CN115304602A - 吡嗪并吡嗪并萘啶二酮类衍生物、其制备方法及其医药上的用途 - Google Patents
吡嗪并吡嗪并萘啶二酮类衍生物、其制备方法及其医药上的用途 Download PDFInfo
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- CN115304602A CN115304602A CN202210100628.3A CN202210100628A CN115304602A CN 115304602 A CN115304602 A CN 115304602A CN 202210100628 A CN202210100628 A CN 202210100628A CN 115304602 A CN115304602 A CN 115304602A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及吡嗪并吡嗪并萘啶二酮类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式(I)所示的吡嗪并吡嗪并萘啶二酮类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是作为KRAS GTP酶抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
技术领域
本发明涉及一种吡嗪并吡嗪并萘啶二酮类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为K-Ras GTP酶抑制剂的用途。
背景技术
RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量),其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下,RAS接收生长因子和各种其它细胞外信号而被激活,负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用,RAS蛋白的开/关状态通过核苷酸结合确定,活性信号传导构象结合GTP,非活性构象结合GDP。当RAS包含结合的GDP时,其处于休眠或静止或关闭状态,并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时,RAS被诱导将结合的GDP转换为GTP。随着GTP被结合,RAS是“开启的”,并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白,其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变,将会导致所述蛋白的延长的活化,并且因此产生到细胞的延长的信号,该信号告知其继续生长和分裂。因此这些信号会使得细胞生长和分裂,过度活化的RAS信号转导可能最终导致癌症。
在结构上,RAS蛋白包含负责RAS的酶促活性-----鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域。其还包括含称为CAAX盒的C端延伸区,其可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋,并且这是具有保守氨基酸残基的结构域的刚性部分,所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸12、苏氨酸26和赖氨酸16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76),其均为蛋白的动态部分,由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键,其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后,此两者松弛成无活性的GDP构象。
在RAS家族成员中,致癌突变最常见于KRAS(85%),而NRAS(12%)和HRAS(3%)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在:胰腺癌(95%)、结肠直肠癌(45%)和肺癌(25%),在包括多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变,而在乳腺癌、卵巢癌和脑癌中很少发现(<2%)。在非小细胞肺癌(NSCLC)中,KRAS G12C是最常见的突变,占所有KRAS突变的近一半,其次是G12V和G12D。在非小细胞肺癌中,特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换),从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。
大型基因组学研究表明,肺癌KRAS突变,包括G12C,与NSCLC中其它已知的驱动致癌突变相互排斥,包括EGFR、ALK、ROS1、RET和BRAF,表明KRAS突变在肺癌中的独特性。而同时,KRAS突变经常与某些共突变同时发生,例如STK11、KEAP1和TP53,它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。
三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是,尽管经过三十多年的研究努力,临床上仍然没有有效的抗RAS疗法,使用小分子靶向该基因是项挑战。因此,本领域迫切需要用于靶向RAS(例如,K-RAS,H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病,例如癌症。
目前,国内外对于KRAS抑制剂的临床开发竞争激烈,其中Mirati TherapeuticsInc公司研发的KRAS酶抑制剂MRTX-849已经进入临床二期,用于预防和治疗晚期实体瘤、转移性结直肠癌和转移性非小细胞肺癌等疾病。同时还有其他在研的KRAS抑制剂,包括AMG-510(Amgen Inc,phase 3)。早期的临床研究表明,KRAS抑制剂显著控制和缓解非小细胞肺癌患者疾病进展,并且显著降低了晚期肺癌和大肠癌患者的肿瘤大小。目前已经公开了一系列的KRAS抑制剂专利申请,其中包括WO2020047192、WO2019099524和WO2018217651等,KRAS抑制剂的研究和应用已取得一定的进展,但是提高的空间仍然巨大,仍有必要继续研究和开发新的KRAS抑制剂。
发明内容
本发明的目的在于提供一种通式(I)所示的吡嗪并吡嗪并萘啶二酮类衍生物,或其立体异构体、互变异构体或其可药用的盐:
其中:
R1选自杂环基、-CH2-NR4R5、-CH2-NR6R7或-CH2-NHR8,其中所述的杂环基任选进一步被卤素、羟基、烷基、卤代烷基、烷氧基或卤代烷氧基的取代基所取代;
R2选自卤素;
R3选自烷基,其中所述的烷基任选进一步被一个或多个卤素、氨基、烷基氨基或-NR4R5所取代;优选为甲基;
