CN116783181A - 取代的稠合双环类化合物作为parp抑制剂及其应用 - Google Patents
取代的稠合双环类化合物作为parp抑制剂及其应用 Download PDFInfo
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- CN116783181A CN116783181A CN202280011128.0A CN202280011128A CN116783181A CN 116783181 A CN116783181 A CN 116783181A CN 202280011128 A CN202280011128 A CN 202280011128A CN 116783181 A CN116783181 A CN 116783181A
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- Prior art keywords
- methyl
- piperazin
- ethyl
- dioxo
- tetrahydroquinazolin
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- 239000012661 PARP inhibitor Substances 0.000 title abstract description 16
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 title abstract description 16
- 125000002619 bicyclic group Chemical group 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 15
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- 239000003814 drug Substances 0.000 claims abstract description 13
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- -1 1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl Chemical group 0.000 claims description 246
- 125000000217 alkyl group Chemical group 0.000 claims description 203
- 150000002367 halogens Chemical class 0.000 claims description 121
- 229910052736 halogen Inorganic materials 0.000 claims description 120
- 229910052739 hydrogen Inorganic materials 0.000 claims description 99
- 125000001424 substituent group Chemical group 0.000 claims description 78
- 125000003545 alkoxy group Chemical group 0.000 claims description 59
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- 239000001257 hydrogen Substances 0.000 claims description 50
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 19
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- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 17
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- 125000004452 carbocyclyl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
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Abstract
本发明提供取代的稠合双环类化合物作为PARP抑制剂及其应用。本发明的取代的稠合双环类化合物具有下式I所示的结构,其中,A1、A2、A3、R1、L、Cy和n为本文所定义。本发明式I的化合物是PARP抑制剂,因而可用于治疗因PARP活性异常而引起的疾病、障碍和病症,如癌症。本发明也涉及含有式I化合物的药物组合物以及该式I化合物在制备治疗或预防因PARP活性异常而引起的疾病或病症的药物中的用途。
Description
技术领域
本发明属于药物化学领域。本发明涉及取代的稠合双环类化合物及其作为治疗上有效的PARP抑制剂和抗癌药物的应用。
背景技术
Poly(ADP-ribose)polymerase(PARP)是指一组蛋白,它们的功能是以NAD+为底物催化向受体蛋白添加ADP-ribose的修饰反应。这是蛋白质转译后修饰的多种方式中的一种。因此它们也可被称为是ADP-ribose转移酶。
根据蛋白的催化区域的氨基酸序列的相似性,在人类细胞中已发现有17种不同的PARP酶(Vyas et al.,2013Nature Communication,DOI:10.1038)。这些PARP酶或者催化对受体蛋白的单一ADP-ribose修饰,或者催化对受体蛋白进行多个ADP-ribose转移形成多聚ADP-ribose,也称poly(ADP-ribose)修饰。PARP的家族成员可以根据催化转移的ADP-ribose是单一还是多个而分为两大亚型。PARP酶对受体蛋白进行的ADP-ribose修饰所导致的生物学功能涵盖非常广泛,许多功能也还不清楚。
PARP1是PARP大家族中细胞内含量最高、被研究的最多的一个。PARP1是一个有1014个氨基酸组成的蛋白(NCBI Accession P09874),分子量大约为116kDa,其结构包括DNA结合和催化等区域。目前所知PARP1参与细胞多项功能,在基因扩展、转录、细胞分裂、细胞分化、细胞凋亡以及DNA损伤应答及修复等机制中都起着重要作用。当DNA损伤发生时,PARP1被激活。碱基切除(BER,Base Excision Repair)机制是DNA单链损伤修复的一个主要机制,PARP1是BER机制的一个重要组成部分。当损伤发生时,PARP1结合到DNA单链损伤(SSB,Single Strand Break)部位,通过参与BER对DNA进行修复。其活性主要体现在对组蛋白、核蛋白的ADP-ribose修饰及对自身的ADP-ribose修饰。细胞应对DNA损伤除了单链损伤BER修复机制外还有修复双链损伤的同源重组(HR,Homologous Recombination)和非同源重组末端连接(NHEJ,Non-homologous Recombination End Joining)两个重要的修复机制。结果显示具有同源重组修复机制缺陷的癌细胞对PARP1抑制剂敏感,即同源重组缺陷和PARP1抑制形成合成致死(Synthetic Lethality)的一对。这个发现在临床上得到验证,多个PARP抑制剂得以获得批准上市用于治疗具有BRCA1/2突变的卵巢癌、乳腺癌、前列腺癌和胰腺癌等。
PARP2是一个有559个氨基酸组成的蛋白,分子量大约为62kDa,其结构包括DNA结合和催化等区域(Ame et al.,1999J Biol Chem 274:17860)。PARP2的催化区域和PARP1的有极高的相似性。研究显示PARP2有和PARP1相似的功能,参与BER机制对DNA损伤的修复(Schreiber et al.,2002J Biol Chem 277:23028)。目前已上市的PARP抑制剂,包括Olaparib、Niraparib、Talazoparib和Rucaparib等,除了抑制PARP1外都对PARP2有相似的抑制活性。从临床试验结果看,这些已上市的PARP抑制剂有着类似的药效,然而它们的毒性却有着较大的区别。比如,这些PARP抑制剂的血液学毒性相似,但是Talazoparib却有着和化疗药类似的脱发的副作用。最近一项比较多个PARP抑制剂选择性的研究显示Talazoparib除了抑制PARP1和PARP2外,还对PARP家族的另外两个成员TNKS1(Tankyrase1)和TNKS2(Tankyrase 2)有相当高的亲和力(Ryan et al.,2021,J Biol Chem 296:100251)。TNKS1和TNKS2氨基酸序列有很高的相似性,二者的整体序列中氨基酸序列83%相同,而催化区域的相同性达89%。TNKS除了也在DNA修复中有一定的作用外,它们还在维持端粒结构以及Wnt/β-catenin信号通路中有一定的作用。打中除PARP1之外的这些靶点有可能是引起机制外毒性,比如脱发和腹泻等的原因。另外,抑制PARP2活性也可能导致血液毒性(Farrés et al.,2013,Blood122:44;Farrés et al.,2015,Cell Death andDifferentiation 22:1144)。这些毒性有可能限制了PARP抑制剂的应用,以及和其他靶向药物的联合使用。
因此,开发具有高度选择性的PARP1抑制剂可能降低与机制相关和机制不相关的毒性,改善、增强和扩大PARP1抑制剂的临床应用。
已有多种选择性PARP1抑制剂被公开。如WO2011006803;WO2013014038;WO2021013735和WO2021260092。
发明内容
本发明提供结构如式I(包括式II、III和IV)所示的化合物,这类化合物可作为PARP抑制剂。特别的,相对于PARP2,本发明的化合物是选择性PARP1抑制剂。
本发明还提供了包含有效量的式I(包括式II、III和IV)化合物的药用组合物,用来治疗癌症。
在一具体实施例中,所述药用组合物还可含有一种或多种可药用载体或稀释剂,用来治疗癌症。
在一具体实施例中,所述药用组合物还可含有至少一种已知的抗癌药物或所述抗癌药物的可药用盐,用来治疗癌症。
本发明也涉及到结构式I(包括式II、III和IV)的新颖化合物的制备方法。
具体实施方式
应理解的是,本文所述的各实施方案的特征可任意组合,形成本文的技术方案;本文对各基团的定义适用于本文所述任一实施方案,例如,本文对烷基的取代基的定义适用于本文所述任一实施方案,除非该实施方案已清楚定义了烷基的取代基。
本文所用“氢(H)”包括其同位素氘(D)和氚(T)。
本文所用“烷基”是指烷基本身或是直链或支链高达十个碳原子的基团。有用的烷基包括直链或支链C1-10烷基,优选C1-6烷基。在某些实施方案中,烷基为C1-4烷基。典型的C1-10烷基包括任选取代的甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基。
本文所用“烯基”是指直链或支链含有2-10个碳原子,除非碳链长度被另外限制,其中至少是链中的两个碳原子之间含有一个双键的基团;优选C2-6烯基。典型的链烯基包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
本文所用“炔基”是指直链或支链含有2-10个碳原子,除非碳链长度被另外限制,其中至少是链中的两个碳原子之间含有一个三键的基团;优选C2-6炔基。典型的炔基包括乙炔基、1-丙炔基、1-甲基-2-丙炔基、2-丙炔基、1-丁炔基和2-丁炔基。
本文所用“烷氧基”指被上述C1-10烷基、优选C1-6烷基或C1-4烷基取代的氧基,例如甲氧基、乙氧基等。烷氧基中的烷基任选取代。烷氧基的取代基包括但不限于卤素、吗啉基、氨基和羧基(包括其酯基),所述氨基包括烷氨基和二烷氨基。
本文所述“氨基”可以–NR′R″表示,其中R′和R″各自独立为氢、任选取代的C1-10烷基、任选取代的C3-8环烷基、任选取代的芳基或任选取代的杂芳基,优选地,R′和R″各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基;或者R″和R′一起与它们所连接的N形成任选取代的4元至7元环氨基团,所述环氨基团任选含有一个或多个(如2、3个)另外的选自O、N和S的杂原子。优选的氨基包括NH2,以及R′和R″中至少有一个是C1-6烷基的基团。
本文所用“氧代”是指=O。
本文所用“芳基”是指芳基本身或是作为其它基团的一部分,含有6到14个碳原子的单环、双环或三环芳族基团。芳基可被一个或多个本文所述的取代基取代。
有用的芳基包括C6-14芳基,优选的是C6-10芳基。典型的C6-14芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、联苯、亚联苯基和茀基。
本文所用“碳环基”包括环烷基和部分饱和的碳环基团。有用的环烷基是C3-8环烷基。在一些优选的实施方案中,环烷基是C3-6环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。有用的部分饱和的碳环基团包括环烯基,如C3-8环烯基,例如环戊烯基、环庚烯基和环辛烯基。碳环基团可被一个或多个本文所述的取代基取代。
有用的卤素或卤素基团包括氟、氯、溴和碘。
有用的酰基氨基(酰氨基)是连接在氨基氮上的任何C1-6酰基(烷酰基),例如乙酰氨基、乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基和己酰氨基,以及例如芳基取代的C1-6酰基氨基,例如苯甲酰氨基。
有用的酰基包括C1-6酰基,如乙酰基。酰基可任选被选自卤素、氨基和芳基的基团取代,其中氨基和芳基任选取代。当被卤素取代时,卤素取代基的数量可在1-5个的范围内。被取代的酰基的例子包括氯乙酰基和五氟苯甲酰基等。当被氨基取代时,氨基可被本文所述的一个或2个取代基取代。在一些实施方案中,氨基酰基为-C(O)-NR′R″,其中R′和R″各自独立为氢、任选取代的C1-10烷基、任选取代的C3-8环烷基、任选取代的芳基或任选取代的杂芳基,优选地,R′和R″各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。本文中,所述R′和R″中的烷基、环烷基、芳基和杂芳基被取代时,取代基如本文任一实施方案所述,优选的取代基包括卤素、羟基、氨基和烷基等。
本文所用“杂环基”是指饱和或部分饱和的3-7元单环基团、7-10元双环基团、螺旋环基团或桥连环基团,它由碳原子和1-4个选自O、N、S的杂原子组成,其中杂原子氮和硫都可以被任意氧化,氮也可以任意季铵化。杂环基也包括所述双环体系中上述定义的任意杂环与苯环的稠并而成的稠杂环。如果产生的化合物是稳定的话,那么杂环的碳原子或氮原子可被取代。杂环基可被一个或多个本文所述的取代基取代。
有用的饱和或部分饱和杂环基团包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、1,4-二氮杂环庚烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异色满基、色满基、吡唑烷基、吡唑啉基、四氢异喹啉基、tetronoyl和tetramoyl,这些基团可被本文所述的一个或多个取代基取代。
本文所用“杂芳基”是指含有5–14个、优选5–10个环原子,并且有6个,10个或14个π电子在环体系上共用的基团。杂芳基所含环原子是碳原子和1–3个选自氧、氮、硫的杂原子。杂芳基可被一个或多个本文所述的取代基取代。
有用的杂芳基包括噻吩基(苯硫基)、苯并[d]异噻唑-3-基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、夹氧蒽基、噻吩恶基(phenoxanthiinyl)、吡咯基、咪唑基、吡唑基、吡啶基(包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基)、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹唑啉基、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮(杂)苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异恶唑基、呋咱基、吩恶嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并嘧啶-4-酮、四氢吡啶并嘧啶基、四氢化五员[c]吡唑-3-基、苯并异恶唑基如1,2-苯并异恶唑-3-基、苯并咪唑基、2-羟吲哚基、噻重氮基、2-氧代苯并咪唑基、咪唑并哒嗪基、咪唑并吡啶基、三氮唑并哒嗪基、四氢吡啶并嘧啶基、吡唑并嘧啶基、吡咯并嘧啶基、吡咯并吡啶基、吡咯并吡嗪基或三氮唑并吡嗪基。当杂芳基在环中含有氮原子时,这样的氮原子可以呈N-氧化物形式,例如吡啶基N-氧化物、吡嗪基N-氧化物和嘧啶基N-氧化物。
