CN115028634B - 一种炔代吡嗪并杂环类fgfr抑制剂及其制备方法和用途 - Google Patents
一种炔代吡嗪并杂环类fgfr抑制剂及其制备方法和用途 Download PDFInfo
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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
- C07D487/04—Ortho-condensed systems
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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
Abstract
本发明公开作为FGFR抑制剂的炔代吡嗪并杂环类化合物、其制备方法及其医药学上的应用。具体而言，本发明涉及一种通式I所示的化合物及其可药用的盐，含有所述化合和或其药用的盐的药物组合物、应用所述化合物或可药用的盐治疗或者预防FGFR激酶相关性病症、特别是肿瘤的药物中的用途，这是一类含有炔代吡嗪并杂环化合物，同时公开了该类化合物的或其可药用的盐的药物组合物的制备方法。其中通式I的各取代基与说明书中的定义相同。
Description
技术领域：
本发明涉及一种作为FGFR抑制剂的炔代吡嗪并杂环化合物或其可药用的盐；含有所述炔代吡嗪并杂环化合物或其可药用的盐的药物组合物；所述炔代吡嗪并杂环化合物或其可药用的盐的制备方法；所述炔代吡嗪并杂环化合物或其可药用的盐、或含有所述炔代吡嗪并杂环化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防FGFR相关性病症、特别是肿瘤的药物中的用途。
背景技术：
成纤维细胞生长因子(fibroblast growth factors，FGFs)结合其受体(fibroblast growth factor receptors，FGFRs)，激活其调控的下游信号通路，在促分裂(胚胎发生、生长发育等)和非促分裂(神经调节、代谢调节等)等生物学过程中起着重要作用。FGFRs是一类典型的受体酪胺酸激酶(RTK)，其家族包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。它们均由胞外区、跨膜区和胞内酪氨酸激酶区三个部分组成。其中胞外区包含3个免疫球蛋白样结构(D1-D3)，D1区具有自抑制功能，D2和D3区及D2-D3的链接区则与配体结合。FGFR1、FGFR2和FGFR3的Ⅲb或Ⅲc部分的D3可发生选择性剪接，从而均会产生FGFRb或FGFRc两种亚型，D3域的不同决定了FGFRs的配体结合特异性。FGFs需要在硫酸乙酰肝素糖胺聚糖(heparan sulphate glycosaminoglycan，HSGAG)的协助下结合FGFRs，引起了FGFR二聚化，导致其胞内酪氨酸激酶区的多个酪氨酸残基自磷酸化而活化。活化的FGFRs通过磷酸化而激活其底物PLCγ和信号衔接蛋白FRS2，其底物再激活下游的MEK/MAPK、PI3K/AKT、PKC、STATS等信号通路。
然而，当FGFR发生突变或者过表达时，会引起FGFR信号通路的过度激活，并进一步诱发正常细胞癌变。其中，RAS-RAF-MAPK的过度激活可刺激细胞增殖与分化；PI3K-AKT过度激活会使得细胞凋亡受抑制；SATA与促进肿瘤侵袭和转移，增强肿瘤免疫逃逸能力密切相关；PLCγ信号通路则是肿瘤细胞转移调控的重要途径。根据2015年发表在ClinicalCancerResearch的一项研究，针对4853个各类实体瘤的下一代测序(NGS)显示，大约有7.1％的癌症中发现FGFR畸变(aberrations)并异常激活，其中大部分是基因扩增(66％)，其次是突变(26％)和重排(8％)。几乎所有检测的恶性肿瘤中均存在FGFR畸变，发生率较高的癌症有尿路上皮癌、胆管癌、乳腺癌、子宫内膜癌、鳞状上皮癌等；同时，在肺癌、肝癌、乳腺癌等肿瘤中也发现了FGFR的异常激活。
目前市场上已有一些非FGFR特异性药物，比如pfizer的Sunitinib、Eisai的lenvatini和Boehringer Ingelheimr的nintedanib。而FDA批准上市的FGFR抑制剂只有Balversa(Erdafitinib)和Pemazyre(pemigatinib)。靶向FGFR的抑制剂药物可以抑制FGF/FGFR信号通路的异常激活，具有治疗以上疾病的潜力，FGFR抑制剂药物成为近年来药物研究的热点之一。
尽管FGFR抑制剂的开发吸引了国内外众多公司布局，但由于其在治疗多种恶性肿瘤所展示的前景，仍需要开发新的化合物。经过不断努力，本发明设计一类拥有自主知识产权的对FGFR-1-4蛋白激酶表现出优异活性的不可逆抑制剂。
发明内容
本发明提供了通式I所示炔代杂环衍生物的化合物或者其前药、稳定同位素衍生物、可药用的盐、溶剂化物、多晶型物或异构体，其可作为一种不可逆FGFR抑制剂，
其中：
X1，X2，X3，X4可以独立地选自N、CR1；
环B为苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G1所取代；
R1独立地选自H、氰基、卤素、C1-6烷基、C3-6环烷基、3-6元杂环烷基、-OR2、-NR2R3、-C(O)NR2R3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR4、-NR4R5、C1-6烷基、C3-6环烷基或3-6元杂环烷基；
U独立地选自-C0-4烷基-、-CR6R7-、-C1-2烷基(R6)(OH)-、-C(O)-、-CR6R7O-、-OCR6R7-、-SCR6R7-、-CR6R7S-、-NR6-、-NR6C(O)-、-C(O)NR6-、-NR6C(O)NR7-、-CF2-、-O-、-S-、-S(O)m-、-NR6S(O)2-、-S(O)2NR6-；
Y不存在或选C3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G2所取代；
Z独立地选自氰基、-NR8CN、
键a为双键或者三键；
当a为双键时，Ra、Rb和Rc各自独立地选自H、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G3所取代；
Ra和Rb或Rb和Rc任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键a为三键时，Ra和Rc不存在，Rb独立选自H、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基被一个或多个G4所取代；
