CN114085212B - 异吲哚啉类化合物、其制备方法、药物组合物及用途 - Google Patents
异吲哚啉类化合物、其制备方法、药物组合物及用途 Download PDFInfo
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- CN114085212B CN114085212B CN202111646994.0A CN202111646994A CN114085212B CN 114085212 B CN114085212 B CN 114085212B CN 202111646994 A CN202111646994 A CN 202111646994A CN 114085212 B CN114085212 B CN 114085212B
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- -1 Isoindoline compound Chemical class 0.000 title claims abstract description 272
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
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- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims abstract description 28
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- 101001019600 Homo sapiens Interleukin-17 receptor B Proteins 0.000 claims abstract description 14
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- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 claims abstract description 3
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- 150000001875 compounds Chemical class 0.000 claims description 349
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- 229910052805 deuterium Inorganic materials 0.000 claims description 197
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 196
- 238000006243 chemical reaction Methods 0.000 claims description 180
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- 239000001257 hydrogen Substances 0.000 claims description 124
- 125000000623 heterocyclic group Chemical group 0.000 claims description 95
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- 125000001424 substituent group Chemical group 0.000 claims description 87
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 72
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- 125000003118 aryl group Chemical group 0.000 claims description 31
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- 238000000034 method Methods 0.000 claims description 30
- 230000000155 isotopic effect Effects 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 26
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
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- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 10
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- 239000003513 alkali Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 8
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 claims description 6
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- HNGKYJPFWVQZSF-UHFFFAOYSA-N spiro[1h-pyrido[2,3-d][1,3]oxazine-4,4'-piperidine]-2-one Chemical compound O1C(=O)NC2=NC=CC=C2C21CCNCC2 HNGKYJPFWVQZSF-UHFFFAOYSA-N 0.000 description 1
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- QXNXVWNYCKUANQ-UHFFFAOYSA-N spiro[indene-1,4'-piperidine] Chemical compound C1CNCCC21C1=CC=CC=C1C=C2 QXNXVWNYCKUANQ-UHFFFAOYSA-N 0.000 description 1
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- HJEZRYIJNHAIGY-UHFFFAOYSA-N tert-butyl 4-bromobutanoate Chemical compound CC(C)(C)OC(=O)CCCBr HJEZRYIJNHAIGY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
- C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Abstract
本发明涉及如通式(I)所表示的多取代异吲哚啉类化合物,其制备方法、药物组合物及应用。具体的,本发明提供的多取代异吲哚啉类化合物作为一类结构新颖的CRL4CRBN E3泛素连接酶调节剂具有更强的抗肿瘤活性和抗肿瘤谱,可以用于制备治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物。
Description
本申请是申请日为2019年9月30日、发明名称为“异吲哚啉类化合物、其制备方法、药物组合物及用途”的第201910939297.0号中国专利申请的分案申请。
优先权声明
本申请要求申请号为201811156797.9,申请日为2018年9月30日,发明名称为:“异吲哚啉类化合物、其制备方法、药物组合物及用途”的中国专利申请的优先权,在此将其全部内容并入本申请作为参考。
1.技术领域
本发明涉及一类新颖结构的多取代异吲哚啉类化合物,其药学上可接受的盐、溶剂合物、药物组合物及其在制备治疗或预防多种疾病的药物中的应用。
2.背景技术
细胞内蛋白质表达的严密调控在细胞行使功能、细胞存活以及分裂过程中发挥着重要作用,许多原发性或获得性疾病通常涉及蛋白质功能异常。传统的调节蛋白功能异常的方法主要是过设计靶向抑制剂或激动剂,这些靶向药物在疾病的治疗中发挥着重要作用。尽管如此,为了获得满意的疗效,这些抑制剂或激动剂通常需要维持在较高的药物浓度以达到有效治疗效果,这也在一定程度上导致了药物的不良反应。另一种调节蛋白质功能异常的方法是改变病理相关蛋白的动态平衡,蛋白质的动态平衡包括蛋白质的合成和降解,例如可以利用小干扰RNA(siRNA)、反义寡聚核苷酸或基因编辑技术来敲除或沉默靶蛋白基因,这些基于核酸的技术通过作用于靶蛋白的转录和翻译过程而改变蛋白质的合成,该类技术最大的局限在于核酸的体内稳定性以及生物利用度较低,进而在一定程度上限制了其应用。另一种调节蛋白质动态平衡的策略是调控蛋白质的降解过程,通过促进或抑制蛋白质的降解可以直接改变靶蛋白在细胞内的表达量。泛素-蛋白酶体系统(UPS)在蛋白质的降解过程中发挥重要作用,在一系列泛素化酶的作用下,靶蛋白可以被泛素化标记,带有特殊泛素标签的蛋白质可以被运送至蛋白酶体并被其降解。
蛋白质泛素化存在多种模式,包括单泛素化(底物蛋白只连接一个泛素)、多-单泛素化(底物蛋白存在多个泛素化位点,每个位点被单泛素化)或多聚泛素化(形成泛素链),此外,多聚泛素化过程也可以发生泛素自身上多个赖氨酸侧链胺基或N端胺基上。根据不同的泛素化模式,蛋白质被泛素化后既可以影响蛋白质在细胞内的过程,包括亚细胞定位、蛋白质贮存以及蛋白-蛋白相互作用等,同时也可以影响蛋白质的功能,包括蛋白质功能激活、抑制或蛋白酶体/溶酶体降解等。
蛋白质的泛素化过程是一个串联的多步反应过程,主要有三类酶参与:E1泛素激活酶,E2泛素结合酶,E3泛素连接酶。首先,泛素C端被ATP激活而与E1泛素激活酶活性中心的半胱氨酸巯基形成活泼的硫酯结构。然后,该活泼中间体通过转硫酯反应将泛素通过新的硫酯结构共价连接到E2泛素结合酶上。最后,E3泛素连接酶招募底物蛋白并同时与E2泛素结合酶-泛素活性中间体结合,将泛素转移至底物蛋白上从而完成底物蛋白的泛素化过程。在整个泛素化过程中,E3泛素连接酶发挥着重要作用,它不仅发挥着桥梁作用,使两个反应组分(E2泛素结合酶-泛素缀合物以及底物蛋白)在空间上相互靠近,同时还发挥着酶催化作用,加速底物蛋白被泛素化的速率。由于E3泛素连接酶需要特异性识别底物,因此哺乳动物基因组编码了超过600种E3泛素连接酶。相比之下,目前只发现了两种E1泛素激活酶和约40中E2泛素结合酶。
