CN114728950A - 可作为helios蛋白质抑制剂的化合物 - Google Patents
可作为helios蛋白质抑制剂的化合物 Download PDFInfo
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- CN114728950A CN114728950A CN202080080392.0A CN202080080392A CN114728950A CN 114728950 A CN114728950 A CN 114728950A CN 202080080392 A CN202080080392 A CN 202080080392A CN 114728950 A CN114728950 A CN 114728950A
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- CN
- China
- Prior art keywords
- methyl
- pyridin
- dione
- piperidine
- oxoisoindolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 250
- 102100037796 Zinc finger protein Helios Human genes 0.000 title claims abstract description 85
- 239000003112 inhibitor Substances 0.000 title description 11
- 101100452383 Homo sapiens IKZF2 gene Proteins 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 90
- 150000003839 salts Chemical class 0.000 claims abstract description 87
- 101000599037 Homo sapiens Zinc finger protein Helios Proteins 0.000 claims abstract description 81
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 37
- 201000011510 cancer Diseases 0.000 claims abstract description 21
- -1 azocanyl Chemical group 0.000 claims description 199
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 150000003254 radicals Chemical class 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000003386 piperidinyl group Chemical group 0.000 claims description 34
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 31
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 28
- 125000003944 tolyl group Chemical group 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 27
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000005605 benzo group Chemical group 0.000 claims description 24
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000002541 furyl group Chemical group 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 22
- 125000002757 morpholinyl group Chemical group 0.000 claims description 20
- 230000014509 gene expression Effects 0.000 claims description 19
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 125000002393 azetidinyl group Chemical group 0.000 claims description 14
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
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- 238000006467 substitution reaction Methods 0.000 claims description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
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- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
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- FOXVJDIFTITBFM-UHFFFAOYSA-N CN(C)CC1=CC(=NC=C1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O Chemical compound CN(C)CC1=CC(=NC=C1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O FOXVJDIFTITBFM-UHFFFAOYSA-N 0.000 claims description 9
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
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- XFUWXHRODPEIRS-UHFFFAOYSA-N ClC=1C(=CC(=NC=1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O)CN1CC(C1)C1=CC=CC=C1 Chemical compound ClC=1C(=CC(=NC=1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O)CN1CC(C1)C1=CC=CC=C1 XFUWXHRODPEIRS-UHFFFAOYSA-N 0.000 claims description 8
- MEQNPIVQXLKYCK-UHFFFAOYSA-N FC=1C(=NC=CC=1CN1CC(C1)C1=CC=CC=C1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O Chemical compound FC=1C(=NC=CC=1CN1CC(C1)C1=CC=CC=C1)C=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O MEQNPIVQXLKYCK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
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- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
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- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 7
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
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- 229910052799 carbon Inorganic materials 0.000 claims description 6
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Abstract
Description
交叉引用
本申请主张2019年11月19日申请的美国临时申请序列号62/937,350的权益,其全文以引用的方式并入本文中。
技术领域
本发明大体上涉及抑制Helios蛋白质的化合物。本文中提供化合物、包含这些化合物的组合物及其使用方法。本发明进一步关于药物组合物,所述药物组合物包含可用于治疗增殖性病症(诸如癌症)及病毒感染的根据本发明的至少一种化合物。
背景技术
调节性T细胞(Treg)在面对剧烈免疫及炎症反应时经由维持抑制活性及失能来控制自身耐受性及免疫稳态中起着必不可少的作用。虽然保留稳定失能且抑制性的表型,但是Treg使过度免疫反应减弱且防止或改善自体免疫性。许多报道已将人类肿瘤组织中存在Treg记录在案。研究证明Treg的数目与T细胞浸润至肿瘤及生存之间的明确负相关(Curiel等人,2004,Nat.Med.10:942-949;Viguier等人,2004,J Immuno.1173:1444-1453;Beyer等人,2006,Blood 108:804-811;Zou等人,2006,Nat.Rev.Immunol.6:295-307),暗示Treg在预防有效抗肿瘤免疫的发展中的潜在关键作用。累积证据指示,Foxp3+CD25+CD4+Treg主要浸润至肿瘤及明显阻碍对啮齿动物及人类中的肿瘤细胞的免疫反应。一旦通过特定抗原活化,Treg于体外以抗原非特异性及旁观者方式抑制反应T细胞(Takahashi等人,1998,IntImmunol.10:1969-80;Thornton等人,1998,J Exp.Med.188:287-96)。Foxp3+CD25+CD4+Treg显然能抑制涉及CD4+辅助T细胞、CD8+T细胞、自然杀伤细胞及自然杀伤T细胞的宽范围的抗肿瘤免疫反应(Tanaka等人,2017,Cell Research 27:109-118)。CD25+CD4+Treg的肿瘤内耗尽诱导建立的肿瘤的消退与肿瘤部位处的细胞因子环境的变化(Yu等人,2005,JExp Med.201:779-91)。此外,Treg耗尽的CD4+T细胞的转移与含Treg的T细胞转移相比显著增强抗肿瘤免疫反应(Antony等人,2005,J Immunol 174:2591–601)。通过肿瘤衍生的自身抗原或肿瘤相关抗原活化的肿瘤浸润性Treg可相似抑制特定抗肿瘤免疫反应。控制Treg分化的关键因子的活性的调节可表示用于治疗某些疾病(包括癌症及病毒感染)的潜在治疗策略。
FoxP3+CD4 Treg为显著稳定的。研究仍在开展以了解在发炎、感染或自体免疫期间于扩增后确保其表型稳定性的遗传机制。负责维持Treg的稳定免疫抑制表型的转录因子(TF)可有助于此过程。Helios(IKZF2)基因(TF的Ikaros家族的成员)不同于其他Ikaros家族成员,基于其通过经历阴性选择的胸腺细胞以及通过CD4及CD8 T细胞的调节谱系的选择性表达。Helios通过对维持自身耐受性必不可少的两个调节性T-细胞谱系FoxP3+CD4+及Ly49+CD8+Treg表达(Kim等人,2015,Science 350:334-339;Sebastian等人,2016,JImmunol196:144-155)。有趣的是,最近研究表明,虽然Helios在稳态下对于Treg活性很大程度上是非必需的,但是在发炎的背景下,通过Helios控制FoxP3+CD4Treg的遗传程序对维持稳定表型及潜在抑制功能必不可少(Thornton等人,2010,J Immunol.184:3433-3441;Kim等人,2015)。证明通过Treg的Helios表达在面对强烈炎症反应时在其维持抑制性且失能表型的能力中是关键的。证明活化IL-2Rα-STAT5路径通过确保Treg生存及稳定性而成为关键贡献者(Kim等人,2015)。Helios在维持FoxP3+CD4 Treg的表型中起着必需作用,其通过发挥显性淋巴细胞固有抑制来在存在来自鳞状(Scurfy)小鼠的高度活化的自身反应性T细胞下预防自体免疫疾病,该鳞状小鼠不具有FoxP3叉形头域。利用Helios–/–/鳞状骨髓(BM)而非Helios+/+/鳞状BM细胞再构成的BM嵌合体快速形成自体免疫性(Kim等人,2015)。这些观察结果指示,Helios对自身反应性T细胞选择、分化及功能的关键贡献。由Treg所发挥的免疫抑制可阻碍抗肿瘤免疫反应。Helios在FoxP3+CD4 Treg中的选择性缺乏会导致增加的Treg不稳定性及肿瘤内CD4 Treg转化成效应T细胞(Teff)。作为Treg转化及降低的Treg抑制活性的组合结果,肿瘤内Treg的不稳定性可增加肿瘤内的Teff细胞的数目。此外,在缺乏Helios的肿瘤内Treg中观察到缺陷IL-2反应,该Treg导致减少的经活化Treg的数目及亦可有助于增加的肿瘤内Teff活性。肿瘤细胞与浸润免疫细胞之间的相互作用导致分泌炎症介质(包括TNF-α、IL-6、IL-17、IL-1及TGF-β),及形成局部发炎环境(Kim等人,2015)。
缺乏Helios的Treg的谱系不稳定性亦伴随减少的FoxP3表达及导致通过产生促发炎细胞因子来获取效应表型。缺乏Helios的Treg在肿瘤-组织微环境内的效应细胞转化与控制Teff表型的基因的增加的表达相关联(Yates等人,2018,PNAS,2018,115:2162-2167)。因Helios缺乏获取不稳定表型不仅于肿瘤微环境(TME)内发生,而且于外周类淋巴器官中发生(Nakagawa等人,2016,PNAS 113:6248-6253)。于慢性炎性TME内,Treg中的Helios缺乏可通过上调与TF及效应细胞因子相关联的T辅助细胞来急剧减轻与T辅助细胞分化相关联的经抑制的遗传程序。缺乏Helios的Treg的这些遗传变化于具有对自身抗原的高亲和力的Treg亚群中最明显,如由增强的GITR/PD-1表达及增加的对自身抗原的反应性所示。其组合效应可促进TME内Treg表型转化成Teff,其中通过Treg增加T-细胞受体(TCR)参与及共刺激受体表达,这表明基因表达的改变,因为Treg转化的中心特征为免疫环境依赖性(Yates等人,2018)。
FoxP3+CD4 Treg中的减少的Helios表达可允许记忆Treg转化成Teff细胞,所述Teff细胞表达具有针对肿瘤抗原的特异性的自身反应性T-细胞受体。改变的Treg特征标记可在生长肿瘤的慢性炎性状况内经选择性诱导。缺乏Helios的Treg可显示歪向针对自身肽/MHC的高亲和力的TCR库,其可促进TME中的稳健活化(Yates等人,2018)。鉴于与常规T细胞相比CD4 Treg中增加的TCR自身反应性,Treg的转化可产生高度强效效应CD4 T细胞伴随TME内的减弱的Treg介导的抑制。更有效策略可取决于将肿瘤内Treg选择性转化成Teff细胞而不影响全身Treg群体的方法。作为在维持Treg大小及对不同免疫扰动的反应的功能稳定性中的关键角色,Helios的药物介入可与加强目前肿瘤免疫疗法的策略相关。因为Treg转化为Teff可局限于炎性肿瘤内微环境,靶向Helios的基于抗体或小分子的方法可导致改善的Treg依赖性癌症免疫疗法。重要的是,缺乏Helios的Treg的转化仅于肿瘤的局部炎性环境内发生。此方法可不激起与Treg的全身减少相关联的自体免疫副作用。因此,特异性驾驭对肿瘤内Treg表型的Helios依赖性控制的策略代表改善癌症免疫疗法的重要前景。此外,亦据报道,移除Foxp3+Treg以增强疫苗诱导的抗肿瘤T-细胞反应(Nishikawa等人,2010,Int.J.Cancer 127:759-767),这表明减少Helios含量可有益于提高癌症疫苗的功效。
除了抗肿瘤免疫疗法外,在病毒感染期间,Treg细胞可限制由过度发炎产生的免疫病理学,又潜在抑制有效抗病毒T细胞反应及促进病毒持久性(Schmitz等人,2013,PLOSPathogens 9:e1003362)。小鼠经淋巴细胞性脉络丛脑膜炎病毒的慢性(但是非急性)感染导致Foxp3+Treg的显著扩增,这暗示某些感染性因子可通过活化及扩增Treg逃避宿主免疫反应的潜在机制(Punkosdy等人,2011,PNAS 108:3677-3682)。于与慢性病毒感染相关的背景下,治疗效益可通过减少经活化Treg中的Helios含量来达成。
存在对可用作Helios蛋白质抑制剂的化合物的需求。
发明内容
本发明提供式(I)化合物或其盐,其可用于减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平。
本发明亦提供药物组合物,其包含式(I)化合物和/或其药学上可接受的盐;及药学上可接受的载剂。
本发明亦提供一种通过减少Helios蛋白质的活性来治疗疾病或病症的方法,该方法包括向患者施用式(I)化合物和/或其药学上可接受的盐。
本发明亦提供用于制备式(I)化合物和/或其盐的方法及中间体。
本发明亦提供式(I)化合物和/或其药学上可接受的盐,其用于疗法中。
本发明亦提供式(I)化合物和/或其药学上可接受的盐的用途,其用于制造减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平以控制Treg分化的药剂,该药剂用于治疗某些疾病,包括癌症及病毒感染。
式(I)化合物及包含式(I)化合物的组合物可用于治疗、预防或治愈病毒感染及各种增殖性病症(诸如癌症)。包含这些化合物的药物组合物可用于治疗、预防各种治疗领域中的疾病或病症(诸如病毒感染及癌症)或减慢其的进展。
本发明的这些及其他特征将随着本发明继续以扩展形式阐述。
具体实施方式
申请者已发现通过促进Helios蛋白质与对应E3泛素连接酶复合体(Cullin4-Cereblon,CUL4-CRBN)的相互作用来抑制Helios蛋白质的化合物。这些化合物减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平以控制Treg分化。这些化合物可用于治疗某些疾病,包括癌症及病毒感染。提供可用作药物的化合物,所述药物具有所需稳定性、生物可利用率、治疗指数及对其可成药性(drugability)重要的毒性值。
本发明的第一方面提供至少一种式(I)化合物或其盐:
其中:
Z为CR6R6或C=O;
环A为:
R1为-(CRzRz)1-2NR1aR1b;
R1a为氢、C1-6烷基、C1-4氟烷基、C1-3氰基烷基、C1-6羟烷基、-(CH2)1-3O(C1-3烷基)、-(CH2)1-3S(O)2(C1-3烷基)、-(CH2)1-3C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-3C(O)NRxRx、-(CH2)1-3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;
R1b为氢、C1-3烷基或-CH2(苯基);
或R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶酮基、哌啶基、吡咯烷基、吡咯烷酮基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代;
R1c为C3-7环烷基、苯基、氧杂环丁烷基、氮杂环丁烷基、呋喃基、吡喃基、吡咯基、吡咯烷基、吡咯烷酮基、吡唑基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、二氧代四氢噻喃基、二氧化四氢噻吩基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被独立地选自以下的0至2个取代基取代:F、Cl、-CN、-OH、C1-3烷基、C1-3氟烷基、C1-3羟烷基、C1-3烷氧基、C1-3氟烷氧基、-C(O)O(C1-3烷基)、-NRyRy、-S(O)2(C1-3烷基)、-S(O)2NRxRx、-CH2(苯基)、-NO2、C3-6环烷基、咪唑基及苯基;
R1d为C1-4烷基、C1-2氟烷基、C1-3烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;
R1e为-CH3;
各R2独立地为卤素、-CN、C1-3烷基、C1-3氟烷基、C1-3烷氧基或C1-3氟烷氧基;NR2(R=H、C1-3烷基)、任选经取代的苯基、任选经取代的杂芳基;
R3为R1a;
各R4独立地为卤素、-CN、C1-3烷基、C1-3氟烷基、C1-3烷氧基或C1-3氟烷氧基;
R5为氢、F或C1-3烷基;
各R6独立地为氢或C1-3烷基;
各Rx独立地为H或-CH3;
各Ry独立地为H或C1-4烷基;
各Rz独立地为H或-CH3;或连接至相同碳原子的两个Rz形成3-至6-元碳环或3-至6-元杂环;
m为0、1或2;且
n为0、1、2或3。
一个实施方案提供式(I)化合物或其盐,其中:
R1a为氢、C1-6烷基、C1-3氟烷基、C1-2氰基烷基、C1-4羟烷基、-(CH2)1-3OCH3、-(CH2)1-3S(O)2(C1-2烷基)、-(CH2)1-2C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-2C(O)NRxRx、-(CH2)1- 3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;
或R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代;
R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、二氧代四氢噻喃基、二氧化四氢噻吩基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被独立地选自以下的0至2个取代基取代:F、Cl、-CN、-OH、C1-2烷基、C1-2氟烷基、C1-2羟烷基、C1-2烷氧基、C1-2氟烷氧基、-C(O)O(C1-2烷基)、-NRxRy、-S(O)2(C1-2烷基)、-S(O)2NRxRx、-CH2(苯基)、-NO2、C3-6环烷基、咪唑基及苯基;
R1d为C1-3烷基、C1-2氟烷基、C1-3烷氧基、-NRxRy、-NRxC(O)(C1-2烷基)、-C(O)(C1-2烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;
各R4独立地为F、Cl、-CN、-CH3、-CHF2、-CF3、-OCH3或-OCF3;
R5为氢、F或-CH3;
m为0或1;且
n为0、1或2。
一个实施方案提供式(I)化合物或其盐,其具有以下结构:
其中:
R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c;
或R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代;
R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被独立地选自以下的0至2个取代基取代:F、Cl、-CN、-OH、-CH3、-CF3、-OCH3、-OCF3、-C(O)OCH3、-NH(CH3)、-N(CH3)2、-S(O)2CH3、-S(O)2N(CH3)2、-CH2(苯基)、-NO2、环丙基、咪唑基及苯基;
R1d为-CH3、-CH(CH3)2、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;且
R1e为-CH3。
一个实施方案提供式(I)化合物或其盐,其具有以下结构:
其中:
R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c;
或R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代;
R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被独立地选自以下的0至2个取代基取代:F、Cl、-CN、-OH、-CH3、-CF3、-OCH3、-OCF3、-C(O)OCH3、-NH(CH3)、-N(CH3)2、-S(O)2CH3、-S(O)2N(CH3)2、-CH2(苯基)、-NO2、环丙基、咪唑基及苯基;
R1d为-CH3、-CH(CH3)2、-OCH3、-OCH2CH3、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH3)2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;且
R1e为-CH3;
R4为-CH3;且
n为0或1。
一个实施方案提供式(I)化合物或其盐,其中Z为CR6R6。此实施方案的化合物具有以下结构:
包含于此实施方案中的是其中各R6独立地为氢或-CH3的化合物。亦包含于此实施方案中的是其中各R6为氢的化合物。
一个实施方案提供式(I)化合物或其盐,其中Z为C=O。此实施方案的化合物具有以下结构:
一个实施方案提供式(I)化合物或其盐,其中R1a为氢、C1-6烷基、C1-4氟烷基、C1-3氰基烷基、C1-6羟烷基、-(CH2)1-3O(C1-3烷基)、-(CH2)1-3S(O)2(C1-3烷基)、-(CH2)1-3C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-3C(O)NRxRx、-(CH2)1-3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;且R1b为氢、C1-3烷基或-CH2(苯基)。
一个实施方案提供式(I)化合物或其盐,其中R1a为氢、C1-6烷基、C1-3氟烷基、C1-2氰基烷基、C1-4羟烷基、-(CH2)1-3OCH3、-(CH2)1-3S(O)2(C1-2烷基)、-(CH2)1-2C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-2C(O)NRxRx、-(CH2)1-3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;且R1b为氢、C1-3烷基或-CH2(苯基)。
一个实施方案提供式(I)化合物或其盐,其中R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c;且R1b为氢、C1-3烷基或-CH2(苯基)。
一个实施方案提供式(I)化合物或其盐,其中R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶酮基、哌啶基、吡咯烷基、吡咯烷酮基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代。包含于此实施方案中的是其中R1d为C1-3烷基、C1-2氟烷基、C1-3烷氧基、-NRxRy、-NRxC(O)(C1-2烷基)、-C(O)(C1-2烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。亦包含于此实施方案中的是其中R1d为-CH3、-CH(CH3)2、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。
一个实施方案提供式(I)化合物或其盐,其中R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代。包含于此实施方案中的是其中R1d为C1-3烷基、C1-2氟烷基、C1-3烷氧基、-NRxRy、-NRxC(O)(C1-2烷基)、-C(O)(C1-2烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。亦包含于此实施方案中的是其中R1d为-CH3、-CH(CH3)2、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。
一个实施方案提供式(I)化合物或其盐,其中R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代。包含于此实施方案中的是其中R1d为C1-3烷基、C1-2氟烷基、C1-3烷氧基、-NRxRy、-NRxC(O)(C1-2烷基)、-C(O)(C1-2烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。亦包含于此实施方案中的是其中R1d为-CH3、-CH(CH3)2、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基的化合物。
一个实施方案提供式(I)化合物或其盐,其中环A为:
一个实施方案提供式(I)化合物或其盐,其中环A为:
一个实施方案提供式(I)化合物或其盐,其中环A为:包含于此实施方案中的是其中R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c;或R1a及R1b与其所连接的氮原子接合在一起以形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代;R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被独立地选自以下的0至2个取代基取代:F、Cl、-CN、-OH、-CH3、-CF3、-OCH3、-OCF3、-C(O)OCH3、-NH(CH3)、-N(CH3)2、-S(O)2CH3、-S(O)2N(CH3)2、-CH2(苯基)、-NO2、环丙基、咪唑基及苯基;R1d为-CH3、-CH(CH3)2、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;且R1e为-CH3的化合物。
一个实施方案提供式(I)化合物或其盐,其中环A为:
一个实施方案提供式(I)化合物或其盐,其中各R4独立地为F、Cl、-CN、C1-2烷基、C1-2氟烷基、C1-2烷氧基或C1-2氟烷氧基。包含于此实施方案中的是其中各R4独立地为F、Cl、-CN、-CH3、-CF3、-OCH3或-OCF3的化合物。亦包含于此实施方案中的是其中各R4独立地为F、-CN、-CH3或-CF3的化合物。
一个实施方案提供式(I)化合物或其盐,其中R5为氢、氘、C1-2烷基或F。
一个实施方案提供式(I)化合物或其盐,其中R5为氢、氘、-CH3或F。
一个实施方案提供式(I)化合物或其盐,其中R5为氢、氘或-CH3。
一个实施方案提供式(I)化合物或其盐,其中R5为氢、氘或F。
一个实施方案提供式(I)化合物或其盐,其中R5为F。
一个实施方案提供式(I)化合物或其盐,其中R5为-CH3。
一个实施方案提供式(I)化合物或其盐,其中R5为氢或氘。
一个实施方案提供式(I)化合物或其盐,其中R5为氘。
一个实施方案提供式(I)化合物或其盐,其中各R6独立地为氢或C1-2烷基。包含于此实施方案中的是其中各R6独立地为氢或-CH3的化合物。亦包含于此实施方案中的是其中各R6为氢的化合物。
一个实施方案提供式(I)化合物或其盐,其中m为0、1或2。包含于此实施方案中的是其中m为0或1的化合物。亦包含于此实施方案中的是其中m为0的化合物。
一个实施方案提供式(I)化合物或其盐,其中n为0、1或2。包含于此实施方案中的是其中n为0或1的化合物。亦包含于此实施方案中的是其中n为0的化合物。
