CN108794493A - 四氢吡咯并[2,1-h]蝶啶-6(5H)-酮衍生物、其药物组合物、制备方法和应用 - Google Patents
四氢吡咯并[2,1-h]蝶啶-6(5H)-酮衍生物、其药物组合物、制备方法和应用 Download PDFInfo
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- CN108794493A CN108794493A CN201810401612.XA CN201810401612A CN108794493A CN 108794493 A CN108794493 A CN 108794493A CN 201810401612 A CN201810401612 A CN 201810401612A CN 108794493 A CN108794493 A CN 108794493A
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Abstract
本发明公开了四氢吡咯并[2,1‑h]蝶啶‑6(5H)‑酮衍生物、其药物组合物、制备方法和应用。所述化合物选自下式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐。本发明化合物具有良好的TRK激酶抑制活性，适于药用，具有临床应用价值。并且，本发明化合物合成步骤简单，因此具备良好的经济利用价值。
Description
技术领域
本发明属于药物化学领域，具体地涉及四氢吡咯并[2,1-h]蝶啶-6(5H)-酮衍生物、其药物组合物、制备方法和应用。
背景技术
人们发明成胶质母细胞系U118MG含有ROS1基因的染色体重排会产生ROS1融合基因(Genes Chromosomes Cancer,37,58-71(2003))。FIG和ROS1之间的融合引起组成性激活ROS1激酶活性的结构性改变，并且FIG-ROS1融合蛋白具有涉及STAT3、ERK、和SHP2的ROS1信号传导通路激活介导的细胞转化活性或致瘤性活性(Proc.Nat1.Acad.Sci.USA,100,916-921(2003)、Cancer Res.,66,7473-7481(2016))。使用FISH(荧光原位杂交)，对患者样品进行大规模筛选，已鉴定ROS1基因与SDC、CD74、EZR、SLC34A2、LRIG3或TPM3的融合基因。此外，患者样品分析表明，ROS1基因在脑瘤中高度表达(Cancer Res.,69,2180-2184(2009))。
ROS1在表达ROS1融合基因的瘤(如非小细胞肺癌、胆管癌或脑癌)中被激活(Cell,131,1190-1203(2007)、PLoS One,6(1),e15640(2011))。因而，抑制ROS1激酶活性的药物可阻断ROS1通路的下游，即STAT3、ERK、SHP2，进而阻止肿瘤生长和存活。ROS1激酶作为治疗癌症的潜在靶点，已报道化合物例如克唑替尼(crizotinb)(J.CliN.Oncol.2011.39.4197(2012))、TAE684(PLoS One,6(1),e15640(2011))、吡唑衍生物(Bioorg.Med.Chem.Lett.,19,4720-4723(2009))和氨基吡嗪衍生物(WO2012/005299)。。
神经营养因子酪氨酸激酶受体，也称为原肌球蛋白相关激酶(Trk)，为神经营养因子(NT)的可溶性生长因子激活的高亲和力受体。NTRK受体家族具有3个成员：NTRK1(也称为TrkA)、NTRK2(也称为TrkB)、NTRK3(也称为TrkC)。NT包括如下蛋白：激活NTRK1的神经生长因子(NGF)，激活NTRK2的脑衍生的神经营养因子(BDNF)和NT-4/5和激活NTRK3的NT3。每种NTRK受体含有胞外结构(配体结合位点)、跨膜结构域和胞内结构域(含有激酶结构域)。在结合于配体时每种激酶催化自磷酸化，然后激活下游信号传导通路。
正常情况下，NTRK在神经自制中广泛表达，并对这些细胞的维持存活起着重要作用，对神经系统的发育和功能起着重要作用(Current Opinion in Neurobiology,11,272-280(2001))。最近大量文献表明，NTRK的过度表达、激活、扩增、融合基因形成或突变与神经细胞瘤(Pediatr Blood Cancer,59,226-232(2012))、分泌性乳腺癌(Cancer Cell,2,367-376(2002))、结肠直肠癌(Science,300,949-949(2003))、卵巢癌(Cinical CancerResearch,9,2248-2259(2003))、头颈癌(PLos ONE 7(1),e30246(2012))、胰腺癌和黑色素瘤、雄激素-非依赖性前列腺癌(Prostate,45,140-148(2000))相关。
已报道的选择性NTRK酪氨酸激酶抑制剂，包括CEP-751，CEP-701(CancerResearch,59,2395-2341(1999))、吲哚并咔唑化合物(WO01/14380)、羟吲哚化合物(WO2/20479、WO02/20513)、吡唑基稠环化合物(日本专利公开号15-231687)、异噻唑化合物(Bioorg.Med.Chem.Lett.,16,3444-3448(2006))以及其他类型化合物(WO2005/049033、WO2005/103010、WO2006/082392、WO2006/087530、WO2006087538)。咪唑并哒嗪骨架化合物(WO2007/013673、WO2007/025540、WO2007/147646、WO2008/052734、WO2012/125667)。
因此，研究和开发新的高效低毒、抗耐药性、具有TRK激酶抑制活性的药物具有较大的社会意义。
发明内容
为改善上述问题，本发明提供下式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐，