R8独立地选自H、C1-6烷基、C3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G5所取代；
G1、G2、G3、G4和G5各自独立选自氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR9、-OC(O)NR9R10、-C(O)OR9、-C(O)NR9R10、-C(O)R9、-NR9R10、-NR9C(O)R10、-NR9C(O)NR10R11、-S(O)mR9或-NR9S(O)mR10，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR12、-OC(O)NR12R13、-C(O)OR12、-C(O)NR12R13、-C(O)R12、-NR12R13、-NR12C(O)R13、-NR12C(O)NR13R14、-S(O)mR12或-NR12S(O)mR13的取代基所取代；
R3、R4、R5、R6、R7、R8、R9、R11、R12、R13和R14各自独立选自氰基，卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；且m为1或2。
本发明的另一个实施方案涉及上述通式I所示的化合物或其前药、稳定同位素衍生物、可药用的盐、多晶型物、溶剂化物、异构体及其混合物形式。
在下文的发明详述中陈述了利用本发明原理的示例性实施方式。通过参考以下发明内容可更好地理解本发明的特征和优点。
以下通过实施形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅于以下的实例。凡基于上述内容所实现的技术均属于本发明的范围。
某些化学术语
除非有相反陈述，否则下列用在说明书和权利要求书中的术语。
具有下述含义在本文中使用的表示方式“Cx-y”表示碳原子数的范围、其中x和y均为整数，例如C3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C3-8”还包含其中的任意亚范围、例如C3-7、C3-6、C4-7、C4-6、C5-6等。
“烷基”指含有1至20个碳原子，例如1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是取代的或未取代的。
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至7个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环、如十氢萘基、所述环烷基可以是取代的或未取代的。
“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共扼的电子系统优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺杂环基的非限制性实施例包含：
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含：
“芳基”或“芳香基”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，更优选为苯基。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。
“杂芳基”或“杂芳香基”是指5-16元环状系统，其包含1-15个碳原子，优选的1-10个碳原子，1-4个选自氮，氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统，只要与分子其它部分的连接点为芳环原子，杂芳环上的氮原子、碳原子和硫原子可以透择性的被氧化，氮原子可选择性的被季铵化。为了本发明，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二恶茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并三唑基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基，噻二唑基、噻唑基、噻吩基、三嗪基，三唑基等。本申请中，杂芳基优选为5-8元杂芳基，其包含1-3选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基。所述杂芳基可以是取代的或未取代的。
“卤素”指氟、氯、溴或碘。
“羟基”指-OH，“氨基”指-NH2，“酰胺基”指-NHCO-，“氰基”指-CN，“硝基”指-NO2，“异氰基”指-NC，“三氟甲基”指-CF3。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子，杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子，在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个原子，较佳为5个、更佳为1～3个原子彼此独立地被相应数目的取代基取代。不言而喻，取代基处在它们的可能的化学位置本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离的胺基或羟基与具有不饱和(如烯烃)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于羟基、胺基、卤素、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基等。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐或前药以及其他分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促对生物体的给药、利于活性成分的吸收进而发挥生物活性。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物称为“异构体”、其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体、制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型、环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
应该理解，本发明包括任何互变异构或立体异构形式和其混合物、并且不仅限于化合物的命名或化学结式中所使用的任何一个互变异构或立体异构形式。