一个实施方案提供式(I)化合物或其盐,其中该化合物为3-(5-{4-[(二甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(1);3-(5-(4-((苄基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(2);3-(5-(4-((甲基(丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3);3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(4);3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(5);3-(5-(4-(((2-甲氧基乙基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(7);3-(5-(4-((丁基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(9);3-(5-(4-(((环丙基甲基)(丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(10);3-(5-(4-((甲基(2-(吡啶-2-基)乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(16);3-(5-(4-((苄基(异丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(19);3-(5-(4-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(21);3-(5-(4-((乙基(吡啶-4-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(22);3-(5-(4-((甲基(1-甲基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(29);2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)-N,N-二甲基乙酰胺(34);3-(5-(4-((甲基(1-甲基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(49);3-(5-(4-((二乙基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(50);3-(5-(4-(((环己基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(54);3-(1-氧代-5-(4-(((1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(55);3-(5-(4-(((2-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(56);3-(5-(4-(((3-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(57);3-(5-(4-(((4-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(58);3-(5-(4-(((环己基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(59);3-(5-(4-((丁氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(61);3-(1-氧代-5-(4-((丙氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(62);3-(1-氧代-5-(4-((苯乙基氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(63);3-(5-(4-(((环丙基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(64);3-(5-(4-((新戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(65);3-(1-氧代-5-(4-((((四氢呋喃-2-基)甲基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(66);3-(5-(4-(((4-甲氧基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(67);3-(5-(4-(((2-甲氧基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(68);3-(5-(4-(((1-环丙基环丁基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(77);3-(5-(4-(((2-甲基四氢-2H-吡喃-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(80);3-(1-氧代-5-(4-((((1R,2R)-2-苯基环戊基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(84);3-(5-(4-((环戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(86);3-(5-(4-((环己基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(87);3-(5-(4-(((2-吗啉基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(88);3-(5-(4-((叔丁基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(89);3-(5-(4-(((2,2-二苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(90);N-(2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙基)乙酰胺(91);3-(5-(4-(((2-羟乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(92);3-(5-(4-(((2-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(93);3-(5-(4-(((4-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(94);3-(5-(4-(((4-甲氧基苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(95);3-(5-(4-(((4-羟基苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(96);3-(5-(4-((异戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(97);3-(1-氧代-5-(4-(((3-苯基丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(98);2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙腈(99);2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙酰胺(100);3-(5-(4-(((4-羟基环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(101);3-(5-(4-(((3-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(102);3-(1-氧代-5-(4-(((2-苯氧基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(103);3-(5-(4-(((1-苄基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(104);3-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)丙酰胺(105);3-(5-(4-(((2-(苯并[d]噻唑-2-基)乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(106);3-(5-(4-(((4-(二甲氨基)环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(107);3-(5-(4-((环丁基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(108);3-(5-(4-((环丙基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(109);3-(1-氧代-5-(4-((((2-苯基噻唑-4-基)甲基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(110);3-(1-氧代-5-(4-((((1R,2S)-2-苯基环丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(111);3-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)丙酸甲酯(112);3-(5-(4-(((3-(1H-咪唑-1-基)丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(113);3-(5-(4-(((3-吗啉基丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(114);3-(1-氧代-5-(4-(((3-(2-氧代吡咯烷-1-基)丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(115);3-(5-(4-((乙氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(116);3-(1-氧代-5-(4-((((R)-1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(122);3-(1-氧代-5-(4-((((S)-1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(123);3-(5-(4-((((1-羟基环己基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(124);3-(5-(4-(((2-甲基四氢-2H-吡喃-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(126);3-(5-(4-(((4-羟基丁基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(128);3-(5-(4-(((氧杂环丁烷-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(129);3-(5-(4-((((R)-3-羟基-1-苯基丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(131);3-(5-(4-((甲基((S)-1-苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(136);3-(5-(4-((甲基((R)-1-苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(137);3-(5-(4-((甲基((1R,2R)-2-(甲氨基)环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(140);3-(5-(4-((甲基(2-苯基丙-2-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(142);3-(1-氧代-5-(4-((3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(144);3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(145);4-{[({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)(甲基)氨基]甲基}-N,N-二甲基苯-1-磺酰胺(146);3-(5-(4-(((4-氟苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147);3-(5-(4-((甲基(3-(三氟甲基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(148);3-(5-(4-((甲基(4-(三氟甲基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(149);4-((((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)甲基)苯甲腈(150);3-(5-(4-((甲基(4-硝基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(151);3-(5-(4-(((3,4-二氟苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(152);4-((((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)甲基)苯甲酸甲酯(153);3-(5-(4-(((4-氯苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(154);3-(5-(4-((甲基(喹啉-8-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(155);3-(5-(4-((甲基(3-(三氟甲氧基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(156);3-(5-(4-((甲基(4-(甲基磺酰基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(157);3-(5-(4-(((3-甲氧基苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(158);3-(5-(4-((甲基(吡啶-3-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(159);3-(5-(4-((甲基(吡啶-4-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(160);3-(5-(4-((甲基(4-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(161);3-(5-(4-((甲基(萘-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(162);3-(5-{4-[(二苄基氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(163);3-[5-(4-{[苄基(甲基)氨基]甲基}吡啶-2-基)-1-氧代-2,3-二氢-1H-异吲哚-2-基]哌啶-2,6-二酮(164);3-{5-[4-({[(6-甲氧基吡啶-3-基)甲基](甲基)氨基}甲基)吡啶-2-基]-1-氧代-2,3-二氢-1H-异吲哚-2-基}哌啶-2,6-二酮(168);3-(5-(4-((((1H-吲唑-4-基)甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(169);3-(5-(4-((甲基(1-甲基哌啶-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(170);3-(5-(4-((甲基(苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(171);3-(5-(4-(((呋喃-3-基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(172);3-(5-(4-(((环丙基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(173);3-(5-(4-((甲基((1-甲基-1H-咪唑-5-基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(174);3-(5-(4-(((环戊基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(175);3-(5-(4-((甲基(噻唑-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(176);3-(5-(4-(((4-(1H-咪唑-1-基)苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(177);3-(5-(4-(((环丁基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(178);3-(5-(4-((异丁基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(179);3-(5-(4-((异戊基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(180);3-(5-(4-(((1-羟基丙-2-基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(181);3-(5-(4-((甲基((四氢呋喃-3-基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(182);3-(5-(4-((甲基(喹喔啉-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(183);3-(5-(4-((甲基(3,3,3-三氟丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(184);3-(5-(4-(((4-羟基丁-2-基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(185);或3-(5-(4-((二甲氨基)甲基)吡啶-2-基)-6-甲基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(194)。
一个实施方案提供式(I)化合物或其盐,其中该化合物为3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(6);3-(1-氧代-5-(4-(吡咯烷-1-基甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(8);3-(1-氧代-5-(4-((4-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(11);3-(5-(4-((4-(苯并[d][1,3]二氧杂环戊烯-5-基甲基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(12);1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)-N,N-二乙基哌啶-3-甲酰胺(13);3-(5-(4-((4-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(14);3-(1-氧代-5-(4-((4-(吡啶-2-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(15);3-(5-(4-([1,4'-联哌啶]-1'-基甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(17);3-(1-氧代-5-(4-((4-(嘧啶-2-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(18);3-(5-(4-((2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(20);3-(1-氧代-5-(4-((4-(吡咯烷-1-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(23);3-(5-(4-((4-(呋喃-2-羰基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(24);3-(1-氧代-5-(4-((4-(吡啶-4-基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(25);3-(1-氧代-5-(4-((4-(吡嗪-2-基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(26);3-(5-(4-((3-甲基-4-(间甲苯基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(27);3-(5-(4-((4-乙酰基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(28);3-(5-(4-((2-(((S)-1-甲基吡咯烷-2-基)甲基)哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(30);N-((3S)-1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)吡咯烷-3-基)乙酰胺(31);3-(1-氧代-5-(4-((4-(四氢呋喃-2-羰基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(32);3-(5-(4-(((S)-3-(二甲氨基)吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(33);3-(5-(4-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(35);3-(5-(4-((4-苄基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(36);3-(1-氧代-5-(4-((3-氧代哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(37);3-(5-(4-((4-苄基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(38);3-(5-(4-((3,4-二氢异喹啉-2(1H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(39);3-(5-(4-((4-(二甲氨基)哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(40);1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)哌啶-4-甲酰胺(41);3-(5-(4-((4-二苯甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(42);3-(5-(4-((4-甲基-1,4-二氮杂环庚烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(43);3-(5-(4-((4-异丙基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(44);3-(5-(4-(((R)-3-(二甲氨基)吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(45);3-(5-(4-((2-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(46);3-(5-(4-((3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(47);3-(5-(4-(氮杂环庚烷-1-基甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(48);3-(5-(4-((3,3-二甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(51);3-(5-(4-((2,2-二甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(52);3-(5-(4-((2,6-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(53);3-(5-(4-((六氢环戊[b]吡咯-1(2H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(60);3-(5-(4-(((S)-2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(69);3-(5-(4-(((R)-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(70);3-(5-(4-(((R)-2-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(71);3-(5-(4-(((S)-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(72);3-(5-(4-(((S)-3-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(73);3-(5-(4-(((S)-2-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(74);3-(5-(4-(((R)-3-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(75);3-(1-氧代-5-(4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(76);3-(5-(4-(((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(78);3-(5-(4-((2-氧杂-5-氮杂双环[2.2.1]庚-5-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(79);3-(5-(4-(((3S,5R)-3,5-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(81);3-(5-(4-((4,4-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(82);3-(1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(83);3-(5-(4-((3,3-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(85);3-(5-(4-((2,2-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(117);3-(5-(4-((3,3-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(118);3-(5-(4-((2,5-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(119);3-(5-(4-(((2R,6S)-2,6-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(120);3-(5-(4-((4-(4-氨基苯基)-4-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(121);3-(5-(4-(((R)-2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(125);3-(5-(4-((6-氮杂螺[2.5]辛-6-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(127);3-(5-(4-((3-异丙氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(130);3-(1-氧代-5-(4-((4-甲苯磺酰基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(132);3-(1-氧代-5-(4-(((S)-2-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(133);3-(1-氧代-5-(4-(((R)-2-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(134);3-(1-氧代-5-(4-(((S)-3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(135);3-(1-氧代-5-(4-(((R)-3-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(138);3-(1-氧代-5-(4-(((S)-3-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(139);3-(1-氧代-5-(4-((4-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(141);3-(1-氧代-5-(4-((3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(143);3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(165);3-(5-{4-[(吗啉-4-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(166);4-({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)-1λ6-硫代吗啉-1,1-二酮(167);3-(5-(5-氯-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(186);3-(5-(5-氯-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(187);3-(5-(5-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(188);3-(5-(5-氟-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(189);3-(5-(5-氟-4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(190);3-(5-(3-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(191);3-(5-(3-氟-4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(192);3-(5-(3-氟-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(193);3-(1-氧代-5-(4-((3-(吡啶-4-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(195);3-(5-(4-((3-甲氧基-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(196);3-(5-(4-((3-甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(197);3-(5-(4-((3-乙氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(198);3-(1-氧代-5-(4-((4-(对甲苯基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(199);3-(5-(4-(((S)-2-苄基氮杂环丙烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(200);3-(5-(4-((2-甲基氮杂环丙烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(201);1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)-N,N-二甲基氮杂环丁烷-3-甲酰胺(202);3-(1-氧代-5-(4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(203);3-(1-氧代-5-(4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(204-205);1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氮杂环丁烷-2-甲酰胺(206);3-(5-(4-((4-甲氧基-3,3-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(207);或3-(4-氟-1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(208)。