G1选自其中R1选自H、无取代或任选被一个或多个Ra取代的下列基团：C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
X选自CRb，其中Rb选自H、＝O、无取代或任选被一个或多个Rc取代的下列基团：C1-40烷基或C1-40烷氧基；
G2、G4相同或不同，彼此独立地选自H、无取代或任选被一个或多个Rd取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
G3选自其中R2、R3相同或不同，彼此独立地选自H、无取代或任选被一个或多个Re取代的下列基团：C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
或者，R2、R3与其所连接的氮原子一起形成选自无取代或任选被一个或多个Re取代的下列环系：3-20元杂环基、5-20元杂芳基；
每一个Ra、Rc、Rd相同或不同，彼此独立地选自-F、-Cl、-Br、-I、或下列基团：C1-40烷基、C1-40烷氧基；
Re选自-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、无取代或任选被一个或多个Rf取代的下列基团：-NH-S(O)2-C1-40烷基、-S(O)2-C1-40烷基、-NH-C1-40烷基、二-(C1-40烷基)氨基、-C(O)-C1-40烷基、C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基；
Rf选自-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
*为连接取代位点的键。
根据本发明示例性的实施方案，G1中R1选自无取代或任选被一个或多个下列基团取代的C6-20芳基或5-20元杂芳基：-F、-Cl、-Br、-I、C1-12烷基、C1-12烷氧基；
例如，G1中R1选自无取代或任选被一个或多个-F、-Cl、-Br、甲氧基或乙氧基取代的下列基团：苯基、吡啶基；
根据本发明示例性的实施方案，G1中X选自CH2、C＝O、-NH2、-OH、或任选被一个或多个-F、-Cl、-Br、取代的下列基团：-C(C1-12烷基)2、-CH-C1-12烷基、-CH-C1-12烷氧基、或-NH-C1-12烷基；
例如，G1选自下列基团：
其中，为连接取代位点的键。
根据本发明示例性的实施方案，G2、G4相同或不同，彼此独立地选自H、无取代或任选被一个或多个C1-12烷基取代的下列基团：C1-12烷基、C1-12烷氧基。
根据本发明示例性的实施方案，G3中R2、R3相同或不同，彼此独立地选自H、无取代或任选被一个或多个如下基团取代的C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基：-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-NH-S(O)2-C1-12烷基、-S(O)2-C1-12烷基、-S(O)2-NH2、-NH-C1-12烷基、二-(C1-12烷基)氨基、-C(O)-C1-12烷基、-C(O)-NH2、C1-12烷基、C1-12烷氧基、3-20元杂环基；
或者，R2、R3与其所连接的氮原子一起形成选自无取代或任选被一个或多个如下基团取代的3-20元杂环基：-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-C(O)-NH2、C1-12烷基、C1-12烷氧基；
例如，G3选自下列基团：
其中，处为连接取代位点的键。
根据示例性的实施方案，所述式A所示的化合物选自包括但不限于如下化合物：
。
本发明还提供一种药物组合物，其包含治疗有效量的式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐中的一种、两种或者多种。
根据本发明的实施方案，所述药物组合物还任选包含其药学上可接受的辅料，例如载体、赋形剂；所述辅料选自下列中的一种、两种或多种：崩解剂、助流剂、润滑剂、稀释剂或填充剂、粘合剂、着色剂。
本发明还提供一种通过抑制TRK激酶活性达到治疗疾病的方法，其包括向需要此种治疗和/或预防的患者给予治疗有效量的式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐中的一种、两种或者多种。
根据本发明的实施方案，所述疾病选自乳腺癌、皮肤癌、膀胱癌、卵巢癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病，慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤、或纤维肉瘤。
本发明还提供式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐中的一种、两种或者多种在制备药物中的用途。
根据本发明的实施方案，所述药物通过抑制TRK激酶活性达到治疗疾病的目的；所述疾病选自乳腺癌、皮肤癌、膀胱癌、卵巢癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病，慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤、或纤维肉瘤。
本发明还提供式A化合物的制备方法，包括：
(1)中间体III的合成
化合物I与化合物II进行反应得到化合物III；
(2)中间体IV的合成
步骤(1)得到的化合物III反应得到化合物IV；
(3)中间体V的合成
步骤(2)得到的化合物IV反应得到化合物V；
(4)中间体VII的合成
步骤(3)得到的化合物V与化合物VI反应得到化合物VIII；(5)式A化合物的合成
步骤(4)得到的化合物VII与化合物VIII反应得到化合物VIII；