本文中,除非另有说明,当被取代时,本文任一实施方案所述的烷基、环烷基、杂环烷基、烷氧基、杂环烷氧基、烯基、杂环烯基、炔基、氨基、酰氨基、酰氧基、羧基、羟基、巯基、烷硫基、磺酰基、亚磺酰基、氨基酰基、硅烷基、膦羧基、膦酰基、碳环基、杂环基、芳基或杂芳基可被一个或多个(例如1、2、3、4、5或6个)选自以下基团的取代基取代:卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C1-6酰基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、杂环基或杂芳基、亚甲基二氧基、脲基、巯基、叠氮基、羰基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也任选取代。更优选地的取代基包括但不限于卤素、羟基、羧基、氨基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、C1-6烷基、C1-6酰基和烷磺酰基。
应理解的是,本文各实施方案中,当取代基为杂环基、芳基或杂芳基时,该杂环基、芳基或杂芳基取代基的数量通常为1个。
具体来说,本发明提供如下式I所示的化合物、其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物:
其中,R1选自任选取代的烷基、任选取代的碳环基、任选取代的烯基和任选取代的炔基;
A1、A2和A3各自独立选自N和CR2;
L选自键和任选被R3和/或R4取代的亚烷基;
Cy选自任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;
R2选自氢、卤素、任选取代的烷基、任选取代的烷氧基和任选取代的碳环基;
R3和R4各自独立选自卤素、氰基、任选取代的烷基、任选取代的烷氧基、任选取代的环烷基、任选取代的烯基和任选取代的炔基;或者R3和R4与连接的C形成环;
n选自0,1和2;
其中,当n不为0时,所示-(CH2)n-任选地被一个=O取代。
本发明所述的式I以及各结构式中,除非另有说明,否则各烷基各自独立为C1-6烷基,优选为C1-4烷基;各亚烷基为C1-6亚烷基,优选C1-3亚烷基;各烯基各自独立为C2-6烯基,优选为C2-4烯基;各炔基各自独立为C2-6炔基,优选为C2-4炔基;各烷氧基各自独立为C1-6烷氧基,优选为C1-4烷氧基。优选地,当烷基、烯基、炔基、烷氧基被取代时,其取代基可选自氰基、羟基、硝基、氨基(–NR′R″)、芳基、杂环基、杂芳基、卤素和羧基等,取代基的数量可以是1-5个,R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。例如,取代的烷基自身或作为其它基团的取代基的取代的烷基可以是羟基烷基、二羟基烷基、烷基氨基烷基、二烷基氨基烷基、杂环基烷基、芳烷基、杂芳基烷基和卤代烷基等。应理解,当取代基为芳基、杂芳基、杂环基、氰基、硝基和羧基时,取代基数量通常为1个;当取代基为例如卤素时,可根据烷基、烯基、炔基和烷氧基的碳链长度,取代基数量可达5个卤素基团;示例性的这类取代基如三氟甲基和五氟乙基等。
本发明所述的式I以及各结构式中,除非另有说明,否则各碳环基的环碳原子数优选为3–8个。优选的碳环基为C3-8环烷基。碳环基上的取代基优选为C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤素、羟基、羧基、氨基(–NR′R″)、芳基、杂环基、杂芳基、卤素和羧基等,取代基的数量可以是1-5个,R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。应理解,当取代基为芳基、杂芳基、杂环基、氰基、硝基、和羧基时,取代基数量通常为1个;当取代基为例如卤素时,取代基数量可达5个卤素基团。
本发明所述的式I以及各结构式中,除非另有说明,否则芳基通常指C6-14芳基,杂芳基通常指5–10元杂芳基,杂环基通常指4–10元杂环基。各芳基、杂芳基和杂环基上的取代基各自可独立选自C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤素、羟基、羧基、氨基(–NR′R″)、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤素、酰氨基、氨基酰基(-C(O)-NR′R″)和羧基等,其中,R′和R″各自独立为氢、任选取代的C1-10烷基、任选取代的C3-8环烷基、可被任选取代的芳基或可被任选取代的杂芳基,优选地,R′和R″各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。取代基的数量可以是1–5个。所述任选取代的芳基、任选取代的杂芳基和任选取代的杂环基各自可任选地被1–5个选自C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤素、羟基、羧基、氨基(–NR′R″)、氨基酰基(-C(O)-NR′R″)、卤素和羧基的取代基取代,其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。应理解,当取代基为芳基、杂芳基、杂环基、氰基、硝基和羧基时,取代基数量通常为1个;当取代基为例如卤素时,取代基数量可达5个卤素基团。
在式I化合物的一个或多个实施方案中,所述芳基优选为苯基;所述杂芳基为含有1或2个氮原子的5-10元杂芳基,包括但不限于吡啶基、吡嗪基、吡咯基、咪唑基、吡唑基、嘧啶基、哒嗪基、吲嗪基、吡啶并嘧啶基、吲哚基、吲唑基和苯并咪唑基等;所述碳环基优选为C3-8环烷基;所述杂环基优选为含O和/或N的4-10元杂环基,包括但不限于氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、哌嗪基、哌啶基、四氢呋喃基、四氢异喹啉基以及吗啉基等。
在式I化合物的一个或多个实施方案中,R2被取代时,取代基可以是1-5个选自卤素和羟基的取代基。优选地,R2为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基,更为优选的R2为氢、C1-3烷基或卤素。在优选的实施方案中,A1、A2和A3有且只有一个为N,另外两个独立为CR2,优选地,R2独立为H、C1-3烷基或卤素。在更优选的实施方案中,A3为CH,A1和A2中有一个为N、另一个为CR2,其中,R2为H、C1-3烷基或卤素。在一些实施方案中,A1为N,A2和A3均为CH。在一些实施方案中,A2为N,A1和A3均为CH。在一些实施方案中,A1、A2和A3均为CR2,各R2独立为H、C1-3烷基或卤素;优选地,A3为CH,A1和A2其中之一为CR2,其中R2为H、C1-3烷基或卤素;更为优选地,A2和A3均为CH,A1为CR2,其中R2为C1-3烷基或卤素。
在式I化合物的一个或多个实施方案中,R1为任选取代的C1-3烷基或C3-6环烷基。优选地,R1被取代时,取代基的数量可为1–5个,可选自卤素、羟基、氨基(–NR′R″)等,其中,R′和R″优选各自独立为H、任选被1–5个选自羟基和卤素的取代基取代的C1-4烷基或C3-6环烷基。优选地,R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基。
在式I化合物的一个或多个实施方案中,R3和R4优选各自独立为卤素或C1-3烷基。
在式I化合物的一个或多个实施方案中,L为键。在一些实施方案中,L为未被取代的亚烷基,更优选为未被取代的C1-3亚烷基,优选为亚甲基。
在式I化合物的一个或多个实施方案中,Cy可能被1-5个取代基取代,优选1-3个取代基,选自:卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基、任选取代的C3-8环烷基和-(CH2)m-C(O)-NRaRb的取代基;其中,Ra和Rb可独立为H、C1-4烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基,m为0-5的整数,优选地,m为0,优选地,Ra和Rb中至少一个为任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基;其中,所述Cy取代基定义中的任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基以及Ra和Rb定义中的任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基各自可独立地被1-5个选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、任选取代的5-10元杂芳基(如任选被1-3个选自卤素和C1-4烷基的取代基取代,优选是含氮和/或氧的5-6元杂芳基)、-S(O)2-NR′R″、–NR′R″和-C(O)-NR′R″的取代基取代,其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基,更优选为H、C1-4烷基、卤代C1-4烷基和C3-6环烷基。在优选的实施方案中,所述Cy取代基定义中的所述任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基以及Ra和Rb定义中的所述任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基的取代基至少包括-C(O)-NR′R″,任选还包括卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个。在优选的实施方案中,Cy被任选取代的5-10元杂芳基所取代,优选被任选取代的含氮5-10元杂芳基所取代,优选地,该含氮5-10元杂芳基至少被所述-C(O)-NR′R″取代,并任选地还被卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个所取代。在一些实施方案中,Cy被如下所述的一个R5取代。在一些实施方案中,杂环基如上所述任选地被取代。在特别优选的实施方案中,Cy是被任选取代的吡啶基取代的哌嗪基,且所述吡啶基至少被所述-C(O)-NR′R″取代。在另外一些优选的实施方案中,Cy被所述-(CH2)m-C(O)-NRaRb的取代基取代,优选地,所述Ra和Rb中至少一个为至少被-C(O)-NR′R″取代的5-10元杂芳基。
优选地,本文的各实施方案中,所述R′和R″被取代时,取代基选自卤素和羟基。在优选的实施方案中,R′和R″优选各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基。
在式I化合物的一个或多个实施方案中,当L为键时,Cy为任选取代的芳基或任选取代的杂芳基。优选地,所述任选取代的芳基和任选取代的杂芳基任选地被选自C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤素和-(CH2)m-C(O)-NRaRb的取代基取代,其中,Ra和Rb可独立为H、C1-4烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基,m为0-5的整数,优选地,m为0。取代基的数量可以是1–5个。优选地,所述任选取代的芳基和任选取代的杂芳基至少被-(CH2)m-C(O)-NRaRb取代,还可任选地被选自卤素、C1-4烷基和卤代C1-4烷基的1-3个取代基取代。优选地,Ra和Rb中至少一个为任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基;更优选地,Ra和Rb中一个为H,另一个为任选取代的5-10元杂芳基。Ra和Rb定义中的所述任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基各自可任选地被1–5个选自C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤素、羟基、羧基、氨基(–NR′R″)、-C(O)-NR′R″、卤素和羧基的取代基取代,其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基,更优选为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基;进一步优选地,所述5-10元杂芳基和4-10元杂环基至少被1个-C(O)-NR′R″取代,还可任选地被选自卤素、C1-4烷氧基、C1-4烷基和卤代C1-4烷基的1-3个取代基取代。
在式I化合物的一个或多个实施方案中,当L为亚烷基时,如-CH2-,Cy为任选取代的含氮5-7元杂环基。优选地,该含氮5-7元杂环基通过其环氮原子与L共价连接。进一步优选地,Cy为任选取代的哌嗪基。优选地,Cy上的取代基选自:卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基;其中,所述任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基各自可独立地被1-5个选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、任选取代的5-10元杂芳基(如任选被1-3个选自卤素和C1-4烷基的取代基取代,优选是含氮和/或氧的5-6元杂芳基)、-S(O)2-NR′R″、–NR′R″和-C(O)-NR′R″的取代基取代,其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基;在优选的实施方案中,所述取代基至少包括-C(O)-NR′R″,任选还包括卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个。在优选的实施方案中,Cy被任选取代的5-10元杂芳基所取代,优选被任选取代的含氮5-10元杂芳基所取代,优选地,该含氮5-10元杂芳基至少被所述-C(O)-NR′R″取代,并任选地还被卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个所取代。在特别优选的实施方案中,Cy是被任选取代的吡啶基取代的哌嗪基,且所述吡啶基至少被所述-C(O)-NR′R″取代。优选地,本文的各实施方案中,所述R′和R″被取代时,取代基选自卤素和羟基。在优选的实施方案中,R′和R″优选各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基。
在式I化合物的一个或多个实施方案中,n为0或1。
本发明式I优选化合物的其中一组表示为式II(包括式IIa和IIb)所示的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物:
其中,R1、A1、A2、A3和n如在式I中所述;
R5选自任选取代的芳基和任选取代的杂芳基;
D1、D2、D3和D4各自独立选自N和CR6;
R6各自选自氢、卤素、任选取代的烷基、任选取代的烷氧基、任选取代的碳环基、任选取代的烯基和任选取代的炔基。
在式IIa和IIb所示的化合物的一个或多个实施方案中,R1为任选取代的C1-3烷基或C3-6环烷基。优选地,R1被取代时,取代基的数量可为1-5个,可选自卤素、羟基、氨基(–NR′R″)等,其中,R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。优选地,R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基。