本发明可在不背离其精神或基本属性下以其他特定形式体现。本发明包涵本文中所指出的本发明的方面和/或实施方案的所有组合。应了解,本发明的任何及所有实施方案可结合任何其他一个或多个实施方案采用以描述另外实施方案。亦应了解,所述实施方案的各个别要素意欲与来自任何实施方案的任何及所有其他要素组合以描述另外实施方案。
定义
本发明的特征及优点可由本领域普通技术人员在阅读下列详细描述后更容易理解。应了解,出于清楚原因,上文及下文在单独实施方案的背景下所述的本发明的某些特征亦可经组合以形成单一实施方案。相反,出于简明原因,在单一实施方案的背景下所述的本发明的各种特征亦可经组合以便形成其子组合。本文中识别为示例性或优选的实施方案意欲为说明性且非限制性。
除非本文中另有明确指定,否则以单数作出的提及亦可包含复数。例如,“一(a/an)”可是指一个,或一个或多个。
如本文中所用,短语“化合物和/或其盐”是指至少一种化合物、化合物的至少一种盐或其组合。例如,式(I)化合物和/或其盐包含式(I)化合物;两种式(I)化合物;式(I)化合物的盐;式(I)化合物及式(I)化合物的一种或多种盐;及式(I)化合物的两种或更多种盐。
除非另有指定,否则假设具有不满足价的任何原子具有足以满足所述价的氢原子。
本文中所阐述的定义优先于以引用的方式并入本文中的任何专利、专利申请和/或专利申请公开中所阐述的定义。
以下所列为用于描述本发明的各种术语的定义。这些定义适用于所述术语,随着其个别地或作为较大基团的一部分在整篇本说明书中使用(除非其于特定实施例中另有限制)。
整篇本说明书,基团及其取代基可由本领域技术人员选择以提供稳定部分及化合物。
根据本领域所用的惯例,
用于本文中结构式中以描述部分或取代基与核或骨架结构的连接点的键。
如本文中所用,术语“卤”及“卤素”是指F、Cl、Br及I。
术语“氰基”是指基团-CN。
术语“氨基”是指基团-NH2。
术语“氧代”是指基团=O。
如本文中所用,术语“烷基”是指含有(例如)1至12个碳原子,1至6个碳原子及1至4个碳原子的分支链及直链饱和脂族烃基二者。烷基的实施例包括(但不限于)甲基(Me)、乙基(Et)、丙基(例如,正丙基及异丙基)、丁基(例如,正丁基、异丁基、第二丁基及叔丁基)及戊基(例如,正戊基、异戊基、新戊基)、正己基、2-甲基戊基、2-乙基丁基、3-甲基戊基及4-甲基戊基。当于符号“C”后的下标中出现数字时,该下标利用更特异性地限定特定基团可含有的碳原子数目。例如,“C1-4烷基”表示具有1至4个碳原子的直链及分支链烷基。
如本文中所用,术语“氟烷基”意欲包含经一个或多个氟原子取代的分支链及直链饱和脂族烃基二者。例如,“C1-4氟烷基”意欲包含经一个或多个氟原子取代的C1、C2、C3及C4烷基。氟烷基的代表性实施例包括(但不限于)-CF3及-CH2CF3。
如本文中所用,术语“烷氧基”是指通过氧原子连接至母体分子部分的烷基,例如,甲氧基(-OCH3)。例如,“C1-3烷氧基”表示具有1至3个碳原子的烷氧基。
术语“氟烷氧基”及“-O(氟烷基)”表示通过氧键联(-O-)连接的如上所定义的氟烷基。例如,“C1-4氟烷氧基”意欲包含C1、C2、C3及C4氟烷氧基。
如本文中所用,术语“环烷基”是指通过自饱和环碳原子移除一个氢原子衍生自非芳族单环或多环烃分子的基团。环烷基的代表性实施例包括(但不限于)环丙基、环戊基及环己基。当于符号“C”后的下标中出现数字时,该下标更具体地限定特定环烷基可含有的碳原子数目。例如,“C3-C6环烷基”表示具有3至6个碳原子的环烷基。
本发明的化合物包含本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子数但是不同质量数的那些原子。作为一般的例子且不限于此,氢的同位素包括氘(D)及氚(T)。碳的同位素包括13C及14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于那些本文中所述的方法,使用适宜同位素标记试剂代替原本采用的非标记试剂来制备。
本文中采用短语“药学上可接受的”是指在健全医疗判断的范围内适用于与人类及动物的组织接触而无过度毒性、刺激性、过敏反应或其他问题或并发症,与合理效益/风险比率相称的那些化合物、材料、组合物和/或剂型。
式(I)化合物可形成亦在本发明的范围内的盐。除非另有指定,否则提及本发明化合物应理解为包含提及其一种或多种盐。术语“盐”表示与无机和/或有机酸及碱形成的酸性和/或碱性盐。此外,该术语“盐”可包括两性离子(内盐),例如,当式(I)化合物含有碱性部分(诸如胺或吡啶或咪唑环)及酸性部分(诸如羧酸)二者时。药学上可接受(即,无毒生理上可接受)的盐是优选的,诸如例如,可接受的金属及胺盐,其中阳离子不显著促进该盐的毒性或生物活性。然而,其他盐可用于(例如)可在制备期间采用的分离或纯化步骤中,并因此涵盖于本发明的范围内。式(I)化合物的盐可(例如)通过使式(I)化合物与一定量(诸如当量)的酸或碱于介质(诸如盐于其中沉淀者)中或于水性介质中反应,接着冻干形成。
示例性酸加成盐包括乙酸盐(诸如与乙酸或三卤乙酸(例如,三氟乙酸)形成的那些)、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与溴化氢形成)、氢碘酸盐、马来酸盐(与马来酸形成)、2-羟基乙磺酸盐、乳酸盐、甲磺酸盐(与甲磺酸形成)、2-萘磺酸盐、烟碱酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如与硫酸形成的那些)、磺酸盐(诸如本文中提及的那些)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate/tosylate)、十一酸盐及类似者。
示例性碱性盐包括铵盐、碱金属盐(诸如钠、锂及钾盐);碱土金属盐,诸如钙及镁盐;钡、锌及铝盐;与有机碱(例如,有机胺),诸如三烷基胺(诸如三乙胺)、普鲁卡因(procaine)、二苄基胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N,N′-二苄基伸乙二胺、脱氢松香胺、N-乙基哌啶、苄胺、二环己胺或类似药学上可接受的胺的盐及与氨基酸(诸如精氨酸、赖氨酸及类似者)的盐。碱性含氮基团可利用诸如以下的剂四级铵化:低碳数烷基卤化物(例如,甲基、乙基、丙基及丁基氯化物、溴化物及碘化物)、二烷基硫酸盐(例如,二甲基、二乙基、二丁基及二戊基硫酸盐)、长链卤化物(例如,癸基、月桂基、肉豆蔻基及硬脂酰基氯化物、溴化物及碘化物)、芳烷基卤化物(例如,苄基及苯乙基溴化物)等等。优选盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
式(I)化合物可呈非晶型固体或晶体固体提供。可采用冻干以提供呈固体的式(I)化合物。
应进一步理解,式(I)化合物的溶剂化物(例如,水合物)亦在本发明的范围内。术语“溶剂化物”意指式(I)化合物与一种或多种溶剂分子(无论有机或无机)的物理缔合。此物理缔合包括氢键合。在某些实施例中,该溶剂化物将能分离,例如,当将一种或多种溶剂分子并入晶体固体的晶格中时。“溶剂化物”包含溶液相及可分离溶剂化物二者。示例性溶剂化物包括水合物、乙醇化物、甲醇化物、异丙醇化物、乙腈溶剂化物及乙酸乙酯溶剂化物。溶剂化的方法为本领域已知。
前药的各种形式为本领域熟知且述于以下中:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth等人,第31章,(Academic Press,1996);
b)Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985);
c)A Textbook of Drug Design and Development,P.Krogsgaard–Larson及H.Bundgaard编辑,第5章,第113至191页(Harwood Academic Publishers,1991);及
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa及JoachimM.Mayer,(Wiley-VCH,203)。
e)Rautio,J.等人,Nature Review Drug Discovery,17,559-587,(2018)。
此外,式(I)化合物继其制备后可经分离及纯化以获得含有以重量计等于或大于99%的式(I)化合物的组合物(“实质上纯”),然后如本文中所述将其使用或调配。此“实质上纯”式(I)化合物亦作为本发明的部分于本文中考虑。
“稳定化合物”及“稳定结构”意欲指示足够稳健以自反应混合物能够分离至可用纯度,及调配成有效治疗剂的化合物。本发明意欲体现稳定化合物。
术语“Helios抑制剂”是指能减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平以控制Treg分化的剂。Helios抑制剂可为可逆或不可逆抑制剂。
如本文中所用,“Helios”蛋白质是指是锌指蛋白的Ikaros家族成员的蛋白质。在人类中,Helios通过IKZF2基因编码。Helios亦称作IKAROS家族锌指2、ANF1A2、ZNF1A2、ZNFN1A2、锌指蛋白亚家族1A,2及Ikaros家族锌指蛋白2。此蛋白质家族的成员包括Ikaros、Helios、Aiolos、Eos、及Pegasus。如本文中所用,Helios蛋白质包含各种同功异型物,所述同功异型物包括以下所列的同功异型物1至5。
同功异型物1(UniProt Q9UKS7-1)
同功异型物2(UniProt Q9UKS7-2)
同功异型物4(UniProt Q9UKS7-4)
同功异型物6(UniProt Q9UKS7-6)
同功异型物7(UniProt Q9UKS7-7)
以上所列的“Helios”同功异型物1、2、4、6及7包含降解决定子FHCNQCGASFTQKGNLLRHIKLH(SEQ ID NO:6)(加粗及加下划线)。降解决定子为蛋白质的一部分,其在调节蛋白质降解速率中起作用。
如本文中所用,“Eos”蛋白质为通过IKZF4基因编码,及亦称作IKAROS家族锌指4、ZNFN1A4、锌指蛋白亚家族1A,4、Ikaros家族锌指蛋白4及KIAA1782。“Eos”蛋白质包含通过下列两种人类同功异型物1(Q9H2S9-1)及2(Q9H2S9-2)编码的同功异型物:
同功异型物1(UniProt Q9H2S9-1)
同功异型物2(UniProt Q9H2S9-2)
以上所列的“Eos”蛋白质同功异型物1及2包含降解决定子FHCNQCGASFTQKGNLLRHIKLH(SEQ ID NO:6)(加粗及加下划线),其与“Helios”蛋白质的降解决定子相同。
如本文中所用,“Ikaros”蛋白质通过IKZF1基因编码。Ikaros亦称作KAROS家族锌指1、ZNFN1A1、锌指蛋白亚家族1A,1、Ikaros家族锌指蛋白1、IK1、淋巴转录因子LyF-1、Hs.54452、PPP1R92、蛋白质磷酸酶1、调节亚单元92、PRO0758、CVID13及CLL相关抗原KW-6。Ikaros蛋白质包含通过氨基酸序列Q13422-1、Q13422-2、Q13422-3、Q13422-4、Q13422-7及Q13422-8编码的同功异型物。Ikaros蛋白质亦包含通过氨基酸序列Q13422-5及Q13422-6编码的同功异型物。
如本文中所用,“Aiolos”蛋白质通过IKZF3基因编码。Aiolos蛋白质亦称作IKAROS家族锌指3、ZNFN1A3、锌指蛋白亚家族1A,3、Ikaros家族锌指蛋白3及AIO。Aiolos蛋白质包含通过氨基酸序列Q9UKT9-1、Q9UKT9-3、Q9UKT9-4、Q9UKT9-6、Q9UKT9-7、Q9UKT9-8、Q9UKT9-9及Q9UKT9-14编码的同功异型物。Aiolos蛋白质亦包含通过氨基酸序列Q9UKT9-2、Q9UKT9-5、Q9UKT9-10、Q9UKT9-11、Q9UKT9-12及Q9UKT9-13、Q9UKT9-15及Q9UKT9-16编码的同功异型物。
如本文中所用,“Pegasus”蛋白质亦称作IKAROS家族锌指5、ZNFN1A5、锌指蛋白亚家族1A,5及Ikaros家族锌指蛋白5。Pegasus通过IKZF5基因编码。
如本文中所用,术语“接触”是指使体外系统或体内系统中的指定部分在一起。例如,使Helios蛋白质与式(I)化合物“接触”包括向具有Helios蛋白质的个体或患者(诸如人类)施用本发明的化合物,以及例如将式(I)化合物引入含有包含Helios蛋白质的细胞或经纯化制剂的样品。
如本文中所用,术语“治疗(treat/treating/treatment)”是指在受试者上进行的任何类型的介入或过程,或向受试者施用活性剂,目的为逆转、减轻、改善、抑制或减慢或防止与疾病相关联的症状、并发症、病状或生化指标的进展、发展、严重度或复发。相比之下,“预防(prophylaxis/prevention)”是指向不患有疾病的受试者施用以防止疾病发生。“治疗(Treat/treating/treatment)”不包含预防。
“治疗有效量”意欲包含单独本发明的化合物的量或所主张的化合物的组合的量或本发明的化合物与有效减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平,或有效治疗或预防病毒感染及增殖性病症(诸如癌症)的其他活性成分组合的量。
如本文中所用,术语“细胞”意欲是指体外、离体或体内细胞。在一些实施方案中,离体细胞可为自生物体(诸如哺乳动物)切除的组织样品的一部分。在一些实施方案中,体外细胞可为细胞培养中的细胞。在一些实施方案中,体内细胞是在生物体(诸如哺乳动物)中活着的细胞。
术语“患者”包括接受治疗性或预防性治疗的人类及其他哺乳动物受试者。
术语“受试者”包括任何人类或非人类动物。例如,本文中所公开的方法及组合物可用于治疗患有癌症的受试者。非人类动物包括所有脊椎动物,例如,哺乳动物及非哺乳动物,包括非人类灵长类动物、绵羊、狗、牛、鸡、两栖动物、爬行动物等。在一个实施方案中,该受试者为人类受试者。
如本文中所用,短语“药学上可接受的载剂”意指药学上可接受的材料、组合物或媒剂,诸如液体或固体填料、稀释剂、赋形剂、制造助剂(例如,润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌,或硬脂酸)或涉及将目标化合物自身体的一个器官或部分携带或转运至身体的另一器官或部分的溶剂封装材料。各载剂自与制剂的其他成分兼容的意义上而言必须为“可接受”,包括(即)佐剂、赋形剂或媒剂,诸如稀释剂、保存剂、填料、流动调节剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、香味剂、抗细菌剂、抗真菌剂、润滑剂及分散剂,取决于施用模式的形式及剂型;且对患者无伤害。
术语“药物组合物”意指包含本发明的化合物与至少一种另外药学上可接受的载剂组合的组合物。
效用
式(I)化合物可用于治疗癌症。
在一个实施方案中,本发明提供式(I)化合物和/或其药学上可接受的盐、其立体异构体或其互变异构体及另外治疗剂的组合制剂,以同时、分开或依序用于治疗和/或预防与Helios蛋白质的活性相关联的多种疾病或病症。该组合制剂可用于降低细胞中的Helios蛋白质含量、Helios活性水平和/或Helios表达水平以控制Treg分化。
式(I)化合物及包含至少一种式(I)化合物的药物组合物可用于治疗或预防与Helios蛋白质的活性相关联的任何疾病或病状。这些包括病毒及其他感染(例如,皮肤感染、GI感染、尿道感染、泌尿生殖感染、全身感染)及增殖性疾病(例如,癌症)。式(I)化合物及包含至少一种式(I)化合物的药物组合物可向动物,优选地哺乳动物(例如,家养动物、猫、狗、小鼠、大鼠)及更优选地人类施用。可使用任何施用方法将化合物或药物组合物递送至患者。在某些实施方案中,式(I)化合物或包含至少一种式(I)化合物的药物组合物经口施用。于其他实施方案中,式(I)或包含至少一种式(I)化合物的药物组合物为经肠施用。
式(I)化合物可选择性地减少细胞的Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平以控制Treg分化。例如,式(I)化合物可用于通过施用抑制量的式(I)化合物或其盐来选择性地减少细胞的Helios活性水平和/或抑制Helios表达水平以控制细胞或需要减少Helios蛋白质含量、减少Helios活性水平和/或抑制Helios表达水平的个体的Treg分化。
在一个方面中,式(I)化合物在施用免疫肿瘤学药剂之前依序施用。在另一方面中,式(I)化合物与免疫肿瘤学药剂同时施用。在又一方面中,式(I)化合物于施用免疫肿瘤学药剂后依序施用。
在另一方面中,式(I)化合物可与免疫肿瘤学药剂共同调配。
免疫肿瘤学药剂包括(例如)小分子药物、抗体或其他生物或小分子。生物免疫肿瘤学药剂的实例包括(但不限于)癌症疫苗、抗体及细胞因子。在一个方面中,该抗体为单克隆单抗。在另一方面中,该单克隆抗体为人源化或人类抗体。
在一个方面中,该免疫肿瘤学药剂为(i)刺激(包括共刺激)受体的激动剂或(ii)抑制(包括共抑制)T细胞上的信号的拮抗剂,其均导致抗原特异性T细胞反应放大(通常称作免疫检查点调节剂)。
刺激及抑制分子中的某些为免疫球蛋白超家族(IgSF)的成员。结合至共刺激或共抑制受体的膜结合配位体的一个重要家族为B7家族,其包含B7-1、B7-2、B7-H1(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)及B7-H6。结合至共刺激或共抑制受体的膜结合配位体的另一家族为结合至同源TNF受体家族成员的分子的TNF家族,其包括CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
在一个方面中,T细胞反应可通过式(I)化合物及下列中的一者或多者的组合来刺激:(i)抑制T细胞活化的蛋白质的拮抗剂(例如,免疫检查点抑制剂),诸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳凝素9、CEACAM-1、BTLA、CD69、半乳凝素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4,及(ii)刺激T细胞活化的蛋白质的激动剂,诸如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3及CD28H。
可与式(I)化合物组合用于治疗癌症的其他剂包括NK细胞上的抑制性受体的拮抗剂或NK细胞上的活化受体的激动剂。例如,式(I)化合物可与KIR的拮抗剂(诸如利鲁单抗(lirilumab))组合。
用于组合疗法的另外的剂包括抑制或耗尽巨噬细胞或单核细胞的剂,包括(但不限于)CSF-1R拮抗剂,诸如CSF-1R拮抗剂抗体,包括RG7155(WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008(WO11/140249;WO13169264;WO14/036357)。
在另一方面中,式(I)化合物可与以下中的一者或多者一并使用:连接阳性共刺激受体的激动剂、使通过抑制性受体的信号传导减弱的阻断剂、拮抗剂、及增加全身性抗肿瘤T细胞的频率的一种或多种剂、克服肿瘤微环境内的不同免疫抑制路径(例如,阻断抑制性受体接合(例如,PD-L1/PD-1相互作用)、耗尽或抑制Treg(例如,使用抗CD25单克隆抗体(例如,达利珠单抗(daclizumab))或通过离体抗CD25珠耗尽)、抑制代谢酶(诸如IDO)或逆转/防止T细胞失能或耗尽)的剂及在肿瘤部位处触发先天免疫活化和/或发炎的剂。
在一个方面中,该免疫肿瘤学药剂为CTLA-4拮抗剂,诸如拮抗性CTLA-4抗体。适宜CTLA-4抗体包括(例如)YERVOY(伊匹单抗(ipilimumab))或曲美木单抗(tremelimumab)。
在另一方面中,该免疫肿瘤学药剂为PD-1拮抗剂,诸如拮抗性PD-1抗体。适宜PD-1抗体包括(例如)OPDIVO(纳武单抗(nivolumab))、KEYTRUDA(派立珠单抗(pembrolizumab))或MEDI-0680(AMP-514;WO2012/145493)。该免疫肿瘤学药剂亦可包括匹迪利珠单抗(pidilizumab)(CT-011),虽然其针对PD-1结合的特异性受到质疑。靶向PD-1受体的另一种方法为由融合至IgG1的Fc部分的PD-L2的细胞外域(B7-DC)组成的重组蛋白,称作AMP-224。
在另一方面中,该免疫肿瘤学药剂为PD-L1拮抗剂,诸如拮抗性PD-L1抗体。适宜PD-L1抗体包括(例如)MPDL3280A(RG7446;WO2010/077634)、度伐单抗(durvalumab)(MEDI4736)、BMS-936559(WO207/005874)及MSB0010718C(WO2013/79174)。
在另一方面中,该免疫肿瘤学药剂为LAG-3拮抗剂,诸如拮抗性LAG-3抗体。适宜LAG3抗体包括(例如)BMS-986016(WO10/19570,WO14/08218)或IMP-731或IMP-321(WO08/132601,WO09/44273)。
在另一方面中,该免疫肿瘤学药剂为CD137(4-1BB)激动剂,诸如促效性CD137抗体。适宜CD137抗体包括(例如)乌鲁单抗(urelumab)及PF-05082566(WO12/32433)。
在另一方面中,该免疫肿瘤学药剂为GITR激动剂,诸如促效性GITR抗体。适宜GITR抗体包括(例如)BMS-986153、BMS-986156、TRX-518(WO06/105021、WO09/009116)及MK-4166(WO11/028683)。
在另一方面中,该免疫肿瘤学药剂为IDO拮抗剂。适宜IDO拮抗剂包括(例如)INCB-024360(WO206/122150,WO07/75598,WO08/36653、WO08/36642)、吲哚昔莫(indoximod)或NLG-919(WO09/73620、WO09/1156652、WO11/56652、WO12/142237)。
在另一方面中,该免疫肿瘤学药剂为OX40激动剂,诸如促效性OX40抗体。适宜OX40抗体包括(例如)MEDI-6383或MEDI-6469。
在另一方面中,该免疫肿瘤学药剂为OX40L拮抗剂,诸如拮抗性OX40抗体。适宜OX40L拮抗剂包括(例如)RG-7888(WO06/029879)。
在另一方面中,该免疫肿瘤学药剂为CD40激动剂,诸如促效性CD40抗体。在又一实施方案中,该免疫肿瘤学药剂为CD40拮抗剂,诸如拮抗性CD40抗体。适宜CD40抗体包括(例如)鲁卡木单抗(lucatumumab)或达土珠单抗(dacetuzumab)。
在另一方面中,该免疫肿瘤学药剂为CD27激动剂,诸如促效性CD27抗体。适宜CD27抗体包括(例如)瓦利鲁单抗(varlilumab)。
在另一方面中,该免疫肿瘤学药剂为MGA271(至B7H3)(WO11/109400)。
组合疗法意欲包涵以依序方式施用这些治疗剂(即,其中在不同时间施用各治疗剂),以及以实质上同时方式施用这些治疗剂或所述治疗剂中的至少两者。实质上同时施用可(例如)通过向个体施用具有各治疗剂的固定比率的单一剂型或针对治疗剂各者的多个单一剂型实现。依序或实质上同时施用各治疗剂可通过任何适宜途径,包括(但不限于)口服途径、静脉内途径、肌肉内途径及通过黏膜组织直接吸收来实现。治疗剂可通过相同途径或通过不同途径施用。例如,所选的组合的第一治疗剂可通过静脉内注射施用,而组合的其他治疗剂可经口施用。或者,例如,所有治疗剂可经口施用或所有治疗剂可通过静脉内注射施用。组合疗法亦可包含施用如上所述的治疗剂进一步与其他生物活性成分及非药物疗法(例如,手术或放射治疗)组合。在组合疗法进一步包含非药物治疗的情况下,该非药物治疗可在任何适宜时间进行,只要自治疗剂及非药物治疗的组合的共同作用的有益效果达成。例如,在适宜情况下,当非药物治疗自治疗剂的施用暂时移除或许几天或甚至几周时,仍达成有益效果。
可利用式(I)化合物治疗的癌症的类型包括(但不限于)脑癌、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、血液癌、肺癌及骨癌。这些癌症类型的实例包括神经母细胞瘤、肠癌(诸如直肠癌、结肠癌、常见腺瘤性息肉病癌及遗传性非息肉病结肠直肠癌)、食道癌、唇癌、喉癌、咽癌、舌癌、唾腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒膜癌、胰腺癌、前列腺癌、睪丸癌、乳腺癌、尿道癌、黑色素瘤、脑瘤(诸如胶质母细胞瘤、星形细胞瘤、脑膜瘤、髓母细胞瘤及外周神经外胚层瘤)、霍奇金氏(Hodgkin)淋巴瘤、非霍奇金氏淋巴瘤、伯基特氏(Burkitt)淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-细胞白血病淋巴瘤、弥漫性大B-细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因氏(Ewing)肉瘤及浆细胞瘤。
一种或多种另外药剂或治疗方法,诸如例如,抗病毒剂、化学治疗剂或其他抗癌剂、免疫增强剂、免疫抑制剂、辐射、抗肿瘤及抗病毒疫苗、细胞因子疗法(例如,IL2及GM-CSF)和/或酪氨酸激酶抑制剂可任选与式(I)化合物组合使用来治疗Helios蛋白质相关疾病、病症或病状。所述剂可以单一剂型与本发明化合物组合,或所述剂可呈分开剂型同时或依序施用。
适宜化学治疗剂或其他抗癌剂包括例如烷基化剂(包括,不限于,氮芥、乙烯亚胺衍生物、烷基磺酸酯、亚硝基脲及三氮烯),诸如尿嘧啶氮芥、氮芥(chlormethine)、环磷酰胺(cyclophosphamide)异环磷酰胺(ifosfamide)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、哌泊溴烷(pipobroman)、三乙烯-三聚氰胺、三乙烯硫代磷酰胺、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、链佐星(streptozocin)、达喀尔巴嗪(dacarbazine)及替莫唑胺(temozolomide)。
在黑色素瘤的治疗中,与式(I)化合物组合使用的适宜剂包括:达喀尔巴嗪(DTIC),任选连同其他化疗药物,诸如卡莫司汀(BCNU)及顺铂(cisplatin);“Dartmouth方案”,其由DTIC、BCNU、顺铂及他莫昔芬(tamoxifen)组成;顺铂、长春碱(vinblastine)及DTIC、替莫唑胺或YERVOYTM的组合。于治疗黑色素瘤中,式(I)化合物亦可与免疫疗法药物,包括细胞因子,诸如干扰素α、介白素2及肿瘤坏死因子(TNF)组合。
式(I)化合物亦可与疫苗疗法组合用于治疗黑色素瘤。在某些方面,抗黑色素瘤疫苗类似于用于预防由病毒引起的疾病(诸如小儿麻痹症(polio)、麻疹及腮腺炎)的抗病毒疫苗。可将称作抗原的弱化黑色素瘤细胞或黑色素瘤细胞的部分注射至患者中以刺激身体的免疫系统以破坏黑色素瘤细胞。
局限于手臂或腿的黑色素瘤亦可利用包含一种或多种式(I)化合物的药剂的组合,使用高温分离肢体灌注技术治疗。此治疗方案暂时将涉及肢体的循环与身体其余部分分开及将高剂量的化疗剂注射至供养肢体的动脉,因此向肿瘤区提供高剂量而不将内部器官暴露于这些剂量,否则所述剂量可引起严重副作用。通常将流体升温至38.9℃至40℃。美法仑为此化疗程序中最常用的药物。此可与称作肿瘤坏死因子(TNF)的另一药剂给予。
适宜化疗剂或其他抗癌剂包括例如抗代谢剂(包括,不限于,叶酸拮抗剂、嘧啶类似物、嘌呤类似物及腺苷脱胺酶抑制剂),诸如甲氨喋呤(methotrexate)、5-氟尿嘧啶(fluorouracil)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨(fludarabine)、喷司他丁(pentostatine)及吉西他滨(gemcitabine)。
适宜化疗剂或其他抗癌剂进一步包括(例如)某些天然产物及其衍生物(例如,长春花生物碱(vinca alkaloid)、抗肿瘤抗生素、酶、淋巴因子及表鬼臼毒素),诸如长春碱、长春新碱(vincristine)、长春地辛(vindesine)、博来霉素(bleomycin)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、ara-C、紫杉醇(paclitaxel)(Taxol)、光神霉素(mithramycin)、脱氧助间型霉素(deoxyco-formycin)、丝裂霉素(mitomycin)-C、L-天冬酰胺酶、干扰素(尤其IFN-a)、依托泊苷(etoposide)及替尼泊苷(teniposide)。
其他细胞毒性剂包括诺维本(navelbene)、CPT-11、阿那曲唑(anastrazole)、来曲唑(letrazole)、卡培他滨(capecitabine)、雷洛昔芬(reloxafine)及屈洛昔芬(droloxafine)。
亦适宜的是细胞毒性剂,诸如表鬼臼毒素;抗赘生酶;拓扑异构酶抑制剂;丙卡巴肼(procarbazine);米托蒽醌(mitoxantrone);铂配合物复合物,诸如,顺铂及卡铂(carboplatin);生物反应修饰剂;生长抑制剂;抗激素治疗剂;甲酰四氢叶酸(leucovorin);替加氟(tegafur);及造血生长因子。
其他抗癌剂亦包括那些阻断免疫细胞迁移的抗癌剂,诸如趋化因子受体,包括CCR2及CCR4的拮抗剂。
其他抗癌剂亦包括那些增强免疫系统的抗癌剂,诸如佐剂或授受性T细胞转移。
抗癌疫苗包括树突状细胞、合成肽、DNA疫苗及重组病毒。
本发明的药物组合物可任选包含至少一种信号转导抑制剂(STI)。“信号转导抑制剂”为选择性抑制于癌症细胞的正常功能中信号传导路径中的一个或多个至关重要步骤,从而导致细胞凋亡的剂。适宜STI包括(但不限于):(i)bcr/abl激酶抑制剂,诸如例如,STI571(ii)表皮生长因子(EGF)受体抑制剂,诸如例如,激酶抑制剂(SSI-774)及抗体(Imclone:C225[Goldstein等人,Clin.Cancer Res.,1:1311-1318(1995)],及Abgenix:ABX-EGF);(iii)her-2/neu受体抑制剂,诸如法呢基转移酶抑制剂(FTI),诸如例如,L-744,832(Kohl等人,Nat.Med.,1(8):792-797(1995));(iv)Akt家族激酶或Akt路径的抑制剂,诸如例如,雷帕霉素(rapamycin)(参见,例如,Sekulic等人,Cancer Res.,60:3504-3513(200));(v)细胞周期激酶抑制剂,诸如例如,夫拉平度(flavopiridol)及UCN-O1(参见,例如,Sausville,Curr.Med.Chem.Anti-Canc.Agents,3:47-56(203));及(vi)磷脂酰肌醇激酶抑制剂,诸如,例如,LY294002(参见,例如,Vlahos等人,J.Biol.Chem.,269:5241-5248(1994))。或者,至少一种STI及至少一种式(I)化合物可于分开药物组合物中。于本发明的特定实施方案中,至少一种式(I)化合物及至少一种STI可同时或依序向患者施用。换言之,可首先施用至少一种式(I)化合物,可首先施用至少一种STI,或可同时施用至少一种式(I)化合物及至少一种STI。另外,当使用超过一种式(I)化合物和/或STI时,所述化合物可以任何顺序施用。
本发明进一步提供用于治疗患者的慢性病毒感染的药物组合物,其包含至少一种式(I)化合物,任选地至少一种治疗性药物及任选地至少一种抗病毒剂于药学上可接受的载剂中。
亦提供一种通过施用有效量的以上药物组合物来治疗患者的慢性病毒感染的方法。
