CN115594682B - Fgfr2抑制剂 - Google Patents
Fgfr2抑制剂 Download PDFInfo
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- CN115594682B CN115594682B CN202211301335.8A CN202211301335A CN115594682B CN 115594682 B CN115594682 B CN 115594682B CN 202211301335 A CN202211301335 A CN 202211301335A CN 115594682 B CN115594682 B CN 115594682B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
本发明提供了一种化合物作为FGFR2抑制剂,其为式(I)所示化合物或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还提供了包含所述化合物的药物组合物,及其在治疗癌症中的用途。
Description
技术领域
本发明属于医药领域,具体涉及FGFR2抑制剂。
背景技术
纤维母细胞生长因子受体(FGFR)是一类受体型酪氨酸激酶,该激酶家族包含了四种高度保守的亚型,即FGFR1、FGFR2、FGFR3和FGFR4,均由胞外区、跨膜区和胞内酪氨酸激酶区三个部分组成。当FGFR与FGF(成纤维细胞生长因子)配体结合以后会被激活,从而发挥激酶功能,促进下游信号通路的激活,在细胞增殖、存活、分化、迁移和血管生成、神经调节、代谢调节等生物学过程中起到重要作用。
失调的FGFR信号传导可经由以下方式发生:FGFR基因扩增或融合、FGFR错义突变、FGFR过度表达或FGF配体在肿瘤微环境中的上调。FGFR表达于许多细胞类型中,异常的FGFR信号传导已涉及到许多肿瘤的形成、肿瘤恶化及对治疗的抗性,目前已经在多种人类癌症中发现了FGFR改变(即扩增、基因融合或突变)。例如,通常在约20%的鳞状非小细胞肺癌中,10-15%的乳腺癌和5%的卵巢癌中观察到FGFR1扩增。FGFR2在约10%的胃癌和4%的三阴性乳腺癌中存在扩增,并且在约12-14%的子宫内膜癌中检测到FGFR2突变。此外,在约38-66%的非浸润性尿路上皮癌中观察到FGFR3的激活突变,并且在膀胱癌中经常发现其扩增和易位。此外,约50%的肝细胞癌表现出FGFR4的过表达。FGFR家族的异常激活与癌细胞的存活和迁移、肿瘤血管生成和不良预后密切相关。因此,开发FGFR抑制剂可以作为抗治疗相关肿瘤的有效策略。
FGFR抑制剂的开发吸引了国内外众多公司布局,目前多种癌症已经对泛FGFR1-3抑制剂产生了临床应答,然而这些抑制剂存在较多的靶毒性,使其治疗窗口较窄。泛FGFR抑制的最常见副作用之一是高酸盐血症。磷酸盐再吸收的调控是由FGFR3和FGFR1介导的。含有FGFR2基因融合体的癌症以及具有FGFR2扩增和/或FGFR2活化突变的癌症已对泛FGFR抑制展现出应答,然而,受到泛抑制剂的毒性限制,应答速率和持续时间均受限。因此,目前迫切需要开发出高活性高选择性的FGFR2抑制剂用于治疗与之相关的肿瘤。
发明内容
在一个方面,本发明提供了式(I)化合物,或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物:
其中,
R1选自C1-6烷基、C1-6卤代烷基、-(CH2)1-4-NH2、-(CH2)1-4-OH、C3-6环烷基或3-10元杂环基、其可任选地被1个、2个、3个或4个R*取代;R*选自卤素、OH、NH2、C1-3烷基、C3-6环烷基或C1-3卤代烷基;
R2选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、CN、OH或NH2;
X1选自N或CR5;R5选自H、卤素、C1-3烷基或C1-3烷氧基;
X2选自N或CR6;R6选自H、卤素、C1-3烷基或C1-3烷氧基;
X3选自CH2、O、S、NH或NMe;
L1选自C2-4烯基,其可任选地被1个或2个卤素取代;
R3选自C6-10芳基、5-10元杂芳基或3-10元杂环基;可任选地被1个、2个或3个卤素、C1-3烷基、C1-3烷氧基或C1-3卤代烷基取代;
R4选自H、卤素或C1-3烷基。
在另一个方面,本发明提供了一种药物组合物,所述药物组合物含有本发明化合物,和任选地药学上可接受的赋形剂。
在另一个方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物,其还含有其它治疗剂。
在另一个方面,本发明提供了本发明化合物在制备用于治疗和/或预防FGFR2激酶介导的疾病的药物中的用途。
在另一个方面,本发明提供了在受试者中治疗和/或预防FGFR2激酶介导的疾病的方法,包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面,本发明提供了本发明化合物或本发明组合物,其用于治疗和/或预防FGFR2激酶介导的疾病。
在具体实施方案中,本发明治疗的疾病包括选自以下的癌症:胆管癌、肝内胆管癌、胃癌(如胃腺癌)、肾上腺癌、肛门癌、血管肉瘤(例如淋巴管肉瘤、淋巴管内皮肉瘤、血管瘤)、阑尾癌、胆管癌、膀胱癌、脑癌(例如脑膜瘤、神经胶质瘤,例如星形胶质细胞瘤、少突胶质细胞瘤、髓母细胞瘤)、宫颈癌(例如宫颈腺癌)、绒(毛)膜癌、脊索瘤、颅咽管瘤、结肠直肠癌(例如结肠癌、直肠癌、大肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如卡波西肉瘤、多发性特发性出血肉瘤)、子宫内膜癌(例如子宫癌、子宫肉瘤)、食道癌(如食管腺癌、巴雷特氏腺癌)、尤因氏肉瘤、眼癌(如眼内黑色素瘤、成视网膜细胞瘤)、嗜酸性粒细胞增多症、胆囊癌、胃肠道间质瘤(GIST)、头颈癌(如头颈部鳞状细胞癌、口腔癌(如口腔鳞状细胞癌、喉癌(如喉癌、咽癌、鼻咽癌、口咽癌)))、造血系统癌症(例如白血病,如急性淋巴细胞白血病(ALL)(例如,B细胞ALL、T细胞ALL)、急性髓细胞白血病(AML)(例如,B细胞AML、T细胞AML)、慢性髓细胞白血病(CML)(例如,B细胞CML、T细胞CML)、慢性淋巴细胞白血病(CLL)(例如,B细胞CLL、T细胞CLL)、滤泡性淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、边缘区B细胞淋巴瘤(如粘膜相关淋巴组织(MALT)淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾脏边缘区B细胞淋巴瘤)、原发性纵隔B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤;以及T细胞非霍奇金淋巴瘤、如前体T淋巴母细胞淋巴瘤/白血病、外周T细胞淋巴瘤(如皮肤T细胞淋巴瘤(如真菌病、Sezary综合征)、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤性T细胞淋巴瘤、肠病型T细胞淋巴瘤;多发性骨髓瘤(MM))、血管母细胞瘤、炎性肌纤维母细胞瘤、免疫细胞性淀粉样变性、肾癌(如肾母细胞瘤、肾细胞癌)、肝癌(如肝细胞癌、恶性肝细胞癌)、肺癌(如支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌、平滑肌肉瘤(LMS)、肥大细胞增多症(如全身肥大细胞增多症)、骨髓增生异常综合征(MDS)、间皮瘤、骨髓增生性疾病(MPD)(如真性红细胞增多症(PV)、原发性血小板增多症(ET)、特发性骨髓外化生(AMM)、慢性特发性骨髓纤维化、慢性粒细胞白血病(CML)、慢性中性粒细胞白血病(CNL)、嗜酸性粒细胞增多综合征(HES)、神经母细胞瘤、神经纤维瘤(如1型或2型神经纤维瘤病、神经鞘瘤病)、神经内分泌癌(如胃肠胰神经内分泌肿瘤(GEP-NET),类癌瘤)、骨肉瘤、卵巢癌(如囊腺癌、卵巢胚胎癌、卵巢腺癌)、乳头状腺癌。