根据E3泛素连接酶的保守结构域和作用模式可以将其分成三大类,其中TECT家族和RBR家族E3泛素连接酶在底物泛素化过程中需要先将泛素从E2泛素激活酶上转移至自身,再将泛素从E3泛素连接酶上转移至底物蛋白上。相比较而言,RING家族E3泛素连接酶在整个E3泛素连接酶中占据较大比例,这类E3泛素连接酶上含有RING结构域或RING样结构域,它们能够与E2泛素结合酶结合,促进泛素直接从E2泛素结合酶直接转移至底物蛋白上。
CRL4CRBNE3泛素连接酶属于RING家族E3泛素连接酶,它是一种由多个亚基组装而成的蛋白复合物,整个复合物包含底物蛋白识别模块(CRBN)、E2泛素结合酶识别模块(RING结构域)以及二者之间的连接部分(Cullin蛋白)。CRBN在整个蛋白复合物中直接结合底物,控制着整个泛素化过程的底物特异性。
直接作用于CRBN的小分子调节剂可以控制CRL4CRBNE3泛素连接酶的底物选择性。新的研究发现,Cereblon(基因名:CRBN)是免疫调节剂—沙利度胺及其类似物的直接靶点(Science,2010,327,1345;Science,2014,343,301;Science,2014,343,305;Nature,2015,523,183.)。研究证明度胺类免疫调节剂在多发性骨髓瘤细胞系中,通过调控CRBN-泛素连接酶复合物的活性,选择性诱导转录因子IKZF1和IKZF3进行泛素化并降解,这一过程改变了T细胞和B细胞的功能,同时对多发性骨髓瘤细胞产生毒性效应,由此达到治疗多发性骨髓瘤在内的恶性髓系肿瘤的作用。最近的研究表明,来那度胺,一种沙利度胺的类似物,能够通过CRL4CRBNE3泛素连接酶选择性诱导CK1α的泛素化并降解,实现治疗5q缺失型骨髓异常性增生综合征(MDS),而沙利度胺的另一种结构类似物(CC-885)则能够通过作用于CRL4CRBNE3泛素连接酶选择性诱导并降解GSPT1,对多种肿瘤细胞展现出很强的细胞毒性。
现有研究结果表明:不同度胺类药物分子与靶点CRBN相互作用后,具有不同底物蛋白降解特异性。如来那度胺在治疗多发性骨髓瘤时,其疗效主要是通过选择性降解IKZF1和IKZF3实现;而在治疗5q缺失的骨髓异常性增生综合症(del(5q)MDS)时主要通过降解CK1α达到治疗效果。由于目前发展的度胺类似物中主要是来那度胺对CK1α表现出较强的降解活性,因此是最主要的临床有效的治疗骨髓异常性增生综合征del(5q)MDS的度胺类药物。随着新的度胺类药物的研发和临床实验的开展,度胺类药物分子的适应症也在不断扩展中,如FDA批准的沙利度胺用于治疗麻风结节性红斑,来那度胺临床实验中用于治疗前列腺癌,泊马度胺临床实验中用于治疗骨髓纤维化症。
来那度胺、泊马度胺、CC-122、CC-220、CC-885这些已经报化合物的结构与沙利度相似,该类化合物的特点在于,结构上的改变和调整后,化合物具有不同的药理活性和完全不同的治疗效果,进而在临床上可用于治疗不同的适应症。
WO2008115516A2、US8153659B2、US9181216B2、US9920027B2公开了通式为S1所代表的化合物:
WO2011100380A1、CN102822165B,公开了一类通式为S2所代表的化合物:
通式S2中R1为取代的多种取代的芳基,代表性的化合物为CC-220:
WO2016065980A1、CN105566290A、US10017492B2
通式S3中代表性的化合物为:
WO2007027527A2、CN101291924A、US8481568B2公开了一类通式为S3所代表的化合物:
通式S4、S5中代表性的化合物为:
WO2008027542A2、US8877780B2、US9447070B2公开了一类通式为S3所代表的化合物:
通式S6、S7中代表性的化合物为:
来那度胺及上述部分分子的作用机制是:不同结构的化合物能够和CRBN结合,引起CRBN结合部分构象的改变,从而招募不同的内源性生物大分子与CRBN的结合;进而对潜在不同的内源性底物蛋白进行泛素化并降解,因而能够产生不同的药理活性,在临床实验中用于治疗不同的适应症。
综上所述,来那度胺主要用于治疗治疗多发性骨髓瘤和骨髓异常增生综合征,对其他适应症效果并不理想;其他上述提到的化合物如CC-122,CC-885和CC-220尚处于临床前或临床研究中。因此,开发结构新颖的化合物作为CRL4CRBNE3泛素连接酶调节剂,可以实现进一步提高肿瘤的治疗效果治疗和扩展度胺类药物的新适应症的临床上的需求;结构不同的度胺类分子的药理学活性和药物学性质都不为人所知,各方面的性质和作用都具有不确定性。基于度胺类分子的作用机制,开发新结构的度胺类分子,能够实现招募新的蛋白底物,进而实现的治疗效果的提高和新适应症的扩展。因此,继续开发新颖结构的CRL4CRBNE3泛素连接酶调节剂以拓展新的适应症具有非常重要研究价值和现实意义。
3.发明内容
本发明的发明人通过对CRBN与小分子作用的复合物晶体结构(PDB ID:4CI2、5HXB)进行分析获得下述重要信息:CRBN与小分子存在多个结合口袋,因此可以发展结构复杂的多个结合位点的小分子,实现CRBN与小分子的有效结合。同时利用分子动力学模拟方法对模型分子和E3泛素连接酶界面进行结构动态和结合位点分析,结合分子对接和基于复合物的药效团匹配,通过打分函数对化合物在E3泛素连接酶活性位点的结合模式和相互作用进行评价,获得新型特异性的CRBN小分子调节剂。基于这些信息,我们设计并合成一系列本申请所述的CRBN的小分子调节剂,并测试了化合物的活性。测试结果表明,新型的小分子调节剂具有非常高的细胞的生长抑制活性,该分子作用于生物体后,通过调节生物体内泛素—蛋白酶体介导的蛋白降解途径,可以调控底物蛋白的降解,进而实现基于CRBN靶点的有效的疾病治疗。
本发明的一个目的是提供如下通式(I)所示的化合物、其对映体、非对映体、消旋体、同位素化合物、代谢前体、代谢产物、可药用的盐、酯、前药或其水合物。
本发明的另一个目的是提供该类化合物的重要中间体及制备方法。
本发明的另一个目的是提供一种药物组合物,其特征在于,包含治疗有效剂量的通式(I)所示的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物,和至少一种药学上可接受的载体。
本发明的另一个目的是提供一种药物组合物,其特征在于,包含治疗有效剂量的通式(I)所示的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物,以及另外一种或多种具有医药学治疗活性的成分。本发明通式(I)所示的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明所述的通式(I)所示的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用,反之亦然。
本发明的另一个目的是提供如上所述的另外一种或多种具有医药学治疗活性的成分,包括大分子化合物,例如蛋白、多糖和核酸等;和小分子化合物,例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等。
本发明的另一个目的是提供如通式(I)的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物,其特征在于,用于制备治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物,优选地,所述的疾病非限制性地包括癌症、疼痛、神经系统疾病和免疫系统疾病。
为了实现上述目的,本发明提供了如下通式(I)表示的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物:
其中X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘、氟或C1-C6直链或支链烃基;
R2、R4各自独立地为氢或氘;
R3为氢、氘或卤素;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羰基、羟基、氨基、氰基、C1-C6烷基、卤素取代的C1-C6烷基、C3-C8环烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代或未取代的C1-6烷基、由卤素、羟基、氰基、硝基取代或未取代的C3-6环烷基;
Y不存在,或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–;
Y为–O–时,A为:6-10元芳基、5-10元杂芳基,(6-10元芳基)–(CH2)b1–、(5-10元杂芳基)–(CH2)b1–,前述芳基或杂芳基可选地被以下一个或多个基团所取代:氘、卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、羟基取代的C1-C6烷氧基、氰基取代的C1-C6烷氧基、C3-C6环烷基、C3-C6环烷基氧基、苯基、5-6元杂芳基、3-6元杂环基、-NHC(O)Ra5、-NHC(O)ORa6、-NRa7Ra8,其中Ra5、Ra6、Ra7和Ra8各自独立地为氢原子、由卤素、羟基、C1-C6烷氧基、氰基、硝基取代或未取代的C1-6烷基、或由卤素、羟基、C1-C6烷氧基、氰基、硝基取代或未取代的C3-6环烷基;
b1为1或2;
Y不存在,或为–CO–或–CO–NH–时,相对应的Y与A、L形成的连接方式分别为A–L–、A–CO–L–、A–CO–NH–L–,A为:i)选自以下的杂环基:
X3为C、N或O;
n4为0、1、2或3;
n5为0、1、2或3;
Y1、Y2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基磺酰基、C1-C6烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C6酰基氨基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
当Y1和Y2各自独立地为氢、氘、C1-C6烷氧基、卤素、C1-C6烷基、C3-C6的环烷基、羧基、C1-C6烷基氨基羰基、C1-C6烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C6烷基、羟基、C1-C6烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y3不存在,或为氢、C1-C6烷基、C3-C6环烷基、C1-C6烷基氨基羰基、C1-C6烷氧基羰基、卤素取代C1-C6烷基、C1-C6烷基磺酰基、C1-C6烷基羰基、氨基羰基、C3-C6杂环基、C1-C6酰基氨基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C5-C10的芳基或杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