在式IIa和IIb所示的化合物的一个或多个实施方案中,R2被取代时,取代基可以是1-5个选自卤素和羟基的取代基。优选地,R2为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基,更为优选的R2为氢、C1-3烷基或卤素。在优选的实施方案中,A1、A2和A3有且只有一个为N,另外两个独立为CR2,优选地,R2独立为H、C1-3烷基或卤素。在更优选的实施方案中,A3为CH,A1和A2中有一个为N、另一个为CR2,其中,R2为H、C1-3烷基或卤素。在一些实施方案中,A1为N,A2和A3均为CH。在一些实施方案中,A2为N,A1和A3均为CH。在一些实施方案中,A1、A2和A3均为CR2,各R2独立为H、C1-3烷基或卤素;优选地,A3为CH,A1和A2其中之一为CR2,其中R2为H、C1-3烷基或卤素;更为优选地,A2和A3均为CH,A1为CR2,其中R2为C1-3烷基或卤素。
在式IIa和IIb所示的化合物的一个或多个实施方案中,R5为任选取代的苯基或含氮5-7元杂环基,更优选为任选取代的苯基、吡啶基、嘧啶基、哒嗪基或吡嗪基。优选地,R5被取代时,取代基的数量可为1-5个,可选自卤素、任选取代的烷基、任选取代的烷氧基、任选取代的5-10元杂芳基(如任选被1-3个选自卤素和C1-4烷基的取代基取代,优选是含氮和/或氧的5-6元杂芳基)、-S(O)2-NR′R″和任选取代的氨基酰基。更为优选地,R5被一个任选取代的氨基酰基在对位取代。优选地,所述任选取代的氨基酰基为-C(O)-NR′R″,其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基,更优选地,所述R′和R″各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基。在式IIa和IIb所示的化合物的一个或多个实施方案中,R5为任选取代的1-氧代-1,2,3,4-四氢异喹啉-6-基或4-氧代-4H-吡啶并[1,2-a]嘧啶-8-基,被取代时,其取代基可为1-5个选自卤素、C1-4烷基、卤代C1-4烷基、C1-4烷氧基和卤代C1-4烷氧基等的取代基。在式IIa和IIb所示的化合物的一个或多个实施方案中,R5为任选取代的吡啶并嘧啶基、吲哚基、吲唑基或苯并咪唑基,被取代时,取代基可为1-3个选自卤素、C1-4烷基和卤代C1-4烷基的取代基。
在式IIa和IIb所示的化合物的一个或多个实施方案中,R5优选为如下基团:
更优选为如下基团:
其中,B1,B2,B3和B4各自独立选自N和CR7;R7选自氢、卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基和–NR′R″;R′和R″各自独立选自氢、任选取代的C1-10烷基、任选取代的C3-8环烷基、任选取代的6-14元芳基或任选取代的5-10元杂芳基,优选各自独立为氢、任选取代的C1-4烷基或任选取代的C3-6环烷基,更优选各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基;*表示所述基团与化合物其它部分连接的位置。优选地,含B1-B4的基团为苯基、吡啶基、嘧啶基或哒嗪基。优选地,R7为H、卤素、C1-3烷基、C1-3烷氧基或卤代C1-3烷基。优选地,B3为N,B4为CR7,B1和B2为CH,其中R7为H、卤素、C1-3烷基、C1-3烷氧基或卤代C1-3烷基。
在式IIa和IIb所示的化合物的一个或多个实施方案中,D1、D2、D3和D4各自独立选自N和CR6,其中R6优选为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基。优选地,R6被取代时,取代基可以是1-5个选自卤素和羟基的取代基。更优选地,R6为氢、C1-3烷基或卤素。在一些优选的实施方案中,含D1-D4的基团为任选被1-3个选自卤素和C1-3烷基取代的苯基或吡啶基。
在式IIa和IIb所示的化合物的一个或多个实施方案中,n为0或1。
在式IIa的一个或多个实施方案中,R1选自所述任选取代的烷基、任选取代的碳环基、任选取代的烯基和任选取代的炔基;A1、A2和A3各自独立选自N和CR2;R5为:
B1、B2、B3和B4各自独立选自N和CR7;R′为H;R″选自氢、所述任选取代的C1-10烷基和任选取代的C3-8环烷基;R2选自氢、卤素、所述任选取代的C1-10烷基、任选取代的C1-10烷氧基和任选取代的C3-8环烷基;R7选自氢、卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基和–NR′R″,R′和R″各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基;n选自0,1和2;其中,当n为1或2时,所述-(CH2)n-任选地被一个=O取代。优选地,A1、A2和A3各自为N和CR2,其中R2优选为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基,更为优选的R2为氢、C1-3烷基或卤素。优选地,A1、A2和A3有且只有一个为N,另外两个独立为CR2,优选地,R2独立为H、C1-3烷基或卤素。优选地,A3为CH,A1和A2中有一个为N、另一个为CR2,其中,R2为H、C1-3烷基或卤素。优选地,A1为N,A2和A3均为CH。在一些实施方案中,A2为N,A1和A3均为CH。在一些实施方案中,A1、A2和A3均为CR2,各R2独立为H、C1-3烷基或卤素;优选地,A3为CH,A1和A2其中之一为CR2,其中R2为H、C1-3烷基或卤素;更为优选地,A2和A3均为CH,A1为CR2,其中R2为C1-3烷基或卤素。优选地,B1、B2、B3和B4各自独立选自N和CR7,其中R7为氢、C1-3烷基、卤代C1-3烷基或卤素。优选地,B1和B2均为CH,B3为N,B4为CR7,其中R7为氢、C1-3烷基、卤代C1-3烷基或卤素。优选地,R1为任选取代的C1-3烷基。优选地,R1被取代时,取代基的数量可为1-5个,可选自卤素、羟基、氨基(–NR′R″)等,其中,R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基。优选地,R1为C1-3烷基或卤代C1-3烷基。优选地,R′和R″各自独立为氢、任选取代的C1-4烷基或任选取代的C3-6环烷基。优选地,R′和R″被取代时,取代基的数量可为1-5个,可选自卤素、羟基、氨基等。优选地,R′为氢;R″为氢、C1-4烷基、卤代C1-4烷基或C3-6环烷基。优选地,R7为氢、卤素、C1-3烷基或卤代C1-3烷基。优选地,n为0或1。
本发明式I优选化合物的其中一组表示为式III(包括式IIIa和IIIb)所示的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物:
其中,R1、A1、A2、A3、B1、B2、B3和B4如前述任一实施方案所述;
R′和R″各自独立选自氢、任选取代的C1-4烷基或任选取代的C3-6环烷基;或
B3和R″与它们所连接的酰氨基形成6元杂环基。
在式IIIa和IIIb所示的化合物的一个或多个实施方案中,R1为任选取代的C1-3烷基或C3-6环烷基;优选地,R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基。
在式IIIa和IIIb所示的化合物的一个或多个实施方案中,R2被取代时,取代基可以是1-5个选自卤素和羟基的取代基。优选地,R2为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基,更为优选的R2为氢、C1-3烷基或卤素。在优选的实施方案中,A1、A2和A3有且只有一个为N,另外两个独立为CR2,优选地,R2独立为H、C1-3烷基或卤素。在更优选的实施方案中,A3为CH,A1和A2中有一个为N、另一个为CR2,其中,R2为H、C1-3烷基或卤素。在一些实施方案中,A1为N,A2和A3均为CH。在一些实施方案中,A2为N,A1和A3均为CH。在一些实施方案中,A1、A2和A3均为CR2,各R2独立为H、C1-3烷基或卤素;优选地,A3为CH,A1和A2其中之一为CR2,其中R2为H、C1-3烷基或卤素;更为优选地,A2和A3均为CH,A1为CR2,其中R2为C1-3烷基或卤素。
在式IIIa和IIIb所示的化合物的一个或多个实施方案中,B1、B2、B3和B4各自独立选自N和CR7,其中R7优选为氢、卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基和–NR′R″,R′和R″各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基。优选的R7各自独立为氢、C1-3烷基或卤素。在优选的实施方案中,B1和B2均为CH,B3为N,B4为CR7,其中R7为氢、C1-3烷基或卤素。
在式IIIa和IIIb所示的化合物的一个或多个实施方案中,R′和R″各自独立为氢、任选取代的C1-3烷基或任选取代的C3-6环烷基;优选地,R′为氢,R″为氢、C1-3烷基,卤代C1-3烷基或C3-6环烷基。
本发明式I优选化合物的其中一组表示为式IV(IVa和IVb)所示的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药:
其中,A1、A2、R1、R7和R″如前述任一实施方案所述。
在式IVa和IVb所示的化合物的一个或多个实施方案中,A1和A2各自为N和CR2,其中R2优选为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基,更为优选的R2为氢、C1-3烷氧基或卤素。在优选的实施方案中,A1和A2中有一个为N,另一个为CR2,其中,R2为H、C1-3烷基或卤素。在一些实施方案中,A1和A2均为CR2,其中,R2为H、C1-3烷基或卤素。
在式IVa和IVb所示的化合物的一个或多个实施方案中,R1为任选取代的C1-3烷基或C3-6环烷基,优选地,R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基。
在式IVa和IVb所示的化合物的一个或多个实施方案中,R″为氢、任选取代的C1-3烷基或任选取代的C3-6环烷基,优选地,R″为氢、C1-3烷基或卤代C1-3烷基。
在式IVa和IVb所示的化合物的一个或多个实施方案中,R7各自独立为氢、卤素、C1-3烷基或卤代C1-3烷基。
应理解的是,上文虽然对式I(包括式II、III和IV)中的R1、A1、A2、A3、L、Cy、R5、B1、B2、B3、B4、D1、D2、D3、D4、R′、R″和n分别进行了描述,但所描述的各特征,尤其是各优选的特征均可任意组合,形成本发明不同的式I(包括式II、III和IV)化合物的范围。例如,针对一个结构式的R2所描述的特征,当在其它结构式中也存在R2基团时,则该特征同样可用于限定其它结构式的R2基团。
式I的优选的化合物实施例包括但不限于:
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例1);
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例2);
5-(4-((3-异丙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例3);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例4);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例5);
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例6);
5-(4-((2,4-二氧代-3-丙基-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例7);
5-(4-((2,4-二氧代-3-(三氟甲基)-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例8);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例9);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例10);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基-6-(三氟甲基)吡啶甲酰胺(实施例11);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例12);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例13);
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例14);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例15);
5-(4-((1-乙基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(实施例16);
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例17);
5-(4-((2,4-二氧代-3-(三氟甲基)-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例18);
5-(4-((2,4-二氧代-3-丙基-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例19);
5-(4-((3-(2-氟乙基)-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例20);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例21);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例22);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基-6-(三氟甲基)吡啶甲酰胺(实施例23);
5-(4-((3-乙基-8-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例24);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例25);
5-(4-((3-异丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例26);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基嘧啶-2-甲酰胺(实施例27);
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基烟酰胺(实施例28);
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基哒嗪-3-甲酰胺(实施例29);
2-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基嘧啶-5-甲酰胺(实施例30);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-乙基-N-甲基吡啶甲酰胺(实施例31);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟吡啶甲酰胺(实施例32);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-乙基吡啶甲酰胺(实施例33);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-异丙基吡啶甲酰胺(实施例34);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-(二氟甲基)-N-甲基吡啶甲酰胺(实施例35);
3-乙基-7-((4-(2-甲基-1-氧代-1,2,3,4-四氢异喹啉-6-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮(实施例36);
3-乙基-7-((4-(1-氧代-1,2,3,4-四氢异喹啉-6-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮(实施例37);
