硫辛酰胺脱氢酶36μg/mL,刃天青30μM),使刃天青转化为试卤灵来测量生成的NADPH。25℃孵育10分钟后通过Tecan INFINITE F FLEX在Ex544/Em590下进行荧光值测定。每个化合物分别在10个浓度下测定酶的活性,反应中设置多个不加酶的背景孔和不含化合物的全酶活性孔。体系中二甲亚砜浓度小于等于百分之二。IC50的值使用XLFit5软件(IDBS Software)通过公式:Y=100/(1+10^((LogIC50-X)*HillSlope))获得。方法中多孔板购自Thermo FisherScientific公司,NADP、α-KG、硫辛酰胺脱氢酶和刃天青购自生工生物工程有限公司,IDH2/WT通过大肠杆菌过表达后纯化得到。部分化合物的测试结果见表3。
表3部分化合物对IDH2/WT的抑制活性
结果显示,本发明的化合物对野生型的IDH2(IDH2/WT)几乎没有活性,具有很好的选择性。
实施例54细胞水平对突变型IDH2活性的抑制检测
2-羟基戊二酸脱氢酶(2HGDH)在2-HG存在的情况下,能够将NAD+还原成NADH。后者可以通过心肌黄酶及其底物Resazurin(刃天青)进行定量测定。
过表达IDH2/R140Q突变的胶质瘤细胞U87MG,培养在1%丙酮酸钠的高糖MEM,10%FBS中,置于CO2培养箱(37℃,5%CO2,95%空气)培养。
细胞通过胰酶消化并以1×104的密度接种于96孔板中,培养基为200μL,37℃培养箱培养过夜。第二天加入待测化合物,DMSO终浓度均为0.1%,在培养24小时后,吸取100μL培养基,使用10KD超滤管(购自PALL公司)14000g离心10分钟,过滤培养基中存在的可能干扰结果的蛋白等成分,使用后续方法检测2-HG的含量。剩余100μL培养基的96孔板中,加入50uLCellTiter-Glo(购自Promega公司),测定细胞存活情况;
细胞外2-HG测定体系:
(1)50μL反应体系:反应缓冲液(50mM Tris pH7.5,100mM NaCl,20mM MgCl2,0.05%BSA),其中NAD+终浓度为40μM,2HGDH终浓度为20nM,待测样品加入5μL培养液;反应液混匀离心,避光25℃反应1小时;
(2)2SμL显色体系:显色缓冲液(50mM Tris pH7.5,100mM NaCl,20mM MgCl2,0.05%BSA),其中心肌黄酶的终浓度为36μg/mL,刃天青钠的终浓度为3μM;将上述2SμL显色液加入(1)中的50μL反应体系中,混匀并离心,立即在Ex544/Em590下进行荧光值测定。
2-HG标准曲线制备:将2-HG储液使用反应缓冲液稀释至20μM,之后进行2倍梯度稀释,共计6个点。之后将上述2-HG按照细胞外2-HG测定体系测定,计算并绘制标准曲线。
细胞外2-HG含量计算:
细胞外2-HG测定体系中获得的荧光值使用2-HG标准曲线计算培养基中2-HG的含量,以DMSO作为阴性对照,计算化合物对IDH2/R140Q突变产生2-HG活性的抑制。
根据本实施例所述的方法对本发明所选的化合物进行分析,其结果如表3所示。其中,表4的“A”指对在细胞水平IDH2/R140Q的IC50≤100nM的抑制活性;“B”指在细胞水平对IDH2/R140Q的100nM<IC50≤1μM的抑制活性;“C”指在细胞水平对IDH2/R140Q的1μM<IC50≤10μM的抑制活性;“D”指在细胞水平对IDH2/R140Q的IC50>10μM的抑制活性。
表4优选化合物在细胞水平对突变型IDH2/R140Q活性的抑制
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结果显示,所测试的化合物能在较低的浓度下抑制IDH2/R140Q突变的细胞产生2-HG,显示了化合物在细胞水平对突变型IDH2的活性抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种嘧啶并五元杂环类化合物或药学上可接受的盐,其中,所述的化合物选自下组:
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或其药学上可接受的盐。
2.如权利要求1所述的化合物,其特征在于,所述化合物选自下组:
,
或其药学上可接受的盐。
3.一种药物组合物,包含:(1)如权利要求1所述的化合物或其药学上可接受的盐;(2)药学上可接受的载体。
4.一种如权利要求1所述的化合物或其药学上可接受的盐或如权利要求3所述的药物组合物的用途,其特征在于,用于制备治疗突变型IDH2介导的疾病的药物。
5.如权利要求4所述的用途,其特征在于,所述突变型IDH2介导的疾病为癌症。
6.如权利要求5所述的用途,其特征在于,所述癌症为膀胱癌、乳腺癌、肾癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌;淋巴系的造血肿瘤;间充质细胞来源的肿瘤;髓系的造血肿瘤;中枢和周围神经系统肿瘤。
7.如权利要求6所述的用途,其特征在于,所述的肺癌为小细胞肺癌;
所述的皮肤癌为:鳞状细胞癌;
所述的淋巴系的造血肿瘤为:白血病、B细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;所述的间充质细胞来源的肿瘤为:纤维肉瘤、横纹肌肉瘤;
所述的髓系的造血肿瘤为:急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞白血病;
所述的中枢和周围神经系统肿瘤为:星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;
所述的肿瘤还可为:黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、色性干皮病、角化棘皮瘤、甲状腺滤泡癌和卡波济氏肉瘤。
8.如权利要求7所述的用途,其特征在于,所述的白血病为:急性淋巴细胞白血病、急性淋巴母细胞白血病。
9.一种突变型IDH2抑制剂,所述抑制剂包含如权利要求1所述的化合物或药学上可接受的盐或如权利要求3所述的药物组合物。