于本发明的特定实施方案中,同时或依序向患者施用至少一种式(I)化合物及至少一种化疗剂。换言之,可首先施用至少一种式(I)化合物,可首先施用至少一种化疗剂,或可同时施用至少一种式(I)化合物及至少一种STI。另外,当使用超过一种式(I)化合物和/或化疗剂时,所述化合物可以任何顺序施用。类似地,与施用式(I)化合物相比,任何抗病毒剂或STI亦可在任何时间点施用。
可使用本发明组合治疗治疗的慢性病毒感染包括(但不限于)由以下引起的疾病:C型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、单纯性疱疹病毒(HSV)、爱泼斯坦-巴尔氏(Epstein-Barr)病毒(EBV)、水痘带状病毒、柯萨奇(coxsackie)病毒、人类免疫缺陷病毒(HIV)。
考虑与式(I)化合物组合使用的适宜抗病毒剂可包括核苷及核苷酸逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTI)、蛋白酶抑制剂及其他抗病毒药物。
适宜NRTI的实施例包括齐多夫定(zidovudine)(AZT)、地达诺新(didanosine)(ddl)、扎西他滨(zalcitabine)(ddC)、司他夫定(stavudine)(d4T)、拉米夫定(lamivudine)(3TC)、阿巴卡韦(abacavir)(1592U89)、阿德福韦酯(adefovir dipivoxil)[双(POM)-PMEA]、洛布卡韦(lobucavir)(BMS-180194)、BCH-I0652、依米他滨(emitricitabine)[(-)-FTC]、β-L-FD4(亦称作β-L-D4C及命名为β-L-2′,3′-二脱氧-5-氟-胞苷)、DAPD((-)-β-D-2,6-二氨基-嘌呤二氧戊环)及洛德腺苷(lodenosine)(FddA)。典型适宜NNRTI包括奈韦拉平(nevirapine)(BI-RG-587)、地尔维啶(delaviradine)(BHAP,U-90152)、依法韦仑(efavirenz)(DMP-266)、PNU-142721、AG-1549、MKC-442(1-(乙氧基-甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶二酮)及(+)-卡兰利德(calanolide)A(NSC-675451)及B。典型适宜蛋白酶抑制剂包括沙奎那韦(saquinavir)(Ro31-8959)、利托那韦(ritonavir)(ABT-538)、茚地那韦(indinavir)(MK-639)、内夫那韦(nelfnavir)(AG-1343)、安普那韦(amprenavir)(141W94)、拉西那韦(lasinavir)(BMS-234475)、DMP-450、BMS-2322623、ABT-378及AG-1549。其他抗病毒剂包括羟基脲、利巴韦林(ribavirin)、IL-2、IL-12、喷他夫西(pentafuside)及Yissum项目编号11607。
组合疗法意欲包涵以依序方式施用这些治疗剂,即,其中在不同时间施用各治疗剂,以及以实质上同时方式施用这些治疗剂或所述治疗剂中的至少两者。实质上同时施用可(例如)通过向个体施用具有各治疗剂的固定比率的单一剂型或针对治疗剂各者的多个单一剂型来实现。各治疗剂的依序或实质上同时施用可通过任何适宜途径,包括(但不限于)口服途径、静脉内途径、肌肉内途径及通过黏膜组织直接吸收来实现。所述治疗剂可通过相同途径或通过不同途径施用。例如,所选组合的第一治疗剂可通过静脉内注射施用,而组合的其他治疗剂可经口施用。或者,例如,所有治疗剂可经口施用或所有治疗剂可通过静脉内注射施用。组合疗法亦可包含施用如上所述的治疗剂进一步与其他生物活性成分及非药物疗法(例如,手术或放射治疗)组合。在组合疗法进一步包含非药物治疗的情况下,该非药物治疗可在任何适宜时间进行只要自治疗剂及非药物治疗的组合的共同作用的有益效果达成。例如,在适宜情况下,当非药物治疗自治疗剂的施用暂时移除或许几天或甚至几周时,仍达成有益效果。
药物组合物
本发明亦提供药物组合物,其包含与一种或多种药学上可接受的载剂(添加剂)和/或稀释剂一起调配的治疗有效量的式(I)化合物中的一者或多者,及任选地上述一种或多种另外治疗剂。
式(I)化合物可通过任何适宜途径,优选地以适应于此途径的药物组合物的形式,及以针对意图治疗有效的剂量施用。所述化合物及式(I)化合物的组合物可针对本文中所述用途中的任一者通过任何适宜方法施用,例如,经口,诸如片剂、胶囊剂(其各者包含持续释放或定时释放制剂)、丸剂、粉末、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微米悬浮液、喷雾干燥分散剂)、糖浆及乳液;经舌下;经颊;非经肠,诸如通过皮下、静脉内、肌肉内或胸骨内注射或输注技术(例如,作为无菌可注射水性或非水性溶液或悬浮液);经鼻,包括向鼻膜施用,诸如通过吸入喷雾;经局部,诸如以乳霜或软膏的形式;或经直肠,诸如以栓剂的形式。其可单独施用,但是一般将利用基于所选施用途径及标准药物实务选择的药物载剂施用。
针对口服施用,该药物组合物可呈(例如)片剂、胶囊剂、液体胶囊、悬浮液或液体的形式。该药物组合物优选地以含有特定量的活性成分的剂量单位的形式制备。例如,该药物组合物可呈包含约0.1至1000mg,优选地约0.25至250mg,及更优选地约0.5至100mg的范围的活性成分的量的片剂或胶囊剂提供。针对人类或其他哺乳动物的适宜每日剂量可取决于患者的病状及其他因素广泛变化,但是可使用常规方法确定。
本文中所考虑的任何药物组合物可(例如)经由任何可接受且适宜口服制剂经口递送。示例性口服制剂包括(但不限于)例如,片剂、片剂、口含片、水性及油性悬浮液、可分散粉末或颗粒、乳液、硬及软胶囊、液体胶囊、糖浆及酏剂。意欲用于口服施用的药物组合物可根据用于制造意欲用于口服施用的药物组合物的技术中已知的任何方法制备。为提供药物上可口制剂,根据本发明的药物组合物可含有选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂及保存剂的至少一种剂。
片剂可(例如)通过将至少一种式(I)化合物和/或其至少一种药学上可接受的盐与适用于制造片剂的至少一种无毒药学上可接受的赋形剂混合来制备。示例性赋形剂包括(但不限于)例如,惰性稀释剂,诸如例如,碳酸钙、碳酸钠、乳糖、磷酸钙及磷酸钠;造粒剂及崩解剂,诸如例如,微晶纤维素、交联羧甲基纤维素钠、玉米淀粉及藻酸;黏合剂,诸如例如,淀粉、明胶、聚乙烯吡咯烷酮及阿拉伯胶;及润滑剂,诸如例如,硬脂酸镁、硬脂酸及滑石。另外,片剂可未经包衣或通过已知技术包衣以掩盖难吃药物的坏味道,或延迟活性成分在胃肠道中的崩解及吸收,从而使活性成分的效果持续更长时间。示例性水溶性味道掩盖材料包括(但不限于)羟丙基-甲基纤维素及羟丙基-纤维素。示例性时间延迟材料包括(但不限于)乙基纤维素及乙酸丁酸纤维素。
硬明胶胶囊可(例如)通过将至少一种式(I)化合物和/或其至少一种盐与至少一种惰性固体稀释剂(诸如,例如,碳酸钙、磷酸钙及高岭土)混合来制备。
软明胶胶囊可(例如)通过将至少一种式(I)化合物和/或其至少一种药学上可接受的盐与至少一种水溶性载剂(诸如,例如,聚乙二醇)及至少一种油性介质(诸如例如,花生油、液体石蜡及橄榄油)混合来制备。
水性悬浮液可(例如)通过将至少一种式(I)化合物和/或其至少一种药学上可接受的盐与适用于制造水性悬浮液的至少一种赋形剂混合来制备。适用于制造水性悬浮液的示例性赋形剂包括(但不限于)例如,悬浮剂,诸如例如,羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、藻酸、聚乙烯吡咯烷酮、黄蓍胶及阿拉伯胶;分散或润湿剂,诸如例如,天然产生的磷脂,例如,卵磷脂;环氧烷烃与脂肪酸的缩合产物,诸如例如,聚氧乙烯脂肪酸酯;环氧乙烷与长链脂族醇的缩合产物,诸如例如,十七乙烯-氧基鲸蜡醇;环氧乙烷与衍生自脂肪酸及己糖醇的部分酯的缩合产物,诸如例如,聚氧乙烯山梨醇单油酸酯;及环氧乙烷与衍生自脂肪酸及己糖醇酐的部分酯的缩合产物,诸如例如,聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液亦可含有至少一种保存剂,诸如例如,对羟基苯甲酸乙酯及对羟基苯甲酸正丙酯;至少一种着色剂;至少一种调味剂;和/或至少一种甜味剂,包括(但不限于)例如,蔗糖、糖精及阿斯巴甜。
油性悬浮液可(例如)通过将至少一种式(I)化合物和/或其至少一种药学上可接受的盐悬浮于植物油(诸如,例如,花生油、橄榄油、芝麻油及椰子油)或矿物油(诸如,例如,液体石蜡)中来制备。任何油性悬浮液亦可含有至少一种增稠剂,诸如例如,蜂蜡、硬石蜡及鲸蜡醇。为提供可口油性悬浮液,可将上文中已述的甜味剂中的至少一者和/或至少一种调味剂添加至油性悬浮液。油性悬浮液可进一步含有至少一种保存剂,包括(但不限于)例如,抗氧化剂,诸如例如,丁基化羟基苯甲醚及α-生育酚。
可分散粉末及颗粒可(例如)通过将至少一种式(I)化合物和/或其至少一种药学上可接受的盐与至少一种分散剂和/或润湿剂、至少一种悬浮剂和/或至少一种保存剂混合来制备。适宜分散剂、润湿剂及悬浮剂为如上已所述。示例性保存剂包括(但不限于)例如,抗氧化剂,例如,抗坏血酸。此外,可分散粉末及颗粒亦可含有至少一种赋形剂,包括(但不限于)例如,甜味剂、调味剂及着色剂。
可(例如)将至少一种式(I)化合物和/或其至少一种药学上可接受的盐的乳液制备成水包油乳液。包含式(I)化合物的乳液的油相可自已知成分以已知方式构成。该油相可通过(但不限于)例如,植物油,诸如,例如,橄榄油及花生油;矿物油,诸如例如,液体石蜡;及其混合物提供。虽然该相可仅包含乳化剂,但是其可包含至少一种乳化剂与脂肪或油或与脂肪及油二者的混合物。适宜乳化剂包括(但不限于)例如,天然产生的磷脂,例如,大豆卵磷脂;衍生自脂肪酸及己糖醇酐的酯或部分酯,诸如,例如,脱水山梨糖醇单油酸酯;及部分酯与环氧乙烷的缩合产物,诸如,例如,聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂与充当稳定剂的亲脂性乳化剂一起被包含。亦优选地包含油及脂肪二者。一并考虑,具有或不具有稳定剂的该(等)乳化剂组成所谓的乳化蜡,及该蜡与油及脂肪一起组成所谓的乳化乳膏基,该软膏基形成乳霜制剂的油性分散相。乳液亦可含有甜味剂、调味剂、保存剂和/或抗氧化剂。适用于本发明的制剂的乳化剂及乳液稳定剂包括吐温(Tween)60、司盘(Span)80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、月桂基硫酸钠、二硬脂酸甘油酯单独或与蜡、或本领域熟知的其他材料。
式(I)化合物和/或其至少一种药学上可接受的盐亦可(例如)经静脉内、经皮下和/或经肌肉内经由任何药学上可接受且适宜注射形式递送。示例性可注射形式包括(但不限于)例如,包含可接受媒剂及溶剂(诸如,例如,水、林格氏(Ringer’s)溶液及等渗氯化钠溶液)的无菌水溶液;无菌水包油微乳液;及水性或油性悬浮液。
用于非经肠施用的制剂可呈水性或非水性等渗无菌注射溶液或悬浮液的形式。这些溶液及悬浮液可使用用于口服施用的制剂中所提及的载剂或稀释剂中的一者或多者或通过使用其他适宜分散或润湿剂及悬浮剂自无菌粉末或颗粒制备。可将化合物溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠、黄蓍胶和/或各种缓冲剂中。其他佐剂及施用模式为药物技术中广泛熟知。活性成分亦可作为与适宜载剂(包括盐水、右旋糖或水),或与环糊精(即,Captisol)、助溶剂增溶(即,丙二醇)或胶束增溶(即,吐温80)的组合物通过注射施用。
无菌可注射制剂亦可为含于无毒非经肠可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如,呈含于1,3-丁二醇中的溶液。可采用的可接受的媒剂及溶剂为水、林格氏溶液及等渗氯化钠溶液。此外,习惯采用固定油作为溶剂或悬浮介质。出于此目的,可采用任何温和固定油,包括合成单甘油酯或二甘油酯。此外,脂肪酸(诸如油酸)可用于制备可注射剂。
无菌可注射水包油微乳液可(例如)通过以下制备:1)将至少一种式(I)化合物溶解于油相(诸如,例如,大豆油及卵磷脂的混合物)中,2)将含有式(I)的油相与水及甘油混合物组合;及3)经该组合处理以形成微乳液。
无菌水性或油性悬浮液可根据本领域已知的方法制备。例如,无菌水溶液或悬浮液可利用无毒非经肠可接受稀释剂或溶剂(诸如例如,1,3-丁二醇)制备;及无菌油性悬浮液可利用无菌无毒可接受溶剂或悬浮介质(诸如例如,无菌固定油,例如,合成单甘油酯或二甘油酯;及脂肪酸,诸如例如,油酸)制备。
药学上可接受的载剂根据本领域普通技术人员的权限内的许多因素来调配。这些包括(不限于):正在调配的活性剂的类型及性质;待经施用含该剂的组合物的个体;组合物的意欲施用途径;及正在靶向的治疗适应症。药学上可接受的载剂包含水性及非水性液体介质二者,以及各种个体及半固体剂型。这些载剂可包含除了活性剂外的许多不同成分及添加剂,这些另外成分出于本领域普通技术人员熟知的各种原因(例如,使活性剂、黏合剂等稳定)包含于制剂中。适宜药学上可接受的载剂及涉及其选择的因素的描述见于各种现成资源,诸如例如,Allen,L.V.Jr.等人,Remington:The Science and Practice ofPharmacy(第2卷),第22版(2012),Pharmaceutical Press。
可用于本发明的药物组合物中的药学上可接受的载剂、佐剂及媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物递送系统(SEDDS)(诸如d-α-生育酚聚乙二醇1000琥珀酸酯)、用于药物剂型中的表面活性剂(诸如吐温、聚乙氧基化蓖麻油(诸如CREMOPHOR表面活性剂(BASF))或其他相似聚合递送基质)、血清蛋白(诸如人类血清白蛋白)、缓冲物质(诸如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质,诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇及羊毛脂。环糊精(诸如α-、β-及γ-环糊精)或化学修饰衍生物(诸如羟烷基环糊精,包括2-及3-羟丙基-环糊精),或其他溶解衍生物亦可有利地用于增强本文中所述式的化合物的递送。
本发明的药物活性化合物可根据常规药剂学方法处理以制备用于向患者(包括人类及其他哺乳动物)施用的药剂。药物组合物可接受常规药物操作(诸如灭菌)和/或可含有常规佐剂(诸如保存剂、稳定剂、润湿剂、乳化剂、缓冲剂等)。片剂及丸剂另外可利用肠涂层制备。这些组合物亦可包含佐剂(诸如润湿剂、甜味剂、调味剂及香味剂)。
出于治疗目的,本发明的活性化合物通常与适用于指定施用途径的一种或多种佐剂组合。若经口施用,则所述化合物可与乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸及硫酸的钠及钙盐、明胶、阿拉伯胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,然后制片或封装以方便施用。这些胶囊或片剂可含有控制释放制剂,正如可以将活性化合物分散于羟丙基甲基纤维素中提供。
施用的化合物的量及利用本发明的化合物和/或组合物治疗疾病病状的剂量方案取决于各种因素,包括受试者的年龄、体重、性别、医疗状况、疾病类型、疾病的严重度、施用途径及频率及采用的特定化合物。因此,剂量方案可广泛变化,但是可使用标准方法常规确定。每日剂量为约0.001至100mg/kg体重,优选地约0.0025与约50mg/kg体重之间及最佳地约0.005至10mg/kg体重可为适宜。每日剂量可以每天一至四个剂量施用。其他给药时程表包括每周一个剂量及每两天一个剂量循环。
本发明的药物组合物包含至少一种式(I)化合物和/或其至少一种药学上可接受的盐,及任选选自任何药学上可接受的载剂、佐剂及媒剂的另外的剂。本发明的替代组合物包含本文中所述的式(I)化合物,或其前药,及药学上可接受的载剂、佐剂或媒剂。
本发明亦包含可用于(例如)治疗或预防Helios蛋白质相关疾病或病症及本文中提及的其他疾病的药物试剂盒,所述试剂盒包括一个或多个容器,该一个或多个容器含有包含治疗有效量的式(I)化合物的药物组合物。若所需,则这些试剂盒可进一步包含各种常规药物试剂盒组分中的一者或多者,诸如,例如,具有一种或多种药学上可接受的载剂的容器,对本领域技术人员显而易见的另外容器。指示待施用的组分的数量、施用指南和/或用于混合组分的指南的作为插入物或作为标签的说明书亦可包含于试剂盒中。
本发明的化合物的剂量方案当然将取决于已知因素,诸如特定剂的药效学特性及其施用模式及途径;接受者的物种、年龄、性别、健康、医疗状况及体重;症状的性质及程度;合并治疗的类型;治疗频率;施用途径、患者的肾及肝功能及所需效应变化。
经由一般指导,当针对指定效应使用时,各活性成分的每日口服剂量范围将为约0.001至约5000mg/天,优选地约0.01至约1000mg/天,及最优选地约0.1至约250mg/天。经静脉内,在恒定速率输注期间,最优选的剂量范围将为约0.01至约10mg/kg/分钟。式(I)化合物可以单一每日剂量施用,或总每日剂量可以每天两次、三次或四次的分开剂量施用。
所述化合物通常以混合物形式进行施用,该混合物利用关于意欲施用形式(例如,口服片剂、胶囊剂、酏剂及糖浆)经适宜选择且与常规药物实务一致的适宜药物稀释剂、赋形剂或载剂(本文中统称作药物载剂)。
适用于施用的剂型(药物组合物)可含有约1毫克至约200毫克的活性成分/剂量单位。在这些药物组合物中,活性成分通常将以基于该组合物的总重量计约0.1至95重量%的量存在。
用于口服施用的典型胶囊含有式(I)化合物中的至少一者(250mg)、乳糖(75mg)及硬脂酸镁(15mg)。将该混合物通过60目筛及包装至1号明胶胶囊中。
典型可注射制剂通过将式(I)化合物中的至少一者(250mg)无菌放入小瓶中,无菌冷冻干燥及密封来制备。对于使用,将小瓶的内容物与2mL生理盐水混合,以产生可注射制剂。
本发明在其范围内包含药物组合物,所述药物组合物单独或与药物载剂组合包含作为活性成分的治疗有效量的式(I)化合物中的至少一者。任选地式(I)化合物可单独、与其他式(I)化合物组合、或与一种或多种其他治疗剂(例如,抗癌剂)或其他药物上活性材料组合使用。
不管所选施用途径,可以适宜水合形式使用的式(I)化合物和/或本发明的药物组合物通过本领域技术人员已知的常规方法调配成药学上可接受的剂型。
本发明的药物组合物中的活性成分的实际剂量水平可变化以便获得一定量的活性成分,其可有效达成对特定患者、组合物及施用模式的所需治疗反应而不对该患者有毒。
所选剂量水平将取决于各种因素,所述因素包括所采用的特定式(I)化合物或其酯、盐或酰胺的活性、施用途径、施用时间、正在采用的特定化合物的排泄或代谢速率、吸收的速率及程度、治疗的持续时间、与所采用的特定化合物组合使用的其他药物、化合物和/或材料、正在治疗的患者的年龄、性别、体重、病状、一般健康及先前医疗史及医疗技术中熟知的类似因素。
具有本领域普通技术知识的医生或兽医可容易确定及开处方所需药物组合物的有效量。例如,医生或兽医可以低于为达成所需治疗效果所需的含量的含量开始药物组合物中所采用的式(I)化合物的剂量并逐渐增加该剂量直至达成所需效果。
一般而言,式(I)化合物的适宜每日剂量将是有效产生治疗效果的最低剂量的化合物的量。此有效剂量一般将取决于上述因素。一般而言,式(I)化合物针对患者的口服、静脉内、脑室内及皮下剂量范围将为约0.01至约50mg/kg体重/天。
若有需要,则活性化合物的有效每日剂量可在整天以适宜间隔分开施用的2、3、4、5、6个或更多个子剂量,任选以单位剂型施用。于本发明的某些方面中,给药为每天一次施用。
虽然单独施用式(I)化合物是可能的,但是优选地呈药物制剂(组合物)施用该化合物。
当与式(I)化合物组合采用时,以上其他治疗剂可(例如)以Physicians’DeskReference(PDR)中所指定或如由本领域普通技术人员以其他方式确定的那些量使用。在本发明的方法中,此(等)其他治疗剂可在施用本发明化合物之前、同时或之后施用。
制备方法
本发明的化合物可通过有机合成领域技术人员熟知的许多方法制备。本发明的化合物可使用以下所述的方法连同如由本领域技术人员所了解的合成有机化学领域中已知的合成方法或其变型合成。优选方法包括(但不限于)以下所述的那些。本文中所引用的所有参考文献的全文以引用的方式并入本文中。
本发明的化合物可使用此节中所述的反应及技术制备。反应在适用于所采用的试剂及材料的溶剂中进行且适用于正在实现的转化。同样,在以下所述的合成方法的描述中,应理解,选择所有提议的反应条件,包括溶剂的选择、反应氛围、反应温度、实验的持续时间及处理程序为该反应的标准条件,其应容易为本领域技术人员认可。有机合成领域技术人员应了解,分子的各种部分上存在的官能团必须与提议的试剂及反应兼容。对与反应条件兼容的取代基的这些限制将是对本领域技术人员显而易见的,并且之后必须使用替代方法。为获得本发明的所需化合物,有时将需要判断以修改合成步骤的顺序或选择优于另一者的一个特定流程方案。亦应知晓,在计划此领域中的任何合成途径时的另一主要考虑因素是用于保护存在于本发明中所述的化合物中的反应性官能团的保护基的明智选择。描述对经培训的从业者的许多备选方案的一个权威性报道是Greene及Wuts(ProtectiveGroups In Organic Synthesis,第4版,Wiley and Sons,207)。
式(I)化合物可参考下列反应图中所说明的方法制备。如其中所示,最终产物为具有与式(I)相同结构式的化合物。应理解,任何式(I)化合物可通过反应图通过适宜选择具有适宜取代基的试剂制备。溶剂、温度、压力及其他反应条件可容易由本领域普通技术人员选择。起始物质为可市面上购得或通过本领域普通技术人员容易制备。化合物的成分为如本文中或本说明书中其他地方所定义。
本发明中所述的化合物的一般途径在反应图1至9中说明,其中R4、R5、R6、Z及A取代基是文本中先前所定义或可转化成所需最终取代基的官能团。取代基L为离去基团,诸如卤化物(优选地I、Br或Cl)或磺酸酯。取代基M为适宜偶联搭档,诸如二羟基硼酸、二羟基硼酸酯或锡烷。取代基R为羧酸保护基,诸如叔丁基、甲基、乙基或苄基。如反应图1中所示,用于制备本发明的化合物的一般程序涉并用经适宜取代的杂环1开始。可使用本领域普通技术人员熟知的条件或本文中所述的方法将1的离去基团L转化成适宜偶联搭档M,以得到中间体2。在M为二羟基硼酸或二羟基硼酸酯的情况下,可使用适宜钯触媒(例如,Pd(PPh3)4或[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)或[1,1′-双(二叔丁基膦基)二茂铁]二氯化钯(II))在存在适宜碱(例如,碳酸铯、磷酸钾或碳酸氢钠)下以铃木-宫浦(Suzuki-Miyaura)偶联反应将2与经适宜取代的杂环3联合,以得到4。在M为锡烷的情况下,可使用适宜触媒系统(例如,Pd(PPh3)4或双(三苯基膦)二氯化钯(II)/CuI)以施蒂勒(Stille)偶联反应将2与经适宜取代的杂环3联合,以得到4。当R=叔丁基时,可经由用质子酸(诸如苯磺酸)处理,将中间体4转化成5。在一些情况下,取决于酸保护基R的选择,可通过用碱(例如,K2CO3、K3PO4或LiHMDS)处理,将4转化成5。在一些情况下,可在制备其所采用的铃木-宫浦偶联或施蒂勒偶联条件下将中间体4自发环化成5。
反应图1
在一些情况下,在合成顺序中较早将杂环A偶联可能是有利的。在这些情况下,可使用本领域普通技术人员熟知的条件或本文中所述的方法将6的离去基团L转化成适宜偶联搭档M,以得到中间体7。在M为二羟基硼酸或二羟基硼酸酯的情况下,可使用适宜钯触媒(例如,Pd(PPh3)4或[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)或[1,1′-双(二叔丁基膦基)二茂铁]二氯化钯(II))在存在适宜碱(例如,碳酸铯、磷酸钾或碳酸氢钠)下以铃木-宫浦偶联反应将7与经适宜取代的杂环3联合,以得到8。在M为锡烷的情况下,可使用适宜触媒系统(例如,Pd(PPh3)4或双(三苯基膦)二氯化钯(II)/CuI)以施蒂勒偶联反应将7与经适宜取代的杂环3联合,以得到8。苄基位置可在存在自由基引发剂(诸如AIBN、过氧化苯甲酰或光)下通过NBS的作用溴化,以得到溴化物9。可在碱存在(例如,二异丙基乙胺或三乙胺)下将溴化物9与3-氨基哌啶-2,6-二酮(10)缩合,以得到11。
反应图2
或者,可在碱存在(例如,二异丙基乙胺或三乙胺)下将溴化物9(反应图2)或化合物12(其中L为离去基团,诸如卤化物或磺酸酯,反应图3)与13(其中R为羧酸保护基,诸如叔丁基、甲基、乙基或苄基)缩合,以得到如反应图3中所示的中间体14。
反应图3
取决于中间体4中的酸保护基的特定选择,可需要不同条件将其转化成化合物5(反应图4)。例如,在R=甲基、乙基或苄基的情况下,在适宜溶剂(例如,四氢呋喃)中使用适宜碱(例如,LiHMDS)的碱诱导的环化4针对4直接转化成5可以是优选的。在R=叔丁基的情况下,在适宜溶剂(例如,乙腈)中使用适宜酸(例如,苯磺酸)的酸诱导的环化4针对4直接转化成5可以是优选的。在一些情况下,其优选地使用两步程序,首先使用适用于特定酸保护基R的条件将游离羧酸15释放。这些方法为有机合成领域普通技术人员熟知。例如,在R=叔丁基的情况下,使用适宜酸(例如,三氟乙酸或盐酸)的酸水解可以是优选的。在R=甲基、乙基或苄基的情况下,使用适宜碱(例如,LiOH)的碱水解可以是优选的。于其他情况下,在R=苄基的情况下,其可有利地通过钯催化的氢解作用脱去保护基。一旦释放,15的羧酸可通过亚硫酰氯/二甲基甲酰胺或羰二咪唑/二甲氨基吡啶的作用朝向通过侧链一级酰胺的分子内攻击而被活化,以得到5。
反应图4
如反应图1中所示,被适宜的离去基团L取代的杂环(诸如化合物1)是合成式(I)化合物的可用中间体。在一些情况下,其可如反应图5中所概述制备,其中L为离去基团,诸如卤化物。为了开始,中间体6的苄基位置可在存在自由基引发剂(诸如AIBN、过氧化苯甲酰或光)下通过NBS的作用溴化,以得到溴化物16。可在碱存在(例如,二异丙基乙胺或三乙胺)下将溴化物16与3-氨基哌啶-2,6-二酮(10)缩合,以得到17。或者,可在碱存在(例如,二异丙基乙胺或三乙胺)下将溴化物16与13缩合,以得到18。
反应图5
为得到经适宜离去基团L取代的杂环的替代顺序在反应图6中概述。为了开始,使19脱水可通过乙酸酐的作用实现,以得到酸酐20。在一些情况下,此过程可通过添加吡啶得以促进。可使用乙酸及乙酸钾的组合将酸酐20与3-氨基哌啶-2,6-二酮(10)缩合,以得到21。或者,可使用乙酸及乙酸钾的组合将酸酐20与13缩合,以得到22。
反应图6
在一些情况下,在合成顺序较早时将杂环A偶联可能是有利的。在这些情况下,可使用本领域普通技术人员熟知的条件或本文中所述方法将19的离去基团L转化成适宜偶联搭档M,以得到中间体23。在M为二羟基硼酸或二羟基硼酸酯的情况下,可使用适宜钯触媒(例如,Pd(PPh3)4或[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)或[1,1′-双(二叔丁基膦基)二茂铁]二氯化钯(II))在存在适宜碱(例如,碳酸铯、磷酸钾或碳酸氢钠)下以铃木-宫浦偶联反应将23与经适宜取代的杂环3联合,以得到24。在M为锡烷的情况下,可使用适宜触媒系统(例如,Pd(PPh3)4或双(三苯基膦)二氯化钯(II)/CuI)以施蒂勒偶联反应将23与经适宜取代的杂环3联合,以得到24。使24脱水可通过乙酸酐的作用实现,以得到酸酐25。在一些情况下,此过程可通过添加吡啶得以促进。可使用乙酸及乙酸钾的组合将酸酐25与3-氨基哌啶-2,6-二酮(10)缩合,以得到26,如反应图7中所示。
反应图7
如先前反应图中所概述,将27的离去基团L转化成28中的适宜偶联搭档M(诸如二羟基硼酸、二羟基硼酸酯或锡烷)通常是方便且有利的。可继而将此与经取代的杂环3偶联,以得到5。在一些情况下,可优选地将偶联搭档逆转,以将27与经取代的杂环29偶联,直接得到5。在29的偶联搭档M为二羟基硼酸或二羟基硼酸酯的情况下,铜辅助的铃木-宫浦可以是优选的(参见Crowley等人,Tetrahedron Letters,2011,5055)。其在反应图8中概述。相似地,可将中间体1(反应图9)与杂环29偶联,以直接得到中间体4。通过上述方法的进一步修饰可导致另外式(I)化合物。
反应图8
反应图9
实施例
下列实施例说明本发明的特定实施方案且不限制本发明的范围。除非另有指定,否则化学缩略语及符号以及科学缩略语及符号具有其通常且习惯的含义。本申请中实施例及其他地方中采用的另外缩略语如上所定义。常见中间体一般可用于制备超过一个实施例。在一些实施例中,描述中间体或实施例的替代制备。频繁地,具有合成领域技术的化学家可设计替代制备,其基于一个或多个考虑因素,诸如较短反应时间、较便宜起始物质、易于操作或分离、提高的产率、催化服从性、避免毒性试剂、专门仪器的可得性及线性步骤的减少的数目等可能是所需要的。描述替代制备的意图是使能进一步制备本发明的实施例。在一些实施例中,所概述实施例及权利要求书中的一些官能团可由本领域已知的公知的生物电等排体置换,例如,以四唑或磷酸酯部分置换羧酸基团来置换。
缩略语
AIBN 偶氮二异丁腈
Boc 叔丁氧羰基
DCM 二氯甲烷
DIEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
ESI 电喷雾电离
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
Hex 己烷
HPLC 高效液相色谱法
许尼希氏(Hunig’s)碱 N,N-二异丙基乙胺
LCMS 液相色谱质谱法
min 分钟
mL 毫升
MS 质谱法
NBS N-溴琥珀酰亚胺
Pd(dppf)Cl2 [1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)
Pd(dtbpf)Cl2 [1,1′-双(二叔丁基膦基)二茂铁]二氯化钯(II)
TEA 三乙胺
分析型HPLC条件
方法A:柱:Waters XBridge C18,2.1mm x 50mm,1.7μm粒子;流动相A:5:95乙腈:水与0.1%三氟乙酸;流动相B:95:5乙腈:水与0.1%三氟乙酸;温度:50℃;梯度:0%B至100%B历时3分钟,然后0.50分钟保持在100%B;流率:1mL/min;检测:MS及UV(220nm)。
方法B:柱:Waters XBridge C18,2.1mm x 50mm,1.7μm粒子;流动相A:5:95乙腈:水与10mM乙酸铵;流动相B:95:5乙腈:水与10mM乙酸铵;温度:50℃;梯度:0%B至100%B历时3分钟,然后0.50分钟保持在100%B;流率:1mL/min;检测:MS及UV(220nm)。
实施例1
3-(5-{4-[(二甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
步骤1:(S)-5-氨基-4-(5-溴-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
向在0℃下的含于乙腈(231mL)中的(S)-4,5-二氨基-5-氧代戊酸叔丁酯盐酸盐(14.46g,60.6mmol)的悬浮液中添加DIEA(20.2mL,115mmol)。在搅拌15分钟后,将反应混合物用呈固体的4-溴-2-(溴甲基)苯甲酸甲酯(22g,57.7mmol)分若干份历时5分钟处理。将反应混合物在0℃下搅拌30分钟然后在室温过夜。将反应混合物于油浴中在回流冷凝器下升温至60℃并保持在该温度下过夜。将反应混合物在搅拌下冷却至室温。在冷却至室温后,沉淀形成。将烧瓶放入0℃浴中伴随搅拌。于30分钟后,通过过滤收集固体,用最少量冷乙腈冲洗,及空气干燥,以得到呈白色固体的20.13g(88%产率)。手性分析型HPLC分析指示,该物质为>98%ee。MS(ES):m/z=397.1[M+H]+。1HNMR(400MHz,CDCl3)δ7.76-7.71(m,1H),7.68-7.62(m,2H),6.22(br s,1H),5.31(br s,1H),4.91(dd,J=8.7,6.3Hz,1H),4.62-4.53(m,1H),4.51-4.40(m,1H),2.47-2.10(m,4H),1.44(s,9H)。
步骤2:(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯
将干燥烧瓶中放入(S)-5-氨基-4-(5-溴-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(10.0g,25.2mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂硼戊环)(7.67g,30.2mmol)及乙酸钾(7.41g,76mmol)并用氮气喷冲。将固体悬浮于二噁烷(100mL)中并用氮气流脱气5分钟伴随搅拌。将反应混合物用[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(0.737g,1.007mmol)处理,脱气5分钟,密封及加热至60℃持续18小时。将反应混合物用EtOAc稀释,通过硅藻土塞过滤,并用另外的EtOAc冲洗。将滤液浓缩并使用220g硅胶柱通过ISCO(0%→20%B/DCM,其中B=15%EtOH/EtOAc+0.1%TEA)纯化,以得到呈白色固体的9.9g(89%产率)。MS(ES):m/z=445.3[M+H]+。1H NMR(400MHz,CDCl3)δ7.99-7.90(m,2H),7.88-7.83(m,1H),6.32(br s,1H),5.36(br s,1H),4.97-4.88(m,1H),4.58-4.41(m,2H),2.48-2.13(m,4H),1.44(s,9H),1.39(s,12H)。