“同位素”是在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于2H、3H、13C、14C、15N、18O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本域技术人员已知的传统技术或通过与所附实施例中描的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的剂制。这样的化合物具有各种潜在用途、例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的胺基被酰化、烷基化或磷酸化，例如二十烷酰基胺基、丙胺酰胺基、新戊酰氧基甲基胺基、或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙胺酰氧基、或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键、这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与胺或有机胺，例如伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。含有碱性基团的本发明的化合物可以盐形式存在并可根据本发明以它们与无机或有机酸的加成的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、磷酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、胺基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所化合物”时，包括所有所述化合物形式、例如其前药、稳定同位素衍生物、可药用的盐、异构体、内消旋体、外消旋体、对映异构体、非对映异体及其混合物。
在本文中、术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中，术语“癌症”包括Bruton's酪氨酸激酶参与其发生的各种恶性肿瘤、包括但不限于非小细胞肺癌、食管癌、黑色素瘤、横纹肌肉榴、细胞癌、多发性骨髓瘤、乳腺癌卵巢癌、子宫膜癌、宫颈癌、胃癌、结癌、膀胱癌、胰腺癌、肺癌、乳腺癌、前列腺癌和肝癌(例如肝细胞癌)，更具体为肝癌、胃癌和膀胱癌。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶型格形态，本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多品型态或其混合物。
本发明化合物的中间体化合物及其多品形物也在本发明的范围内。
结晶经常产生本发明化合物的溶剂化物，本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用的跟制剂，组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂等渗剂、溶剂、或乳化剂。
文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物，哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛，马、绵羊，山羊，猪；家养动物，例如兔，狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴露在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即，控制其发展；
(iii)缓解疾病或病症，即，使疾病或病症消退缓；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法这些方法。包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
合成方法
本发明还提供制备所述化合物的方法。本发明通式I所述化合物的制备，可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可地本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述的方法。每步应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需要的起始原料和化学试剂可以根据文献(reaxys)常规合成或购买。
本发明通式I所述炔代吡嗪并杂环类化合物可按照下述路线合成：1、起始物A1与前体H-U-Y-Boc在碱作用下发生芳香亲核取代反应生成A2；2、A2在NBS的作用下溴代生成A3；3、A3通过sonogashira偶联得到A4；3、A4中胺基去保护得到A5；4、A5中的胺基被含有和激酶配体结合域内半胱胺酸残基志反应的功能团的化学试剂(例如，烯丙酰氯等)衍生得到通式I所述化合物。
除非另有说明，温度是摄氏温度。试剂购自Chemblocks Inc、Astatech Inc或麦克林等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在室温、无水溶剂中、氮气或气的正压下或使用干燥管进行；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用ThernoLCD Fleet型(ESI)液相色谱-质谱联用仪。
核磁数据(1H NMR)使用BrukerAvance-400MHz或Varian Oxford-400Hz核磁仪，核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMSO-d6等，以四甲基硅烷(0.000ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；DMSO-d6:2.50ppm)当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。
实施例1：2-(1-丙烯酰胺基-3-吡咯烷基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物1)的制备
步骤1：化合物1b的合成
于反应瓶中加入化合物1a(1.98g,10.0mmol)，3-叔丁氧羰基氨基吡咯烷(2.24g,12.0mmol)，碳酸钾(2.07g,15.0mmol)和N,N-二甲基甲酰胺40ml。搅拌下80℃反应过夜。冷却至室温，反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物1b(2.61g，产率86％)为黄色固体。LC/MS(ESI):m/z＝204.1[M+H]+.