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WO2024035771A2 (en) * | 2022-08-09 | 2024-02-15 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Ulk3 inhibitors and uses thereof |
CN116478172B (zh) * | 2023-06-20 | 2023-09-05 | 英矽智能科技(上海)有限公司 | 吡咯并[3,2-d]嘧啶类化合物及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017035118A1 (en) * | 2015-08-25 | 2017-03-02 | Bristol-Myers Squibb Company | Tgf beta receptor antagonists |
WO2017069960A1 (en) * | 2015-10-19 | 2017-04-27 | The Scripps Research Institute | Inhibitors of sulfur metabolism with potent bactericidal activity against mdr and xdr m. tuberculosis |
WO2017140758A1 (en) * | 2016-02-19 | 2017-08-24 | Debiopharm International S.A. | Derivatives of 2-amino-4-(2-oxazolidinon-3-yl)-pyrimidine fused with a five-membered heteroaromatic ring in 5,6-position which are useful for the treatment of various cancers |
WO2019024908A1 (zh) * | 2017-08-04 | 2019-02-07 | 厦门大学 | 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6897307B2 (en) * | 2002-03-28 | 2005-05-24 | Novartis Ag | Process for preparing 2,6-diaminopurine derivatives |
EP1551410A2 (en) * | 2002-09-06 | 2005-07-13 | Smithkline Beecham Corporation | Novel compounds |
CA2577745C (en) * | 2004-09-30 | 2012-11-27 | Tibotec Pharmaceuticals Ltd. | Hcv inhibiting bi-cyclic pyrimidines |
EP2920180A4 (en) * | 2012-11-15 | 2016-04-13 | Pharmacyclics Inc | PYRROLOPYRIMIDINE COMPOUNDS AS KINASE INHIBITORS |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017035118A1 (en) * | 2015-08-25 | 2017-03-02 | Bristol-Myers Squibb Company | Tgf beta receptor antagonists |
CN108349976A (zh) * | 2015-08-25 | 2018-07-31 | 百时美施贵宝公司 | TGFβ受体拮抗剂 |
WO2017069960A1 (en) * | 2015-10-19 | 2017-04-27 | The Scripps Research Institute | Inhibitors of sulfur metabolism with potent bactericidal activity against mdr and xdr m. tuberculosis |
WO2017140758A1 (en) * | 2016-02-19 | 2017-08-24 | Debiopharm International S.A. | Derivatives of 2-amino-4-(2-oxazolidinon-3-yl)-pyrimidine fused with a five-membered heteroaromatic ring in 5,6-position which are useful for the treatment of various cancers |
WO2019024908A1 (zh) * | 2017-08-04 | 2019-02-07 | 厦门大学 | 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 |
Non-Patent Citations (3)
Title |
---|
Chemical Library等数据库.未收录于CA的化合物.《STN检索结果》.2011, * |
Phosphorus pentoxide in organic synthesis. XV. A new synthesis of adenines from 4-acylamino-1H-imidazole-5-carbonitriles;Nielsen, Flemming E.等;《Chemica Scripta》;19841231;第24卷(第4-5期);208-223 * |
刃天青法检测K562细胞对几种抗肿瘤药物的敏感性;李宙阳等;《山地农业生物学报》;20141231;第33卷(第02期);全文 * |
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EP3967691A1 (en) | 2022-03-16 |
CN111825674A (zh) | 2020-10-27 |
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