R4各自独立地选自氢原子或烷基,其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基或卤代烷氧基的取代基所取代;
R5各自独立地选自环烷基,其中所述的环烷基任选进一步被一个或多个选自卤素、羟基、烷基、卤代烷基、烷氧基或卤代烷氧基的取代基所取代;
R6和R7各自独立地选自C2-C4烷基,其中所述的烷基任选进一步被一个或多个选自卤素、烷氧基或卤代烷氧基的取代基所取代;
R8选自烷基,其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基或卤代烷氧基的取代基所取代。
本发明提供一种通式(I)所示的化合物,或其立体异构体、互变异构体或其可药用的盐,其为通式(II)或(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐,
其中:R1、R2和R3的定义如权利要求1中所述。
本发明提供一种通式(I)、(II)或(III)所示的化合物,或其立体异构体、互变异构体或其可药用的盐,其中R1选自:
本发明提供一种通式(I)、(II)或(III)所示的化合物,或其立体异构体、互变异构体或其可药用的盐,其中R2选自Cl或F。
本发明提供一种通式(I)、(II)或(III)所示的化合物,或其立体异构体、互变异构体或其可药用的盐,其中R2选自Cl。
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。
本发明的典型化合物的立体异构体、互变异构体或其可药用的盐包括,但不限于:
在另一方面,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的本发明所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
在另一方面,本发明提供一种抑制KRAS GTP酶方法,其中所述的方法包括,给予病人一种药物组合物,所述的药物组合物含有有效剂量的本发明所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合,其中KRAS GTP酶优选为KRAS G12C酶。
本发明还提供了一种本发明所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由KRAS突变介导的疾病的药物中的用途,其中所述的由KRAS突变介导的疾病选自癌症,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌;其中所述的肺癌优选为非小细胞肺癌,其中所述的KRAS突变优选为KRAS G12C突变。
在另一方面,本发明提供一种本发明所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备KRAS GTP酶抑制剂中的用途,其中KRAS GTP酶抑制剂优选为KRAS G12C抑制剂。
本发明的另一方面涉及一种预防和/或治疗KRAS突变介导的疾病的方法,其包括向患者施用治疗有效剂量的本发明所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物,其中所述的KRAS突变优选为KRAS G12C突变。
本发明还提供了一种本发明所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌;其中所述的肺癌优选为非小细胞肺癌。
本发明的药物制剂可以经局部、口服、经皮、经直肠、经阴道、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
本发明的制剂适合以单位计量的形式存在,并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合,从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。
用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合,并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。
当本发明的化合物以药物的形式对人类及动物进行给药时,所述化合物可进行单独提供或者以药物组合物的形式提供,所述药物组合物含有与药学上可接受的载剂进行组合的活性成分,例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分。
药学上可接受的载剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸盐缓冲溶液;(21)环糊精,例如连接于纳米粒子的靶向配体,例如AccurinsTM;及(22)用于药物制剂中的其它无毒兼容物质,例如聚合物基组合物。
药学上可接受的抗氧化剂的实例包括但不限于:(1)水溶性抗氧化剂,例如抗坏血酸、半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物;及(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂,例如柠檬酸钠或者磷酸二钙,和/或以下任意其中之一:(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸;(2)黏合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收加速剂,例如四级铵化合物;(7)湿润剂,例如十六醇及甘油单硬脂酸酯;(8)吸收剂,例如高岭土及膨润土;(9)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外,液体剂型可含有通常用于本技术领域中的惰性稀释剂,例如水或其它溶剂;增溶剂及乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。
除活性化合物之外,悬浮液也可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。
除活性化合物之外,软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂,例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。