其中G1、G2、G3、G4、R1、R2、R3、X具有如上所述定义。
根据本发明的制备方法，步骤(1)中，
所述反应在20℃至100℃温度下进行；
所述反应在碱的存在下进行；所述碱选自三乙胺、二异丙基乙胺、N-甲基吗啉、DMAP中的一种、两种或更多种；
所述反应在缩合剂的存在下进行；所述缩合剂选自EDCI、HATU、BoPCl、DCC、POCl3中的一种、两种或更多种。
根据本发明的制备方法，步骤(2)中，
所述反应在20℃至100℃温度下进行；
所述反应在酸的存在下进行；所述酸选自甲基磺酸、三氟乙酸、盐酸中的一种、两种或更多种。
根据本发明的制备方法，步骤(3)中，
所述反应在20℃至100℃温度下进行；
所述反应在碱的存在下进行；所述碱选自碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、六甲基氨基硅基锂、二异丙基氨基锂中的一种、两种或更多种。
根据本发明的制备方法，步骤(4)中，
所述反应在20℃至100℃温度下进行；
所述反应在催化剂的存在下进行；所述催化剂选自PdCl2(PPh3)2、Pd(PPh3)4、Pd(dba)2、Pd(OAc)2、Pd(dppf)2Cl2中的一种、两种或更多种；
所述反应在配体的存在下进行；所述配体选自2-双环己基膦-2',4',6'-三异丙基联苯(XPhos)、2-双环己基膦-2',6'-二甲氧基联苯(SPhos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(XantPhos)中的一种、两种或更多种；
所述反应在碱的存在下进行；所述碱选自碳酸铯、叔丁醇钠、叔丁醇钾、磷酸钾、醋酸钠中的一种、两种或更多种。
根据本发明的制备方法，步骤(4)中，
所述反应在20℃至100℃温度下进行；
所述反应在还原剂的存在下进行；所述还原剂选自硼氢化钠、硼氢化钾、硼氢化锂、醋酸硼氢化钠；氰基硼氢化钠、钯碳中的一种、两种或更多种。
有益效果
本发明化合物具有良好的TRK激酶抑制活性，适于药用，具有临床应用价值。并且，本发明化合物合成步骤简单，因此具备良好的经济利用价值。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
术语“C1-40烷基”应理解为优选表示具有1～40个碳原子的直链或支链饱和一价烃基，优选为C1-10烷基。“C1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5、6、个碳原子(“C1-6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C2-40烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2～40个碳原子，优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，特别是2或3个碳原子(“C2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-40炔基”应理解为表示直链或支链的一价烃基，其包含一个或多个三键并且具有2～40个碳原子，优选“C2-C10炔基”。术语“C2-C10炔基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子，特别是2或3个碳原子(“C2-C3-炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-20环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～20个碳原子，优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个独立选自N、O和S的杂原子，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“C6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离目标化合物。
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
药学上可接受的盐可以是例如在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐，例如与如下无机酸形成的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
由于本发明的化合物可存在多个成盐位点，所述“药学上可接受的盐”不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述“药学上可接受的盐”中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1～1:4，如3:1、2:1、1:1、1:2、1:3等。
根据本发明，药学上可接受的阴离子包括选自由无机酸或有机酸电离生成的阴离子。所述“无机酸”包括但不限于盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸。所述“有机酸”包括但不限于甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
术语“辅料”是指可药用惰性成分。赋形剂种类的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的药学上可接受的载体的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
N-(4-(((6aS,8S)-2-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-6-氧代-5,6,6a,7,8,9-四氢吡咯并[2,1-h]蝶啶-8-基)氨基)苯基)甲基磺酰胺的制备