当Y3为氢、C1-C6烷基、C3-C6环烷基、C1-C6烷基氨基羰基、C1-C6烷氧基羰基、卤素取代C1-C6烷基、C1-C6烷基磺酰基或Y3不存在时,并且Y不存在时,X1不为-O-;
Y4、Y5为其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、氧、C1-C3烷基、C1-C3环烷基、卤素取代的C1-C3烷基或苯基;
ii)选自以下的稠杂环基:
X4为C、N或O;
n6为0、1、2或3;
n7为0、1、2或3;
n8为0、1、2、3或4;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基;
当上述R8各自独立地选自下列任意取代基:氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、C1-C3烷基、C1-C3环烷基、卤素取代的C1-C3烷基;
或者iii)选自以下的螺杂环基:
nc1为0、1、2或3;
nc2为0、1、2或3;
nc3为1、2或3;
n9为0、1、2、3或4;
R9独立选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8可选地被氘、卤素、C1-C3烷基、C1-C3环烷基、卤素取代的C1-C3烷基取代基所取代;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–时,相对应地Y与A、L形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHRa9)–L–或A–CH(NHRa9)–L–,其中A为:
6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH2–、(5-10元杂芳基)–CH2–,所述芳基或杂芳基可选地一个或多个R5取代基所取代,
或者A为选自以下基团:
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基氨基羰基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C1-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
优选地,通式(I)所示的化合物,其中X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘、氟或C1-C3直链或支链烃基;
R2、R4各自独立地为氢或氘;
R3为氢、氘或卤素;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羰基、羟基、氨基、氰基、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代的C1-6烷基、由卤素、羟基、氰基、硝基取代的C3-6环烷基;
Y不存在,或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–;
Y为–O–时,A为:取代或未取代的9-10元芳基、9-10元杂芳基,(9-10元芳基)–(CH2)b1–、(9-10元杂芳基)–(CH2)b1–,
其中,b1为1或2;
上述取代或未取代的9-10元芳基或9-10元杂芳基选自以下基团:
n2为0、1、2或3;
n3为0、1、2或3;
R6、R7各自独立地选自以下基团:氘、卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、羟基取代的C1-C6烷氧基、氰基取代的C1-C6烷氧基、C3-C6环烷基、C3-C6环烷基氧基、苯基、C5-C6杂芳基、C3-C6杂环基,-NHC(O)Ra5、-NHC(O)ORa6、-NRa7Ra8;其中Ra5、Ra6、Ra7和a8各自独立地为氢原子、由卤素、羟基、C1-C6烷氧基、氰基、硝基取代基取代或未取代的C1-6烷基、或由卤素、羟基、C1-C6烷氧基、氰基、硝基取代基取代或未取代的C3-6环烷基,其中当n2>1或者n3>1时,R6和R7各自可以相同或不同;
Y不存在,或为–CO–或–CO–NH–时,相对应地Y与A、L所形成的连接方式为–A–L–、–A–CO–L–或–A–CO–NH–L–,A为:
i)选自以下的杂环基:
其中,Y1、Y2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基磺酰基、C1-C6烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C6酰基氨基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
当Y1和Y2各自独立地为:氢、氘、C1-C6烷氧基、卤素、C1-C6烷基、C3-C6的环烷基、羧基、C1-C6烷基氨基羰基、C1-C6烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C6烷基、羟基、C1-C6烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y3不存在,或为C1-C6烷基羰基、氨基羰基、C3-C6杂环基、C1-C6酰基氨基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C5-C10的芳基或杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,前述6-10元芳基优选选自苯基、萘基,前述5-10元杂芳基优选选自噻吩基、吡啶基、苯并噻吩基、苯并咪唑基、吲哚基、喹啉基、异喹啉基。
当Y3为氢、C1-C6烷基、C3-C6环烷基、C1-C6烷基氨基羰基、C1-C6烷氧基羰基、卤素取代C1-C6烷基、C1-C6烷基磺酰基或Y3不存在时,并且Y不存在时,X1不为-O-;
Y4、Y5为其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、氧、C1-C3烷基、C1-C3环烷基或苯基;
ii)选自以下的稠杂环基:
n8为0、1、2、3或4;
X4为C、N或O;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基;
当上述R8各自独立地选自下列任意取代基:氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y为不存在时,X1不为-O-;
Y6、Y7为其所在杂环上的一个或多个取代基,且各自独立选自氘、卤素、C1-C3烷基、C1-C3环烷基、卤素取代的C1-C3烷基;
或者iii)选自以下的螺杂环基:
其中,n9为0、1、2、3或4;
R9独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8可选地被氘、卤素、C1-C3烷基、C1-C3环烷基、卤素取代的C1-C3烷基取代基所取代;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–时,相对应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHRa9)–L–或A–CH(NHRa9)–L–,其中A为:
6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH2–、(5-10元杂芳基)–CH2–,前述芳基或杂芳基可选地一个或多个R5取代基所取代,或者A为选自以下基团:
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基氨基羰基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9独立地选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C1-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
进一步优选地,通式(I)所示的化合物,其中X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或者由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–;
Y为–O–时,A为:选自9-10元芳基、9-10元杂芳基,(9-10元芳基)–(CH2)b1–、(9-10元杂芳基)–(CH2)b1–,所述9-10元芳基或9-10元杂芳基可以是未取代或被取代;
所述的取代或未取代的9-10元芳基或9-10元杂芳基选自以下基团:
b1为1或2;
n2为0、1、2或3;
n3为0、1、2或3;
R6、R7各自独立选自以下基团:氘、卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、羟基取代的C1-C6烷氧基、氰基取代的C1-C6烷氧基、C3-C6环烷基、C3-C6环烷基氧基、苯基、C5-C6杂芳基、C3-C6杂环基,-NHC(O)Ra5、-NHC(O)ORa6、-NRa7Ra8;其中Ra5、Ra6、Ra7和Ra8各自独立地为氢原子、由卤素、羟基、氰基取代的C1-6烷基、或由卤素、羟基、氰基取代的C3-6环烷基,其中当n2>1或者n3>1时,R6和R7各自可以相同或不同;
Y不存在,或为–CO–或–CO–NH–,相应地Y与A、L所形成的连接方式为–A–CO–L–、–A–CO–NH–L–、–A–L–、A部分至少含有一个氮原子且Y与氮原子连接,A为:
i)选自以下的杂环基:
n10为0、1、2、3、4或5;
Y1选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基磺酰基、C1-C6烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C6酰基氨基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
R10各自独立地为氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,R10可以相同或不同;
Y4、Y5为其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、甲基、乙基、环丙基或苯基;
ii)选自以下的稠杂环基:
n8为0、1、2、3或4;
X4为C、N或O;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基,其中当n8>1时,各个R8可以相同或不同;