由随后的具体实施方案、实施例和权利要求,本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时,既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中,C1-4烷基和C1-2烷基是优选的。C1-6烷基的例子包括:甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括:Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3)或i-Bu(-CH2CH(CH3)2)。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此,“C1-6卤代烷基”是指上述“C1-6烷基”,其被一个或多个卤素基团取代。在一些实施方案中,C1-4卤代烷基是特别优选的,更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于:-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基,等等。卤代烷基基团可以在任何可用的连接点上被取代,例如,1至5个取代基、1至3个取代基或1个取代基。
“C3-6环烷基”是指具有3至6个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C4-6环烷基、C3-6环烷基和C3-5环烷基是特别优选的,更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在环烷基环上,且在这样的情况中,碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于:环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6),等等。环烷基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
“3-10元杂环基”是指具有环碳原子和1至5个环杂原子的3至10元非芳香环系的基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中,只要化合价允许,连接点可为碳或氮原子。在一些实施方案中,优选4-9元杂环基,其为具有环碳原子和1至5个环杂原子的4至9元非芳香环系;在一些实施方案中,优选5-8元杂环基,其为具有环碳原子和1至5个环杂原子的5至8元非芳香环系;在一些实施方案中,优选3-8元杂环基,其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系;优选3-7元杂环基,其为具有环碳原子和1至3个环杂原子的3至7元非芳香环系;优选4-7元杂环基,其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系;优选4-6元杂环基,其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系;更优选5-6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系,其中连接点在环烷基环上,或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。杂环基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
“C1-3烷氧基”是指通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
“C2-4烯基”是指“具有2至4个碳原子和至少一个碳碳双键的直链或支链烃基团。C2-4烯基的例子包括:乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4),等等。术语“C2-4烯基”还包括杂烯基,其中一或多个(例如,1、2)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代,例如,被1至3个取代基或1个取代基取代。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如,双环)4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中,芳基具有六个环碳原子(“C6芳基”;例如,苯基)。在一些实施方案中,芳基具有十个环碳原子(“C10芳基”;例如,萘基,例如,1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
“5-10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5-9元杂芳基是优选的,其为具有环碳原子和1-4个环杂原子的5-9元单环或双环的4n+2芳族环体系。在另一些实施方案中,5-6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基(例如,1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代,例如,被1至5个取代基、1至3个取代基或1个取代基取代。
本文定义的烷基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(=O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(=O)Raa、-OCO2Raa、-C(=O)N(Rbb)2、-OC(=O)N(Rbb)2、-NRbbC(=O)Raa、-NRbbCO2Raa、-NRbbC(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-OC(=NRbb)Raa、-OC(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-OC(=NRbb)N(Rbb)2、-NRbbC(=NRbb)N(Rbb)2、-C(=O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(=O)Raa、-OS(=O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(=S)N(Rbb)2、-C(=O)SRaa、-C(=S)SRaa、-SC(=S)SRaa、-SC(=O)SRaa、-OC(=O)SRaa、-SC(=O)ORaa、-SC(=O)Raa、-P(=O)2Raa、-OP(=O)2Raa、-P(=O)(Raa)2、-OP(=O)(Raa)2、-OP(=O)(ORcc)2、-P(=O)2N(Rbb)2、-OP(=O)2N(Rbb)2、-P(=O)(NRbb)2、-OP(=O)(NRbb)2、-NRbbP(=O)(ORcc)2、-NRbbP(=O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
或者在碳原子上的两个偕氢被基团=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb或=NORcc取代;