步骤3:(S)-5-氨基-4-(5-(4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将烧瓶中放入(2-氯吡啶-4-基)甲醇(1.00g,6.97mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(3.87g,8.71mmol)、Pd(dtbpf)Cl2(0.136g,0.209mmol)、二噁烷(50mL)及K3PO4水溶液(3M,11.61mL,34.8mmol)。将容器密封并将空气用氮气置换。将反应在70℃下加热过夜。将反应冷却至室温,用EtOAc稀释,用盐水洗涤,及分离层。将有机物经硫酸钠干燥,过滤及浓缩。将所得残余物通过急骤色谱法使用120g ISCO柱及利用0至100%B/DCM[其中B=15%EtOH/EtOAc+0.1%三乙胺]洗脱纯化,以得到1.38g(47%)。MS(ES):m/z=426.4[M+H]+。
步骤4:3-(5-(4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐
向在0℃下的含于DCM(15mL)中的(S)-5-氨基-4-(5-(4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(1.00g,2.35mmol)的溶液中逐滴添加亚硫酰氯(0.511mL,7.05mmol)。在5分钟后,移除冰浴并允许将反应升温至室温。于30分钟后,将反应浓缩。将所得残余物溶解于乙腈(15mL)中。向此中添加苯磺酸(0.818g,5.17mmol)。将反应在130℃下经由微波加热30分钟。将反应浓缩至干。向此中添加20mL的2M HCl的乙醚溶液并将所得混合物搅拌30分钟。通过倾析移除母液及丢弃。将剩余固体在真空下干燥,以获得呈盐酸盐的708mg(81%)。MS(ES):m/z=370.2[M+H]+。
步骤5:3-(5-{4-[(二甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
将小瓶中放入3-(5-(4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐(71mg,0.175mmol)、二甲胺盐酸盐(42.8mg,0.524mmol)及DMF(1mL)。向此中添加N-乙基-N-异丙基丙-2-胺(0.304mL,1.748mmol)。将反应在70℃下加热3小时。将反应冷却至室温并用乙酸(0.5mL)处理。将产物通过制备型HPLC纯化,以得到40mg(52%)。1H NMR(400MHz,DMSO-d6)δ11.37-10.73(m,1H),8.66(d,J=5.0Hz,1H),8.33(s,1H),8.25(dd,J=8.0,1.4Hz,1H),7.98(s,1H),7.84(d,J=8.1Hz,1H),7.36(dd,J=5.3,1.0Hz,1H),5.21-5.11(m,1H),4.61-4.39(m,2H),3.02-2.87(m,1H),2.71-2.59(m,1H),2.53(m,2H),2.47-2.38(m,1H),2.22(s,6H),2.12-2.00(m,1H)。LCMS(方法B):保留时间1.09分钟,[M+H]+379.3。
实施例2至143
根据针对实施例1所述的程序,将二甲胺用适宜一级胺或二级胺置换来制备表1中的化合物:
表1
实施例144
3-{5-[4-(氨基甲基)吡啶-2-基]-1-氧代-2,3-二氢-1H-异吲哚-2-基}哌啶-2,6-二酮
步骤1:((2-氯吡啶-4-基)甲基)氨基甲酸叔丁酯
将小瓶中放入(2-氯吡啶-4-基)甲胺2HCl(300mg,1.39mmol)、DCM(8mL)及二碳酸二叔丁酯(365mg,1.670mmol)。在室温搅拌5分钟后,添加三乙胺(0.775mL,5.57mmol)并将反应搅拌3小时。将反应混合物浓缩及通过ISCO使用24g硅胶柱及利用5至100%EtOAc/己烷洗脱纯化,以得到325mg(96%)。MS(ES):m/z=243.1[M+H]+。
步骤2:3-{5-[4-(氨基甲基)吡啶-2-基]-1-氧代-2,3-二氢-1H-异吲哚-2-基}哌啶-2,6-二酮
将2mL微波小瓶中装入((2-氯吡啶-4-基)甲基)氨基甲酸叔丁酯(24mg,0.099mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(54.9mg,0.124mmol)、Pd(dtbpf)Cl2(1.933mg,2.97μmol)、1,4-二噁烷(1mL)及K3PO4水溶液(0.165mL,0.494mmol)。将反应小瓶密封并将空气用氮气置换。将反应混合物经由微波在120℃加热10分钟。将反应混合物冷却至室温,用EtOAc稀释,用盐水洗,经硫酸钠干燥,并浓缩。将粗制物溶解于PhSO3H溶液于MeCN中的溶液(0.5mL,
1.44g于40mL中)中并经由微波在130℃加热30分钟。将反应物浓缩至干。将所得残余物通过制备型HPLC纯化,得到34.6mg(30%)。1H NMR(500MHz,DMSO-d6)δ11.02(s,1H),8.75(d,J=4.9Hz,1H),8.42(br s,2H),8.31(s,1H),8.22(br d,J=8.1Hz,1H),8.14(brs,1H),7.90(d,J=8.1Hz,1H),7.48(br d,J=4.7Hz,1H),5.17-5.07(m,1H),4.63-4.53(m,1H),4.49-4.39(m,1H),4.19(br s,2H),2.97-2.86(m,1H),2.64(br d,J=16.7Hz,1H),2.49-2.36(m,1H),2.11-2.01(m,1H)。LCMS(方法A):保留时间0.74分钟,[M+H]+351.1。
实施例145
3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
步骤1:((2-氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯
将小瓶中装入((2-氯吡啶-4-基)甲基)氨基甲酸叔丁酯(40mg,0.165mmol)、DMF(1.5mL)及碘甲烷(35.1mg,0.247mmol)。在室温搅拌5分钟后,添加氢化钠(26.4mg,0.659mmol)并将反应混合物搅拌3小时。将反应混合物用EtOAc稀释并用盐水洗。将混合物浓缩及通过制备型HPLC纯化,得到29mg(69%)。MS(ES):m/z=257.1[M+H]+。
步骤2:3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
将微波小瓶中放入((2-氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(25mg,0.097mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(54.1mg,0.122mmol)、Pd(dtbpf)Cl2(1.90mg,2.92μmol)、1,4-二噁烷(1mL)及K3PO4水溶液(0.162mL,0.487mmol)。将小瓶密封并将空气用氮气置换。将反应混合物在120℃下经由微波加热10分钟。将反应混合物用EtOAc稀释,用盐水洗涤,经硫酸钠干燥,及浓缩。将所得残余物溶解于含PhSO3H溶液的MeCN溶液(0.5mL,1.44g含于40mL中)中及在120℃下经由微波加热10分钟。将混合物通过制备型HPLC纯化,以得到产物(15.1mg,43%)。1H NMR(500MHz,DMSO-d6)δ8.64(d,J=4.9Hz,1H),8.32(s,1H),8.24(d,J=7.9Hz,1H),8.03(s,1H),7.86(d,J=7.9Hz,1H),7.39(br d,J=4.9Hz,1H),5.14(dd,J=13.3,5.3Hz,1H),4.61-4.51(m,1H),4.49-4.39(m,1H),3.80(s,2H),2.98-2.87(m,1H),2.69-2.60(m,1H),2.49-2.39(m,1H),2.33(s,3H),2.07(br d,J=5.5Hz,1H)。LCMS(方法A):保留时间0.55分钟,[M+H]+365.5。
实施例146
4-{[({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)(甲基)氨基]甲基}-N,N-二甲基苯-1-磺酰胺
步骤1:3-(5-(4-((甲氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮二盐酸盐
将烧瓶中放入(S)-5-氨基-4-(5-(4-(((叔丁氧羰基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(2.0g,3.71mmol)、苯磺酸(1.762g,11.14mmol)及乙腈(60mL)。将所得混合物加热至回流及保持在该温度下持续4小时。将反应混合物浓缩。将所得残余物用50mL的2M HCl的乙醚溶液处理及搅拌15分钟。通过过滤收集所得固体,用乙醚冲洗,及空气干燥,以得到呈二HCl盐的产物(1.4g,78%)。MS(ES):m/z=365.2[M+H]+。
步骤2:4-{[({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)(甲基)氨基]甲基}-N,N-二甲基苯-1-磺酰胺
将小瓶中放入3-(5-(4-((甲氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮二盐酸盐(20mg,0.046mmol)、4-(溴甲基)-N,N-二甲基苯磺酰胺(25.4mg,0.091mmol)及DMF(1mL)。向其中添加N-乙基-N-异丙基丙-2-胺(35.5mg,0.274mmol)。将反应混合物升温至50℃并保持在该温度下持续4小时。将反应通过添加乙酸(0.2mL)中止。将反应混合物通过HPLC纯化,以得到产物(12.1mg,46%)。1H NMR(500MHz,DMSO-d6)δ11.02(s,1H),8.66(d,J=4.9Hz,1H),8.30(s,1H),8.22(br d,J=7.9Hz,1H),8.01(s,1H),7.86(d,J=7.9Hz,1H),7.75-7.69(m,2H),7.69-7.63(m,2H),7.45(d,J=4.3Hz,1H),5.12(br dd,J=13.1,4.9Hz,1H),4.62-4.52(m,1H),4.49-4.39(m,1H),3.61(br s,4H),2.98-2.85(m,1H),2.65(br d,J=16.2Hz,1H),2.52(br s,6H),2.44(qd,J=13.1,4.4Hz,1H),2.19(s,3H),2.11-2.00(m,1H)。LCMS(方法A):保留时间1.10分钟,[M+H]+562.1。
实施例147至162
根据针对实施例146所述的程序,将4-(溴甲基)-N,N-二甲基苯磺酰胺用适宜溴化物置换来制备表2中的化合物:
表2
实施例163
3-(5-{4-[(二苄基氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
步骤1:N,N-二苄基-1-(2-氯吡啶-4-基)甲胺
向溶解于DMF(1mL)中的(2-氯吡啶-4-基)甲胺2HCl(40mg,0.186mmol)的溶液中添加氢化钠(29.7mg,0.742mmol)及(溴甲基)苯(69.8mg,0.408mmol)。将所得混合物在室温搅拌16小时。将反应混合物用EtOAc稀释并用盐水洗涤。将有机物浓缩并通过制备型HPLC纯化,以得到产物(31mg,52%)。MS(ES):m/z=323.2[M+H]+。
步骤2:3-(5-{4-[(二苄基氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
根据用于制备3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮的一般方法,制备实施例163。1H NMR(500MHz,DMSO-d6)δ11.02(brd,J=4.0Hz,1H),8.67(d,J=4.9Hz,1H),8.28(s,1H),8.21(br d,J=7.9Hz,1H),8.00(s,1H),7.86(d,J=7.9Hz,1H),7.49(br d,J=4.6Hz,1H),7.47-7.42(m,4H),7.38(t,J=7.5Hz,4H),7.31-7.24(m,2H),5.17(br dd,J=13.3,5.0Hz,1H),4.63-4.53(m,1H),4.51-4.39(m,1H),3.67(s,2H),3.61(s,4H),3.00-2.89(m,1H),2.71-2.60(m,1H),2.46(td,J=13.3,9.2Hz,1H),2.07(br dd,J=10.8,5.6Hz,1H)。LCMS(方法B):保留时间2.36分钟,[M+H]+531.2。
实施例164
3-[5-(4-{[苄基(甲基)氨基]甲基}吡啶-2-基)-1-氧代-2,3-二氢-1H-异吲哚-2-基]哌啶-2,6-二酮
步骤1:N-苄基-1-(2-氯吡啶-4-基)-N-甲基甲胺
向含于DMF(1mL)中的(2-氯吡啶-4-基)甲胺2HCl(43.4mg,0.201mmol)的溶液中添加氢化钠(32.2mg,0.805mmol)及(溴甲基)苯(36.1mg,0.211mmol)。将所得混合物在室温搅拌1小时。向此中添加碘甲烷(30mg,0.211mmol)。将反应混合物搅拌过夜。将产物通过制备型HPLC分离,以得到23mg(46%)。MS(ES):m/z=247.1[M+H]+。
步骤2:3-[5-(4-{[苄基(甲基)氨基]甲基}吡啶-2-基)-1-氧代-2,3-二氢-1H-异吲哚-2-基]哌啶-2,6-二酮
根据用于制备3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮的一般方法,制备实施例164。1H NMR(500MHz,DMSO-d6)δ11.03(s,1H),8.81(d,J=4.9Hz,1H),8.32(s,1H),8.24(d,J=8.2Hz,1H),8.21(s,1H),7.90(d,J=7.9Hz,1H),7.60-7.53(m,3H),7.51-7.45(m,3H),5.14(dd,J=13.4,5.2Hz,1H),4.63-4.54(m,1H),4.50-4.35(m,4H),3.62-3.48(m,1H),2.98-2.87(m,1H),2.68-2.61(m,4H),2.49-2.37(m,1H),2.13-2.02(m,1H)。LCMS(方法B):保留时间1.66分钟,[M+H]+455.1。
实施例165
3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
步骤1:4-(氮杂环丁烷-1-基甲基)-2-氯吡啶
将小瓶中放入2-氯-4-(氯甲基)吡啶(44mg,0.187mmol)、THF(1.5mL)及氮杂环丁烷(13.44mg,0.234mmol)。在搅拌5分钟后,添加N-乙基-N-异丙基丙-2-胺(0.130mL,0.749mmol)。将反应混合物升温至40℃并保持在该温度下持续3小时。将反应混合物用EtOAc稀释,用盐水洗涤,经硫酸钠干燥,及浓缩,以得到产物(31mg,91%)。MS(ES):m/z=182.9[M+H]+。
步骤2:3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
将微波小瓶中放入4-(氮杂环丁烷-1-基甲基)-2-氯吡啶(17.4mg,0.095mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(52.9mg,0.119mmol)、Pd(dtbpf)Cl2(1.863mg,2.86μmol)、1,4-二噁烷(1mL)及K3PO4水溶液(0.159mL,0.476mmol)。将小瓶密封并将空气用氮气置换。将反应混合物在120℃下经由微波加热10分钟。将反应混合物冷却,用EtOAc稀释,并用盐水洗涤。将有机物经硫酸钠干燥及浓缩。将所得残余物溶解于含PhSO3H溶液的乙腈溶液(0.5mL,1.44g含于40mL中)中及在120℃下经由微波加热10分钟。将反应混合物浓缩并通过制备型HPLC纯化,以得到实施例165(8.1mg,18%)。1H NMR(500MHz,DMSO-d6)δ8.61(d,J=4.9Hz,1H),8.29(s,1H),8.21(br d,J=7.6Hz,1H),7.90(s,1H),7.84(d,J=8.1Hz,1H),7.31(br d,J=4.9Hz,1H),5.17-5.08(m,1H),4.60-4.39(m,2H),3.65(br s,2H),3.20(t,J=7.0Hz,3H),2.96-2.85(m,1H),2.68-2.60(m,1H),2.48-2.35(m,2H),2.11-1.96(m,3H)。LCMS(方法A):保留时间0.91分钟,[M+H]+390.9。
实施例166
3-(5-{4-[(吗啉-4-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮
根据用于制备3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮的一般程序,制备实施例166。1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.64(d,J=5.0Hz,1H),8.30(s,1H),8.22(br d,J=8.0Hz,1H),7.97(s,1H),7.84(d,J=8.0Hz,1H),7.38(d,J=4.5Hz,1H),5.19-5.05(m,1H),4.62-4.35(m,2H),3.56-3.54(m,6H),2.97-2.84(m,1H),2.67-2.59(m,1H),2.46-2.34(m,5H),2.12-1.99(m,1H)。LCMS(方法B):保留时间1.23分钟,[M+H]+421.1。
实施例167
4-({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)-1λ6-硫代吗啉-1,1-二酮
根据用于制备3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮的一般程序,制备实施例167。1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.66(d,J=5.0Hz,1H),8.32(br s,1H),8.24(br d,J=8.0Hz,1H),8.02(brs,1H),7.85(d,J=8.0Hz,1H),7.41(d,J=4.8Hz,1H),5.18-5.07(m,1H),4.60-4.38(m,2H),3.17(br s,3H),2.94(br s,4H),2.63(br d,J=15.3Hz,1H),2.51(br s,4H),2.48-2.36(m,1H),2.12-1.99(m,1H)。LCMS(方法B):保留时间1.13分钟,[M+H]+469.0。
实施例168
3-{5-[4-({[(6-甲氧基吡啶-3-基)甲基](甲基)氨基}甲基)吡啶-2-基]-1-氧代-2,3-二氢-1H-异吲哚-2-基}哌啶-2,6-二酮
将小瓶中放入3-(5-(4-((甲氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮二盐酸盐(20mg,0.046mmol)、6-甲氧基烟碱醛(18.8mg,0.137mmol)及DMF(1mL)。在室温搅拌10分钟后,添加三乙酰氧基硼氢化钠(29.1mg,0.137mmol)。将反应混合物升温至50℃并保持在该温度下过夜。将反应混合物过滤并通过制备型HPLC纯化,以得到2.5mg(11%)。1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.73(d,J=4.8Hz,1H),8.27(s,1H),8.22(s,1H),8.19(d,J=8.0Hz,1H),8.08(s,1H),7.87(d,J=8.0Hz,1H),7.79(dd,J=8.6,2.3Hz,1H),7.49(d,J=4.6Hz,1H),6.86(d,J=8.6Hz,1H),5.09(br dd,J=13.1,5.1Hz,1H),4.56(d,J=17.6Hz,1H),4.48-4.37(m,1H),3.80-3.78(m,7H),2.88(ddd,J=18.0,13.3,5.1Hz,1H),2.69-2.61(m,1H),2.49(br s,3H),2.42(br dd,J=12.7,4.1Hz,1H),2.11-2.01(m,1H)。LCMS(方法A):保留时间1.02分钟,[M+H]+486.3。
实施例169至185
根据针对实施例168所述的一般程序,将6-甲氧基烟碱醛用适宜醛或酮置换来制备表3中的化合物:
表3
实施例186
3-(5-(5-氯-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
步骤1:(S)-5-氨基-4-(5-(5-氯-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将20mL小瓶中放入(2,5-二氯吡啶-4-基)甲醇(0.2g,1.124mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(0.749g,1.685mmol)、Pd(dtbpf)Cl2(0.022g,0.034mmol)、1,4-二噁烷(5.62mL)及3MK3PO4水溶液(1.873mL,5.62mmol)。将小瓶密封并将空气用氮气置换。将其在60℃下加热16小时。将反应混合物冷却至室温,用EtOAc(25mL)稀释,用盐水洗涤,及分离层。将有机物经硫酸钠干燥,过滤,及浓缩。将粗产物使用硅胶柱通过ISCO柱色谱法(40g Gold柱,利用0至100%的20%甲醇胺/DCM-DCM洗脱)纯化,以得到呈浅棕色固体的(S)-5-氨基-4-(5-(5-氯-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(320mg,0.668mmol,59.4%产率)。未测定此物质及随后中间体的对映异构体过量。MS(ES):m/z=460.05[M+H]+。
步骤2:3-(5-(5-氯-4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
将亚硫酰氯(0.132mL,1.826mmol)逐滴添加至含于DCM(3.00mL)中的(S)-5-氨基-4-(5-(5-氯-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(0.280g,0.609mmol)的冰冷(0℃)溶液中。于10分钟后,移除冰浴,并允许将反应混合物升温至室温。于30分钟后,将反应混合物浓缩至干。将残余物溶解于乙酸(3mL)中并添加苯磺酸(0.212g,1.339mmol)并将反应混合物于微波烘箱中在120℃下加热25分钟。将反应混合物浓缩至干,并添加2mL的3M HCl的MeOH溶液及在0℃(冰水浴)下搅拌直至存在完全溶解。然后添加8mLEtOAc,及搅拌。于5分钟后,允许将反应混合物仍保持在冰水浴中30分钟。过滤沉淀,用EtOAc洗涤,然后空气干燥,以得到呈HCl盐的3-(5-(5-氯-4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(180mg,0.401mmol,65.8%产率)。MS(ES):m/z=404.3,406.3[M+H]+。
步骤3:3-(5-(5-氯-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
向含于DMF(0.5mL)中的3-(5-(5-氯-4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮HCl(40mg,0.091mmol)的溶液中添加3-苯基氮杂环丁烷HCl(17.71mg,0.104mmol),接着添加许尼希氏碱(95μL,0.545mmol)。将所得混合物加热至80℃,同时搅拌3小时。然后将其冷却及进一步用DMF(0.5mL)稀释。将粗物质经由制备型LC/MS利用下列条件纯化:柱:XBridge C18,200mm x 19mm,5-μm粒子;流动相A:5:95乙腈:水与乙酸铵;流动相B:95:5乙腈:水与乙酸铵;梯度:在35%B下保持0分钟,35至75%B历时22分钟,然后在100%B下保持0分钟;流率:20mL/min;柱温度:25℃。通过MS信号触发洗脱份收集。合并含有所需产物的洗脱份并经由离心蒸发干燥,以获得3-(5-(5-氯-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(15.5mg,0.030mmol,33.1%产率)。LCMS(方法A):保留时间1.28分钟;MS(ES):m/z=501.17[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.82(s,1H),8.33(s,1H),8.24(m,m 1H),7.99(s,1H),7.84(d,J=8.0Hz,1H),7.41-7.31(m,5H),7.26-7.20(m,1H),5.16(m,1H),4.56(d,J=17.4Hz,1H),4.44(d,J=17.4Hz,1H),3.80-3.66(m,5H),3.26-3.18(m,2H),3.00-2.88(m,1H),2.49-2.37(m,1H),2.10-2.01(m,1H)。
实施例187
根据针对实施例186所述的一般程序,将3-苯基氮杂环丁烷用适宜胺置换来制备表4中的化合物。
表4
实施例188
3-(5-(5-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
步骤1:5-氨基-4-(5-(5-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将20mL小瓶中放入(2-氯-5-氟吡啶-4-基)甲醇(0.4g,2.476mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(1.650g,3.71mmol)、Pd(dtbpf)Cl2(0.048g,0.074mmol)、1,4-二噁烷(12.38mL)及3M K3PO4水溶液(4.13mL,12.38mmol)。将小瓶密封并将空气用氮气置换。将其在60℃下加热16小时。将反应混合物冷却至室温,用EtOAc(25mL)稀释,用盐水洗涤,及分离层。将有机物经硫酸钠干燥,过滤,及浓缩。将粗产物使用硅胶柱通过ISCO柱色谱法(40g Gold柱,利用0至100%的20%甲醇胺/DCM-DCM洗脱)纯化,以得到呈浅棕色固体的5-氨基-4-(5-(5-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(650mg,1.466mmol,59.2%产率)。未测定此物质及随后中间体的对映异构体过量。MS(ES):m/z=444.04[M+H]+。
步骤2:3-(5-(5-氟-4-(氯甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
将亚硫酰氯(0.319mL,4.40mmol)逐滴添加至含于DCM(7.5mL)中的5-氨基-4-(5-(5-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(0.65g,1.466mmol)的冷(0℃)溶液中。于10分钟后,移除冰浴,并允许将反应混合物升温至室温。于30分钟后,将反应混合物浓缩至干。将残余物溶解于乙酸(3mL)中并添加苯磺酸(0.510g,3.22mmol)并将反应混合物于微波烘箱中在120℃下加热25分钟。将反应混合物浓缩至干,并添加4mL的3MHCl的MeOH溶液及在0℃(冰水浴)下搅拌直至存在完全溶解。然后添加12mLEtOAc,及搅拌。于5分钟后,允许将反应混合物仍保持在冰水浴中30分钟。过滤沉淀,用EtOAc洗涤,然后空气干燥,以得到呈HCl盐的3-(5-(4-(氯甲基)-5-氟吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(480mg,1.238mmol,84%产率)。MS(ES):m/z=388.2[M+H]+。
步骤3:3-(5-(5-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
向溶解于DMF(650μL)中的3-(5-(3-(氯甲基)-4-氟苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮HCl(55mg,0.130mmol)中添加3-苯基氮杂环丁烷HCl(25.4mg,0.149mmol),接着添加许尼希氏碱(136μL,0.780mmol)。将所得混合物加热至80℃,同时搅拌3小时。然后将其冷却及进一步用DMF(0.5mL)稀释。将粗物质经由制备型LC/MS利用下列条件纯化:柱:XBridge C18,200mm x 19mm,5-μm粒子;流动相A:5:95乙腈:水与乙酸铵;流动相B:95:5乙腈:水与乙酸铵;梯度:在35%B下保持0分钟,35至75%B历时22分钟,然后在100%B下保持0分钟;流率:20mL/min;柱温度:25℃。通过MS信号触发洗脱份收集。合并含有所需产物的洗脱份并经由离心蒸发干燥,以获得3-(5-(5-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(7.1mg,0.015mmol,11.28%产率)。LCMS(方法A):保留时间1.78分钟;MS(ES):m/z=485.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ9.1(s,1H),8.9(s,1H),8.43(s,1H),8.30(m,m 1H),8.01(s,1H),7.81(d,J=8.0Hz,1H),7.5-7.38(m,5H),7.26-7.20(m,1H),5.3(m,1H),4.61(d,J=17.4Hz,1H),4.51(d,J=17.4Hz,1H),3.80-3.66(m,5H),3.26-3.18(m,2H),3.00-2.88(m,1H),2.49-2.37(m,1H),2.10-2.01(m,1H)。
实施例189至190
根据本文中所述的程序,将3-苯基氮杂环丁烷用适宜胺置换来制备表5中的化合物:
表5
实施例191
3-(5-(3-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
步骤1:5-氨基-4-(5-(3-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将20mL小瓶中放入(2-氯-3-氟吡啶-4-基)甲醇(400mg,2.476mmol)、(S)-5-氨基-5-氧代-4-(1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)戊酸叔丁酯(1.650g,3.71mmol)、Pd(dtbpf)Cl2(0.048g,0.074mmol)、1,4-二噁烷(12.38mL)及3M K3PO4水溶液(4.13mL,12.38mmol)。将小瓶密封并将空气用氮气置换。将其在60℃下加热16小时。将反应混合物冷却至室温,用EtOAc(25mL)稀释,用盐水洗涤,及分离层。将有机物经硫酸钠干燥,过滤,及浓缩。将粗产物使用硅胶柱通过ISCO柱色谱法(40g Gold,利用0至100%的20%甲醇胺/DCM-DCM洗脱)纯化,以得到呈棕色固体的5-氨基-4-(5-(3-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(630mg,1.421mmol,57.4%产率)。未测定此物质及随后中间体的对映异构体过量。MS(ES):m/z=444.4[M+H]+。
步骤2:3-(5-(4-(氯甲基)-3-氟吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