当上述R8各自独立地选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、甲基、乙基、环丙基、三氟甲基;
或者iii)选自以下的螺杂环基:
其中,n9为0、1、2、3或4;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–时,相应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHRa9)–L–或A–CH(NHRa9)–L–,其中A为:
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基氨基羰基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C1-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-1)至(I-8)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地选自为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或者由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或者为–CO–或–CO–NH–;
n9为0、1、2、3或4;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,其中当n9>1时,各个R9可以相同或不同;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-9)至(I-16)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢、氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n9为0、1、2、3或4;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-17)、(I-18)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3选自为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n10为0、1、2、3、4或5;
Y1各自独立地选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基磺酰基、C1-C6烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C6酰基氨基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基、C1-C3烯基、C1-C3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C1-C3的直链或支链烷基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-19)至(I-23)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n8为0、1、2、3或4;
X4为C、N或O;
R8各自独立地为氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基,其中当n8>1时,各个R8可以相同或不同;
当R8选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、甲基、乙基、环丙基、三氟甲基;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-24)至(I-32)表示的化合物:
其中,X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3选自为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n8、n9、n10各自独立地选自0、1、2、3或4;
X4为C、N或O;
R9选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,其中当n9>1时,各个R9可以相同或不同;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基,当n8>1时,各个R8可以相同或不同;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-33)至(I-40)表示的化合物:
其中,X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–、–CO–NH–;
n8、n9、n10各自独立地为0、1、2、3或4;
X4选自C、N或O;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C3-C6环烷基或杂环烷基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基、苯基、5-6元杂芳基,当n9>1时,各个R9可以相同或不同;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基羰基、C1-C3烷氧基羰基、C1-C3烷基磺酰基、C1-C3烷基氨基羰基、C3-C6的环烷基或杂环基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、C3-C6的杂环基、卤素取代C1-C3烷氧基、苯基或5-6元杂芳基,其中当n8>1时,各个R8可以相同或不同;
当R8选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、C3-C6的环烷基、羧基、C1-C3烷基氨基羰基、C1-C3烷氧基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-41)至(I-48)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
n2为0、1、2或3;
n3为0、1、2或3;
R6、R7各自独立地选自以下基团:氘、卤素、氰基、硝基、氨基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、羟基取代的C1-C6烷氧基、氰基取代的C1-C6烷氧基、C3-C6环烷基、C3-C6环烷基氧基、苯基、C5-C6杂芳基、C3-C6杂环基,-NHC(O)Ra5、-NHC(O)ORa6、-NRa7Ra8,其中Ra5、Ra6、Ra7和Ra8各自独立地选自氢原子、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C1-6烷基、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C3-6环烷基,当n2>1或者n3>1时,R6和R7各自可以相同或不同;
在一优选实施方式中,其中通式(I)表示的化合物为通式(I-49)至(I-53)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地选自氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NHC(O)ORa2、-NRa3Ra4,其中Ra1、Ra2、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–;
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基氨基羰基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C1-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
最优选地,通式(I)表示的化合物为下列化合物之一:
其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、同位素化合物、可药用的盐、酯、前药或其水合物。
通式(I)所示的化合物可以含有一个或多个不对称或手性中心,因此可以以不同立体异构体形式存在。本发明化合物包括所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋体),均包括在本发明的范围内。
术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中有相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环共用一个碳原子。
本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。本发明中相关结构上的取代,包括取代和未取代,如“可选地”被某种取代基取代,是指包括被某种取代基取代或者未取代的含义。
本发明中提到的当取代基数>1时,R取代基可以为相同或不同的取代基,指当某一种结构中取代基数为多个时,R的取代基组合可以为选自多种不同类型的取代基。
术语“取代”只适用于能够被取代基所取代的位点,不包括在现有的化学知识上不能实现的取代。
通式(I)所示的化合物还可以以不同互变异构体形式存在,所有这些形式均包括在本发明范围内。
术语“互变异构体”是指经由低能垒相互转化的具有不同能量的构造异构体,反应一般导致伴随单键和相邻双键转变的氢原子或质子的形式移动。
术语“对映体”是指互为镜像而不可重叠的立体异构体。
“非对映体”是指具有两个或者两个以上的手性中性,并且不成镜像的立体异构体。
“消旋体”是指两个互为镜像的立体异构体,旋光性相反,互相抵消了旋光性。
“可药用的盐”是指药物分子与对应的有机酸、无机酸或者有机碱、无机碱形成相应的盐的,例如盐酸、甲酸、三氟乙酸、琥珀酸、甲磺酸盐等。
“前药”是指在体外无活性或者活性较小,在体内经过酶或者非酶的转化释放出活性药物而发挥药效的一类化合物。
“水合物”是指含有水的化合物。
术语“卤素”包括氟、氯、溴或碘。
术语“烃基”是指只含有碳原子和氢原子的取代基,非限制性地包括甲基、乙基、异丙基、丙基、环己基、苯基等。
术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等。
术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