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Raa基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rbb的每个独立地选自:氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)2N(Rcc)2、-P(=O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rbb基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rcc基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rdd的每个独立地选自:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(=O)Ree、-CO2H、-CO2Ree、-OC(=O)Ree、-OCO2Ree、-C(=O)N(Rff)2、-OC(=O)N(Rff)2、-NRffC(=O)Ree、-NRffCO2Ree、-NRffC(=O)N(Rff)2、-C(=NRff)ORee、-OC(=NRff)Ree、-OC(=NRff)ORee、-C(=NRff)N(Rff)2、-OC(=NRff)N(Rff)2、-NRffC(=NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(=O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(=S)N(Rff)2、-C(=O)SRee、-C(=S)SRee、-SC(=S)SRee、-P(=O)2Ree、-P(=O)(Ree)2、-OP(=O)(Ree)2、-OP(=O)(ORee)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代,或者两个偕Rdd取代基可结合以形成=O或=S;
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rff基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rgg的每个独立地是:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(=O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(=O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(=O)NH2、-C(=O)N(C1-6烷基)2、-OC(=O)NH(C1-6烷基)、-NHC(=O)(C1-6烷基)、-N(C1-6烷基)C(=O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(=O)N(C1-6烷基)2、-NHC(=O)NH(C1-6烷基)、-NHC(=O)NH2、-C(=NH)O(C1-6烷基)、-OC(=NH)(C1-6烷基)、-OC(=NH)OC1-6烷基、-C(=NH)N(C1-6烷基)2、-C(=NH)NH(C1-6烷基)、-C(=NH)NH2、-OC(=NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(=NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(=S)N(C1-6烷基)2、C(=S)NH(C1-6烷基)、C(=S)NH2、-C(=O)S(C1-6烷基)、-C(=S)SC1-6烷基、-SC(=S)SC1-6烷基、-P(=O)2(C1-6烷基)、-P(=O)(C1-6烷基)2、-OP(=O)(C1-6烷基)2、-OP(=O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基;或者两个偕Rgg取代基可结合形成=O或=S;其中,X-为反离子。
示例性的氮原子上取代基包括但不局限于:氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRbb)Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)2N(Rcc)2、-P(=O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代,且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐,它们在可靠的医学判断范围内适用于与患者组织接触,不会产生不恰当的毒性、刺激作用、变态反应等,与合理的益处/风险比相称,就它们的预期应用而言是有效的,包括(可能的话)本发明化合物的两性离子形式。
本发明还包括同位素标记的化合物(同位素变体),它们等同于本发明所述的那些化合物,但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的,因为它们容易制备和检测。进而,被更重的同位素取代,例如氘、即2H,由于代谢稳定性更高可以提供治疗上的益处,例如延长体内半衰期或减少剂量需求,因而在有些情况下可能是优选的。同位素标记的本发明化合物及其前体药物一般可以这样制备,在进行下述流程和/或实施例与制备例所公开的工艺时,用容易得到的同位素标记的试剂代替非同位素标记的试剂。
本发明化合物还可能以互变异构体存在。在不同的互变异构形式存在的化合物,一个所述化合物并不局限于任何特定的互变异构体,而是旨在涵盖所有的互变异构形式。
本发明化合物可包括一个或多个不对称中心,且因此可以存在多种立体异构体形式,例如,对映异构体和/或非对映异构体形式。例如,本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体),或者可为立体异构体的混合物的形式,包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离,所述方法包括:手性高压液相色谱法(HPLC)以及手性盐的形成和结晶;或者优选的异构体可通过不对称合成来制备。
前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella,Prodrugs as Novel Delivery Systems,A.C.S.Symposium Series的Vol.14,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,AmericanPharmaceutical Association and Pergamon Press,1987,以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery:solubility limitations overcome by theuse of prodrugs”,Advanced Drug Delivery Reviews(1996)19(2)115-130,每篇引入本文作为参考。
本发明化合物可以是无定形或结晶形式(多晶型)。此外,本发明化合物可以以一种或多种结晶形式存在。因此,本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
术语“水合物”是指与水相结合的化合物。通常,包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此,化合物的水合物可用例如通式R·xH2O代表,其中R是该化合物,和x是大于0的数。给定化合物可形成超过一种水合物类型,包括,例如,单水合物(x为1)、低级水合物(x是大于0且小于1的数,例如,半水合物(R·0.5H2O))和多水合物(x为大于1的数,例如,二水合物(R·2H2O)和六水合物(R·6H2O))。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成,例如,结晶形式,且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下,所述溶剂合物将能够分离,例如,当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
给药的“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在一些实施方案中,受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
通常,化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样,本发明化合物的有效量可以根据下列因素而改变:例如,生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如,本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药,或与其它治疗剂一起在单一单位剂型中同时给药。