3-乙基-7-((4-(4-氧代-4H-吡啶并[1,2-a]嘧啶-8-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮(实施例38);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N,N-二甲基吡啶甲酰胺(实施例39);
5-(3-(3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)N-甲基吡啶甲酰胺(实施例40);
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺(实施例41);
5-(3-(3-异丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺(实施例42);
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)-5-氟苯甲酰胺基)-N-甲基吡啶甲酰胺(实施例43);
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-6-氟-N-甲基吡啶甲酰胺(实施例44);
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺(实施例45);
6-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)-N-(6-(甲基氨基甲酰基)吡啶-3-基)吡啶甲酰胺(实施例46);
5-(3-(3-丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺(实施例47);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氟-N-甲基吡啶甲酰胺(实施例48);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N-甲基吡啶甲酰胺(实施例49);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4-二甲基吡啶甲酰胺(实施例50);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3-二甲基吡啶甲酰胺(实施例51);
5-(4-((3-乙基-6-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例52);
5-(4-((3-乙基-6-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例53);
3-乙基-7-((4-(2-甲基-6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮(实施例54);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶-2-甲磺酰胺(实施例55);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例56);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡嗪-2-甲酰胺(实施例57);
5-(1-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌啶-4-基)-N,6-二甲基吡啶酰胺(实施例58);
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例59);
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例60);
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例61);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例62);
5-(4-((3-乙基-5-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例63);
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例64);
5-(4-((3-乙基-6-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例65);
5-(4-((3-乙基-6-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例66);
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例67);
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺(实施例68);
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N-甲基苯甲酰胺(实施例69);
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N-甲基苯甲酰胺(实施例70);
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-甲基-N-甲基苯甲酰胺(实施例71);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4,6-三甲基吡啶甲酰胺(实施例72);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氯-N,6-二甲基吡啶甲酰胺(实施例73);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例74);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4-二甲基嘧啶-2-甲酰胺(实施例75);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡嗪-2-甲酰胺(实施例76);
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,5-二甲基哒嗪-3-甲酰胺(实施例77);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-环丙基吡啶甲酰胺(实施例78);
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,5-二甲基烟酰胺(实施例79);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-异丙基-N-甲基吡啶甲酰胺(实施例80);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例81);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例82);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例83);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例84);
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例85);
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例86);
5-(4-((2,4-二氧代-3-(2,2,2-三氟乙基)-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例87);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氟-N,6-二甲基吡啶甲酰胺(实施例88);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3,6-三甲基吡啶甲酰胺(实施例89);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N,6-二甲基吡啶甲酰胺(实施例90);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N,6-二甲基吡啶甲酰胺(实施例91);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N,3-二甲基吡啶甲酰胺(实施例92);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N,4-二甲基吡啶甲酰胺(实施例93);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例94);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例95);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-三氟甲基-N-乙基吡啶甲酰胺(实施例96);
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-三氟甲基吡啶甲酰胺(实施例97);
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例98);
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例99);
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例100);
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例101);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例102);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例103);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例104);
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例105);
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例106);
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例107);
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例108);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲氧基-N-甲基吡啶甲酰胺(实施例109);
7-((4-(1H-吲哚-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮(实施例110);
7-((4-(1H-吲唑-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮(实施例111);
7-((4-(1H-吲唑-5-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮(实施例112);
7-((4-(1H-苯并[d]咪唑-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮(实施例113);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺(实施例114);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例115);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例116);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例117);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例118);
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(实施例119);
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺(实施例120);
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺(实施例121);
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺(实施例122);
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺(实施例123);
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶酰胺(实施例124);
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-乙基-6-甲基吡啶酰胺(实施例125);
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶酰胺(实施例126);
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺(实施例127);
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶酰胺(实施例128);
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-乙基-6-甲基吡啶酰胺(实施例129);
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶酰胺(实施例130);
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-环丙基吡啶酰胺(实施例131);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-环丙基吡啶酰胺(实施例132);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-乙基吡啶酰胺(实施例133);
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例134);
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-环丙基吡啶酰胺(实施例135);
5-(4-((5-氯-3-乙基-2,4-二氧-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例136);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-环丙基吡啶酰胺(实施例137);
5-(4-((8-氟-3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例138);
5-(4-((8-氟-3-甲基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例139);
5-(4-((3-环丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例140);
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-环丙基吡啶酰胺(实施例141);