除活性化合物之外,粉末及喷雾剂也可以含有赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂,例如氯氟烃、以及挥发性的未被取代的烃,例如丁烷及丙烷。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、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、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统。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、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,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电子的芳香系统,优选为6至12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元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,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电子的芳香系统,优选为6至12元,更优选为7至10元。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、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代硫代吗啉基,哌啶基,2-氧代哌啶基,吡咯烷基,2-氧代吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团,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电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine)。
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,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电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”是指烷基任选进一步被一个或多个卤素所取代的基团,其中烷基见本文有关定义。
“氨基烷基”是指氨基任选进一步被一个或多个烷基所取代的基团,其中烷基见本文有关定义。
“卤代烷氧基”是指(烷基-O-)的烷基任选进一步被一个或多个卤素所取代的基团,其中烷氧基见本文有关定义。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“Ts”指对甲苯磺酰基。
“T3P”指丙基磷酸酐。
“DPPA”指叠氮磷酸二苯酯。
“DEA”指二乙胺。
“TFA”指三氟乙酸。
“CaCl2”指氯化钙。
“MgCl2”指氯化镁。
“KCl”指氯化钾。
“NaCl”指氯化钠。
“Glucose”指葡萄糖。
“HEPES”指N-2-羟乙基哌嗪-N'-2-乙磺酸。
“EGTA”指乙二醇双(2-氨基乙基醚)四乙酸。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅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,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-NR4R5的取代基所取代;
本发明化合物可以含有不对称中心或手性中心,因此以不同的立体异构体形式存在。所预期的是,本发明化合物的所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物,如外消旋体混合物,均在本发明的范围内。
除非另外指出,本发明描述的结构还包括此结构的所有异构体(如,非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式;例如,各不对称中心的R和S构型,(Z)和(E)双键异构体,以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1HNMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于上海皓鸿生物医药科技有限公司,上海韶远试剂有限公司,上海毕得医药科技有限公司,萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用柱层析和薄层色谱法的洗脱剂体系,其中该体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷和乙酸乙酯体系,D:二氯甲烷和乙醇体系,其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行条件,如醋酸或三乙胺等。
实施例1
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-3-((E)-3-((R)-1-methylpyrrolidin-2-yl)acryloyl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-3-((R)-1-甲基吡咯烷-2-基)丙烯酰基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
第一步
2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸
将2,5,6-三氯烟酸1a(20g,88.32mmol)和(2-氟-6-甲氧基苯基)硼酸(30.02g,176.64mmol)溶于1,4-二氧六环(200mL)和水(40mL)中,加入四(三苯基膦)钯(2.00g,1.73mmol)和碳酸钠(28.08g,264.97mmol),氩气保护下,加热至100℃,反应过夜。反应结束后,冷却,加入100mL水,以乙酸乙酯萃取(100mL×2),合并有机相,水相用1M稀盐酸调至酸性,以乙酸乙酯萃取(100mL×2),合并有机相,以无水硫酸钠干燥,过滤,减压浓缩,得到粗品产物2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸1b(27g,85.41mmol),产率:96.71%。
MS m/z(ESI):315.8[M+1]+
第二步
2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸甲酯
将2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸1b(26g,82.25mmol)溶于甲醇(200mL)中,室温搅拌下滴加氯化亚砜(19.57g,164.50mmol,11.93mL),加热至90℃反应6小时。反应结束后,冷却,减压浓缩,加入200mL水,滴加饱和碳酸氢钠溶液调节pH至碱性,用乙酸乙酯萃取(100mL×2),合并有机相,有机相用饱和食盐水(100mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)纯化,得到2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸甲酯1c(17.16g,51.98mmol),产率:63.20%。
MS m/z(ESI):329.8[M+1]+
1H NMR(400MHz,CDCl3-d)δ8.28-8.23(m,1H),7.42-7.36(m,1H),6.82-6.77(m,2H),3.99(s,3H),3.78(s,3H).