实施例
本发明所采用的试剂为直接购买的商业化试剂或经本领域熟知的常用方法合成。
如下示例的具体反应路线或步骤为本发明所用,具体如下:
实施例1
关键中间体的制备
中间体a1的合成
步骤1:将原料a1-1(16.0g,92.5mmol)和a1-2(9.3g,83.2mmol)溶于DMF(320mL)中,在室温下加入Cs2CO3(60.3g,185.0mmol),所得混合物在氮气保护下加热至120℃搅拌反应12小时。反应完毕,将固体物质过滤,滤饼用乙酸乙酯洗涤,向滤液体系中加入水1L,乙酸乙酯萃取,有机相合并,无水硫酸钠干燥。减压浓缩滤液,通过硅胶柱层析分离纯化(PE/EA,50/1),得到白色固体中间体a1-3(15.0g),收率:61.4%。LC-MS:ESI-MS m/z[M+H]+=264。
步骤2:氮气保护下,将原料a1-3(9.0g,34.1mmol),双联硼酸频那醇酯B2Pin2(13.0g,51.1mmol)和KOAc(6.7g,68.2mmol)溶于1,4-二氧六环(180mL)中,加入Pd(dppf)Cl2(2.5g,3.4mmol),混合物升温至100℃下反应12小时。冷却至室温,向体系加水,乙酸乙酯萃取,有机相合并,无水硫酸钠干燥,通过硅胶柱层析分离纯化(PE/EA,10/1),得到白色固体中间体a1(9.0g),收率:84.8%。LC-MS:ESI-MS m/z[M+H]+=312。
参照中间体a1的合成路线,合成如下中间体。
中间体a6的合成
步骤1:在氮气保护下,将原料a6-1(4.0g,14.60mmol),a1(6.0g,19.00mmol)溶于DMF(72mL)和水(7.2mL)中,加入K3PO4(9.3g,43.80mmol),Pd(PPh3)4(0.4g,0.30mmol),混合物升温至90℃反应12小时。冷却至室温,向体系加水,乙酸乙酯萃取,有机相合并,无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体a6-2(2.0g),收率:41.4%。LC-MS:ESI-MS m/z[M+H]+=332。
步骤2:氮气保护下,将原料a6-2(2.0g,6.00mmol),三氟乙酸(2.1g,18.10mmol)溶于DCM(30mL)中,再向体系中分批加入NIS(1.5g,6.60mmol),在室温下反应2小时。反应完毕,使用Na2S2O3饱和水溶液(20mL)淬灭反应,反应体系采用二氯甲烷萃取,有机相用无水硫酸钠干燥,浓缩得到白色固体中间体a6(2.6g),收率:94.2%。LC-MS:ESI-MS m/z[M+H]+=458。
参照中间体a6的合成路线,合成如下中间体。
中间体a8的合成
步骤1:氮气保护下,将原料a8-1(3.0g,13.2mmol),三氟乙酸(7.5g,66.1mmol)溶于DCM(45mL)中,再在0℃下向体系中分批加入NIS(3.0g,13.2mmol),在室温下反应2小时。反应完毕,在0℃下使用Na2S2O3饱和水溶液(20mL)淬灭反应,过滤得到的析出的固体,滤饼用水洗涤,干燥后得到黄色固体中间体a8-2(3.2g),收率:68.6%。LC-MS:ESI-MS m/z[M+H]+=353/355。
步骤2:氮气保护下,将原料a8-2(1.7g,4.8mmol),a8-3(1.3g,5.3mmol)溶于DMF和水的混合溶剂(34mL,v/v=10:1)中,随后加入Pd(PPh3)4(0.6g,0.5mmol),K3PO4(3.1g,14.4mmol),混合物在50℃下反应2小时,反应完毕,反应体系采用二氯甲烷萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体a8(0.8g),收率:48.3%。LC-MS:ESI-MS m/z[M+H]+=344/346。
中间体a9的合成
步骤1:氮气保护下,将原料a6-1(4.5g,16.4mmol)溶于DMF(40mL)中,随后加入NBS(2.9g,16.4mmol),在室温下反应1小时,反应完毕向体系加水,析出固体物质,过滤得到滤饼,干燥后得到黄色固体混合物中间体a9-1(4.1g),收率:56.6%。LC-MS:ESI-MS m/z[M+H]+=353/355。
步骤2:氮气保护下,将原料a9-1(3.0g,8.4mmol)溶于二氧六环(45mL)和水(15mL),加入原料a1(3.9g,12.9mmol),K3PO4(3.6g,25.2mmol)和Pd(PPh3)4(1.0g,0.84mmol),混合物在90℃下反应2小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过高效反相制备柱层析分离(CH3OH/H2O)得到白色固体中间体a9(0.2g),收率:5.7%。LC-MS:ESI-MS m/z[M+H]+=410/412。
中间体a10的合成
步骤:氮气保护下,将原料a10-1(550.0mg,3.13mmol),a10-2(577.5mg,3.75mmol),溶于二氧六环(9.2mL)和水(1.8mL),加入K2CO3(863.7mg,6.25mmol)和Pd(dppf)Cl2(228.6mg,0.31mmol),混合物在100℃下反应4小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过硅胶柱层析(PE/EA,10/1)分离得到黄色固体中间体a10(370mg),收率:76.9%。LC-MS:ESI-MS m/z[M+H]+=124。
实施例2:目标分子P1、P2、P3的合成
步骤1:氮气保护下,将原料a6(200.0mg,0.44mmol),P-1(129.4mg,0.66mmol)溶于DMF(4mL),加入三乙胺(132.8mg,1.31mmol),Pd(PPh3)2Cl2(30.7mg,0.04mmol),反应体系加热至100℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体P-2(145mg),收率:63.0%。LC-MS:ESI-MS m/z[M+H]+=527。
步骤2:氮气保护下,将原料P-2(145.0mg,0.28mmol)溶于二氧六环(0.3mL)中,加入盐酸-二氧六环溶液(4M,0.6mL),室温下搅拌30分钟,反应完毕,直接将溶剂蒸除,得到黄色固体中间体P-3(70mg),收率59.6%。LC-MS:ESI-MS m/z[M+H]+=427。
步骤3:氮气保护下,在冰水浴条件下,将原料P-3(70mg,0.16mmol)溶于DCM(1.4mL)中,加入三乙胺(49.8mg,0.49mmol)和丙烯酰氯(14.9mg,0.16mmol),继续在冰水浴中反应30分钟。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,随后采用反相制备色谱分离(CH3CN/H2O),分别得到产物P1(4.9mg),收率6.2%;P2(2.4mg),收率6.2%;P3(3.1mg),收率3.1%。LC-MS:ESI-MS m/z[M+H]+=481。
目标分子P1核磁数据:
1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.74(t,J=7.8Hz,1H),7.49–7.35(m,2H),7.18(dd,J=8.6,2.4Hz,2H),7.02(d,J=7.6Hz,1H),6.80(d,J=8.1Hz,1H),6.46(ddd,J=19.6,16.8,10.0Hz,1H),6.07(ddd,J=16.6,14.0,2.4Hz,1H),5.68(d,J=9.4Hz,1H),5.59(ddd,J=21.2,10.0,2.4Hz,1H),5.48(d,J=4.2Hz,1H),3.64(s,3H),3.58–3.50(m,1H),3.39(dt,J=11.2,6.4Hz,2H),3.16(d,J=9.0Hz,1H),2.80(dt,J=42.0,7.8Hz,1H),2.33(d,J=4.4Hz,3H),1.97–1.78(m,1H),1.62(ddd,J=44.8,12.4,8.8Hz,1H).