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例142);
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺(实施例143);
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(实施例144);
4-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3-二甲基苯甲酰胺(实施例145);
4-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N-甲基苯甲酰胺(实施例146);
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物。
一些本发明化合物可能作为立体异构体,包括旋光异构体存在。本发明包括所有立体异构体和这样的立体异构体的外消旋混合物,以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
可药用盐的例子包括无机和有机酸盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS,氨丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明化合物的前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-C4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-C4羧酸、C3-C6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-C4醛或酮缩合而获得的亚胺);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.42:3623-3628(1999))和Greenwald等人(J.Med.Chem.42:3657-3667(1999))描述的那些酯;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
本发明化合物可使用本领域技术人员已知的方法或本发明新方法制得。具体来说,具有式I(包括式II、III和IV)的本发明化合物可如反应方案1中的反应实施例所示制得。3-氨基-5-溴吡啶甲酸甲酯与Boc酸酐在DMAP、DIEA的催化下反应,得到产物3-(双(叔丁氧基羰基)氨基)-5-溴吡啶甲酸甲酯。3-(双(叔丁氧基羰基)氨基)-5-溴吡啶甲酸甲酯与三甲基环三硼氧烷在Pd(dppf)Cl2的催化下发生Suzuki偶联反应,得到产物3-(双(叔丁氧基羰基)氨基)-5-甲基吡啶甲酸甲酯。3-(双(叔丁氧基羰基)氨基)-5-甲基吡啶甲酸甲酯与NBS在BPO(过氧化二苯甲酰)的催化下发生溴代反应,得到产物3-(双(叔丁氧基羰基)氨基)-5-(溴甲基)吡啶甲酸甲酯。3-(双(叔丁氧基羰基)氨基)-5-(溴甲基)吡啶甲酸甲酯与N-甲基-5-(哌嗪-1-基)吡啶甲酰胺在DIEA的催化下发生反应,得到产物3-(双(叔丁氧基羰基)氨基)-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯。3-(双(叔丁氧基羰基)氨基)-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯在TFA催化下发生脱Boc反应,得到产物3-氨基-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯。3-氨基-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯与乙基异氰酸酯发生关环反应,得到目标化合物5-(4-((3-乙基-2,4-氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺。
反应方案1
其它相关化合物可用类似方法制得。例如,用甲基异氰酸酯替代乙基异氰酸酯,可制得目标化合物5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺。用异丙基异氰酸酯替代乙基异氰酸酯,可制得目标化合物5-(4-((3-异丙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺。用6-氟-N-甲基-5-(哌嗪-1-基)吡啶甲酰胺替代N-甲基-5-(哌嗪-1-基)吡啶甲酰胺,可制得目标化合物5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺。
本发明化合物可如反应方案2中的反应实施例所示制得。2-氨基对苯二甲酸二甲酯、异氰酸乙酯和三乙胺在甲苯中封管加热反应,得到产物3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯。3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯经过氢化铝锂催化还原酯基,得到产物3-乙基-7-(羟甲基)喹唑啉-2,4(1H,3H)-二酮。3-乙基-7-(羟甲基)喹唑啉-2,4(1H,3H)-二酮与氯化亚砜发生氯代反应,得到产物7-(氯甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮。7-(氯甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮与N-甲基-5-(哌嗪-1-基)吡啶甲酰胺在N,N-二异丙基乙胺的催化下发生取代反应,得到目标化合物5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺。
反应方案2
其它相关化合物可用类似方法制得。例如,用6-氟-N-甲基-5-(哌嗪-1-基)吡啶甲酰胺替代N-甲基-5-(哌嗪-1-基)吡啶甲酰胺,可制得目标化合物5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺。用2-氨基-5-氟对苯二甲酸二甲酯替代2-氨基对苯二甲酸二甲酯,可制得目标化合物5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺。用异氰酸丙酯替代异氰酸乙酯,可制得目标化合物5-(4-((2,4-二氧代-3-丙基-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺。
本发明化合物可如反应方案3中的反应实施例所示制得。3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸与草酰氯先反应,然后与5-氨基-N-甲基吡啶甲酰胺在TEA催化下缩合,得到产物N-甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺基)吡啶甲酰胺。N-甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺基)吡啶甲酰胺和7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮在Pd(dppf)Cl2的催化下发生Suzuki偶联反应,得到目标化合物5-(3-(3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)N-甲基-吡啶甲酰胺。
反应方案3
其它相关化合物可用类似方法制得。例如,用7-溴-3-乙基喹唑啉-2,4(1H,3H)-二酮替代7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮可制得目标化合物5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;7-溴-3-异丙基喹唑啉-2,4(1H,3H)-二酮替代7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮可制得目标化合物5-(3-(3-异丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;用7-溴-3-乙基吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮替代7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮可制得目标化合物5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;7-溴-3-丙基喹唑啉-2,4(1H,3H)-二酮替代7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮可制得目标化合物5-(3-(3-丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺。
本发明化合物可如反应方案4中的反应实施例所示制得。4-甲基-3-硝基苯甲酸甲酯与NBS在BPO的催化下发生溴代反应,得到产物4-(溴甲基)-3-硝基苯甲酸甲酯。4-(溴甲基)-3-硝基苯甲酸甲酯与乙胺在DIEA的催化下发生取代反应,得到产物4-((乙氨基)甲基)-3-硝基苯甲酸甲酯。4-((乙氨基)甲基)-3-硝基苯甲酸甲酯在Fe/NH4Cl条件下发生还原反应,得到产物3-氨基-4-((乙氨基)甲基)苯甲酸甲酯。3-氨基-4-((乙氨基)甲基)苯甲酸甲酯与CDI在加热条件下发生关环反应,得到产物3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯。3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯与LiAlH4发生还原反应,得到产物3-乙基-7-(羟甲基)-3,4-二氢喹唑啉-2(1H)-酮。3-乙基-7-(羟甲基)-3,4-二氢喹唑啉-2(1H)-酮与SOCl2在DMF催化下发生氯代反应,得到产物7-(氯甲基)-3-乙基-3,4-二氢喹唑啉-2(1H)-酮。7-(氯甲基)-3-乙基-3,4-二氢喹唑啉-2(1H)-酮与N-甲基-5-(哌嗪-1-基)吡啶甲酰胺在DIEA的催化下发生反应,得到目标化合物5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺。
反应方案4
其它相关化合物可用类似方法制得。例如,用6-氟-N-甲基-5-(哌嗪-1-基)吡啶甲酰胺替代N-甲基-5-(哌嗪-1-基)吡啶甲酰胺可制得目标化合物5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;用6-氯-N-甲基-5-(哌嗪-1-基)吡啶甲酰胺替代N-甲基-5-(哌嗪-1-基)吡啶甲酰胺可制得目标化合物5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;用N,6-二甲基-5-(哌嗪-1-基)吡啶甲酰胺替代N-甲基-5-(哌嗪-1-基)吡啶甲酰胺可制得目标化合物5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺。
本发明的一个重要方面是发现了式I(包括式II、III和IV)化合物是PARP抑制剂,尤其是PARP1的选择性抑制剂。因此,式I(包括式II、III和IV)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药可用于治疗多种因PARP活性异常(尤其是PARP1活性异常)而引起的疾病或病症,或用于制备治疗因PARP活性异常(尤其是PARP1活性异常)而引起的疾病或病症的药物。
本发明中,所述因PARP活性异常(尤其是PARP1活性异常)而引起的疾病或病症包括癌症。癌症可以是实体瘤或血液肿瘤,包括但不限于肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、非小细胞肺癌、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌。优选地,所述癌症与PARP活性异常相关。
因此,本发明提供一种治疗或预防因PARP活性异常(尤其是PARP1活性异常)而引起的疾病或病症的方法,所述方法包括给予需要的对象(尤其是哺乳动物,更具体是人)有效量的式I(包括式II、III和IV)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐盐,或其混合物,或其前药,或含有有效量的式I(包括式II、III和IV)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药的药物组合物。
在实施本发明治疗方法时,给有一种或多种这些症状的病人施用有效量的药物制剂。所述药物制剂含有有效治疗浓度的式I(包括式II、III和IV)化合物,被配制成用于口服、静脉注射、局部或外用给药的形式,用于治疗癌症和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗,有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用,或者可依据有效的治疗方案给药。给药量也许可治愈疾病,但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。
在另一个实施方案中提供了一种药用组合物,其中含有PARP抑制剂的式I(包括式II、III和IV)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,或含有可药用的载体。
本发明另一个实施方案涉及能有效地治疗癌症的药用组合物,其中包含PARP抑制剂的式I(包括式II、III和IV)化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,与至少一种已知的抗癌药物或抗癌药物的可药用盐联合共用。特别是和其他与DNA损伤和修复机理有关的抗癌药物的联合共用,PARP抑制剂olaparib、niraprib、rucaparib、talazoparib、pamiparib、fluzoparib和senaparib;HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他等等。以及和其他与细胞分裂检测点有关的抗癌药物的联合共用,包括Chk1/2抑制剂,CDK4/6抑制剂如帕博西尼,ATM/ATR抑制剂,Wee1抑制剂等等。其他可用于抗癌联合治疗的已知抗癌药物包括但不限于烷化剂例如白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素和卡铂;拓扑异构酶I抑制剂例如喜树碱、伊立替康和托泊替康;拓扑异构酶Ⅱ抑制剂例如阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱和铭托泊普;RNA/DNA抗代谢物例如5-氮杂胞苷、吉西他滨、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物例如5-氟-2′-去氧尿苷、氟达拉滨,奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲和硫代鸟嘌呤;抗有丝分裂剂例如秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇,伊沙匹隆、卡巴他赛和多西他赛;抗体例如单抗,帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀和美罗华;激酶抑制剂例如伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适和依维莫司。其他可用于抗癌组合治疗的已知抗癌药物包括他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(前列腺癌治疗疫苗)。
在实施本发明的方法时,本发明化合物与至少一种已知的抗癌药物可作为单一的药用组合物一起给药。另外,本发明化合物也可与至少一种已知抗癌药分开给药。在一个实施方案,本发明化合物和至少一种已知的抗癌药差不多同时给药,即所有的药物同时施用或陆续施用,只要化合物在血液中同时达到治疗浓度即可。在另外一个实施方案,本发明的化合物和至少一种已知的抗癌药根据各自的剂量方案给药,只要化合物在血液中达到治疗浓度即可。