步骤2：化合物1c的合成
于反应瓶中加入化合物1b(1.82g,6.0mmol)，N,N-二甲基甲酰胺20ml，分批次加入NBS(1.60g,9.0mmol)，搅拌下50℃反应过夜。冷却至室温，反应液倒入100ml水中，用乙酸乙酯萃取。所得有机相再用饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物1c(1.42g，产率62％)为黄色固体。LC/MS(ESI):m/z＝282.0[M+H]+.
步骤3：化合物1d的合成
于反应瓶中加入化合物1c(1.15g,3.0mmol)，3,5-二甲氧基苯乙炔(0.58g,3.6mmol)，双三苯基磷二氯化钯(211mg,0.3mmol)，碘化亚铜(57mg,0.3mmol)，三乙胺(1.01g,10.0mmol)和N,N-二甲基甲酰胺6ml。氮气置换3次，搅拌下80℃反应过夜。冷却至室温，反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物1d(1.10g，产率79％)为黄色固体。LC/MS(ESI):m/z＝364.2[M+H]+.
步骤4：化合物1e的合成
于反应瓶中加入中间体1d(0.93g,2.0mmol)，4ml乙酸乙酯，4N HCl的1,4-二氧六环溶液4ml。室温下搅拌1小时，反应液用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物1e(0.68g，产率93％)为黄色油状物，直接用于下一步。LC/MS(ESI):m/z＝364.2[M+H]+.
步骤5：化合物1的合成
于反应瓶中加入化合物1e(363mg,1.0mmol)，三乙胺(152mg,1.5mmol)，4ml二氯甲烷，冰水浴冷却后缓慢滴加丙烯酰氯(136mg,1.5mmol)的0.5ml二氯甲烷溶液。加完后继续搅拌3小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物1(225mg，产率54％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.52(s,1H),8.37(s,1H),7.98(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.17(dd,1H),5.53(dd,1H),4.25(s,1H),3.80(s,6H),3.72-3.30(m,4H),3.02-2.83(m,1H),2.04-1.71(m,2H)；LC/MS(ESI):m/z＝418.2[M+H]+.
实施例2：(R)-2-(1-丙烯酰胺基-3-吡咯烷基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物2)的制备
参照实施例1，步骤一中间体换为(R)-3-叔丁氧羰基氨基吡咯烷。核磁和质谱数据与实施例1相同。
实施例3：(S)-2-(1-丙烯酰胺基-3-吡咯烷基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物3)的制备
参照实施例1，步骤一中间体换为(S)-3-叔丁氧羰基氨基吡咯烷。核磁和质谱数据与实施例1相同。
实施例4：2-(1-丙烯酰胺基-3-氮杂环丁烷基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物4)的制备
用与实施例1相似的方法(中间体换为3-叔丁氧羰基氨基氮杂环丁烷)得到化合物3(138mg，产率32％，此为最后一步产率，下同)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.55(s,1H),8.38(s,1H),7.94(s,1H),6.72(d,2H),6.50(t,1H),6.38(dd,1H),6.12(dd,1H),5.47(dd,1H),4.23(s,1H),4.03-3.91(m,3H),3.80(s,6H),3.27-2.83(m,2H)；LC/MS(ESI):m/z＝404.2[M+H]+.