将亚硫酰氯(0.304mL,4.19mmol)逐滴添加至含于DCM(7.5mL)中的5-氨基-4-(5-(3-氟-4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(0.62g,1.398mmol)的冷(0℃)溶液中。于10分钟后,移除冰浴,并允许将反应混合物升温至室温。于30分钟后,将反应混合物浓缩至干。将残余物溶解于乙酸(4mL)中并添加苯磺酸(0.486g,3.08mmol)并将反应混合物于微波烘箱中在120℃下加热30分钟。将反应混合物浓缩至干,并添加4mL的3MHCl的MeOH溶液及在0℃(冰水浴)下搅拌直至存在完全溶解。然后添加12mLEtOAc,及搅拌。于5分钟后,允许将反应混合物仍保持在冰水浴中30分钟。过滤沉淀,用EtOAc洗涤,然后空气干燥,以得到呈HCl盐的3-(5-(4-(氯甲基)-3-氟吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(465mg,1.199mmol,86%产率)。MS(ES):m/z=388.2[M+H]+。
步骤3:3-(5-(3-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
向溶解于DMF(30mL)中的3-(5-(4-(氯甲基)-3-氟吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮HCl(35mg,0.082mmol)中添加3-苯基氮杂环丁烷HCl(16.10mg,0.095mmol),接着添加许尼希氏碱(0.086mL,0.495mmol)。将所得混合物加热至80℃,同时搅拌3小时。然后将其冷却及进一步用DMF(0.5mL)稀释。将粗物质经由制备型LC/MS利用下列条件纯化:柱:XBridge C18,200mm x 19mm,5-μm粒子;流动相A:5:95乙腈:水与乙酸铵;流动相B:95:5乙腈:水与乙酸铵;梯度:在35%B下保持0分钟,35至75%B历时22分钟,然后在100%B下保持0分钟;流率:20mL/min;柱温度:25℃。通过MS信号触发洗脱份收集。合并含有所需产物的洗脱份并经由离心蒸发干燥,以获得3-(5-(3-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(15.4mg,0.032mmol,38.5%产率)。LCMS(方法A):保留时间1.12分钟;MS(ES):m/z=485.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.6(s,1H),8.3(s,1H),8.21(m,1H),8.11(m,1H),7.81(s,1H),7.6(m,1H),7.5-7.38(m,5H),7.26-7.20(m,1H),5.2(m,1H),4.51(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),3.80-3.66(m,5H),3.26-3.18(m,2H),3.00-2.88(m,1H),2.49-2.37(m,1H),2.10-2.01(m,1H)。
实施例192至193
根据实施例191所述的一般程序,将3-苯基氮杂环丁烷用适宜胺置换来制备表6中的化合物:
表6
实施例194
3-(5-(4-((二甲氨基)甲基)吡啶-2-基)-6-甲基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
步骤1:(S)-5-氨基-4-(6-甲基-1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将40mL压力瓶中放入(S)-5-氨基-4-(5溴-6-甲基-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(300mg,0.729mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼戊环)(278mg,1.094mmol)及乙酸钾(215mg,2.188mmol)然后用氮气喷冲。将固体悬浮于二噁烷(10mL)中并用氮气流脱气5分钟,同时搅拌。将反应用PdCl2(dppf)2(16.01mg,0.022mmol)处理,再次脱气5分钟,及在氮气下加热至95℃持续3小时。将反应混合物用EtOAc稀释,用盐水洗涤,及经MgSO4干燥。将滤液浓缩并通过24g硅胶柱通过ISCO纯化并使用0至40%B/DCM(其中B=15%EtOH/EtOAc+0.1%TEA)洗脱,以获得95%产率的标题化合物。
步骤2:3-(5-(4-((二甲氨基)甲基)吡啶-2-基)-6-甲基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
将2mL微波小瓶中放入1-(2-氯吡啶-4-基)-N,N-二甲基甲胺(13mg,0.076mmol)、(S)-5-氨基-4-(6-甲基-1-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)异吲哚啉-2-基)-5-氧代戊酸叔丁酯(38.4mg,0.084mmol)、PdCl2(dtbpf)(1.490mg,2.286μmol)、二噁烷(1.5mL)及3M K3PO4水溶液(0.102mL,0.305mmol)。将其密封并将空气用氮气置换,然后在120℃下微波10分钟。将反应混合物用EtOAc稀释,用盐水洗涤,及分离有机层及浓缩。将粗制物使用制备型HPLC方法1纯化,以获得4.1mg标题化合物。分析型HPLC方法B保留时间0.89分钟,[M+H]+393.3;1H NMR(500MHz,DMSO-d6)δ8.62(d,J=5.0Hz,1H),7.68(s,1H),7.60(s,1H),7.47(s,1H),7.35(d,J=4.8Hz,1H),5.13(dd,J=13.2,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.35(d,J=17.1Hz,1H),3.51(s,1H),3.46-3.42(m,1H),2.97-2.88(m,1H),2.62(br d,J=16.4Hz,1H),2.45-2.40(m,1H),2.39(s,3H),2.20(s,6H),2.13(s,1H),2.07-1.99(m,1H)。
实施例195
根据本文中所述的一般程序,使用可市售胺制备表7中的化合物。
表7
实施例196至201
根据本文中所述的程序,将(4-((7-氮杂螺[3.5]壬-2-基)氧基)苯基)氨基甲酸叔丁酯用适宜一级胺或二级胺置换来制备表8中的化合物:
表8
实施例202至207
根据本文中所述的一般程序,制备表9中的化合物:
表9
*未测定绝对立体化学。
分析型HPLC条件
方法A:ACQUITYBEH C18(3.0x 50mm)1.7μm;流动相A:95:5水:乙腈与2.5mM NH4OAc;流动相B:5:95水:乙腈与2.5mM NH4Oac;温度:40℃;梯度:20%B至100%B历时2分钟;流率:0.7mL/min;检测:MS及UV(220nm)。
方法B:柱:XBridge BEH XP C18(50x 2.1)mm,2.5μm;流动相A:95:5水:乙腈与10mM NH4Oac;流动相B:5:95水:乙腈与10mM NH4Oac;温度:50℃;梯度:0%B至100%B历时3分钟;流率:1.1mL/min;检测:MS及UV(220nm)。
方法C:XBridge BEH XP C18(50x 2.1)mm,2.5μm;流动相A:95:5水:乙腈与0.1%三氟乙酸;流动相B:5:95水:乙腈与0.1%三氟乙酸;温度:50℃;梯度:0%B至100%B历时3分钟;流率:1.1mL/min;检测:MS及UV(220nm)。
方法D:柱-Kinetex XB-C18(75X 3mm-2.6μm);流动相A:5mM NH4COOH/水;流动相B:乙腈;梯度:10%B至50%B历时3分钟,流率:1.0mL/min;50%B至100%B上至4.1分钟,流率:1.0mL/min;保持直至4.5分钟;4.5分钟至5.0分钟90%B,流率:1.5mL/min;检测:MS及UV(220nm)。
方法E:柱-Kinetex XB-C18(75X 3mm-2.6μm);流动相A:0.1%TFA/水;流动相B:乙腈;梯度:20%B至100%B历时4.6分钟;流率:1.0mL/min;检测:MS及UV(220nm)。
方法F:柱-Kinetex XB-C18(75X 3mm-2.6μm);流动相A:0.1%TFA/水;流动相B:乙腈;梯度:5%B至40%B历时4分钟,流率:1.0mL/min;40%B至100%B上至4.6分钟,流率:1.5mL/min;保持直至4.7分钟;4.7分钟至5.0分钟5%B,流率:1.5mL/min;检测:MS及UV(220nm)。
方法G:柱-Kinetex XB-C18(75X 3mm-2.6μm);流动相A:10mM NH4COOH/水;流动相B:乙腈;梯度:20%B至100%B历时4分钟,流率:1.0mL/min;保持直至4.6分钟,然后4.7至5.0分钟20%B,流率:0.7mL/min;检测:MS及UV(220nm)。
实施例208
3-(4-氟-1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮
步骤1:(2-(三甲基甲锡烷基)吡啶-4-基)甲醇
将经搅拌的含于甲苯(10mL)中的(2-氯吡啶-4-基)甲醇(200mg,1.393mmol)及六甲基二锡(0.433mL,2.090mmol)的溶液用氩气净化5分钟,接着添加[1,1’-双(二叔丁基膦基)二茂铁]二氯化钯(II)(45.4mg,0.070mmol)。将反应混合物在100℃下搅拌2小时,冷却至室温及过滤。将滤液在减压下浓缩,以得到(2-(三甲基甲锡烷基)吡啶-4-基)甲醇(350mg,74%产率)。LCMS(方法A):保留时间1.72分钟,[M+H]+274.2。
步骤2:(S)-5-氨基-4-(4-氟-5-(4-(羟乙基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
将经搅拌的含于二噁烷(20mL)中的(S)-5-氨基-4-(5-溴-4-氟-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(229mg,0.552mmol)及(2-(三甲基甲锡烷基)吡啶-4-基)甲醇(150mg,0.552mmol)的溶液用氩气净化5分钟并添加双(三苯基膦)氯化钯(II)(38.7mg,0.055mmol)。将反应混合物加热至100℃及搅拌16小时。将反应混合物冷却至室温,过滤并将滤液在减压下浓缩,以得到粗产物,将该粗产物通过急骤色谱法(SiO2,80g柱,0至100%B(B=15%EtOH/EtOAc,0.5%TEA)/氯仿)纯化,以得到(S)-5-氨基-4-(4-氟-5-(4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(180mg,66%产率)。LCMS(方法A):保留时间1.04分钟,[M+H]+444.3。
步骤3:(S)-5-氨基-4-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯
在0℃下,向经搅拌的含于二氯甲烷(10mL)中的(S)-5-氨基-4-(4-氟-5-(4-(羟甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(0.180g,0.406mmol)的溶液中添加SOCl2(0.089mL,1.218mmol)。将反应混合物在25℃下搅拌1小时及在减压下浓缩,以得到(S)-5-氨基-4-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(0.175g,74.7%产率)。LCMS(方法A):保留时间1.48分钟,[M+H]+462.3。
步骤4:3-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
向经搅拌的含于乙酸(2mL)中的(S)-5-氨基-4-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯(175mg,0.379mmol)的溶液中添加苯磺酸(120mg,0.758mmol)。将反应混合物加热至120℃及搅拌2小时。在减压下移除挥发物,以得到3-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(130mg,66%产率)。LCMS(方法A):保留时间1.12分钟,[M+H]+388.3。
步骤5:3-(4-氟-1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮
在25℃下,向经搅拌的含于DMF(2mL)中的3-(5-(4-(氯甲基)吡啶-2-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(0.080g,0.206mmol)及3-苯基氮杂环丁烷HCl(0.082g,0.619mmol)的溶液中添加DIPEA(0.216mL,1.238mmol)。将反应混合物加热至80℃及搅拌3小时。在减压下移除挥发物并将所得粗产物经由制备型HPLC利用下列条件纯化:柱:Gemini NX C18(250mm x 21mm ID,5μm);流动相A=10mM乙酸铵/水pH 4.5;流动相B=乙腈:MeOH(1:1);流率19mL/min;梯度:时间:20至70%B历时20分钟。将洗脱份冻干,以得到3-(4-氟-1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(23mg,22%产率)。LCMS(方法G):保留时间1.60分钟,[M+H]+485.1;1H NMR(400MHz,DMSO-d6)δ11.03(br s,1H),8.69(d,J=5.0Hz,1H),8.09(t,J=7.3Hz,1H),7.83(s,1H),7.71(d,J=8.0Hz,1H),7.44-7.28(m,5H),7.25-7.20(m,1H),5.16(dd,J=13.1,5.0Hz,1H),4.76-4.38(m,2H),3.79(s,2H),3.75-3.63(m,3H),3.22(br t,J=5.3Hz,2H),3.02-2.90(m,1H),2.66-2.60(m,1H),2.43(br d,J=4.5Hz,1H),2.11-2.02(m,1H)。
生物学分析
本发明的化合物的药理学性质可通过许多生物学分析证实。已利用本发明的化合物进行以下的示例性生物学分析。
Helios细胞降解分析
将Jurkat细胞于384孔细胞培养板中于40μL RPMI+10%FBS中以80,000个细胞/孔平板接种,之后使用声学分配技术来添加所关注的化合物。将细胞培养物在37℃及5%CO2下培育72小时。为方便分析,将细胞培养物在200rpm下旋转下来5分钟及丢弃上清液。在振荡板以取出细胞集结块后,将细胞在室温再悬浮于50μL固定缓冲液(eBioScience FoxP3缓冲液组00-5523-00)中60分钟。在离心并丢弃上清液后,将细胞在室温用50μL渗透缓冲液(eBioScience FoxP3缓冲液组00-5523-00)渗透10分钟。在渗透后,将细胞旋转下来并将上清液用20μL荧光标记的针对Helios及Ikaros或对应同型对照的抗体的1x渗透缓冲液(Ikaros-Alexa488[Biolegend,目录号368408,1:50],Helios-PE[CST,目录号29360,1:50])置换并将染色反应在室温孵育1小时;避光。随后,添加30μL 1x渗透缓冲液,之后将细胞离心及丢弃上清液。将经染色的细胞再悬浮于25μL流动式细胞测量术染色缓冲液(PBS+0.2%BSA)中并使用Intellicyt Ique加上流动式细胞分析仪分析。
表10Helios及Ikaros降解活性
SEQUENCE LISTING
<110> 百时美施贵宝公司
<120> 可作为HELIOS蛋白质抑制剂的化合物
<130> 13354-WO-PCT
<150> US62/937,350
<151> 2019-11-19
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 526
<212> PRT
<213> 智人
<400> 1
Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu
1 5 10 15
Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser
20 25 30
Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn
35 40 45
Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
50 55 60
Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
65 70 75 80
Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
85 90 95
Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu
100 105 110
Lys Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met
115 120 125
Val His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln
130 135 140
Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys
145 150 155 160
Leu His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Ser Tyr Ala
165 170 175
Cys Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val
180 185 190
Gly Lys Pro His Lys Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Arg
195 200 205
Ser Ser Leu Glu Glu His Lys Glu Arg Cys His Asn Tyr Leu Gln Asn
210 215 220
Val Ser Met Glu Ala Ala Gly Gln Val Met Ser His His Val Pro Pro
225 230 235 240
Met Glu Asp Cys Lys Glu Gln Glu Pro Ile Met Asp Asn Asn Ile Ser
245 250 255
Leu Val Pro Phe Glu Arg Pro Ala Val Ile Glu Lys Leu Thr Gly Asn
260 265 270
Met Gly Lys Arg Lys Ser Ser Thr Pro Gln Lys Phe Val Gly Glu Lys
275 280 285
Leu Met Arg Phe Ser Tyr Pro Asp Ile His Phe Asp Met Asn Leu Thr
290 295 300
Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser His Met Met Asp Gln Ala
305 310 315 320
Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala Glu Ala Leu His Pro Leu
325 330 335
Met Gln His Pro Pro Ser Thr Ile Ala Glu Val Ala Pro Val Ile Ser
340 345 350
Ser Ala Tyr Ser Gln Val Tyr His Pro Asn Arg Ile Glu Arg Pro Ile
355 360 365
Ser Arg Glu Thr Ala Asp Ser His Glu Asn Asn Met Asp Gly Pro Ile
370 375 380
Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln Glu Arg Glu Ala Ser Pro
385 390 395 400
Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser Glu Ser Ser His Asp Asp
405 410 415
His Gln Ser Tyr Gln Gly His Pro Ala Leu Asn Pro Lys Arg Lys Gln
420 425 430
Ser Pro Ala Tyr Met Lys Glu Asp Val Lys Ala Leu Asp Thr Thr Lys
435 440 445
Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr Lys Val Phe Asn Gly Glu
450 455 460
Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu His Cys Arg Val Leu Phe
465 470 475 480
Leu Asp His Val Met Tyr Thr Ile His Met Gly Cys His Gly Tyr Arg
485 490 495
Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr Arg Ser Gln Asp Arg Tyr
500 505 510
Glu Phe Ser Ser His Ile Val Arg Gly Glu His Thr Phe His
515 520 525
<210> 2
<211> 500
<212> PRT
<213> 智人
<400> 2
Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu
1 5 10 15
Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser
20 25 30
Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn
35 40 45
Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
50 55 60
Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
65 70 75 80
Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
85 90 95
Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg
100 105 110
Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
115 120 125
Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys
130 135 140
Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
145 150 155 160
Leu Arg Thr His Ser Val Gly Lys Pro His Lys Cys Asn Tyr Cys Gly
165 170 175
Arg Ser Tyr Lys Gln Arg Ser Ser Leu Glu Glu His Lys Glu Arg Cys
180 185 190
His Asn Tyr Leu Gln Asn Val Ser Met Glu Ala Ala Gly Gln Val Met
195 200 205
Ser His His Val Pro Pro Met Glu Asp Cys Lys Glu Gln Glu Pro Ile
210 215 220
Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala Val Ile
225 230 235 240
Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr Pro Gln
245 250 255
Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His
260 265 270
Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser
275 280 285
His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala
290 295 300
Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile Ala Glu
305 310 315 320
Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn
325 330 335
Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn
340 345 350
Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln
355 360 365
Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser
370 375 380
Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu
385 390 395 400
Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys
405 410 415
Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr
420 425 430
Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu
435 440 445
His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile His Met
450 455 460
Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr
465 470 475 480
Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu
485 490 495
His Thr Phe His
500
<210> 3
<211> 452
<212> PRT
<213> 智人
<400> 3
Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu
1 5 10 15
Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser
20 25 30
Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn
35 40 45
Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
50 55 60
Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
65 70 75 80
Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
85 90 95
Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg
100 105 110
Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
115 120 125
Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys
130 135 140
Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
145 150 155 160
Leu Arg Thr His Ser Val Gly Lys Pro His Lys Cys Asn Tyr Cys Gly
165 170 175
Arg Ser Tyr Lys Gln Arg Ser Ser Leu Glu Glu His Lys Glu Arg Cys
180 185 190
His Asn Tyr Leu Gln Asn Val Ser Met Glu Ala Ala Gly Gln Val Met
195 200 205
Ser His His Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His
210 215 220
Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser
225 230 235 240
His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala
245 250 255
Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile Ala Glu
260 265 270
Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn
275 280 285
Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn
290 295 300
Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln
305 310 315 320
Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser
325 330 335
Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu
340 345 350
Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys
355 360 365
Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr
370 375 380
Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu
385 390 395 400
His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile His Met
405 410 415
Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr
420 425 430
Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu
435 440 445
His Thr Phe His
450
<210> 4
<211> 239
<212> PRT
<213> 智人
<400> 4
Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu
1 5 10 15
Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser
20 25 30
Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn
35 40 45
Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
50 55 60
Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
65 70 75 80
Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
85 90 95
Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu
100 105 110
Lys Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met
115 120 125