实施例3:目标分子P4的合成
步骤1:氮气保护下,将原料a6(400.0mg,0.88mmol)、P4-1(400.0mg,0.88mmol)溶于DMF(8mL)中,加入三乙胺(265.6mg,2.63mmol)和Pd(PPh3)2Cl2(61.4mg,0.09mmol),混合物在100℃下反应2小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P4-2(200mg),收率:39.0%。LC-MS:ESI-MS m/z[M+H]+=587。
步骤2:氮气保护下,冰浴下将原料P4-2(180.0mg,0.31mmol)溶于二氧六环(0.9mL)中,加入盐酸-二氧六环溶液(4M,1.8mL),室温下搅拌30分钟,反应完毕,直接将溶剂蒸除,首先通过flash反相柱层析分离(CH3CN/H2O)得到粗品(100mg),再通过高效液相制备色谱分离得到产物P4-3(40mg),收率33.7%。LC-MS:ESI-MS m/z[M+H]+=387。
步骤3:氮气保护下,在冰水浴条件下,将原料P4-3(40mg,0.10mmol)溶于DCM(0.8mL)中,滴加入三乙胺(21.0mg,0.21mmol)和丙烯酰氯(9.4mg,0.10mmol),继续在冰水浴中反应30分钟。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,随后采用反相制备色谱分离(CH3CN/H2O),得到粗产品(20mg),再经过高效液相制备色谱分离得到产物P4(7.7mg),收率16.9%。LC-MS:ESI-MS m/z[M+H]+=441。
1H NMR(300MHz,DMSO-d6):δ8.31(t,J=5.7Hz,1H),8.14(s,1H),7.76(dd,J=8.1,7.2Hz,1H),7.43–7.32(m,2H),7.25–7.17(m,2H),7.04(d,J=7.5Hz,1H),6.83(d,J=8.1Hz,1H),6.48(dt,J=16.2,1.5Hz,1H),6.21(dd,J=17.1,9.9Hz,1H),6.10(d,J=2.4Hz,1H),6.06–6.00(m,1H),6.00–5.92(m,1H),3.94–3.84(m,2H),3.80(s,3H),2.37(s,3H).
实施例4:目标分子P5的合成
步骤1:氮气保护下,将原料a6(100.0mg,0.20mmol)和原料P5-1(65.0mg,0.24mmol)溶于DMF(2mL)和水(0.2mL),加入K3PO4(139.3mg,0.70mmol)和Pd(PPh3)4(25.3mg,0.02mmol),混合物在90℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体P5-2(60mg),收率:61.2%。LC-MS:ESI-MS m/z[M+H]+=449。
步骤2:氮气保护下,在冰水浴条件下,将原料P5-2(60mg,0.13mmol)溶于DCM(1.2mL)中,先后滴加入三乙胺(40.6mg,0.40mmol)和丙烯酰氯(12.1mg,0.13mmol),继续在冰水浴中反应2小时。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,随后经过高效液相制备色谱分离得到产物P5(12.5mg),收率18.6%。LC-MS:ESI-MS m/z[M+H]+=503。
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.16(s,1H),7.77(t,J=7.8Hz,1H),7.66(d,J=8.4Hz,2H),7.51–7.44(m,2H),7.39(d,J=8.6Hz,2H),7.30–7.23(m,2H),7.13–7.03(m,2H),6.88(d,J=8.0Hz,1H),6.76(d,J=16.8Hz,1H),6.44(dd,J=17.0,10.0Hz,1H),6.26(dd,J=17.0,2.0Hz,1H),5.76(dd,J=10.0,2.0Hz,1H),3.91(s,3H),2.38(s,3H).
实施例5:目标分子P6的合成
步骤1:氮气保护下,将原料a9(100.0mg,0.24mmol)、P6-1(61.8mg,0.29mmol)溶于DMF(2mL)中,加入三乙胺(74.0mg,0.73mmol)和Pd(PPh3)2Cl2(17.11mg,0.024mmol),混合物在130℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P6-2(33mg),收率:25.0%。LC-MS:ESI-MS m/z[M+H]+=541。
步骤2:氮气保护下,冰浴下将原料P6-2(33.0mg,0.06mmol)溶于二氧六环(0.16mL)中,加入盐酸-二氧六环溶液(4M,0.33mL),室温下搅拌30分钟,反应完毕,直接将溶剂蒸除,得到白色产物P6-3(25.0mg),收率93.0%。LC-MS:ESI-MS m/z[M+H]+=441。
步骤3:氮气保护下,在冰水浴条件下,将原料P6-3(25.0mg,0.06mmol)溶于DCM(0.5mL)中,先后滴加入三乙胺(17.2mg,0.17mmol)和丙烯酰氯(5.1mg,0.06mmol),继续在冰水浴中反应30分钟。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,随后采用flash反相制备色谱分离(CH3CN/H2O),得到粗产品(15mg),再经过高效液相制备色谱(CH3CN/H2O)分离得到产物P6(6.6mg),收率23.5%。LC-MS:ESI-MS m/z[M+H]+=495。
1H NMR(400MHz,DMSO-d6):δ8.12(d,J=4.4Hz,1H),7.80–7.73(m,1H),7.39(dd,J=8.4,4.4Hz,2H),7.23(d,J=8.0Hz,2H),7.04(d,J=7.6Hz,1H),6.81(dd,J=16.8,9.6Hz,2H),6.16–6.06(m,1H),5.86–5.76(m,1H),5.67–5.61(m,1H),5.33(s,1H),3.74(d,J=23.2Hz,3H),3.49(t,J=7.2Hz,4H),2.36(d,J=9.6Hz,4H),2.14(s,3H),1.24(s,1H).