第一步
将化合物1a(16.4g,100mmol)，1b(22.92g,100mmol)，DIPEA(19.4g,150mmol)溶于DMF(200ml)中，室温下加入HATU(45.6g,120mmol)，搅拌反应4小时，TLC检测反应，反应完毕后加入水(200ml)淬灭反应，乙酸乙酯提取(300mlx2)，合并有机层，有机层干燥，过滤，浓缩，柱层析分离得到类白色固体26.3g，收率70.1％。
第二步
将第一步得到的化合物1c(26.0g,69.3mmol)溶于二氯甲烷中(100ml)中，室温下加入三氟乙酸(40ml)，搅拌反应4小时，TLC检测反应，反应完毕，减压浓缩除去溶剂得到黄色油状物，加入乙酸乙酯(200ml)，用饱和碳酸氢钠调pH至7-8，静置，分层，浓缩，柱层析分离得到类白色固体15.2g,收率79.7％。
第三步
将第二步得到的化合物1d(15.0g,54.5mmol)溶于DMF(100ml)中，室温下加入氢化钠(5.5g,136.4mmol)搅拌反应，TLC检测反应，反应完毕，加入纯化水(50ml)淬灭反应，用乙酸乙酯(100mlx2)提取，合并有机层，干燥，浓缩，柱层析分离得到类白色固体9.4g，收率72.3％。
第四步
将第三步得到的化合物1e(1.2g,5.0mmol)、化合物1f(0.9g,5.0mmol)、碳酸铯(2.4g,7.5mmol)、Pd(dba)2(180mg,0.3mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(180mg,0.3mmol)溶于DMF(20ml)中，升温至100℃搅拌反应12小时，TLC检测反应，反应完毕后将反应液倒入水(20ml)中，乙酸乙酯(100mlx2)提取，合并有机相干燥，过滤，浓缩，柱层析分离得到类白色固体1.3g，收率67.5％。
第五步
将第四步得到的化合物1g(1.0g,2.6mmol)和化合物1h(0.5g,2.7mmol)溶于乙醇(20ml)中，室温搅拌1小时，然后加入硼氢化钠(0.4g,10.4mmol)，搅拌反应4小时，TLC检测反应，反应完毕后加水(20ml)淬灭反应，加压除去乙醇，加入乙酸乙酯(50mlx2)提取，合并有机层，干燥，浓缩，柱层析分离得到类白色固体0.7g，收率48.6％。MS-ESI:m/z＝556.6[M+1]。
实施例2
(6aS,8S)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-((4-(二甲氨基苯基)氨基)-6a,7,8,9-四氢吡咯[2,1-h]蝶啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝506.6[M+1]。
实施例3
4-(((6aS,8S)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-6-氧代-5,6,6a,7,8,9-六氢吡咯并[2,1-h]蝶啶-8-基)氨基)苯磺酰胺的制备
参考实施例1的方法制备，MS-ESI:m/z＝542.6[M+1]。
实施例4
4-(((6aS,8S)-2-(2-(2,5-二氟苯基)吡咯烷-1-yl)-6-氧代-5,6,6a,7,8,9-六氢吡咯并[2,1-h]蝶啶-8-基)氨基)苯甲酰胺的制备
参考实施例1的方法制备，MS-ESI:m/z＝506.5[M+1]。
实施例5
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-8-((4-(2-羟基丙烷-2-基)苯基)氨基)-6a,7,8,9-四氢吡咯并[2,1-h]蝶啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝521.6[M+1]。
实施例6
(6aS,8S)-2-((R)-2-(2-氟苯基)-4,4-二甲基吡咯烷-1-基)-8-((4-甲氧基苯基)氨基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝503.2[M+1]。
实施例7
(6aS,8S)-2-((R)-2-(2-氟苯基)-4,4-二甲基吡咯烷-1-基)-8-(苯并[d][1,3]二氧戊烷-5-基氨基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝517.2[M+1]。
实施例8
(6aS,8S)-2-((R)-2-(2-氟苯基)-4,4-二甲基吡咯烷-1-基)-8-((4-氰基苯基)氨基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝498.2[M+1]。
实施例9
(6aS,8S)-2-((R)-2-(2-氟苯基)-4,4-二甲基吡咯烷-1-基)-8-((2-甲氧基吡啶-4-基)氨基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝504.2[M+1]。
实施例10
(6aS,8S)-2-((R)-2-(2-氟苯基)-4,4-二甲基吡咯烷-1-基)-8-(嘧啶-2-基氨基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝475.2[M+1]。
实施例11
(6aS,8S)-2-((R)-2-(6-氟-吡啶-2-基)吡咯烷-1-基)-8-((S)-3-羟基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝440.2[M+1]。
实施例12
(6aS,8S)-2-((R)-2-(6-氟-吡啶-2-基)吡咯烷-1-基)-8-((S)-3-氨基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝439.2[M+1]。
实施例13