实施例5：(R)-2-(丁-2-炔酰胺基-3-吡咯烷)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物5)的制备
用实施例2中间体(R)-2-(3-胺基吡咯烷)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪和2-丁炔酰氯反应得到化合物5(159mg，产率38％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.55(s,1H),8.35(s,1H),8.01(s,1H),6.73(d,2H),6.50(t,1H),4.39(s,1H),3.91-3.58(m,10H),3.24-3.16(m,1H),2.32-1.74(m,5H)；LC/MS(ESI):m/z＝430.2[M+H]+.
实施例6：(S)-2-(丁-2-炔酰胺基-3-吡咯烷)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物6)的制备
用实施例3中间体(S)-2-(3-胺基吡咯烷)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪和2-丁炔酰氯反应得到化合物6(142mg，产率34％)为黄色固体。核磁和质谱数据与实施例5相同。
实施例7：2-(1-丙烯酰胺基-3-哌啶基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物7)的制备
用与实施例1相似的方法(中间体换为3-叔丁氧羰基氨基哌啶)得到化合物3(196mg，产率47％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.52(s,1H),8.35(s,1H),7.98(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.17(dd,1H),5.52(dd,1H),4.29(s,1H),3.93-3.40(m,10H),3.15-3.04(m,1H),2.23-1.67(m,4H)；LC/MS(ESI):m/z＝432.2[M+H]+.
实施例8：2-(1-丙烯酰胺基-4-哌啶基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物8)的制备
用与实施例1相似的方法(中间体换为4-叔丁氧羰基氨基哌啶)得到化合物8(212mg，产率51％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.54(s,1H),8.37(s,1H),7.99(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.21(dd,1H),5.50(dd,1H),4.33(s,1H),3.80(s,6H),3.69-3.31(m,4H),3.01-2.85(m,1H),2.34-1.73(m,4H)；LC/MS(ESI):m/z＝432.2[M+H]+.
实施例9：2-(2-丙烯酰基-2-氮杂螺[3,3]庚烷-6-胺基)-7-(3,5-二甲氧基苯乙炔基)-5H-吡咯[2,3-b]吡嗪(化合物9)的制备
用与实施例1相似的方法(中间体换为6-氨基-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯)得到化合物9(97mg，产率23％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.57(s,1H),8.37(s,1H),8.04(s,1H),6.72(d,2H),6.50(t,1H),6.11(dd,1H),5.84(s,1H),5.36(dd,1H),3.80(s,6H),3.67-3.31(m,4H),3.11-3.02(m,1H),2.21-1.83(m,4H)；LC/MS(ESI):m/z＝432.2[M+H]+.
实施例10：对激酶FGFR1、FGFR2、FGFR3和FGFR4的体外活性抑制作用测试
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定FGFR1、FGFR2、FGFR3和FGFR4蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液稀释，在384孔板中加入5μL的5倍反应终浓度的化合物(10％DMS0)。加入10μL的2.5倍酶(分别用FGFR1、FGFR2、FGFR3和FGFR4)溶液后在室温下孵育10分钟,再加入10μL的2.5倍底物(FAM-labeledpeptide andATP)溶液。28℃下孵育30-60分钟后加25μL终止液(pH 7.5100mMHEPES,0.015％Brij-35,0.2％Coating Reagent#3,50mM EDTA)终止反应。Caliper EZReader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-样品转化率)/(max-min)*100)。其中max是指DMSO对照的转化率,min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。测定结果见下表显示化合物1-9对于激酶FGFR1、FGFR2、FGFR3和FGFR4的活性数据。活性利用IC50表征，其中“A”表示IC50≤10nM；“B”表示10<IC50≤100nM；“C”表示100<IC50≤500nM；“D”表示500<IC50≤2000nM。
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Claims (4)
1.一种炔代吡嗪并杂环类FGFR抑制剂，其特征在于，选自以下任一种化合物：
或其药学上可接受的盐及其混合物形式。
2.一种药物组合物，包含权利要求1所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
3.根据权利要求1所述的化合物或其药学上可接受的盐在制备用来治疗FGFR介导的疾病的药物中的用途。
4.根据权利要求3所述的用途，其中所述FGFR介导的疾病为非小细胞肺癌、食管癌、黑色素瘤、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、子宫内膜癌、宫颈癌、膀胱癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤中的一种或多种。
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