实施例6:目标分子P7的合成
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步骤1:氮气保护下,将原料a6(200mg,0.44mmol),P7-1(61.5mg,0.52mmol)溶于THF(4mL)中,加入三乙胺(132.8mg,1.31mmol),Pd(PPh3)4(50.5mg,0.04mmol),CuI(16.7mg,0.09mmol),反应体系在110℃下反应1.5小时,反应完毕,蒸除溶媒,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P7-2(123.0mg),收率:63.0%。LC-MS:ESI-MS m/z[M+H]+=447。
步骤2:氮气保护下,将原料P7-2(102.0mg,0.23mmol)溶于DCM(2mL)中,在冰浴条件下加入丙烯酰氯(20.7mg,0.23mmol),继续反应30分钟,反应完毕,蒸除溶剂,采用flash反相柱层析分离(CH3CN/H2O)得到白色固体产物P7(25.3mg),收率:22.1%。LC-MS:ESI-MSm/z[M+H]+=501。
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.23(s,1H),7.90(s,1H),7.76(t,J=7.6Hz,1H),7.64(t,J=8.8Hz,3H),7.38(t,J=8.0Hz,1H),7.31(d,J=8.0Hz,2H),7.21(d,J=7.6Hz,1H),7.03(d,J=7.2Hz,1H),6.87(d,J=8.0Hz,1H),6.42(dd,J=16.8,10.0Hz,1H),6.26(d,J=16.8Hz,1H),5.78(d,J=10.0Hz,1H),3.84(s,3H),2.36(s,3H).
实施例7:目标分子P8的合成
步骤1:氮气保护下,将原料a6(200.0mg,0.44mmol)、P8-1(138.6mg,0.66mmol)溶于DMF(4mL)中,加入三乙胺(132.8mg,1.31mmol)和Pd(PPh3)2Cl2(30.7mg,0.04mmol),混合物在100℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体粗产品(120mg),再经高效液相制备色谱(CH3CN/H2O)分离得到黄色固体中间体P8-2(84mg),收率35.5%。LC-MS:ESI-MS m/z[M+H]+=541。
1H NMR(300MHz,DMSO-d6)δ8.13(s,1H),7.76(t,J=7.8Hz,1H),7.43–7.34(m,2H),7.28–7.17(m,2H),7.04(d,J=7.2Hz,1H),6.84(d,J=8.1Hz,1H),6.44(d,J=16.5Hz,1H),6.07(s,2H),5.78(dd,J=16.5,7.3Hz,1H),3.77(s,3H),2.35(s,3H),1.36(d,J=2.4Hz,9H).
步骤2:氮气保护下,将原料P8-2(84.0mg,0.16mmol)溶于二氧六环(0.4mL)中,加入盐酸-二氧六环溶液(4M,0.8mL),室温下搅拌30分钟,反应完毕,直接将溶剂蒸除,得到黄色固体产物P8-3(40.0mg),收率58.4%。LC-MS:ESI-MS m/z[M+H]+=441。
步骤3:氮气保护下,在冰水浴条件下,将原料P8-3(40.0mg,0.09mmol)溶于DCM(0.8mL)中,先后滴加入三乙胺(17.0mg,0.18mmol)和丙烯酰氯(8.2mg,0.09mmol),继续在冰水浴中反应30分钟。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,固体产物经过高效液相制备色谱(CH3CN/H2O)分离得到白色固体产物P8(13.3mg),收率29.6%。LC-MS:ESI-MS m/z[M+H]+=495。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.80–7.72(m,1H),7.44–7.35(m,2H),7.27–7.19(m,2H),7.04(d,J=7.6Hz,1H),6.88–6.74(m,2H),6.45(dd,J=16.4,4.4Hz,1H),6.07(dd,J=16.8,2.4Hz,1H),5.83(td,J=16.6,14.4,7.2Hz,1H),5.68–5.59(m,1H),4.15(dd,J=29.8,12.8Hz,1H),3.88(d,J=13.6Hz,1H),3.78(s,3H),3.10–2.97(m,1H),2.80–2.58(m,1H),2.35(s,3H),2.21(d,J=13.6Hz,1H),1.79(d,J=10.0Hz,1H),1.62(s,1H),1.35(s,2H).
实施例8:目标分子P9的合成
步骤1:氮气保护下,将原料a8(187.5mg,0.5mmol)和a2(170.0mg,0.5mmol)溶于DMF(4mL)和H2O(0.4mL),加入Pd(dtbpf)Cl2(35.5mg,0.1mmol)和CsF(248.2mg,1.6mmol),随后在90℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P9-1(189.0mg),收率77.2%。LC-MS:ESI-MS m/z[M+H]+=450。
步骤2:氮气保护下,将原料P9-1(170.0mg,0.4mmol)溶于DCM(4mL)中,在冰浴条件下加入三乙胺(38.3mg,0.4mmol)和丙烯酰氯(34.2mg,0.4mmol),在室温下继续反应30分钟,反应完毕,蒸除溶剂,采用高效液相制备色谱分离(CH3CN/H2O)得到黄色固体产物P9(21.6mg),收率:11.3%。LC-MS:ESI-MS m/z[M+H]+=504。
1H NMR(300MHz,DMSO-d6):δ10.25(s,1H),8.51(d,J=5.0Hz,1H),8.17(s,1H),7.66(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.38(t,J=9.0Hz,4H),7.20(d,J=5.2Hz,2H),6.75(d,J=16.8Hz,1H),6.44(dd,J=16.8,9.6Hz,1H),6.26(d,J=17.4Hz,1H),5.77(d,J=9.6Hz,1H),3.91(s,3H),2.44(s,3H).