(6aS,8S)-2-((R)-2-(6-氟-吡啶-2-基)吡咯烷-1-基)-8-(3-氧代吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝438.2[M+1]。
实施例14
(6aS,8S)-2-((R)-2-(6-氟-吡啶-2-基)吡咯烷-1-基)-8-(3,3-二氟吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝460.2[M+1]。
实施例15
(6aS,8S)-2-((R)-2-(6-氟-吡啶-2-基)吡咯烷-1-基)-8-((S)-2-氨基羰基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝467.2[M+1]。
实施例16
(6aS,8S)-2-((R)-2-(5-氯-2-氟苯基)吡咯烷-1-基)-8-吗啉-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝473.2[M+1]。
实施例17
(6aS,8S)-2-((R)-2-(5-氯-2-氟苯基)吡咯烷-1-基)-8-(哌嗪-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝472.2[M+1]。
实施例18
(6aS,8S)-2-((R)-2-(5-氯-2-氟苯基)吡咯烷-1-基)-8-(3,5-二甲基哌嗪-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝500.2[M+1]。
实施例19
(6aS,8S)-2-((R)-2-(5-氯-2-氟苯基)吡咯烷-1-基)-8-(4-甲基哌嗪-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝486.2[M+1]。
实施例20
(6aS,8S)-2-((R)-2-(5-氯-2-氟苯基)吡咯烷-1-基)-8-(4-氧代哌啶-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝485.2[M+1]。
实施例21
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)-4,4-二氟吡咯烷-1-基)-8-(3-羟基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝493.2[M+1]。
实施例22
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)-4,4-二氟吡咯烷-1-基)-8-((S)-3-氨基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝492.2[M+1]。
实施例23
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)-4,4-二氟吡咯烷-1-基)-8-(3-氧代吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝491.2[M+1]。
实施例24
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)-4,4-二氟吡咯烷-1-基)-8-(3,3-二氟吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝513.2[M+1]。
实施例25
(6aS,8S)-2-((R)-2-(2,5-二氟苯基)-4,4-二氟吡咯烷-1-基)-8-((S)-2-氨基羰基吡咯烷-1-基)-6a,7,8,9-四氢吡咯并[2,1-h]喋啶-6(5H)-酮的制备
参考实施例1的方法制备，MS-ESI:m/z＝520.2[M+1]。
实施例26生物活性测定
生物活性的测定
TrkA ELISA测定
在抑制剂存在下使用酶联免疫吸附测定评价TrkA激酶活性。用0.025mg/ml聚(Glu,Ala,Tyr；6:3:1)溶液涂布Immulon 4HBX384孔微量滴定板，在涂布的板中在环境温度下将各浓度的测试化合物，2.5nM TrkA(组氨酸标记的重组人TrkA细质结构)和500μM ATP孵育25分钟，同时振荡，测定缓冲液由25mM MOPS pH7.5，0.005％(V/V)Triton X-100与5mMMgCl2组成。通过用含有0.1％(V/V)吐温20的PBS洗涤，从板去除反应混合物。使用偶合辣根过氧化物酶的0.2μg/mL磷酸酪氨酸特异性单克隆抗体结合TMB过氧化合物酶物质系统检测磷酸化反应产物。在添加1M磷酸后，经有450nm下的吸光率定量显色物质颜色变强。使用参数对数曲线拟合计算IC50值。
经测试，实施例1-25化合物对TrkA的IC50值介于15nM至10μM之间，其中实施例1、16的IC50值低于18nM，实施例2、15、24的IC50值高于1μM，而实施例25的IC50值高于5μM。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.式A所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐，
G1选自其中R1选自H、无取代或任选被一个或多个Ra取代的下列基团：C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
X选自CRb，其中Rb选自H、＝O、无取代或任选被一个或多个Rc取代的下列基团：C1-40烷基或C1-40烷氧基；
G2、G4相同或不同，彼此独立地选自H、无取代或任选被一个或多个Rd取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