本发明的另一个实施方案,是一种由所述化合物组成的能有效的抑制肿瘤的,作为激酶抑制剂的生物耦合物。这个能抑制肿瘤的生物耦合物由所述化合物与至少一种已知的有医疗作用的抗体,如赫赛汀或美罗华,或生长因子,如EGF或FGF,或细胞激素,如白细胞介素2或4,或任意能与细胞表面结合的分子组成。该抗体与其他分子能把所述化合物递送到其靶点,使之成为有效的抗癌药物。此生物耦合物也可以提高有医疗作用的抗体,如赫赛汀或美罗华的抗癌效果。
本发明的另一实施例涉及一种能有效抑制肿瘤的药用组合物,包含式I(包括式II、III和IV)所示的PARP抑制剂,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,与放射疗法联合治疗。在此实施例,本发明化合物与放射治疗可在相同时间或不同时间给药。
本发明的另一实施例涉及一种能有效的用于癌症手术后治疗的药用组合物,包含式I(包括式II、III和IV)所示的PARP抑制剂,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药。本发明还涉及用手术切除肿瘤,然后用本发明的药用组合物治疗该哺乳动物的癌症的治疗方法。
本发明的药用组合物包括所有本发明化合物的含有量能有效地实现其预期目标的药品制剂。虽然每个人的需求各不相同,本领域技术人员可确定药品制剂中每个部分的最佳剂量。一般情况下,所述化合物,或其可用药盐,对哺乳动物每天口服给药,药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克/公斤。如果也施用一个已知的抗癌药物,其剂量应可有效地实现其预期的目的。这些已知的抗癌药物的最佳剂量是本领域技术人员所熟知的。
单位口服剂量可以包括约0.01到50毫克,最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次,每天为一片或多片,每片含有约0.1到50毫克,合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
在外用制剂中,本发明化合物的浓度可以是每克载体约0.01到100毫克。
本发明化合物可作为未加工药品给药。本发明化合物也可以作为含有可药用载体(包括辅料和助剂)的一个合适的药物制剂的一部分给药。这些可药用载体有利于把化合物加工成可药用的药物制剂。优选的药物制剂,特别是那些口服的和优选的给药方式类型,如片剂,锭剂和胶囊,以及适合于注射或口服的溶液,包含约0.01%到99%,最好从约0.25%到75%的活性化合物以及辅料。
本发明的范围也包括本发明化合物的无毒性可药用盐。酸加成盐由混合一个无毒性可药用酸溶液和本发明的化合物溶液而形成。所述酸例如盐酸,富马酸,马来酸,琥珀酸,乙酸,柠檬酸,酒石酸,碳酸,磷酸,草酸等。碱加成盐由混合一个无毒性可药用碱溶液和本发明的化合物溶液而形成。所述碱例如氢氧化钠,氢氧化钾,氢胆碱,碳酸钠,三羟甲基氨基甲烷,N-甲基-葡萄糖胺等。
本发明的药物制剂可以给予任何哺乳动物,只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类和兽医动物,虽然本发明不打算如此受限。
本发明的药物制剂可通过任何途径给药以达到其预期目的。例如,可以通过肠外,皮下,静脉,肌肉,腹腔内,透皮,口腔,鞘内,颅内,鼻腔或外用途径给药。作为替代或并行地,可以通过口服给药。药的剂量将根据病人的年龄,健康与体重,并行治疗的种类,治疗的频率,以及所需治疗效益来决定。
本发明的药物制剂可用已知的方式制造。例如,由传统的混合,制粒,制锭,溶解,或冷冻干燥过程制造。制造口服制剂时,可结合固体辅料和活性化合物,选择性研磨混合物。如果需要或必要时加入适量助剂后,加工颗粒混合物,获得片剂或锭剂芯。
合适的辅料特别是填料,例如糖类如乳糖或蔗糖,甘露醇或山梨醇;纤维素制剂和/或钙磷酸盐,例如磷酸三钙或磷酸氢钙;以及粘结剂,例如淀粉糊,包括玉米淀粉,小麦淀粉,大米淀粉,马铃薯淀粉,明胶,黄芪胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要,可增加崩解剂,比如上面提到的淀粉,以及羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,或褐藻酸或其盐,如海藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如,硅石,滑石,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。如果需要,可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此,可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣,可使用适当的纤维素溶液,例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如,用于识别或为了表征活性成分剂量的组合。
其他可口服的药物制剂包括明胶制成的压接式胶囊,以及用明胶和甘油或山梨醇等增塑剂制成的密封软胶囊。该压接式胶囊可含有颗粒形式的活性化合物,与填料例如乳糖;粘结剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,以及稳定剂混合而成。在软胶囊,活性化合物最好是溶解或悬浮在适当的液体例如油脂或液体石蜡中,其中可加入稳定剂。
合适于肠外给药的制剂包括活性化合物的水溶液,如水溶性盐的溶液和碱性溶液。此外,可施用适当的活性化合物的油性注射悬浮液。合适的亲脂性溶剂或载体包括油脂例如香油,合成脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇400,或氢化蓖麻油,或环糊精。水性注射悬浮液可含有增加悬浮液黏度的物质,例如羧甲基纤维素钠,山梨醇,和/或葡聚糖。也可以含有悬浮稳定剂。
按照本发明的一个方面,本发明的化合物采用外用和肠外配方,并用于治疗皮肤癌。
本发明的外用制剂可通过优选合适的载体来制成油剂,霜剂,乳液剂,药膏等。合适的载体包括植物或矿物油,白矿油(白软石蜡),支链脂肪或油脂,动物脂肪和高分子醇(大于C12)。优选的载体是活性成分能溶解在其中的那些载体。也可包括乳化剂,稳定剂,保湿剂和抗氧化剂,以及如果需要的话,给予颜色或香味的试剂。此外,这些外用制剂可包含透皮渗透增强剂。这种增强剂的例子可参见美国专利号3,989,816和4,444,762。
霜剂优选用矿物油,自乳化蜂蜡和水的混合物配制,与溶解于少量油例如杏仁油的活性成分混合而成。一个典型的霜剂例子包括约40份水,20份蜂蜡,40份矿物油和1份杏仁油。
药膏可以这样配制,将含有活性成分的植物油例如杏仁油和温热的软石蜡混合,然后使该混合物冷却。一个典型的药膏例子包括约30%重量的杏仁油和70%重量的白软石蜡。
本发明也涉及应用本发明的化合物制备治疗对抑制PARP有效果的临床病症的药物。这些药物可包括上述药用组合物。
下列实施例是举例说明,而不是限制本发明的方法和制剂。其他对于本领域技术人员来说是显而易见的,和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进,都在本发明的精神和范围内。
实施例
一般性说明
所用试剂均是商品品质,溶剂均按照标准方法干燥纯化。使用电喷雾的单四级杆质谱仪(平台Ⅱ,安捷伦6110)分析质谱样品。使用Brücker Ascend 400核磁仪在300MHz或400MHz记录1H NMR光谱,化学位移记录为以TMS作为内标(0.00ppm)从低场始以ppm为单位,耦合常数J值以Hz为单位。
实施例1
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺
(a)3-(双(叔丁氧基羰基)氨基)-5-溴吡啶甲酸甲酯:将3-氨基-5-溴吡啶甲酸甲酯(3.0g,13.0mmol,1.0eq)、(Boc)2O(7.1g,32.6mmol)、DIEA(5.1g,39.1mmol)和DMAP(318.2mg,2.6mmol)溶于THF(60mL)。所得混合液室温搅拌过夜。反应完全后,减压浓缩反应液,粗品加水(30mL)稀释并用DCM(30mL×3)萃取。合并有机相用饱和食盐水洗涤、无水Na2SO4干燥然后减压浓缩。粗品通过硅胶柱层析纯化(EtOAc/PE,1-5%)得到产物(3.5g,白色固体,收率:62.5%)。MS(ESI,m/z):431.20[M+1]+。
(b)3-(双(叔丁氧基羰基)氨基)-5-甲基吡啶甲酸甲酯:将3-(双(叔丁氧基羰基)氨基)-5-溴吡啶甲酸甲酯(3.0g,7.0mmol)、三甲基环三硼氧烷(6.0mL,21.0mmol,3.5M THF溶液)、Cs2CO3(4.6g,14.0mmol)和Pd(dppf)Cl2(768.6g,1.05mmol)溶于二氧六环(60mL))。反应体系脱气并用氮气置换三次,于100℃搅拌过夜。反应液过滤,减压浓缩滤液。粗品通过硅胶柱层析纯化(EtOAc/PE,10-50%)得到产物(2.3g,白色固体,收率:88.2%)。MS(ESI,m/z):367.30[M+1]+。
(c)3-(双(叔丁氧基羰基)氨基)-5-(溴甲基)吡啶甲酸甲酯:将3-(双(叔丁氧基羰基)氨基)-5-甲基吡啶甲酸甲酯(50.0mg,0.14mmol)、NBS(24.3mg,0.14mmol)和BPO(3.3mg,0.01mmol)溶于CCl4(3mL),并于100℃搅拌过夜。检测显示原料有剩余,补加NBS(12.1mg,0.07mmol)并于100℃搅拌6小时。反应完全后,除去溶剂,粗品通过制备薄层色谱纯化(DCM/MeOH=10:1)得到产物(30.0mg,黄色固体,收率:49.5%)。MS(ESI,m/z):445.30[M+1]+。
(d)3-(双(叔丁氧基羰基)氨基)-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯:将3-(双(叔丁氧基羰基)氨基)-5-(溴甲基)吡啶甲酸甲酯(30.0mg,0.07mmol)、N-甲基-5-(哌嗪-1-基)吡啶甲酰胺(17.5mg,0.08mmol)、DIEA(43.2mg,0.34mmol)和KI(1.1mg,0.01mmol)溶于乙腈(6mL)。反应液于80℃搅拌过夜。反应完全后,反应液过滤,减压浓缩滤液。粗品通过制备薄层色谱纯化(DCM/MeOH=10:1)得到产物(40.0mg粗品),无需纯化直接用于下一步反应。MS(ESI,m/z):585.25[M+1]+。
(e)3-氨基-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯:将3-(双(叔丁氧基羰基)氨基)-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯(40.0mg,0.07mmol)和TFA(39.0mg,0.34mmol)溶于DCM(5mL)。反应液于室温搅拌3小时。反应完全后,反应液加水(10mL)稀释并用DCM(10mL×3)萃取。合并有机相用饱和食盐水洗涤、无水Na2SO4干燥然后减压浓缩。得到目标产物(30.0mg,黄色固体,粗品)。无需纯化直接用于下一步反应。MS(ESI,m/z):385.15[M+1]+。
(f)5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺:将3-氨基-5-((4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)吡啶甲酸甲酯(30.0mg,0.08mmol)、乙基异氰酸酯(1mL)和TEA(1mL)溶于甲苯(10mL)。反应液于120℃搅拌过夜。反应完全后,反应液加水(10mL)稀释并用DCM(10mL×3)萃取。合并有机相用饱和食盐水洗涤、无水Na2SO4干燥然后减压浓缩。粗品通过制备薄层色谱纯化(DCM/MeOH=10:1)得到产物粗品,然后用EA(2mL)打浆得到目标化合物(3.5mg,白色固体,收率:12.3%)。
采用类似的方法制备实施例2-11的化合物。结果如下所示。
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实施例12
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺
(a)3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯:将2-氨基对苯二甲酸二甲酯(200.0mg,1.0mmol)、异氰酸乙酯(228.0mg,3.2mmol)和三乙胺(180.0mg,1.6mmol)在封管中混合于甲苯(3mL)中加热至90℃反应过夜,反应结束浓缩反应液。向剩余物中加入甲醇(5mL)和浓盐酸(3mL),室温搅拌过夜。浓缩反应液后,剩余物依次用水(20mL)和甲醇(20mL)洗,干燥得目标产物粗品(480.0mg,白色固体)。MS(ESI,m/z):249.10[M+1]+,247.00[M-1]-。
(b)3-乙基-7-(羟甲基)喹唑啉-2,4(1H,3H)-二酮:在0℃及氮气保护下,向3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯(200.0mg,0.8mmol)的四氢呋喃(5mL)溶液中加入氢化铝锂(62.0mg,1.6mmol)。反应液恢复至室温后搅拌2小时,用1N盐酸(2mL)淬灭。浓缩混合液加水(10mL)稀释得到黄色漂浮物。将固体过滤,依次用水(10mL)和乙醚(10mL)洗,干燥得到目标产物(80.0mg,2步收率:91%,黄色固体)。MS(ESI,m/z):221.20[M+1]+,219.15[M-1]-。
(c)7-(氯甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮:将3-乙基-7-(羟甲基)喹唑啉-2,4(1H,3H)-二酮(80.0mg,0.2mmol)溶于二氯甲烷(3mL),加入N,N-二甲基甲酰胺(2.4mg,0.03mmol),在0℃下滴加氯化亚砜(231.0mg,1.9mmol)。反应液恢复至室温反应2小时。反应完全后,浓缩反应液得到目标产物粗品(70.0mg)。MS(ESI,m/z):239.35[M+1]+,237.10[M-1]-。
(d)5-(4-((3-乙基-2,4-二氧-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺:室温下,将7-(氯甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮(70.0mg,粗品)、碘化钾(11.0mg,0.1mmol)和N-甲基-5-(哌嗪-1-基)吡啶啉盐酸盐(71.0mg,0.3mmol)溶于乙腈(4mL)中,加入N,N-二异丙基乙胺(209.0mg,1.6mmol)后反应液加热至80℃反应2小时。反应完全后,旋蒸除去溶剂。粗品加水(10mL)稀释,固体过滤。滤饼用甲醇(10mL)洗、乙酸乙酯(10mL)洗,得到目标产物(35mg,2步收率:23%,灰色粉末)。
采用实施例12类似的方法制备实施例13-14的化合物。结果如下所示。
实施例15
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺
(a)4-(溴甲基)-3-硝基苯甲酸甲酯:将4-甲基-3-硝基苯甲酸甲酯(6.9g,35.4mmol)、NBS(6.3g,35.4mmol)和BPO(858.0mg,3.5mmol)溶于CCl4(140mL),加热至100℃反应15小时。反应完全后,除去溶剂,粗品通过硅胶柱层析(EtOAc/PE,2-5%)纯化得到目标产物(4.2g,收率:43.3%,黄色固体)。
(b)4-((乙氨基)甲基)-3-硝基苯甲酸甲酯:将乙胺(6.9mL,13.8mmol,2M in THF)和DIEA(1.4g,10.4mmol)溶于THF(20mL),在-78℃下将4-(溴甲基)-3-硝基苯甲酸甲酯(1.9g,6.9mmol)加入上述溶液中,然后反应液自然升至室温搅拌过夜。反应完全后,除去溶剂,粗品通过硅胶柱层析(EtOAc/PE,10-20%)纯化得到目标产物(1.2g,收率:72.7%,黄色固体)。MS(ESI,m/z):239.20[M+1]+。