术语“C1-C6烷氧基羰基”非限制性地包括甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基和已氧基羰基等。
术语“环烷基”是指饱和或部分不饱和单环或者多环环状烃取代基。单环环烷基非限制性包括环丙基、环丁基、环戊烯基、环己基。多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环基”是指含有一个或多个饱和和/或部分饱和单环或者多环环状取代基,其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基;杂环基可以稠合与芳基、杂芳基、或环烷基环上,与母体结构连接在一起的环为杂环基。
术语“芳基”是指具有共轭的p电子体系的6-14元全碳单环或稠合多环基团,优选为6至10元环,优选为6至10元,更优选苯基和萘基,最优选苯基。所述芳基环可以稠合与杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
术语“杂芳基”是指具有1至4个杂原子作为环原子,其余的环原子为碳的5-14元芳基,其中杂原子包括氧、硫和氮。优选为5-10元。杂芳基优选为5元或6元,如噻吩基、吡啶基、吡咯基等。所述杂芳基环可以稠合与芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,
术语“螺杂环基”是指单环之间共用一个原子(称为螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧,硫或者S(O)m(其中m是0至2的整数)的杂原子,其余环原子为碳。螺杂环可以稠合与6-10元芳基或5-10元杂芳基环上,其中与母体结构连接在一起的环为螺杂环。
术语“卤素取代烷基”是指由单个或者多个卤素取代的直链、支链或者环状烷基,非限制性地包括2-溴乙基、2-溴丙基等。
术语“烯基”是指可以为2-10个碳的烯基,如乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基。
术语“炔基”是指可以为2-10个碳的炔基,如乙炔基、丙炔基、丁炔基、苯乙炔基、苯丙烯基。
术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基等。
术语“5-10元杂环基”是指含有一个或多个饱和和/或部分饱和环,其包括5至10个环原子,其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。
术语“C3-C6杂环基”是指含有一个或多个饱和和/或部分饱和环,其包括3至6个环原子,其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基。
术语“羟基取代烷基”是指由单个或者多个羟基取代的直链、支链或者环状烷基,非限制性地包括(S)-1-羟基异丁-2-基、(R)-1-羟基异丁-2-基等。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
本发明也包含这里公布的任何一种新的中间体。
本发明有一个方面提供了通式(I)所示的化合物的制备方法,所述方法选自如下方法之一:
起始化合物,1A、2A、3D、4A、5A、6A和7A的合成参考文献WO2008115516A2、WO2011100380A1、WO2016065980A1、WO2007027527A2、WO2008027542A2。
合成方法1:
其中,R1、R2、R3、R4和X2的定义与前述定义相同;
m1为1~7的整数;
步骤1-1:化合物1A与1B在DMF、DMA等偶极有机溶剂为溶剂,Pd催化剂(如Pd(PPh3)4、Pd(PPh3)2Cl2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下,在室温或加热条件通过Sonogashira偶联反应得到化合物1C;
步骤1-2:化合物1C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物1D,
步骤1-3:化合物1D与羟基喹啉1E(或为取代或未取代羟基喹啉及其类似物,取代或未取代萘酚及其类似物等)在三苯基膦和偶氮二甲酸二异丙酯条件下反应得到化合物1F;
步骤1-4:化合物1D在三苯基膦和四溴化碳存在下,反应得到化合物1G;
步骤1-5:化合物1G和含氮杂环化合物1H(化合物1H为前述定义中含有A基团的各种胺类化合物)在碘化钠存在下反应得到化合物1I;
合成方法2:
其中,R1、R2、R3、R4和X2的定义与前述的定义相同;
m1为1~7的整数;
G2为保护基,选自TBS、Trit、苄基;
步骤2-1:化合物2A与2B在非质子溶剂为反应溶剂(如乙腈、DMF等),Pd催化剂(乙酸钯(II)、Pd(PPh3)4等)、膦配体(如三苯基膦、s-Phos等)、有机碱(三乙胺或二异丙基乙基胺等)存在下加热反应生成多取代烯烃衍生物(Heck偶联反应),生成多取代烯烃衍生物2C;
步骤2-2:化合物2C在在Pd/C或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物2D;
步骤2-3:以干燥四氢呋喃为溶剂,在叔丁醇钾存在条件下关环得到哌啶酮衍生物2E;
步骤2-4:化合物2E在酸性条件下或者在TBAF存在条件下,脱除保护基得到化合物2F;
步骤2-5:化合物2F在三苯基膦和四溴化碳存在下,反应得到化合物2G;
步骤2-6:化合物2G和含氮杂环化合物2H(化合物2H为前述定义中含有A基团的各种胺类化合物)在碘化钠存在下反应得到化合物2I;
合成方法3:
其中,R1、R2、R3、R4、和X2的定义与前述的定义相同;
m2为1~7的整数;
G3-NH2为本发明实施例中使用的各类芳香胺或脂肪胺化合物;
步骤3-1:化合物3A与3B在三氟乙酸酐和叔丁醇存在下,反应得到化合物3C;
步骤3-2:化合物3C和3D在碳酸钾存在的条件下,反应得到化合物3E;
步骤3-3:化合物3E叔丁醇钾存在条件下关环得到哌啶酮衍生物3F;
步骤3-4:化合物3F在盐酸条件下,脱除保护基获得化合物3G;
步骤3-5:化合物3G和含氮杂环化合物3H(化合物3H为前述定义中含有A基团的各种胺类化合物)在缩合剂(HATU、HOBt)及碱(三乙胺)存在下,缩合获得化合物3I;
步骤3-6:化合物3G和化合物3J在缩合剂(HATU、HOBt)及碱(三乙胺)存在下,缩合获得化合物3K;
合成方法4:
其中,R1、R2、R3、R4、X2、Ra9、R11和n11的定义与前述的定义相同;
G4、G5为保护基选自叔丁氧羰基或苄基;
G6-NH2为各类芳香胺或脂肪胺化合物;
步骤4-1:化合物4A与4B在Pd催化剂(如Pd(PPh3)4、Pd(PPh3)2Cl2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下,在室温或加热条件、一价铜催化剂和碱的存在下,通过Sonogashira偶联反应得到化合物4C;
步骤4-2:化合物4C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物4D;
步骤4-3:化合物4D在胺类衍生物4E和缩合剂HATU及HOBt条件下缩合得到化合物4F;
步骤4-4:化合物4F在盐酸条件下脱除保护基,反应后旋干与相应的酰氯或羧酸反应获得化合物4G;
步骤4-5:化合物4D和邻苯二胺衍生物4H在缩合剂HATU及HOBt条件下反应后,在酸性条件下加热条件下获得化合物4I;
步骤4-6:化合物4I在盐酸条件下脱除保护基,反应后旋干与相应的酰氯或羧酸反应获得化合物4J;
合成方法5:
其中,R1、R2、R3、R4、和X2的定义与前述的定义相同;
m3为1~7的整数;
Ar为6-10元芳基、5-10元杂芳基,所述芳基或杂芳基可选地一个或多个R5取代基所取代,R5定义与前述的定义相同;
步骤5-1:化合物5A与5B在三苯基膦和偶氮二甲酸二异丙酯条件下,反应得到化合物5C;
步骤5-2:化合物5C在碳酸钾存在的条件下,反应得到化合物5D;
步骤5-3:化合物5D在盐酸条件下脱除保护基,得到化合物5E;
步骤5-4:化合物5E和化合物5F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应得到化合物5G;
步骤5-5:化合物5E和含氮杂环化合物5H(化合物5H为前述定义中含有A基团的各种胺类化合物)在N,N'-羰基二咪唑和碱性条件下,反应得到化合物5I。
合成方法6:
其中,R1、R2、R3、R4、和X2的定义与前述定义相同;
m4为1~7的整数;
步骤6-1:化合物6A与6B在碳酸钾存在条件下,反应得到化合物6C;
步骤6-2:化合物6C在叔丁醇钾存在的条件下,反应得到化合物6D;
步骤6-3:化合物6D和含氮杂环化合物6E(化合物6E为前述定义中含有A基团的各种胺类化合物)在碱性条件下,反应得到化合物6F。
合成方法7
其中,R1、R2、R3、和R4的定义与前述的定义相同;
m4为1~7的整数;
步骤7-1:化合物7A与7B氯甲基甲醚在氢化钠存在的条件下反应,得到化合物7C;
步骤7-2:化合物7C在7D和偶氮二异丁腈存在的条件下反应,得到化合物7E;
步骤7-3:化合物7E在7F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应,得到化合物7G;
步骤7-4:化合物7G在酸性条件下(盐酸,二氧六环)反应,得到化合物7H;
步骤7-5:化合物7I和7F在碱(如三乙胺或而二异丙基乙基胺等)性条件下反应,得到化合物7H;
步骤7-6:化合物7H与6B在碳酸钾存在条件下,反应得到化合物7J;
步骤7-7:化合物7J和含氮杂环化合物7K(化合物7K为前述定义中含有A基团的各种胺类化合物)在碱性(如三乙胺或而二异丙基乙基胺等)条件下,反应得到化合物7L。
本发明的另一个目的是提供如通式(I)所示的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,其特征在于,可调控CRL4CRBN E3泛素连接酶的活性。
本发明的另一个目的是提供一种药物组合物,其特征在于,包含治疗有效剂量的如通式(I)所示的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,和至少一种其它药学上可接受的载体。
本发明的另一个目的是提供一种药物组合物,其特征在于,包含治疗有效剂量的如通式(I)的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,以及另外一种或多种具有医药学治疗活性的成分。本发明权利要求1所述的如式(I)的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明权利要求1所述的如式(I)的化合物,其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用,反之亦然。