G3选自其中R2、R3相同或不同，彼此独立地选自H、无取代或任选被一个或多个Re取代的下列基团：C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
或者，R2、R3与其所连接的氮原子一起形成选自无取代或任选被一个或多个Re取代的下列环系：3-20元杂环基、5-20元杂芳基；
每一个Ra、Rc、Rd相同或不同，彼此独立地选自-F、-Cl、-Br、-I、或下列基团：C1-40烷基、C1-40烷氧基；
Re选自-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、无取代或任选被一个或多个Rf取代的下列基团：-NH-S(O)2-C1-40烷基、-S(O)2-C1-40烷基、-NH-C1-40烷基、二-(C1-40烷基)氨基、-C(O)-C1-40烷基、C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基；
Rf选自-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
*为连接取代位点的键。
2.根据权利要求1所述的化合物，其中，G1中R1选自无取代或任选被一个或多个下列基团取代的C6-20芳基或5-20元杂芳基：-F、-Cl、-Br、-I、C1-12烷基、C1-12烷氧基；
优选地，G1中R1选自无取代或任选被一个或多个-F、-Cl、-Br、甲氧基或乙氧基取代的下列基团：苯基、吡啶基；
优选地，G1中X选自CH2、C＝O、-NH2、-OH、或任选被一个或多个-F、-Cl、-Br、取代的下列基团：-C(C1-12烷基)2、-CH-C1-12烷基、-CH-C1-12烷氧基、或-NH-C1-12烷基；
优选地，G1选自下列基团：
其中，为连接取代位点的键。
3.根据权利要求1或2所述的化合物，其中，G2、G4相同或不同，彼此独立地选自H、无取代或任选被一个或多个C1-12烷基取代的下列基团：C1-12烷基、C1-12烷氧基。
4.根据权利要求1-3任一项所述的化合物，其中，G3中R2、R3相同或不同，彼此独立地选自H、无取代或任选被一个或多个如下基团取代的C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基：-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-NH-S(O)2-C1-12烷基、-S(O)2-C1-12烷基、-S(O)2-NH2、-NH-C1-12烷基、二-(C1-12烷基)氨基、-C(O)-C1-12烷基、-C(O)-NH2、C1-12烷基、C1-12烷氧基、3-20元杂环基；
或者，R2、R3与其所连接的氮原子一起形成选自无取代或任选被一个或多个如下基团取代的3-20元杂环基：-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-C(O)-NH2、C1-12烷基、C1-12烷氧基；
例如，G3选自下列基团：
其中，处为连接取代位点的键。
5.根据权利要求1-4任一项所述的化合物，其中，所述化合物选自包括但不限于如下化合物：
6.一种药物组合物，其包含治疗有效量的权利要求1-5任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐中的一种或者多种。
7.根据权利要求6所述的药物组合物，其中，所述组合物还任选包含其药学上可接受的辅料，例如载体、赋形剂；
所述辅料选自下列中的一种、两种或多种：崩解剂、助流剂、润滑剂、稀释剂或填充剂、粘合剂、着色剂。
8.权利要求1-5任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、溶剂合物或其药学上可接受的盐中的一种或者多种在制备药物中的用途。
9.根据权利要求8所述的用途，其中，所述药物通过抑制TRK激酶活性达到治疗疾病的目的；所述疾病选自乳腺癌、皮肤癌、膀胱癌、卵巢癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病，慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、横纹肌肉瘤、软骨肉瘤、肌肉瘤、或纤维肉瘤。
10.根据权利要求1-5任一项所述化合物的制备方法，包括：
(1)中间体III的合成
化合物I与化合物II进行反应得到化合物III；
(2)中间体IV的合成
步骤(1)得到的化合物III反应得到化合物IV；
(3)中间体V的合成
步骤(2)得到的化合物IV反应得到化合物V；
(4)中间体VII的合成
步骤(3)得到的化合物V与化合物VI反应得到化合物VIII；
(5)式A化合物的合成
步骤(4)得到的化合物VII与化合物VIII反应得到化合物VIII；
其中G1、G2、G3、G4、R1、R2、R3、X具有权利要求1-5任一项所述定义。
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| US20130225549A1 (en) * | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Dihydropteridinones i |
| WO2017001853A1 (en) * | 2015-06-30 | 2017-01-05 | Redx Pharma Plc | Antiviral compounds |
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| US20130225549A1 (en) * | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Dihydropteridinones i |
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