(c)3-氨基-4-((乙氨基)甲基)苯甲酸甲酯:将4-((乙氨基)甲基)-3-硝基苯甲酸甲酯(1.0g,4.2mmol)溶于乙醇(30mL),然后加入铁粉(Fe,941.0mg,16.8mmol)和NH4Cl(2.2g,42.0mmol)。室温反应3小时。反应完全后,反应液过滤,乙醇(50mL)洗涤滤饼,合并滤液减压除去溶剂,粗品加水(50mL)稀释,并用DCM(50mL×3)萃取。合并有机相,减压除去溶剂,粗品通过硅胶柱层析(EtOAc/PE,10-50%)纯化得到目标产物(400mg,收率:46.0%,黄色固体)。MS(ESI,m/z):209.05[M+1]+。
(d)3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯:将3-氨基-4-((乙氨基)甲基)苯甲酸甲酯(200.0mg,1.0mmol)溶于乙(5mL),氮气保护下向上述溶液加入N,N'-羰基二咪唑(CDI,623.1mg,3.9mmol)。反应液在80℃搅拌过夜。反应完全后,浓缩反应液,粗品通过制备薄层色谱板纯化(EtOAc/PE,1/1)得到目标化合物(40mg,收率:17.8%,黄色固体)。MS(ESI,m/z):235.00[M+1]+。
(e)3-乙基-7-(羟甲基)-3,4-二氢喹唑啉-2(1H)-酮:将3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-羧酸甲酯(40.0mg,0.2mmol)溶于THF(5mL),0℃氮气保护下向上述溶液加入LiAlH4(26.0mg,0.7mmol)。反应液恢复至室温反应2小时,然后用1M HCl(1mL)淬灭反应。浓缩反应液,再加水(10mL)稀释得到黄色析出物。然后过滤,滤饼先用水洗(10mL)、再用乙醚洗涤(10mL)。干燥后得到目标化合物(35mg,收率:99.0%,黄色固体)。MS(ESI,m/z):207.10[M+1]+。
(f)7-(氯甲基)-3-乙基-3,4-二氢喹唑啉-2(1H)-酮:将3-乙基-7-(羟甲基)-3,4-二氢喹唑啉-2(1H)-酮(35.0mg,0.2mmol)溶于DCM(3mL),0℃下加入DMF(1滴),再滴加SOCl2(80.9mg,0.7mmol)。室温反应2小时。反应完全后,浓缩反应液得到目标化合物粗品(30.0mg,收率:61.2%,灰色固体)。MS(ESI,m/z):225.05[M+1]+。直接用于下一步反应。
(g)5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺:将7-(氯甲基)-3-乙基-3,4-二氢喹唑啉-2(1H)-酮(30.0mg,0.13mmol)、KI(4.4mg,0.03mmol)和N-甲基-5-(哌嗪-1-基)吡啶甲酰胺盐酸盐(37.6mg,0.16mmol)溶于乙腈,然后加入DIEA(86.4mg,0.67mmol)。在80℃下反应2小时。反应完全后,减压除去溶剂。粗品加水稀释(10mL),然后过滤得到固体析出物。滤饼用甲醇(10mL)和乙酸乙酯(10mL)洗涤,干燥后得到目标化合物(22.8mg,收率:41.7%,黄色固体)。MS(ESI,m/z):409.10[M+1]+。CDCl3:δ8.96(s,1H),8.45(d,J=8.0Hz,1H),8.36(d,J=7.9Hz,1H),7.86(d,J=5.4Hz,1H),7.69–7.63(m,1H),7.58(d,J=8.1Hz,1H),7.42(s,1H),4.42–4.36(m,2H),3.99(s,2H),3.62–3.57(m,4H),3.35(d,J=4.6Hz,3H),3.05–2.99(m,4H),2.09(dd,J=14.5,7.3Hz,2H),1.34(t,J=7.2Hz,3H)。
采用实施例12类似的方法制备实施例16-39的化合物。结果如下所示。
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实施例40
5-(3-(3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)N-甲基吡啶甲酰胺
(a)N-甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺基)吡啶甲酰胺:向3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸(1.8g,7.15mmol)的DCM(20mL)溶液中加入草酰氯(2.7g,21.45mmol)和DMF(2滴)。反应液室温搅拌30分钟。旋蒸除去溶剂,剩余物溶于DCM(10mL)备用。低温下向5-氨基-N-甲基吡啶甲酰胺(0.9g,5.96mmol)的DCM(20mL)溶液中加入Et3N(0.9g,8.94mmol),滴加上述制备的溶液。反应液室温搅拌1小时。反应完全后,旋蒸除去溶剂,粗品通过柱色谱纯化(乙酸乙酯-石油醚:0-50%)得到产物(1.3g,收率:48%,白色固体)。MS(ESI,m/z):381.90[M+1]+。
(b)5-(3-(3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)N-甲基-吡啶甲酰胺:将N-甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺基)吡啶甲酰胺(452.0mg,1.2mmol)、7-溴-3-甲基喹唑啉-2,4(1H,3H)-二酮(250.0mg,1.0mmol)、Pd(dppf)Cl2(74.0mg,0.1mmol)和碳酸铯(965.0mg,3.0mmol)溶于DMF(4mL)和水(1mL)。反应体系氮气置换三次,然后100℃反应过夜。反应完全后,反应液过滤,滤饼用甲醇(10mL)洗涤。收集滤饼并溶于DMSO(10mL),过滤除去不溶物,然后除去溶剂得到目标化合物(120.0mg,收率:28%,白色固体)。
采用实施例40类似的方法制备实施例41-47的化合物。结果如下所示。
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采用实施例12类似的方法制备实施例48-113的化合物。结果如下所示。
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采用实施例15类似的方法制备实施例114-146的化合物。结果如下所示。
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实施例147
应用化学发光检测法测定本发明化合物对PARP1和PARP2酶活性的抑制效应
将溶有重组多聚ADP核糖转移酶1和2(PARP1和PARP2)的稀释液(40ng酶/孔)和待测化合物加入到用重组蛋白包被的96孔板中,室温孵育1小时,之后每孔加入50μL 0.3ng/mL辣根过氧化酶的链霉亲和素(Streptavidin-HRP),室温孵育30分钟。最后加入相应底物并用EnviSion仪器读板,记录化学发光信号,按照以下公式计算出待测化合物对PAPP1和PARP2酶活性的抑制率。
注:阴性对照孔读数为只加酶稀释液(不加酶和待测化合物)孔读数,表示酶0%活性;阳性对照孔读数为1%DMSO(不加待测化合物)孔读数,表示酶100%活性;X为待测化合物孔的读数。
表1汇总了本发明化合物的PARP1和PARP2酶活性的抑制效应(IC50)。其中,+++++表示IC50≤1nM;++++表示1<IC50≤10nM;+++表示10nM<IC50≤100nM;++表示100nM<IC50≤1μM;+表示IC50>1μM。
表1
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本发明的大部分化合物对PARP1酶活性有选择性抑制作用。
实施例148
应用CCK-8检测法测定本发明化合物对人乳腺癌细胞MDA-MB-436的抑制作用
细胞复苏后用完全培养基(DMEM培养基+10% FBS+insulin+谷胱甘肽)培养传代。待细胞汇合度达到80%左右后,用1mL移液器轻轻将细胞从培养皿底部吹离,收集细胞悬液,500rpm离心3min;弃去上清液,加入完全培养基重悬细胞,按合适比例接种到培养皿后置于37℃,5% CO2培养箱静置培养。细胞培养传代至生长状态良好、融合度80%左右,开始用于实验。用1mL移液器轻轻将处于对数生长期的细胞轻轻吹下,500rpm离心3min,弃上清,用新鲜培基重悬,分散成单个细胞,并计数,以每孔3000个细胞的密度接种至96孔细胞培养板(第一列空置),置于37℃,5% CO2培养箱培养过夜。次日,化合物母液用DMSO按1:3比例分别进行连续系列稀释共8个浓度,每个浓度取5μL加入到120μL培基(25倍稀释),同时做DMSO对照孔,振荡混匀。从CO2培养箱中取出细胞,吸弃孔里的旧培基,每孔加入195uL新鲜培基,然后在对应孔中分别加入5μL在培基中稀释好的含相应浓度的化合物,随后将培养板置于37℃5% CO2培养箱培养共7天,其中于第4天换一次药。7天后,每孔加20μL CCK-8震荡后,继续培养。4h后震荡5min,置于多功能读数仪上分别读取450nm和650nm波长的吸光值(OD值=吸光值450nm-吸光值650nm)。
用软件GraphPad Prism 6.0分析数据,化合物对细胞增殖的抑制活性以细胞存活率和化合物浓度为坐标绘图。细胞存活率%=(OD化合物-OD背景)/(ODDMSO-OD背景)×100。IC50值以S形剂量反应曲线方程拟合,曲线方程为:Y=100/(1+10^(LogC-LogIC50)),C是化合物浓度。
表2汇总了化合物对人乳腺癌细胞MDA-MB-436增长的抑制作用数据(IC50)。其中,++++表示1<IC50≤10nM;+++表示10nM<IC50≤100nM;++表示100nM<IC50≤1μM;+表示IC50>1μM。
表2
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本发明化合物对有BRCA突变的MDA-MB-436细胞的生长具有抑制作用。
虽然已经充分地描述了本发明,但是本领域技术人员应当理解,可在不影响本发明范围或其任何实施方案的情况下,在广泛且等同的条件、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。
Claims (15)
1.下式I所示的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物:
其中,R1选自任选取代的烷基、任选取代的碳环基、任选取代的烯基和任选取代的炔基;
A1、A2和A3各自独立选自N和CR2;
L选自键和任选被R3和/或R4取代的亚烷基;
Cy选自任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;
R2选自氢、卤素、任选取代的烷基、任选取代的烷氧基和任选取代的碳环基;
R3和R4各自独立选自卤素、氰基、任选取代的烷基、任选取代的烷氧基、任选取代的环烷基、任选取代的烯基和任选取代的炔基;或者R3和R4与连接的C形成环;
n选自0,1和2;
其中,当n不为0时,所示-(CH2)n-任选地被一个=O取代。
2.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药;其中,R1为任选被1–5个选自卤素、羟基和-NR'R”的取代基取代的C1-3烷基或C3-6环烷基,其中,R′和R″优选各自独立为H、任选被1–5个选自羟基和卤素的取代基取代的C1-4烷基或C3-6环烷基;优选地,R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基。
3.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其中,R3和R4优选各自独立为卤素或C1-3烷基;L为键或未被取代的亚烷基,优选为未被取代的C1-3亚烷基,更优选为亚甲基。
4.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其中,R2为氢、卤素、任选被1-5个选自卤素和羟基的取代基取代的C1-3烷基或C1-3烷氧基,优选的R2为氢、C1-3烷基或卤素。
5.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药;其中,
A1、A2和A3有且只有一个为N,另外两个独立为CR2,优选地,R2独立为H、C1-3烷基或卤素;或
A3为CH,A1和A2中有一个为N、另一个为CR2,其中,R2为H、C1-3烷基或卤素;或
A1为N,A2和A3均为CH;或
A2为N,A1和A3均为CH;或
A1、A2和A3均为CR2,各R2独立为H、C1-3烷基或卤素;或
A3为CH,A1和A2其中之一为CR2,其中R2为H、C1-3烷基或卤素;或
A2和A3均为CH,A1为CR2,其中R2为C1-3烷基或卤素。
6.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其中,Cy可能被1-5个取代基取代,选自:卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基、任选取代的C3-8环烷基和-(CH2)m-C(O)-NRaRb的取代基;
其中,Ra和Rb可独立为H、C1-4烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基;优选地,Ra和Rb中至少一个为任选取代的6-14元芳基、任选取代的5-10元杂芳基或任选取代的4-10元杂环基;
m为0-5的整数,优选地,m为0;
其中,所述任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基各自可独立地被1-5个选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、-S(O)2-NR'R”、-NR'R”、-C(O)-NR'R”和任选取代的5-10元杂芳基;优选地,Cy取代基定义中的所述任选取代的5-10元杂芳基、任选取代的4-10元杂环基和任选取代的C3-8环烷基以及Ra和Rb定义中的所述任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基的取代基至少包括-C(O)-NR′R″,任选还包括卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个;
其中,所述R′和R″优选各自独立为H、任选取代的C1-4烷基或任选取代的C3-6环烷基,优选为H、C1-4烷基、卤代C1-4烷基和C3-6环烷基;
优选地,Cy被5-10元杂芳基所取代,优选地,被含氮5-10元杂芳基所取代,该含氮5-10元杂芳基至少被所述-C(O)-NR′R″取代,并任选地还被卤素、C1-4烷氧基和C1-4烷基中的任意一个或两个所取代。
7.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药;其中,Cy被R5取代,R5优选为如下基团:
其中,B1,B2,B3和B4各自独立选自N和CR7;R7选自氢、卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基和–NR′R″;R′和R″各自独立选自氢、任选取代的C1-4烷基或任选取代的C3-6环烷基;*表示所述基团与化合物其它部分连接的位置。
8.如权利要求1所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其特征在于,所述式I化合物具有下式IIa和IIb所示结构:
其中,R1、A1、A2、A3和n如权利要求1、2和5所定义;
R5选自任选取代的芳基和任选取代的杂芳基,或者如权利要求6所定义;
D1、D2、D3和D4各自独立选自N和CR6;
R6各自选自氢、卤素、任选取代的烷基、任选取代的烷氧基、任选取代的碳环基、任选取代的烯基和任选取代的炔基,优选地,R6为氢、卤素、任选取代的C1-3烷基或任选取代的C1-3烷氧基。
9.如权利要求8所述的式I的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其中,
R1为C1-3烷基、卤代C1-3烷基或C3-4环烷基;
A1、A2和A3各自独立选自N和CR2;
R5为氨基酰基在对位取代的苯基、吡啶基、嘧啶基或哒嗪基;或R5为任选取代的1-氧代-1,2,3,4-四氢异喹啉-6-基或4-氧代-4H-吡啶并[1,2-a]嘧啶-8-基;或R5为任选取代的吡啶并嘧啶基、吲哚基、吲唑基或苯并咪唑基;