本发明的另一个目的是提供如上述的另外一种或多种具有医药学治疗活性的成分,包括大分子化合物,例如蛋白、多糖和核酸等;和小分子化合物,例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等。
本发明的另一个目的是提供如通式(I)的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,其特征在于,用于制备治疗与CRL4CRBNE3泛素连接酶相关的疾病的药物,优选地,所述的疾病非限制性地包括癌症、炎症、疼痛、神经系统疾病和免疫系统疾病。
本发明化合物中含有碱性基团时可以制备成药学上可接受的盐,包括无机酸盐和有机酸盐。适合形成盐的酸非限制性包括:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸等。
本发明的又一个目的是提供了一种药物组合物,其包括治疗有效量的通式(I)表示的化合物、其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用盐、前药、溶剂化物、水合物和晶型中的一种或多种,以及至少一种赋形剂、稀释剂或载剂。
典型的配方是通过混合本发明的通式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的,包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。所用的特定载体、稀释剂或赋形剂,将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言,安全的溶剂是无毒性含水溶剂诸如制药用水,以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使式(I)表示的化合物以可被接受的形式制造或使用。
本发明如式(I)的化合物与至少一种其它药物组合使用时,两种药物或多种药物可以分开使用也可以组合使用,优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式,分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中,本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质,或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等;粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等;湿润剂如甘油等;崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等;溶液阻滞剂如石蜡等;吸收促进剂如季铵化合物等;吸附剂如高岭土、膨润土等;润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下,该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料,其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其组合物之外,该液态剂型可含有本领域中常用的惰性稀释剂,诸如水或其他溶剂;增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等);甘油;四氢糠基醇;聚乙二醇与脱水山梨糖醇的脂肪酸酯;或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外,该组合物也可包括赋形剂,诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言,除了本发明的化合物或组合之外,可进一步含有载剂诸如悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶,或这些物质中几种的混合物等。
用于直肠或阴道投药之组合物优选栓剂,可通过将本发明的化合物或组合与适宜的非刺激性赋形剂或载剂混合而制备,赋形剂或载剂诸如可可豆脂、聚乙二醇或栓剂蜡,其在一般室温为固态而在体温为液态,可在直肠或阴道中熔化而释出活性化合物。
本发明化合物或药物组合物可采用其它局部给药剂型给药,包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液,亦意欲涵盖于本发明的范围内。
本发明的又一个目的是提供了如通式(I)的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,或晶型可用于单一治疗或联合治疗中。当用于联合治疗中时,包含治疗有效剂量的权利要求1所述的式(I)的化合物,其对映异构体、非对映异构体、外消旋体及其混合物,以及其药学上可接受的盐、结晶水合物及溶剂合物,以及另外一种或多种具有医药学治疗活性的成分。所述的另外一种或多种具有医药学治疗活性的成分,包括大分子化合物,例如蛋白(抗体或多肽)、多糖和核酸(DNA或RNA)等;和小分子化合物,例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等;此外还包括辐射、外科手术、细胞疗法、激素疗法或细胞因子疗法等。本发明权利要求1所述的如式(I)的化合物,其前药、对映异构体、非对映异构体、外消旋体及其混合物,以及其药学上可接受的盐、结晶水合物及溶剂合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明权利要求1所述的如式(I)的化合物,其前药、对映异构体、非对映异构体、外消旋体及其混合物,以及其药学上可接受的盐、结晶水合物及溶剂合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用,反之亦然。
本发明的又一个目的是提供了如通式(I)的化合物,其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物,用于制备治疗或预防CRL4CRBNE3泛素连接酶参与的疾病的药物的用途。本发明阐述的由CRL4CRBNE3泛素连接酶参与的相关疾病非限制性包括肿瘤、中枢系统疾病和免疫性疾病。
在一优选例中,所述的疾病或功能紊乱包括但不限于:癌症、与血管生成相关的疾病或功能紊乱、疼痛(包括但不限于复杂性局部疼痛综合症)、黄斑退化及相关功能紊乱、皮肤疾病、肺部功能紊乱、免疫缺陷型疾病、中枢神经系统的损伤及功能紊乱、TNFα相关的疾病或功能紊乱。
在另一优选例中,所述的癌症包括(但不限于):皮肤癌症(如黑色素瘤)、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌,喉癌以及与艾滋病相关的癌症。本发明所提供的化合物同样对血液瘤和骨髓瘤有效,如能用于治疗多发性骨髓瘤、淋巴瘤和急慢性白血病。本发明所提供的化合物也可用于预防或治疗原发肿瘤和转移性肿瘤。
本发明中所用术语“氘(D)”是氢的一中稳定形态的非放射性同位素,其原子量为2.0144。天然中的氢是以H(氢或氕)、D(2H或氘)和T(3H或氚)同位素混合物的形式存在的,其中氘的丰度为0.0156%。根据本领域普通技术知识,所有含有天然氢原子的化合物结构式中,氢原子实际上表示的是H、D与T的混合物。因此,化合物中任何位点处的氘丰度大于其自然丰度0.0156%时,这些化合物都应该被认为是非天然的或氘富集的。
本发明中所用术语“同位素化合物”是指本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、立体异构体、代谢物,或前药中含有一个或多个天然或非天然丰度的原子同位素。本发明也涵盖经同位素标记的本发明化合物,除了一个或多个原子是被原子质量或质量数不同于自然中常见的原子质量或质量数之一原子所置换的事实之外,其是与此述者相同。可纳入本发明的化合物中的同位素实例,包括氢、碳、氮、氧、磷、硫、氟、碘及氯之同位素,其分别诸如:2氢、3氢、11碳、13碳、14碳、13氮、15氮、15氧、17氧、18氧、31磷、32磷、35硫、18氟、123碘、125碘及36氯。
某些同位素标记的本发明的化合物(例如用3H和14C标记的那些)用于化合物和/或底物组织分布试验。特别优选氚化(即3H)和碳-14(即14C)同位素,因为它们容易制备和检测。而且,较重的同位素如氘(即2H)进行取代可以提供由较大的代谢稳定性导致的某些治疗优点(例如体内半衰期增加或剂量需求减小),因而在某些情况下可能是优选的。正电子发射同位素,例如15O、13N、11C和18F用于正电子发射体层摄影术(PET)研究,以检查底物受体占用率。同位素标记的本发明的化合物一般可以遵循类似于在方案和/或下文实施例中所公开的方法,通过用同位素标记的试剂替代非同位素标记的试剂来制备。本发明的化合物的所有同位素变体,无论是否具有放射性,都包括在本发明的范围内。
具体实施方法
下面结合具体实施例对本发明作进一步的阐述,但这些实施例并不限制本发明的范围。
一、制备实施例
所有实施例中,1H NMR由Bruker Avance III-300或Avance III-400型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由MS质谱UPLC-MS(ESI)测定;其中UPLC型号是WatersHPLC H-CLASS,MS(ESI)的型号是Waters SQ Detector 2;无水四氢呋喃由二苯甲酮/金属钠回流干燥除氧制得,无水甲苯和无水二氯甲烷由氯化钙回流干燥制得;石油醚、乙酸乙酯、二氯甲烷等用于柱层析流动相的溶剂均购置于国药集团化学试剂有限公司;反应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司;化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。本发明中原料可以从商业途径获得,如主要试剂购买于国药集团化学试剂有限公司,或者通过本领域抑制的方法制备,或者根据本发明中所述方法制备。
1.中间体化合物的合成
参考上述合成方法1-合成方法7中的合成方法。
3-溴-2-溴甲基苯甲酸甲酯:
反应完毕,减压除去溶剂,所得残余物经硅胶柱层析得到3-溴-2-溴甲基苯甲酸甲酯5.3g,无色油状物,收率98%;1H NMR(400MHz,CDCl3)δ7.88(dd,J=7.8,1.3Hz,1H),7.76(dd,J=8.0,1.3Hz,1H),7.22(t,J=7.9Hz,1H),5.12(s,2H),3.95(s,3H).