实施例9:目标分子P10的合成
步骤1:氮气保护下,将原料a8(110.0mg,0.3mmol)和a2(126.2mg,0.3mmol)溶于DMF(1.8mL)和H2O(0.2mL),加入Pd(dtbpf)Cl2(20.8mg,0.1mmol)和CsF(145.6mg,0.9mmol),随后在90℃下反应2小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P10-1(80.0mg),收率53.6%。LC-MS:ESI-MS m/z[M+H]+=467。
步骤2:氮气保护下,将原料P10-1(40.0mg,0.1mmol)溶于DCM(1mL)中,在冰浴条件下加入三乙胺(8.7mg,0.1mmol)和丙烯酰氯(7.8mg,0.1mmol),在室温下继续反应30分钟,反应完毕,蒸除溶剂,采用flash反相柱层析分离(CH3CN/H2O)得到黄色固体产物P10(4.5mg),收率:10.1%。LC-MS:ESI-MS m/z[M+H]+=521。
1H NMR(300MHz,DMSO-d6):δ10.25(s,1H),8.17(s,1H),7.78(t,J=7.8Hz,1H),7.67(d,J=8.1Hz,2H),7.42(dd,J=8.7,5.1Hz,4H),7.29(d,J=8.1Hz,1H),7.11(d,J=16.5Hz,2H),7.05(d,J=7.5Hz,1H),6.95(d,J=8.1Hz,1H),6.74(d,J=16.8Hz,1H),6.44(dd,J=16.8,9.9Hz,1H),6.26(d,J=17.1Hz,1H),5.77(d,J=9.9Hz,1H),3.90(s,3H),2.34(s,3H),1.24(s,1H).
实施例10:目标分子P11的合成
步骤1:氮气保护下,将原料a8(200.0mg,0.6mmol)和a4(230.2mg,0.7mmol)溶于DMF(4mL)和H2O(0.4mL),加入Pd(dtbpf)Cl2(37.9mg,0.06mmol)和CsF(264.8mg,1.7mmol),随后在90℃下反应2小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P11-1(80.0mg),收率29.5%。LC-MS:ESI-MS m/z[M+H]+=468。
步骤2:氮气保护下,将原料P11-1(80.0mg,0.2mmol)溶于DCM(1.6mL)中,在冰浴条件下加入三乙胺(17.3mg,0.2mmol)和丙烯酰氯(15.5mg,0.2mmol),在室温下继续反应30分钟,反应完毕,蒸除溶剂,采用高效液相制备色谱分离(CH3CN/H2O)得到黄色固体产物P11(8.9mg),收率:9.7%。LC-MS:ESI-MS m/z[M+H]+=522。
1H NMR(300MHz,DMSO-d6):δ10.27(s,1H),8.53(d,J=5.1Hz,1H),8.17(s,1H),7.67(d,J=8.1Hz,2H),7.58–7.32(m,4H),7.24-7.11(d,J=5.1Hz,2H),6.73(d,J=16.8Hz,1H),6.44(dd,J=17.1,9.9Hz,1H),6.26(d,J=16.8Hz,1H),6.02(s,1H),5.77(d,J=9.9Hz,1H),3.90(s,3H),2.45(s,3H).
实施例11:目标分子P12的合成
步骤1:氮气保护下,将原料a7(270.0mg,0.6mmol)和原料P12-1(158.9mg,0.6mmol)溶于DMF(4.5mL)和水(0.5mL),加入K2CO3(244.3mg,1.8mmol)和Pd(PPh3)4(68.1mg,0.1mmol),混合物在50℃下反应2小时,反应完毕向体系加水,二氯甲烷萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体P12-2(126.1mg),收率:47.6%。LC-MS:ESI-MS m/z[M+H]+=450。
步骤2:氮气保护下,在冰水浴条件下,将原料P12-2(60.0mg,0.1mmol)溶于吡啶(1.0mL)中,滴加入甲基丙烯酰氯(27.9mg,0.3mmol),继续在冰水浴中反应2小时。反应完毕,加入甲醇(1mL)淬灭反应,蒸除反应溶媒,随后经过高效液相制备色谱分离得到黄色固体产物P12(9.2mg),收率13.3%。LC-MS:ESI-MS m/z[M+H]+=518。
1H NMR(400MHz,DMSO-d6):δ9.80(s,1H),8.50(d,J=5.2Hz,1H),8.18(s,1H),7.68(t,J=2.0Hz,1H),7.60(d,J=8.0Hz,1H),7.55–7.47(m,2H),7.40–7.33(m,2H),7.30(t,J=8.0Hz,1H),7.18-7.10(d,J=5.2Hz,3H),6.80(d,J=16.8Hz,1H),5.81(s,1H),5.52(d,J=2.0Hz,1H),3.92(s,3H),2.43(s,3H),1.94(t,J=1.2Hz,3H).
实施例12:目标分子P13的合成
步骤1:氮气保护下,将原料a7(500.0mg,1.09mmol)和a10(161.3mg,1.31mmol)溶于DMF(16mL),加入Pd(PPh3)2Cl2(76.6mg,0.11mmol)和三乙胺(331.2mg,3.27mmol),随后在100℃下反应12小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到白色固体中间体P13-1(40.0mg),收率8.1%。LC-MS:ESI-MS m/z[M+H]+=454。
步骤2:氮气保护下,将原料P13-1(40.0mg,0.09mmol)溶于吡啶(0.8mL)中,在冰浴条件下加入甲基丙烯酰氯(9.2mg,0.09mmol),在室温下继续反应1小时,反应完毕,蒸除溶剂,采用高效液相制备色谱分离(CH3CN/H2O)得到黄色固体产物P13(10.3mg),收率:22.4%。LC-MS:ESI-MS m/z[M+H]+=454。
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.50(d,J=5.2Hz,1H),8.18(s,1H),7.56–7.48(m,2H),7.42–7.32(m,2H),7.19(d,J=5.2Hz,1H),7.06(d,J=16.4Hz,1H),6.85(s,1H),6.67(d,J=16.4Hz,1H),5.86(s,1H),5.50–5.45(m,1H),3.92(s,3H),3.58(s,3H),2.44(s,3H),1.92(d,J=1.2Hz,3H).