Val His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln
130 135 140
Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys
145 150 155 160
Leu His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Ser Tyr Ala
165 170 175
Cys Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val
180 185 190
Gly Lys Pro His Lys Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Arg
195 200 205
Ser Ser Leu Glu Glu His Lys Glu Arg Cys His Asn Tyr Leu Gln Asn
210 215 220
Val Ser Met Glu Ala Ala Gly Gln Val Met Ser His His Asp Ser
225 230 235
<210> 5
<211> 454
<212> PRT
<213> 智人
<400> 5
Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu
1 5 10 15
Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser
20 25 30
Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn
35 40 45
Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
50 55 60
Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
65 70 75 80
Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
85 90 95
Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg
100 105 110
Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
115 120 125
Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys
130 135 140
Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
145 150 155 160
Leu Arg Thr His Ser Val Pro Pro Met Glu Asp Cys Lys Glu Gln Glu
165 170 175
Pro Ile Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala
180 185 190
Val Ile Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr
195 200 205
Pro Gln Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp
210 215 220
Ile His Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met
225 230 235 240
Gln Ser His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu
245 250 255
Gly Ala Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile
260 265 270
Ala Glu Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His
275 280 285
Pro Asn Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His
290 295 300
Glu Asn Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg
305 310 315 320
Pro Gln Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr
325 330 335
Asp Ser Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro
340 345 350
Ala Leu Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp
355 360 365
Val Lys Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp
370 375 380
Ile Tyr Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys
385 390 395 400
Cys Glu His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile
405 410 415
His Met Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys
420 425 430
Gly Tyr Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg
435 440 445
Gly Glu His Thr Phe His
450
<210> 6
<211> 23
<212> PRT
<213> 智人
<400> 6
Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu
1 5 10 15
Leu Arg His Ile Lys Leu His
20
<210> 7
<211> 585
<212> PRT
<213> 智人
<400> 7
Met His Thr Pro Pro Ala Leu Pro Arg Arg Phe Gln Gly Gly Gly Arg
1 5 10 15
Val Arg Thr Pro Gly Ser His Arg Gln Gly Lys Asp Asn Leu Glu Arg
20 25 30
Asp Pro Ser Gly Gly Cys Val Pro Asp Phe Leu Pro Gln Ala Gln Asp
35 40 45
Ser Asn His Phe Ile Met Glu Ser Leu Phe Cys Glu Ser Ser Gly Asp
50 55 60
Ser Ser Leu Glu Lys Glu Phe Leu Gly Ala Pro Val Gly Pro Ser Val
65 70 75 80
Ser Thr Pro Asn Ser Gln His Ser Ser Pro Ser Arg Ser Leu Ser Ala
85 90 95
Asn Ser Ile Lys Val Glu Met Tyr Ser Asp Glu Glu Ser Ser Arg Leu
100 105 110
Leu Gly Pro Asp Glu Arg Leu Leu Glu Lys Asp Asp Ser Val Ile Val
115 120 125
Glu Asp Ser Leu Ser Glu Pro Leu Gly Tyr Cys Asp Gly Ser Gly Pro
130 135 140
Glu Pro His Ser Pro Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu Lys
145 150 155 160
Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met Val
165 170 175
His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln Cys
180 185 190
Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys Leu
195 200 205
His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Asn Tyr Ala Cys
210 215 220
Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val Ser
225 230 235 240
Ser Pro Thr Val Gly Lys Pro Tyr Lys Cys Asn Tyr Cys Gly Arg Ser
245 250 255
Tyr Lys Gln Gln Ser Thr Leu Glu Glu His Lys Glu Arg Cys His Asn
260 265 270
Tyr Leu Gln Ser Leu Ser Thr Glu Ala Gln Ala Leu Ala Gly Gln Pro
275 280 285
Gly Asp Glu Ile Arg Asp Leu Glu Met Val Pro Asp Ser Met Leu His
290 295 300
Ser Ser Ser Glu Arg Pro Thr Phe Ile Asp Arg Leu Ala Asn Ser Leu
305 310 315 320
Thr Lys Arg Lys Arg Ser Thr Pro Gln Lys Phe Val Gly Glu Lys Gln
325 330 335
Met Arg Phe Ser Leu Ser Asp Leu Pro Tyr Asp Val Asn Ser Gly Gly
340 345 350
Tyr Glu Lys Asp Val Glu Leu Val Ala His His Ser Leu Glu Pro Gly
355 360 365
Phe Gly Ser Ser Leu Ala Phe Val Gly Ala Glu His Leu Arg Pro Leu
370 375 380
Arg Leu Pro Pro Thr Asn Cys Ile Ser Glu Leu Thr Pro Val Ile Ser
385 390 395 400
Ser Val Tyr Thr Gln Met Gln Pro Leu Pro Gly Arg Leu Glu Leu Pro
405 410 415
Gly Ser Arg Glu Ala Gly Glu Gly Pro Glu Asp Leu Ala Asp Gly Gly
420 425 430
Pro Leu Leu Tyr Arg Pro Arg Gly Pro Leu Thr Asp Pro Gly Ala Ser
435 440 445
Pro Ser Asn Gly Cys Gln Asp Ser Thr Asp Thr Glu Ser Asn His Glu
450 455 460
Asp Arg Val Ala Gly Val Val Ser Leu Pro Gln Gly Pro Pro Pro Gln
465 470 475 480
Pro Pro Pro Thr Ile Val Val Gly Arg His Ser Pro Ala Tyr Ala Lys
485 490 495
Glu Asp Pro Lys Pro Gln Glu Gly Leu Leu Arg Gly Thr Pro Gly Pro
500 505 510
Ser Lys Glu Val Leu Arg Val Val Gly Glu Ser Gly Glu Pro Val Lys
515 520 525
Ala Phe Lys Cys Glu His Cys Arg Ile Leu Phe Leu Asp His Val Met
530 535 540
Phe Thr Ile His Met Gly Cys His Gly Phe Arg Asp Pro Phe Glu Cys
545 550 555 560
Asn Ile Cys Gly Tyr His Ser Gln Asp Arg Tyr Glu Phe Ser Ser His
565 570 575
Ile Val Arg Gly Glu His Lys Val Gly
580 585
<210> 8
<211> 544
<212> PRT
<213> 智人
<400> 8
Met Asp Ser Arg Tyr Leu Gln Leu Gln Leu Tyr Leu Pro Ser Cys Ser
1 5 10 15
Leu Leu Gln Gly Ser Gly Asp Ser Ser Leu Glu Lys Glu Phe Leu Gly
20 25 30
Ala Pro Val Gly Pro Ser Val Ser Thr Pro Asn Ser Gln His Ser Ser
35 40 45
Pro Ser Arg Ser Leu Ser Ala Asn Ser Ile Lys Val Glu Met Tyr Ser
50 55 60
Asp Glu Glu Ser Ser Arg Leu Leu Gly Pro Asp Glu Arg Leu Leu Glu
65 70 75 80
Lys Asp Asp Ser Val Ile Val Glu Asp Ser Leu Ser Glu Pro Leu Gly
85 90 95
Tyr Cys Asp Gly Ser Gly Pro Glu Pro His Ser Pro Gly Gly Ile Arg
100 105 110
Leu Pro Asn Gly Lys Leu Lys Cys Asp Val Cys Gly Met Val Cys Ile
115 120 125
Gly Pro Asn Val Leu Met Val His Lys Arg Ser His Thr Gly Glu Arg
130 135 140
Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
145 150 155 160
Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys
165 170 175
Pro Phe Cys Asn Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
180 185 190
Leu Arg Thr His Ser Val Ser Ser Pro Thr Val Gly Lys Pro Tyr Lys
195 200 205
Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Gln Ser Thr Leu Glu Glu
210 215 220
His Lys Glu Arg Cys His Asn Tyr Leu Gln Ser Leu Ser Thr Glu Ala
225 230 235 240
Gln Ala Leu Ala Gly Gln Pro Gly Asp Glu Ile Arg Asp Leu Glu Met
245 250 255
Val Pro Asp Ser Met Leu His Ser Ser Ser Glu Arg Pro Thr Phe Ile
260 265 270
Asp Arg Leu Ala Asn Ser Leu Thr Lys Arg Lys Arg Ser Thr Pro Gln
275 280 285
Lys Phe Val Gly Glu Lys Gln Met Arg Phe Ser Leu Ser Asp Leu Pro
290 295 300
Tyr Asp Val Asn Ser Gly Gly Tyr Glu Lys Asp Val Glu Leu Val Ala
305 310 315 320
His His Ser Leu Glu Pro Gly Phe Gly Ser Ser Leu Ala Phe Val Gly
325 330 335
Ala Glu His Leu Arg Pro Leu Arg Leu Pro Pro Thr Asn Cys Ile Ser
340 345 350
Glu Leu Thr Pro Val Ile Ser Ser Val Tyr Thr Gln Met Gln Pro Leu
355 360 365
Pro Gly Arg Leu Glu Leu Pro Gly Ser Arg Glu Ala Gly Glu Gly Pro
370 375 380
Glu Asp Leu Ala Asp Gly Gly Pro Leu Leu Tyr Arg Pro Arg Gly Pro
385 390 395 400
Leu Thr Asp Pro Gly Ala Ser Pro Ser Asn Gly Cys Gln Asp Ser Thr
405 410 415
Asp Thr Glu Ser Asn His Glu Asp Arg Val Ala Gly Val Val Ser Leu
420 425 430
Pro Gln Gly Pro Pro Pro Gln Pro Pro Pro Thr Ile Val Val Gly Arg
435 440 445
His Ser Pro Ala Tyr Ala Lys Glu Asp Pro Lys Pro Gln Glu Gly Leu
450 455 460
Leu Arg Gly Thr Pro Gly Pro Ser Lys Glu Val Leu Arg Val Val Gly
465 470 475 480
Glu Ser Gly Glu Pro Val Lys Ala Phe Lys Cys Glu His Cys Arg Ile
485 490 495
Leu Phe Leu Asp His Val Met Phe Thr Ile His Met Gly Cys His Gly
500 505 510
Phe Arg Asp Pro Phe Glu Cys Asn Ile Cys Gly Tyr His Ser Gln Asp
515 520 525
Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu His Lys Val Gly
530 535 540
Claims (18)
1.一种式(I)化合物或其盐
其中:
Z为CR6R6或C=O;
环A为:
R1为-(CRzRz)1-2NR1aR1b;
R1a为氢、C1-6烷基、C1-4氟烷基、C1-3氰基烷基、C1-6羟烷基、-(CH2)1-3O(C1-3烷基)、-(CH2)1- 3S(O)2(C1-3烷基)、-(CH2)1-3C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-3C(O)NRxRx、-(CH2)1- 3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;
R1b为氢、C1-3烷基或-CH2(苯基);
或R1a及R1b与其所连接的氮原子接合在一起形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基(azocanyl)、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶酮基、哌啶基、吡咯烷基、吡咯烷酮基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代;
R1c为C3-7环烷基、苯基、氧杂环丁烷基、氮杂环丁烷基、呋喃基、吡喃基、吡咯基、吡咯烷基、吡咯烷酮基、吡唑基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、二氧代四氢噻喃基、二氧化四氢噻吩基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被0至2个独立地选自以下的取代基取代:F、Cl、-CN、-OH、C1-3烷基、C1-3氟烷基、C1-3羟烷基、C1-3烷氧基、C1-3氟烷氧基、-C(O)O(C1-3烷基)、-NRyRy、-S(O)2(C1-3烷基)、-S(O)2NRxRx、-CH2(苯基)、-NO2、C3-6环烷基、咪唑基及苯基;
R1d为C1-4烷基、C1-2氟烷基、C1-3烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基(dioxolyl))、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;
R1e为-CH3;
各R2独立地为卤素、-CN、C1-3烷基、C1-3氟烷基、C1-3烷氧基或C1-3氟烷氧基;NR2(R=H、C1-3烷基)、任选经取代的苯基、任选经取代的杂芳基;
R3为R1a;
各R4独立地为卤素、-CN、C1-3烷基、C1-3氟烷基、C1-3烷氧基或C1-3氟烷氧基;
各R4独立地为卤素、-CN、-OH、C1-3烷基、C1-3氟烷基、C1-3烷氧基、C1-3氟烷氧基或-NRyRy;
R5为氢、F或C1-3烷基;
各R6独立地为氢或C1-3烷基;
各Rx独立地为H或-CH3;
各Ry独立地为H或C1-4烷基;
各Rz独立地为H或-CH3;或连接至相同碳原子的两个Rz形成3-至6-元碳环或3-至6-元杂环;
m为0、1或2;且
n为0、1、2或3。
2.根据权利要求1的化合物或其盐,其中:
R1a为氢、C1-6烷基、C1-3氟烷基、C1-2氰基烷基、C1-4羟烷基、-(CH2)1-3OCH3、-(CH2)1-3S(O)2(C1-2烷基)、-(CH2)1-2C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-2C(O)NRxRx、-(CH2)1-3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1- 3R1c、-(CRxRx)1-3OR1c或-C(O)R1c;
或R1a及R1b与其所连接的氮原子接合在一起形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、氮杂环辛烷基、二氮杂环庚烷基、二氧化硫代吗啉基、异吲哚啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至2个R1e取代;
R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、二氧代四氢噻喃基、二氧化四氢噻吩基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被0至2个独立地选自以下的取代基取代:F、Cl、-CN、-OH、C1-2烷基、C1-2氟烷基、C1-2羟烷基、C1-2烷氧基、C1-2氟烷氧基、-C(O)O(C1-2烷基)、-NRxRy、-S(O)2(C1-2烷基)、-S(O)2NRxRx、-CH2(苯基)、-NO2、C3-6环烷基、咪唑基及苯基;
R1d为C1-3烷基、C1-2氟烷基、C1-3烷氧基、-NRxRy、-NRxC(O)(C1-2烷基)、-C(O)(C1-2烷基)、-C(O)NRyRy、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;
各R4独立地为F、Cl、-CN、-CH3、-CHF2、-CF3、-OCH3或-OCF3;
R5为氢、F或-CH3;
m为0或1;且
n为0、1或2。
4.根据权利要求1至3中任一项的化合物或其盐,其具有以下结构:
其中:
R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c;
或R1a及R1b与其所连接的氮原子接合在一起形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代;
R1c为C3-6环烷基、苯基、氧杂环丁烷基、呋喃基、吡咯烷基、吡咯烷酮基、咪唑基、吲唑基、噻唑基、哌啶基、吡啶基、四氢呋喃基、四氢吡喃基、吗啉基、苯并[d]噻唑基、萘基、喹啉基或喹喔啉基,各被0至2个独立地选自以下的取代基取代:F、Cl、-CN、-OH、-CH3、-CF3、-OCH3、-OCF3、-C(O)OCH3、-NH(CH3)、-N(CH3)2、-S(O)2CH3、-S(O)2N(CH3)2、-CH2(苯基)、-NO2、环丙基、咪唑基及苯基;
R1d为-CH3、-CH(CH3)2、-OCH3、-OCH2CH3、-OCH(CH3)2、-N(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH3)2、-C(O)N(CH2CH3)2、-CH2(苯基)、-CH2(甲基吡咯烷基)、-CH2(苯并[d][1,3]二氧杂环戊烯基)、-CH(苯基)2、-C(O)(四氢呋喃基)、-C(O)(呋喃基)、-S(O)2(甲基苯基)、苯基、甲基苯基、氨基苯基、哌啶基、吡嗪基、吡啶基、嘧啶基、吡咯烷基或二氢苯并[d]咪唑酮基;且
R1e为-CH3;
R4为-CH3;且
n为0或1。
5.根据权利要求1至4中任一项的化合物或其盐,其中Z为CR6R6。
6.根据权利要求1至5中任一项的化合物或其盐,其中R1a为氢、C1-6烷基、C1-4氟烷基、C1-3氰基烷基、C1-6羟烷基、-(CH2)1-3O(C1-3烷基)、-(CH2)1-3S(O)2(C1-3烷基)、-(CH2)1-3C(O)O(C1-3烷基)、-(CH2)1-3NRxRx、-(CH2)1-3C(O)NRxRx、-(CH2)1-3NRxC(O)(C1-3烷基)、-C(O)(C1-3烷基)、-CH(苯基)(C1-2羟烷基)、-CRxRxCRx(苯基)2、R1c、-(CRxRx)1-3R1c、-(CRxRx)1-3OR1c或-C(O)R1c。
7.根据权利要求1至5中任一项的化合物或其盐,其中R1a为氢、C1-6烷基、-CH2CH2CF3、-CH2CN、-CH2CH2OH、-CH(CH3)CH2OH、-CH2CH2CH2CH2OH、-CH(CH3)CH2CH2OH、-CH2CH2OCH3、-CH2CH2C(O)OCH3、-CH2CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2CH2C(O)NH2、-CH2CH2NHC(O)CH3、-CH(苯基)(CH2CH2OH)、-CH2CH(苯基)2、R1c、-CRxRxR1c、-CH2CH2R1c、-CH2CH2CH2R1c或-CH2CH2OR1c。
8.根据权利要求1至5中任一项的化合物或其盐,其中R1a及R1b与其所连接的氮原子接合在一起形成选自以下的环状基团:氮杂螺[2.5]辛基、氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧化硫代吗啉基、吗啉基、八氢环戊[b]吡咯基、八氢吡咯并[3,4-c]吡咯基、氧杂氮杂双环[2.2.1]庚基、哌嗪酮基、哌嗪基、哌啶基、吡咯烷基及四氢异喹啉基,各被0至1个R1d及0至1个R1e取代。
10.根据权利要求1的化合物或其盐,其中该化合物为:
3-(5-{4-[(二甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(1);
3-(5-(4-((苄基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(2);
3-(5-(4-((甲基(丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3);
3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(4);
3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(5);
3-(5-(4-(((2-甲氧基乙基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(7);
3-(5-(4-((丁基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(9);
3-(5-(4-(((环丙基甲基)(丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(10);
3-(5-(4-((甲基(2-(吡啶-2-基)乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(16);
3-(5-(4-((苄基(异丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(19);
3-(5-(4-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(21);
3-(5-(4-((乙基(吡啶-4-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(22);
3-(5-(4-((甲基(1-甲基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(29);
2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)-N,N-二甲基乙酰胺(34);
3-(5-(4-((甲基(1-甲基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(49);
3-(5-(4-((二乙基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(50);
3-(5-(4-(((环己基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(54);
3-(1-氧代-5-(4-(((1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(55);
3-(5-(4-(((2-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(56);
3-(5-(4-(((3-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(57);
3-(5-(4-(((4-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(58);
3-(5-(4-(((环己基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(59);
3-(5-(4-((丁氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(61);
3-(1-氧代-5-(4-((丙氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(62);
3-(1-氧代-5-(4-((苯乙基氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(63);
3-(5-(4-(((环丙基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(64);
3-(5-(4-((新戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(65);
3-(1-氧代-5-(4-((((四氢呋喃-2-基)甲基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(66);
3-(5-(4-(((4-甲氧基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(67);
3-(5-(4-(((2-甲氧基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(68);
3-(5-(4-(((1-环丙基环丁基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(77);
3-(5-(4-(((2-甲基四氢-2H-吡喃-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(80);
3-(1-氧代-5-(4-((((1R,2R)-2-苯基环戊基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(84);