3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6二酮:
22.88mmol),反应混合液于80℃反应18小时。反应完毕,减压除去溶剂,出品分散于水-乙酸乙酯-石油醚(v/v/v,2:1:1)的混合溶液中,过滤所得沉淀,减压干燥得3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6二酮(3.35g,60%).1H NMR(400MHz,DMSO)δ11.03(s,1H),7.87(dd,J=7.9,0.7Hz,1H),7.79–7.75(m,1H),7.51(t,J=7.7Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.6Hz,1H),4.26(d,J=17.6Hz,1H),2.92(ddd,J=17.5,13.7,5.4Hz,1H),2.64–2.55(m,1H),2.55–2.39(m,1H),2.02(dtd,J=12.5,5.2,2.0Hz,1H).
3-(4-(5-羟基戊基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
(118mg,0.62mmol)溶解于10mL干燥DMF.反应液用高纯氮气置换3次,再加入10mL三乙胺,反应液再用高纯氮气置换一次.反应液升温至60℃反应过夜.反应完毕,减压除去溶剂,粗品经硅胶柱层析得到产物3-(4-(5-羟基戊基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮1.03g,白色固体,收率100%;1H NMR(400MHz,DMSO)δ11.02(s,1H),7.71(d,J=7.6Hz,0.8Hz,1H),7.64(dd,J=7.6,0.8Hz,1H),7.53(t,J=7.6Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.57(t,J=5.1Hz,1H),4.46(d,J=17.8Hz,1H),4.31(d,J=17.8Hz,1H),3.54(dd,J=11.4,6.1Hz,2H),2.99–2.86(m,1H),2.65–2.57(m,1H),2.56–2.39(m,3H),2.06–1.97(m,1H),1.77–1.67(m,2H).
3-(4-(6-羟己基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
到3-(4-(6-羟己基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮665mg,氮黄色固体,收率84%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.70(d,J=7.0Hz,1H),7.63(d,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.50–4.40(m,2H),4.30(d,J=17.7Hz,1H),3.44(q,J=5.9Hz,2H),2.91(ddd,J=17.5,13.7,5.4Hz,1H),2.64–2.55(m,1H),2.50–2.40(m,3H),2.01(ddd,J=10.2,5.0,3.2Hz,1H),1.58(ddd,J=11.3,6.4,2.6Hz,4H).
3-(4-(5-羟戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
(200mg),在氢气存在条件(260psi)下加热至40℃反应7小时.反应完全后,过滤除去催化剂.滤液减压浓缩并经硅胶柱层析得到3-(4-(5-羟戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮1.02g,白色固体,收率100%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.58–7.53(m,1H),7.48–7.43(m,2H),5.13(dd,J=13.2,5.2Hz,1H),4.46(d,J=17.1Hz,1H),4.35(t,J=5.1Hz,1H),4.30(d,J=17.1Hz,1H),3.38(dd,J=11.6,6.4Hz,2H),2.92(ddd,J=17.4,13.8,5.6Hz,1H),2.68–2.56(m,3H),2.48–2.37(m,1H),2.06–1.96(m,1H),1.66–1.54(m,2H),1.45(td,J=13.4,6.5Hz,2H),1.33(dt,J=9.4,7.5Hz,2H).
3-(4-(5-溴戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
mg,3.036mmol)溶解于40mL干燥四氢呋喃中,向反应液中加入四溴化碳(1.506g,4.54mmol),所得反应混合物于室温下反应1小时。T反应完毕后,减压除去溶剂,所得残余物经硅胶柱层析得到3-(4-(5-溴戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮588mg,白色固体,收率99%;1H NMR(500MHz,DMSO)δ11.01(s,1H),7.62(dd,J=11.8,7.3Hz,1H),7.56(dd,J=6.5,4.0Hz,1H),7.48–7.43(m,1H),5.14(dd,J=13.4,5.2Hz,1H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),3.54(t,J=6.6Hz,2H),2.98–2.87(m,1H),2.63(dd,J=22.8,14.8Hz,3H),2.43(ddd,J=26.4,13.4,4.3Hz,1H),2.06–1.97(m,1H),1.94–1.76(m,2H),1.63(dt,J=15.3,7.6Hz,2H),1.44(dt,J=14.8,7.5Hz,2H).
3-(4-(4-羟丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
兰尼镍。所得混合体系在260psi氢气压力下反应30小时。反应完毕,将反应液用硅藻土过滤,滤液减压浓缩,所得残余物经硅胶柱层析得到3-(4-(4-羟基丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮0.75g,收率100%;1H NMR(400MHz,DMSO)δ11.01(s,1H),7.58–7.54(m,1H),7.46(d,J=4.3Hz,2H),5.14(dd,J=13.3,5.0Hz,1H),4.46(d,J=17.2Hz,1H),4.41(t,J=5.2Hz,1H),4.30(d,J=17.1Hz,1H),3.42(dd,J=11.7,6.3Hz,2H),3.14-3.04(m,1H),2.98-2.87(m,1H),2.69–2.60(m,3H),2.05-1.96(m,1H),1.68–1.57(m,2H),1.50–1.42(m,2H),1.17(t,J=7.4Hz,1H).ESI-MS[M+H]+m/z=317.24。
3-(4-(3-羟丙基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.39(t,J=5.2Hz,1H),4.30(d,J=17.2Hz,1H),3.42(dd,J=11.6,6.3Hz,2H),2.92(ddd,J=17.5,13.7,4.7Hz,1H),2.69–2.56(m,3H),2.48–2.36(m,1H),2.01(ddd,J=9.8,4.9,2.9Hz,1H),1.70–1.56(m,2H),1.51–1.40(m,2H).