第三步
5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸甲酯
methyl
5-chloro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinate
将2,5-二氯-6-(2-氟-6-甲氧基苯基)烟酸甲酯1c(16.8g,50.89mmol)和2-异丙基-4-甲基吡啶-3-胺1d(8.41g,55.98mmol)溶于无水1,4-二氧六环(200mL)中,加入碳酸铯(49.74g,152.66mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(4.75g,10.18mmol)和甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(4.26g,5.09mmol),氩气保护下,加热至100℃,反应过夜。反应结束后,向体系中加入250mL水,用乙酸乙酯萃取(200mL),有机相以饱和食盐水(100m×2)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)纯化,得到5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸甲酯1d(7.4g,16.67mmol),产率:32.76%。
MS m/z(ESI):443.9[M+1]+
第四步
5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸
5-chloro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid
将5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸甲酯1d(15g,33.79mmol)溶于甲醇(50mL)和水(10mL)的混合溶剂中,加入氢氧化锂一水合物(7.09g,168.96mmol),加热至90℃,反应过夜。反应结束后,冷却,减压浓缩除去甲醇,加入100mL水,用100mL乙酸乙酯萃取,有机相以饱和氯化铵溶液(100mL)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到粗品5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸1e(11.4g,26.52mmol),产率:78.48%。
MS m/z(ESI):429.9[M+1]+
第五步
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione
6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮
将5-氯-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸1e(3g,6.98mmol)、2-硝基乙酸乙酯(2.79g,20.94mmol)和碳酸钾(2.89g,20.94mmol)溶于30mL N,N-二甲基甲酰胺中,加入2-氯-1-甲基吡啶碘化物(3.57g,13.96mmol),室温下反应16小时。反应结束后,加入100mL水,以乙酸乙酯萃取(100mL×2),合并有机相,有机相用饱和食盐水洗涤(100mL×3),以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1f(800mg,1.60mmol),产率:22.9%。
MS m/z(ESI):499.0[M+1]+
第六步
4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one
4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮
将6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1f(800mg,1.60mmol)溶于三氯氧磷(18g,117.39mmol)中,加热至100℃,反应3小时。反应结束后,将反应液倒入100mL冰水中,以二氯甲烷(100mL×2)萃取,合并有机相,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:B体系)纯化,得到产物4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮1g(550mg,1.1mmol),产率:68.75%。
MS m/z(ESI):517.0[M+1]+
第七步
1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯
将4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮1g(550mg,1.1mmol)和(3R,6R)-1-N-叔丁氧基羰基-6-甲基哌嗪-3-甲酸甲酯1j(458.33mg,1.77mmol)溶于乙腈(10mL)中,氩气保护,90℃下反应16小时。反应结束后,加入100mL水,以乙酸乙酯萃取(100mL×2),合并有机相,有机相用饱和食盐水洗涤(100mL×3),以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:B体系)纯化,得到产物1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯1h(400mg,541.13μmol),产率:49.28%。
MS m/z(ESI):739.1[M+1]+
第八步
tert-butyl
(2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯
将1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯1h(40mg,54.11μmol)溶于甲醇(5mL)中,加入10%的钯碳(16.33mg,153.45μmol),置换氢气3次后,氢气保护下室温反应2小时。反应结束后,将反应液过滤,将滤液减压浓缩,得到粗品产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯1i(36.5mg)。
MS m/z(ESI):677.3[M+1]+
第九步
tert-butyl
(2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯
将(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯1i(250mg,369.19μmol)和碳酸钾(100mg,723.56μmol)溶于丙酮(10mL)中,滴加碘甲烷(52.40mg,369.19μmol),50℃下反应3小时。反应结束后,加入200mL水,以乙酸乙酯萃取(100mL×2),合并有机相,有机相用饱和食盐水洗涤(100mL×3),以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:B体系)纯化,得到产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯1j(160mg,231.48μmol),产率:62.70%。MS m/z(ESI):691.3[M+1]+
第十步