实施例13:目标分子P14的合成
步骤1:氮气保护下,将原料a8(83.8mg,0.2mmol)和a4(100.0mg,0.3mmol)溶于DMF(4mL)和H2O(0.4mL),加入Pd(dtbpf)Cl2(15.9mg,0.1mmol)和CsF(264.8mg,1.7mmol),随后在90℃下反应3小时,反应完毕向体系加水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,通过flash反相柱层析分离(CH3CN/H2O)得到黄色固体中间体P14-1(60.0mg),收率52.7%。LC-MS:ESI-MS m/z[M+H]+=480。
步骤2:氮气保护下,将原料P14-1(60.0mg,0.1mmol)溶于DCM(1.2mL)中,在冰浴条件下加入三乙胺(13.0mg,0.1mmol)和丙烯酰氯(11.6mg,0.1mmol),在室温下继续反应1小时,反应完毕,蒸除溶剂,采用高效液相制备色谱分离(CH3CN/H2O)得到黄色固体产物P14(13.4mg),收率:19.6%。LC-MS:ESI-MS m/z[M+H]+=534。
1H NMR(400MHz,DMSO-d6):δ10.25(s,1H),8.49–8.42(m,1H),8.17(s,1H),7.70–7.64(m,2H),7.20(d,J=2.0Hz,2H),7.16–7.09(m,1H),7.09–6.94(m,4H),6.80(d,J=16.8Hz,1H),6.44(dd,J=16.8,10.0Hz,1H),6.26(dd,J=16.8,2.0Hz,1H),5.76(dd,J=10.0,2.0Hz,1H),3.91(d,J=1.2Hz,3H),3.67(d,J=1.6Hz,3H),2.43(s,3H).
实施例14:目标分子P15的合成
步骤:氮气保护下,将原料P11-1(80.0mg,0.2mmol)溶于吡啶(1.6mL)中,在冰浴条件下加入甲基丙烯酰氯(17.9mg,0.2mmol),在室温下继续反应30分钟,反应完毕,蒸除溶剂,采用高效液相制备色谱分离(CH3CN/H2O)得到黄色固体产物P15(5.0mg),收率:5.5%。LC-MS:ESI-MS m/z[M+H]+=536。
1H NMR(400MHz,DMSO-d6):δ9.87(s,1H),8.52(d,J=5.2Hz,1H),8.17(s,1H),7.70(d,J=8.4Hz,2H),7.52-7.45(t,J=8.4Hz,4H),7.41(d,J=8.4Hz,1H),7.32(dt,J=8.0,1.2Hz,1H),7.23(d,J=5.2Hz,1H),7.11(d,J=16.8Hz,1H),6.72(d,J=16.8Hz,1H),5.81(s,1H),3.90(s,3H),2.45(s,3H),1.95(t,J=1.2Hz,3H).
实施例15:目标分子对FGFR的激酶抑制活性测试
将化合物用DMSO溶解后用激酶缓冲液稀释,使用Echo将化合物稀释液转移到384孔板中,离心1分钟。然后在激酶缓冲溶液中配置含有靶蛋白FGFR的溶液,向384孔分析板中加入5μl的2倍靶蛋白缓冲溶液,离心30秒后,静置孵育10min;然后加入5μl的2倍底物(HTRF试剂-TK-substrate-biotin和ATP的混合物),离心30秒,静置孵育50min,随后再加入5μlSa-XL 665and 5μl TK-antibody-Cryptate,然后离心30秒,静置孵育1小时,最后在酶标仪Envision 2104plate reader上读取615nm和665nm的荧光信号值,并使用GraphPad Prism软件计算IC50值。实施例测试了目标化合物对于FGFR2WT,FGFR2V564F和FGFR1的激酶抑制活性。
表1.目标化合物对于FGFR1/2的激酶抑制活性
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以上实验结果表明,本发明的化合物对于FGFR2和FGFR2V564F突变体具有优异的抑制活性,对于FGFR1抑制较弱,体现了本发明对于FGFR2具有较好的选择性。
实施例16:目标分子对FGFR变异细胞的增殖抑制活性
将细胞系培养于包含20%FBS和1%青链霉素的IMDM培养基中,置于37℃,5%CO2恒温培养箱培养。在384孔微板中每孔加入30μL细胞悬液。使用Echo在每孔中加入30nL不同浓度的化合物,置于37℃,5%CO2恒温培养箱培养96小时。在每孔中加入30μL的CTG溶液(Promega,Cat No.G7573),置于37℃,5%CO2恒温培养箱避光温孵30分钟。用Envision多功能酶标仪(Perkin Elmer,目录号Envision 2104)读取发光值,光信号和体系中ATP量成正比,而ATP的含量直接表征体系中的活细胞数。
IC50值计算:
Y=下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X:化合物浓度log值
Y:抑制率(%)
本发明测试了化合物P5对于FGFR2扩增细胞系(KATO III,SNU-16)、FGFR2突变细胞系(MFE-296,FGFR2N549K),以及FGFR1扩增细胞系(JIMT-1,CAL-120)的抑制活性,见表2。
表2.化合物P5对FGFR变异细胞的增殖抑制活性
细胞系 | 化合物P5的增殖抑制活性(IC50,nM) |
KATO III(胃癌) | 43 |
SNU-16(胃癌) | 25 |
MFE-296(子宫内膜癌) | 29 |
JIMT-1(乳腺癌) | 2765 |
CAL-120(乳腺癌) | 5458 |
以上实验结果表明,本发明的化合物P5对于FGFR2依赖的肿瘤细胞具有良好的抑制效果,而对于FGFR1依赖的肿瘤细胞作用较弱,在细胞水平上证明本发明的分子对于FGFR2的高选择性。
Claims (3)
1.化合物,或其药学上可接受的盐,其中所述化合物选自:
2.药物组合物,其含有权利要求1中任一项的化合物,或其药学上可接受的盐,和药学上可接受的赋形剂。
3.权利要求1-2中任一项的化合物或其药学上可接受的盐在制备用于治疗和/或预防FGFR2激酶介导的疾病的药物中的用途,其中所述FGFR2激酶介导的疾病为选自:胃癌、子宫内膜癌。
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