D1、D2、D3和D4各自独立选自N和CR6,其中,R6为氢、C1-3烷基、卤代C1-3烷基或卤素;和
n为0或1。
10.如权利要求1所述的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其特征在于,所述式I化合物具有下式IIIa或IIIb所示的结构:
其中,R1、A1、A2和A3如权利要求1、2和5所定义;
B1,B2,B3和B4如权利要求7所定义;
R′和R″各自独立选自氢、任选取代的C1-4烷基或任选取代的C3-6环烷基,如权利要求2所定义;或
B3和R″可与所连接的酰氨基形成6元杂环基。
11.如权利要求1所述的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物,或其前药,其特征在于,所述式I化合物具有下式IVa或IVb所示的结构:
其中,R1、A1、A2如权利要求1、2和5所定义;R″如权利要求2所定义;
R7为氢、卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基和–NR′R″,R′和R″各自独立为H、C1-4烷基、卤代C1-4烷基或C3-6环烷基。
12.如权利要求1的化合物,其特征在于,所述化合物选自:
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-异丙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((2,4-二氧代-3-丙基-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((2,4-二氧代-3-(三氟甲基)-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯--N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基-6-(三氟甲基)吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((1-乙基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺;
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((2,4-二氧代-3-(三氟甲基)-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((2,4-二氧代-3-丙基-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-(2-氟乙基)-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基-6-(三氟甲基)吡啶甲酰胺;
5-(4-((3-乙基-8-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-异丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基嘧啶-2-甲酰胺;
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基烟酰胺;
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基哒嗪-3-甲酰胺;
2-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基嘧啶-5-甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-乙基-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-异丙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-(二氟甲基)-N-甲基吡啶甲酰胺;
3-乙基-7-((4-(2-甲基-1-氧代-1,2,3,4-四氢异喹啉-6-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
3-乙基-7-((4-(1-氧代-1,2,3,4-四氢异喹啉-6-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
3-乙基-7-((4-(4-氧代-4H-吡啶并[1,2-a]嘧啶-8-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N,N-二甲基吡啶甲酰胺;
5-(3-(3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)N-甲基吡啶甲酰胺;
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;
5-(3-(3-异丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)-5-氟苯甲酰胺基)-N-甲基吡啶甲酰胺;
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-6-氟-N-甲基吡啶甲酰胺;
5-(3-(3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;
6-(3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)-N-(6-(甲基氨基甲酰基)吡啶-3-基)吡啶甲酰胺;
5-(3-(3-丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)苯甲酰胺基)-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3-二甲基吡啶甲酰胺;
5-(4-((3-乙基-6-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
3-乙基-7-((4-(2-甲基-6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)哌嗪-1-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶-2-甲磺酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基吡嗪-2-甲酰胺;
5-(1-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌啶-4-基)-N,6-二甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氯-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-6-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-6-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺;
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N-甲基苯甲酰胺;
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N-甲基苯甲酰胺;
4-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-甲基-N-甲基苯甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4,6-三甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氯-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,4-二甲基嘧啶-2-甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡嗪-2-甲酰胺;
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,5-二甲基哒嗪-3-甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-环丙基吡啶甲酰胺;
6-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,5-二甲基烟酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-异丙基-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((2,4-二氧代-3-(2,2,2-三氟乙基)-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-4-氟-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3,6-三甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氟-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N,3-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N,4-二甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-三氟甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-三氟甲基吡啶甲酰胺;
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-甲基2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-甲基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-6-甲氧基-N-甲基吡啶甲酰胺;
7-((4-(1H-吲哚-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮;
7-((4-(1H-吲唑-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮;
7-((4-(1H-吲唑-5-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮;
7-((4-(1H-苯并[d]咪唑-6-基)哌嗪-1-基)甲基)-3-乙基喹唑啉-2,4(1H,3H)-二酮;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶甲酰胺;
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺;
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-乙基-6-甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶酰胺;
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N-乙基-6-甲基吡啶酰胺;
5-(4-((5-氯-3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-乙基吡啶酰胺;
5-(4-((5-氯-3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-环丙基吡啶酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氯-N-环丙基吡啶酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-乙基吡啶酰胺;
5-(4-((3-乙基-5-氟-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-乙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-环丙基吡啶酰胺;
5-(4-((5-氯-3-乙基-2,4-二氧-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-甲基-N-环丙基吡啶酰胺;
5-(4-((8-氟-3-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((8-氟-3-甲基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-环丙基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-乙基-5-氟-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-环丙基吡啶酰胺;
5-(4-((3-乙基-5-甲基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-乙基-5-甲氧基-2,4-二氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-6-氟-N-甲基吡啶酰胺;
5-(4-((3-乙基-2-氧代-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺;
4-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-N,3-二甲基苯甲酰胺;
4-(4-((3-乙基-2-氧代-1,2,3,4-四氢喹唑啉-7-基)甲基)哌嗪-1-基)-3-氯-N-甲基苯甲酰胺;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物。
13.权利要求1~12中任一项所述的化合物、或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物在制备治疗或预防因PARP活性异常而引起的疾病或病症的药物中的用途;优选地,所述疾病或病症是癌症;其特征在于,所述癌症是肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、非小细胞肺癌、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌;
优选地,所述药物还包括至少一种已知的抗癌药物,或所述抗癌药物的可药用盐;优选地,所述抗癌药物选自下组中的一种或多种:伏立诺他、罗咪地辛、帕比司他、贝利司他、帕博西尼、白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适、依维莫司、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(前列腺癌治疗疫苗);
优选地,所述药物与放射治疗联用。
14.一种药用组合物,包括权利要求1~12中任一项所述的化合物、或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、同位素标记化合物或可药用盐,或其混合物与可药用载体。
15.如权利要求14所述的药用组合物,其特征在于,所述药用组合物还含有至少一种已知的抗癌药物,或所述抗癌药物的可药用盐;优选地,所述至少一种已知的抗癌药物选自下组:伏立诺他、罗咪地辛、帕比司他、贝利司他、帕博西尼、白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适、依维莫司、伏立诺他、罗咪地辛、帕比司他、贝利司他、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(前列腺癌治疗疫苗)。
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