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯1j(160mg,231.48μmol)溶于二氯甲烷(5mL)中,降温至0℃,滴加三溴化硼的二氯甲烷溶液(579.92mg,2.31mmol),室温反应12小时。反应结束后,以二氯甲烷萃取(100mL×2),合并有机相;水相用饱和碳酸钠溶液调至碱性,以乙酸乙酯萃取(100mL×2),合并有机相。将萃取所得二氯甲烷溶液和乙酸乙酯溶液合并,用饱和食盐水洗涤(100mL×3),以无水硫酸钠干燥,过滤,减压浓缩,得到粗品产物(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(150mg,259.94μmol)。
MS m/z(ESI):577.1[M+1]+
第十一步
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-3-((E)-3-((R)-1-methylpyrrolidin-2-yl)acryloyl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-3-((R)-1-甲基吡咯烷-2-基)丙烯酰基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酸(16.35mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-3-((R)-1-甲基吡咯烷-2-基)丙烯酰基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(5mg),产率:8.06%。
MS m/z(ESI):714.3[M+1]+
实施例2
(2R,4aR)-11-chloro-3-((E)-4-(diethylamino)but-2-enoyl)-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-3-((E)-4-(二乙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(戊)-4-(二乙氨基)丁-2-烯酸(16.35mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物((2R,4aR)-11-氯-3-((E)-4-(二乙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(5mg),产率:8.06%。
MS m/z(ESI):716.3[M+1]+
实施例3
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-3-((E)-3-((S)-1-methylpyrrolidin-2-yl)acryloyl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-3-((S)-1-甲基吡咯烷-2-基)丙烯酰基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(S,E)-3-(1-甲基吡咯烷-2-基)丙烯酸(16.35mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-3-((S)-1-甲基吡咯烷-2-基)丙烯酰基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(5mg),产率:8.06%。
MS m/z(ESI):714.3[M+1]+
实施例4
(2R,4aR)-11-chloro-3-((E)-4-(cyclopropylamino)but-2-enoyl)-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-3-((E)-4-(环丙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(E)-4-(环丙基氨基)丁-2-烯酸(14.66mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物(2R,4aR)-11-氯-3-((E)-4-(环丙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮4(5mg),产率:8.24%。
MS m/z(ESI):700.1[M+1]+
实施例5
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-3-((E)-4-(methylamino)but-2-enoyl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-4-(甲基氨基)丁-2-烯酰基)-2,3,4,4a,6,8--六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(E)-4-(甲基氨基)丁-2-烯酸(11.96mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-3-((E)-4-(甲基氨基)丁-2-烯酰基)-2,3,4,4a,6,8--六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮5(5mg),产率:8.56%。
实施例6
(2R,4aR)-11-chloro-3-((E)-4-(ethylamino)but-2-enoyl)-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-3-((E)-4-(乙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮1k(50mg,86.65μmol)加入到N,N-二甲基甲酰胺(5mL)中,加入(E)-4-(乙基氨基)丁-2-烯酸(13.43mg,103.98μmol),三乙胺(17.54mg,173.30μmol),O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(65.89mg,173.30μmol),室温下反应。反应结束后,加入10mL水,乙酸乙酯萃取(10mL×2),有机相用饱和食盐水洗(10mL×3),无水硫酸钠干燥,得到的残留物制备纯化得产物(2R,4aR)-11-氯-3-((E)-4-(乙基氨基)丁-2-烯酰基)-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮6(5mg),产率:8.39%。
生物学评价
测试例1、本发明化合物与KRAS G12C蛋白共价结合能力测定
以下方法用于测定本发明化合物在体外条件下与重组人源KRAS G12C蛋白的共价结合能力。
将实验流程简述如下:使用反应缓冲液(20mM HEPES,150mM NaCl,1mM MgCl2,1mMDTT)配置重组人源KRAS G12C蛋白(aa1-169),浓度为4μM备用。受试化合物溶解于DMSO中制备为10mM贮存液,随后使用反应缓冲液进行稀释备用。首先向孔中加入1.5μL使用反应缓冲液稀释的受试化合物(反应体系终浓度为3μM),随后加入23.5μL反应缓冲液混匀,随后加入25μL 4μM的重组人源KRAS G12C蛋白,室温条件下孵育5分钟后,加入5μL乙酸终止反应,并将样品转移至进样瓶中。使用Agilent 1290/6530仪器检测受试化合物与KRAS G12C蛋白发生共价结合的比率,样品在液相色谱柱(XBridge Protein BEH C4,3.5μm,2.1mm×50mm)中分析,检测过程中流动相A是0.1%甲酸水溶液,流动相B是乙腈,流动相洗脱程序为:0~0.5分钟,保持流动相A:95%,2.5分钟时,流动相A变为30%,并保持0.5分钟,3.1分钟,流动相A变为95%,并保持1.9分钟;流速:0.5mL/min;最后使用MassHunterWorkstation Software Bioconfirm Version B.08.00软件分析数据,获得受试化合物浓度在3μM,孵育5min条件与KRAS G12C蛋白共价结合率(Binding Rate)。