3-(5-(4-((环戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(86);
3-(5-(4-((环己基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(87);
3-(5-(4-(((2-吗啉基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(88);
3-(5-(4-((叔丁基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(89);
3-(5-(4-(((2,2-二苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(90);
N-(2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙基)乙酰胺(91);
3-(5-(4-(((2-羟乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(92);
3-(5-(4-(((2-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(93);
3-(5-(4-(((4-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(94);
3-(5-(4-(((4-甲氧基苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(95);
3-(5-(4-(((4-羟基苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(96);
3-(5-(4-((异戊基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(97);
3-(1-氧代-5-(4-(((3-苯基丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(98);
2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙腈(99);
2-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)乙酰胺(100);
3-(5-(4-(((4-羟基环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(101);
3-(5-(4-(((3-氯苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(102);
3-(1-氧代-5-(4-(((2-苯氧基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(103);
3-(5-(4-(((1-苄基吡咯烷-3-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(104);
3-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)丙酰胺(105);
3-(5-(4-(((2-(苯并[d]噻唑-2-基)乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(106);
3-(5-(4-(((4-(二甲氨基)环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(107);
3-(5-(4-((环丁基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(108);
3-(5-(4-((环丙基氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(109);
3-(1-氧代-5-(4-((((2-苯基噻唑-4-基)甲基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(110);
3-(1-氧代-5-(4-((((1R,2S)-2-苯基环丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(111);
3-(((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氨基)丙酸甲酯(112);
3-(5-(4-(((3-(1H-咪唑-1-基)丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(113);
3-(5-(4-(((3-吗啉基丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(114);
3-(1-氧代-5-(4-(((3-(2-氧代吡咯烷-1-基)丙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(115);
3-(5-(4-((乙氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(116);
3-(1-氧代-5-(4-((((R)-1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(122);
3-(1-氧代-5-(4-((((S)-1-苯基乙基)氨基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(123);
3-(5-(4-((((1-羟基环己基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(124);
3-(5-(4-(((2-甲基四氢-2H-吡喃-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(126);
3-(5-(4-(((4-羟基丁基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(128);
3-(5-(4-(((氧杂环丁烷-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(129);
3-(5-(4-((((R)-3-羟基-1-苯基丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(131);
3-(5-(4-((甲基((S)-1-苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(136);
3-(5-(4-((甲基((R)-1-苯基乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(137);
3-(5-(4-((甲基((1R,2R)-2-(甲氨基)环己基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(140);
3-(5-(4-((甲基(2-苯基丙-2-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(142);
3-(1-氧代-5-(4-((3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(144);
3-(5-{4-[(甲氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(145);
4-{[({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)(甲基)氨基]甲基}-N,N-二甲基苯-1-磺酰胺(146);
3-(5-(4-(((4-氟苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147);
3-(5-(4-((甲基(3-(三氟甲基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(148);
3-(5-(4-((甲基(4-(三氟甲基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(149);
4-((((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)甲基)苯甲腈(150);
3-(5-(4-((甲基(4-硝基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(151);
3-(5-(4-(((3,4-二氟苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(152);
4-((((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)(甲基)氨基)甲基)苯甲酸甲酯(153);
3-(5-(4-(((4-氯苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(154);
3-(5-(4-((甲基(喹啉-8-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(155);
3-(5-(4-((甲基(3-(三氟甲氧基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(156);
3-(5-(4-((甲基(4-(甲基磺酰基)苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(157);
3-(5-(4-(((3-甲氧基苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(158);
3-(5-(4-((甲基(吡啶-3-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(159);
3-(5-(4-((甲基(吡啶-4-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(160);
3-(5-(4-((甲基(4-甲基苄基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(161);
3-(5-(4-((甲基(萘-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(162);
3-(5-{4-[(二苄基氨基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(163);
3-[5-(4-{[苄基(甲基)氨基]甲基}吡啶-2-基)-1-氧代-2,3-二氢-1H-异吲哚-2-基]哌啶-2,6-二酮(164);
3-{5-[4-({[(6-甲氧基吡啶-3-基)甲基](甲基)氨基}甲基)吡啶-2-基]-1-氧代-2,3-二氢-1H-异吲哚-2-基}哌啶-2,6-二酮(168);
3-(5-(4-((((1H-吲唑-4-基)甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(169);
3-(5-(4-((甲基(1-甲基哌啶-4-基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(170);
3-(5-(4-((甲基(苯乙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(171);
3-(5-(4-(((呋喃-3-基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(172);
3-(5-(4-(((环丙基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(173);
3-(5-(4-((甲基((1-甲基-1H-咪唑-5-基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(174);
3-(5-(4-(((环戊基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(175);
3-(5-(4-((甲基(噻唑-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(176);
3-(5-(4-(((4-(1H-咪唑-1-基)苄基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(177);
3-(5-(4-(((环丁基甲基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(178);
3-(5-(4-((异丁基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(179);
3-(5-(4-((异戊基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(180);
3-(5-(4-(((1-羟基丙-2-基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(181);
3-(5-(4-((甲基((四氢呋喃-3-基)甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(182);
3-(5-(4-((甲基(喹喔啉-2-基甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(183);
3-(5-(4-((甲基(3,3,3-三氟丙基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(184);
3-(5-(4-(((4-羟基丁-2-基)(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(185);或
3-(5-(4-((二甲氨基)甲基)吡啶-2-基)-6-甲基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(194)。
11.根据权利要求1的化合物或其盐,其中该化合物为选自以下的化合物:
3-(5-(4-((乙基(甲基)氨基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(6);
3-(1-氧代-5-(4-(吡咯烷-1-基甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(8);
3-(1-氧代-5-(4-((4-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(11);
3-(5-(4-((4-(苯并[d][1,3]二氧杂环戊烯-5-基甲基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(12);
1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)-N,N-二乙基哌啶-3-甲酰胺(13);
3-(5-(4-((4-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(14);
3-(1-氧代-5-(4-((4-(吡啶-2-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(15);
3-(5-(4-([1,4'-联哌啶]-1'-基甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(17);
3-(1-氧代-5-(4-((4-(嘧啶-2-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(18);
3-(5-(4-((2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(20);
3-(1-氧代-5-(4-((4-(吡咯烷-1-基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(23);
3-(5-(4-((4-(呋喃-2-羰基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(24);
3-(1-氧代-5-(4-((4-(吡啶-4-基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(25);
3-(1-氧代-5-(4-((4-(吡嗪-2-基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(26);
3-(5-(4-((3-甲基-4-(间-甲苯基)哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(27);
3-(5-(4-((4-乙酰基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(28);
3-(5-(4-((2-(((S)-1-甲基吡咯烷-2-基)甲基)哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(30);
N-((3S)-1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)吡咯烷-3-基)乙酰胺(31);
3-(1-氧代-5-(4-((4-(四氢呋喃-2-羰基)哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(32);
3-(5-(4-(((S)-3-(二甲氨基)吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(33);
3-(5-(4-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(35);
3-(5-(4-((4-苄基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(36);
3-(1-氧代-5-(4-((3-氧代哌嗪-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(37);
3-(5-(4-((4-苄基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(38);
3-(5-(4-((3,4-二氢异喹啉-2(1H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(39);
3-(5-(4-((4-(二甲氨基)哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(40);
1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)哌啶-4-甲酰胺(41);
3-(5-(4-((4-二苯甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(42);
3-(5-(4-((4-甲基-1,4-二氮杂环庚烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(43);
3-(5-(4-((4-异丙基哌嗪-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(44);
3-(5-(4-(((R)-3-(二甲氨基)吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(45);
3-(5-(4-((2-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(46);
3-(5-(4-((3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(47);
3-(5-(4-(氮杂环庚烷-1-基甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(48);
3-(5-(4-((3,3-二甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(51);
3-(5-(4-((2,2-二甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(52);
3-(5-(4-((2,6-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(53);
3-(5-(4-((六氢环戊[b]吡咯-1(2H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(60);
3-(5-(4-(((S)-2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(69);
3-(5-(4-(((R)-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(70);
3-(5-(4-(((R)-2-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(71);
3-(5-(4-(((S)-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(72);
3-(5-(4-(((S)-3-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(73);
3-(5-(4-(((S)-2-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(74);
3-(5-(4-(((R)-3-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(75);
3-(1-氧代-5-(4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(76);
3-(5-(4-(((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(78);
3-(5-(4-((2-氧杂-5-氮杂双环[2.2.1]庚-5-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(79);
3-(5-(4-(((3S,5R)-3,5-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(81);
3-(5-(4-((4,4-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(82);
3-(1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(83);
3-(5-(4-((3,3-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(85);
3-(5-(4-((2,2-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(117);
3-(5-(4-((3,3-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(118);
3-(5-(4-((2,5-二甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(119);
3-(5-(4-(((2R,6S)-2,6-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(120);
3-(5-(4-((4-(4-氨基苯基)-4-甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(121);
3-(5-(4-(((R)-2-甲基吡咯烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(125);
3-(5-(4-((6-氮杂螺[2.5]辛-6-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(127);
3-(5-(4-((3-异丙氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(130);
3-(1-氧代-5-(4-((4-甲苯磺酰基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(132);
3-(1-氧代-5-(4-(((S)-2-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(133);
3-(1-氧代-5-(4-(((R)-2-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(134);
3-(1-氧代-5-(4-(((S)-3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(135);
3-(1-氧代-5-(4-(((R)-3-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(138);
3-(1-氧代-5-(4-(((S)-3-苯基吡咯烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(139);
3-(1-氧代-5-(4-((4-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(141);
3-(1-氧代-5-(4-((3-苯基哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(143);
3-(5-{4-[(氮杂环丁烷-1-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(165);
3-(5-{4-[(吗啉-4-基)甲基]吡啶-2-基}-1-氧代-2,3-二氢-1H-异吲哚-2-基)哌啶-2,6-二酮(166);
4-({2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基]吡啶-4-基}甲基)-1λ6-硫代吗啉-1,1-二酮(167);
3-(5-(5-氯-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(186);
3-(5-(5-氯-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(187);
3-(5-(5-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(188);
3-(5-(5-氟-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(189);
3-(5-(5-氟-4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(190);
3-(5-(3-氟-4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(191);
3-(5-(3-氟-4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(192);
3-(5-(3-氟-4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(193);
3-(1-氧代-5-(4-((3-(吡啶-4-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(195);
3-(5-(4-((3-甲氧基-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(196);
3-(5-(4-((3-甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(197);
3-(5-(4-((3-乙氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(198);
3-(1-氧代-5-(4-((4-(对-甲苯基)哌啶-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(199);
3-(5-(4-(((S)-2-苄基氮杂环丙烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(200);
3-(5-(4-((2-甲基氮杂环丙烷-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(201);
1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)-N,N-二甲基氮杂环丁烷-3-甲酰胺(202);
3-(1-氧代-5-(4-((3-(吡啶-3-基)氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(203);
3-(1-氧代-5-(4-((2-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(204-205);
1-((2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡啶-4-基)甲基)氮杂环丁烷-2-甲酰胺(206);
3-(5-(4-((4-甲氧基-3,3-二甲基哌啶-1-基)甲基)吡啶-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(207);或
3-(4-氟-1-氧代-5-(4-((3-苯基氮杂环丁烷-1-基)甲基)吡啶-2-基)异吲哚啉-2-基)哌啶-2,6-二酮(208)。
12.一种药物组合物,其包含根据权利要求1至11中任一项的化合物或其药学上可接受的盐;及药学上可接受的载剂。
13.根据权利要求1至11中任一项的化合物在用于治疗癌症中的用途。
14.根据权利要求13的用途,其中该癌症为选自以下的癌症:结肠癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、子宫颈癌、肾癌、头颈癌、淋巴瘤、白血病及黑色素瘤。
15.一种降低细胞中的Helios蛋白质含量、Helios活性水平或Helios表达水平的方法,该方法包括使该Helios蛋白质与根据权利要求1至11中任一项的化合物或其药学上可接受的盐接触。
16.根据权利要求15的方法,其中Helios蛋白质是由SEQ ID NO:1、2、3、4或5编码的氨基酸序列。
17.一种降低细胞中的Eos蛋白质含量、Eos活性水平或Eos表达水平的方法,该方法包括使该Eos蛋白质与根据权利要求1至11中任一项的化合物或其药学上可接受的盐接触。
18.根据权利要求17的方法,其中Eos蛋白质是由SEQ ID NO:7或8编码的氨基酸序列。
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MX2022005839A (es) | 2022-06-09 |
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JP2023503052A (ja) | 2023-01-26 |
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IL293027A (en) | 2022-07-01 |
WO2021101919A1 (en) | 2021-05-27 |
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