化合物编号 | 蛋白共价结合率(%) |
6 | 50.42 |
结论:本发明化合物与KRAS G12C蛋白在3μM,5min条件下,具有较好的共价结合率。
测试例2、本发明化合物对NCI-H358细胞增殖抑制测定
以下方法用于测定本发明化合物对NCI-H358细胞增殖的影响。NCI-H358细胞(含有KRAS G12C突变)购于中国科学院上海生命科学研究院细胞资源中心,培养于含10%胎牛血清、100U青霉素,100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过CellTiter-Luminescent Cell Viability Assay试剂盒(Promega,货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作,简述如下:受试化合物首先溶解于DMSO中制备为10mM贮存液,随后以培养基进行稀释,配制成测试样品,化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以800个细胞每孔的密度接种至96孔细胞培养板中,在37℃,5%CO2培养箱中培养过夜,随后加入受试化合物后继续培养120小时。培养结束后,向每孔加入50μL体积的CellTiter-Glo检测液,震荡5分钟后静置10分钟,随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3%DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率,之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析,获得化合物抑制细胞增殖的IC50值。
化合物编号 | IC<sub>50</sub>(nM) |
5 | 47 |
结论:本发明的化合物对NCI-H358(人非小细胞肺癌)细胞具有较好的增殖抑制作用。
测试例3、本发明化合物对NCI-H358细胞中p-ERK1/2抑制活性的测定
以下方法用于测定本发明化合物对NCI-H358细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH),详细实验操作可参考试剂盒说明书。NCI-H358细胞(含有KRAS G12C突变)购于中国科学院上海生命科学研究院细胞资源中心。
将实验流程简述如下:NCI-H358细胞培养于含10%胎牛血清、100U青霉素,100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640完全培养基中。NCI-H358细胞按每孔30000个铺于96孔板中,培养基为完全培养基,在37℃,5%CO2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液,随后使用RPMI 1640基础培养基进行稀释,每孔加入90μL含对应浓度受试化合物的RPMI 1640基础培养基,受试化合物在反应体系中的终浓度范围为1000nM-0.015nM,置于细胞培养箱培养3小时40分钟。随后加入10μL用RPMI 1640基础培养基配制的hEGF(购自Roche,货号11376454001),使其终浓度为5nM,置于培养箱培养20分钟。弃去细胞上清,使用冰浴的PBS清洗细胞,之后每孔加入45μL的1×cell phospho/totalprotein lysis buffer(Advanced phospho-ERK1/2试剂盒组分)进行裂解,96孔板置于冰上裂解半小时,随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nM的激发波长下,各孔发射波长为620nM和665nM的荧光强度,并计算各孔665/620的荧光强度比值。通过与对照组(0.1%DMSO)的荧光强度比值进行比较,计算受试化合物在各浓度下的百分比抑制率,并通过GraphPad Prism5软件以受试化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值。
结论:本发明化合物对NCI-H358细胞中p-ERK1/2具有较好的增殖抑制作用,优选化合物的IC50<500nM,更优选化合物的IC50<200nM。
Claims (12)
1.一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,
其中:
R1选自杂环基、-CH2-NR4R5、-CH2-NR6R7或-CH2-NHR8,其中所述的杂环基任选进一步被卤素、羟基、烷基、卤代烷基、烷氧基或卤代烷氧基的取代基所取代;
R2选自卤素;
R3选自烷基,其中所述的烷基任选进一步被一个或多个卤素、氨基、烷基氨基或-NR4R5所取代;优选为甲基;
R4各自独立地选自氢原子或烷基,其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基或卤代烷氧基的取代基所取代;
R5各自独立地选自环烷基,其中所述的环烷基任选进一步被一个或多个选自卤素、羟基、烷基、卤代烷基、烷氧基或卤代烷氧基的取代基所取代;
R6和R7各自独立地选自C2-C4烷基,其中所述的烷基任选进一步被一个或多个选自卤素、烷氧基或卤代烷氧基的取代基所取代;
R8选自烷基,其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基或卤代烷氧基的取代基所取代。
4.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R2选自Cl或F。
5.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R2选自Cl。
8.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~7任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
9.根据权利要求求1~7任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求8所述的药物组合物在制备KRAS GTP酶抑制剂中的用途,其中KRASGTP酶抑制剂优选为KRAS G12C抑制剂。
10.根据权利要求求1~7任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求8所述的药物组合物在制备治疗由KRAS突变介导的疾病的药物中的用途,其中所述的由KRAS突变介导的疾病选自癌症,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌,其中所述的KRAS突变优选为KRAS G12C突变。
11.根据权利要求求1~7任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求8所述的药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌。
12.根据权利要求10或11所述的用途,其中所述的肺癌为非小细胞肺癌。
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