3-(4-(2-溴乙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
乙烷(643mg,3.42mmol,5.0eq)和无水碳酸钾(96mg,0.68mmol,1.0eq),50℃下剧烈搅拌24小时。反应完成后,旋走乙腈,柱层析纯化得到100mg,白色固体,产率为37%;1H NMR(400MHz,DMSO)δ7.61(s,1H),7.47(t,J=7.8Hz,1H),7.32(d,J=7.3Hz,1H),7.25(d,J=8.0Hz,1H),7.20(d,J=9.8Hz,1H),4.74(dd,J=10.4,5.0Hz,1H),4.55(d,J=17.6Hz,1H),4.51–4.43(m,2H),4.39(d,J=17.6Hz,1H),3.91–3.81(m,2H),3.53(d,J=14.0Hz,3H),2.33–2.14(m,3H),2.12-2.03(m,1H).
步骤2:将5-胺基-4-(4-(2-溴乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg,0.25mmol,1.0eq)溶于20mL无水四氢呋喃中,-78℃条件下搅拌15分钟。加入叔丁醇钾(31mg,0.28mmol,1.1eq),继续反应90分钟。反应完成后,-78℃条件下加入1mL 1N盐酸淬灭反应。反应体系逐渐升值室温,旋走溶剂,柱层析纯化得到90mg,白色固体,收率为98%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.35(d,J=7.4Hz,1H),7.27(d,J=8.1Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.47(dt,J=8.1,4.9Hz,2H),4.43–4.34(m,1H),4.26(d,J=17.4Hz,1H),3.83(t,J=5.3Hz,2H),2.90(ddd,J=13.6,12.4,5.4Hz,1H),2.58(d,J=18.1Hz,1H),2.49–2.40(m,1H),1.99(s,1H).
3-(4-(3-溴丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
吲哚啉-2-)哌啶-2,6-二酮634mg,白色固体,收率为95%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.49(t,J=7.8Hz,1H),7.32(d,J=7.4Hz,1H),7.27(d,J=8.0Hz,1H),5.12(dd,J=13.3,5.0Hz,1H),4.41(d,J=17.5Hz,1H),4.23(dd,J=14.3,8.4Hz,3H),3.71(t,J=6.6Hz,2H),2.96–2.86(m,1H),2.58(d,J=17.2Hz,1H),2.47–2.38(m,2H),2.32–2.22(m,2H),2.03–1.94(m,1H).
3-(4-(5-溴戊氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
代异吲哚啉-2-)哌啶-2,6-二酮322mg,白色固体,收率为97%;1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.48(dd,J=7.6,0.9Hz,1H),7.43(t,J=7.7Hz,1H),7.04–6.99(m,1H),5.23(dd,J=13.3,5.1Hz,1H),4.43(d,J=16.5Hz,1H),4.30(d,J=16.5Hz,1H),4.08(t,J=6.2Hz,2H),3.45(t,J=6.7Hz,2H),2.86(ddd,J=23.2,15.9,4.1Hz,2H),2.44–2.32(m,1H),2.22(dtd,J=10.3,5.2,2.6Hz,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.71–1.60(m,2H).
3-(4-(6-溴己氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮:
氧代异吲哚啉-2-)哌啶-2,6-二酮474mg,白色固体,收率为95%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.23(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.11(t,J=6.3Hz,2H),3.54(t,J=6.7Hz,2H),2.99–2.84(m,1H),2.58(d,J=18.0Hz,1H),2.45(dd,J=13.1,4.4Hz,1H),1.99(t,J=5.1Hz,1H),1.89–1.68(m,4H),1.46(dd,J=7.1,3.5Hz,4H).
(S)-2-((叔丁氧羰基)氨基)-4-戊炔酸苄酯:
冷却至0℃,向反应液中逐滴加入氯甲酸苄酯(2.08mL,14.77mmol)。所得反应液在0℃反应4小时,反应完毕,反应液依次用1N硫酸氢钾水溶液洗涤,有机相用无水硫酸钠干燥,反应液过滤,减压浓缩,所得残余物经硅胶柱层析得到目标产物3.321g,无色油状物,产率78%。
(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-4-戊炔酸苄酯:
向100mL反应瓶中加入(S)-2-((叔丁氧羰基)氨基)-4-戊炔酸苄酯(3.18g,10.47mmol),3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(2.26g,6.98mmol),双三苯基膦二氯化钯(491mg,0.70mmol)和碘化亚酮(267mg,1.40mmol),将反应体系用氮气置换,在氮气保护下加入干燥的DMF(20mL)和干燥的三乙胺(20mL),将反应液升温至60℃反应过夜。反应完毕,减压除去溶剂,残余物经硅胶柱层析得到(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-4-戊炔酸苄酯3.64g,灰白色固体,收率95%。
(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酸:
10%Pd/C(50mg),将反应体系在氢气(8bar)条件下反应过夜,反应完毕,过滤除去催化剂,滤液减压浓缩得到化合物(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酸107mg,收率100%;1H NMR(400MHz,DMSO)δ12.43(s,1H),10.99(s,1H),7.57(dd,J=6.5,2.0Hz,1H),7.49–7.41(m,2H),7.09(d,J=7.8Hz,1H),5.75(s,1H),5.14(ddd,J=13.3,4.9,2.0Hz,1H),4.46(d,J=17.1Hz,1H),4.30(dd,J=17.2,1.3Hz,1H),3.97–3.86(m,1H),3.00–2.87(m,1H),2.71–2.57(m,3H),2.41(ddd,J=26.4,13.3,4.2Hz,1H),2.09–1.91(m,1H),1.78–1.56(m,4H),1.37(s,9H).
2.实施例化合物的合成:
参考上述合成方法1-合成方法7中的合成方法。
实施例1:3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(1)
膦(159mg,0.605mmol,2eq.)溶解于20mL干燥THF中,氮气保护下加入偶氮二甲酸二异丙酯(120μL,0.605mmol,2eq.)。所得混合液继续于室温下搅拌反应2小时,反应完毕,减压除去溶剂,所得残余物先经硅胶柱层析分离,再经HPLC纯化得到3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮52mg,白色固体,收率38%;1H NMR(400MHz,DMSO)δ11.00(s,1H),8.71(d,J=5.2Hz,1H),8.12–8.07(m,1H),7.93(dd,J=8.4,0.5Hz,1H),7.73(ddd,J=8.4,6.9,1.5Hz,1H),7.57(dd,J=7.3,1.3Hz,1H),7.55–7.51(m,1H),7.48(dd,J=7.5,1.4Hz,1H),7.47–7.42(m,1H),7.01(d,J=5.3Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),4.26(t,J=6.3Hz,2H),2.91(ddd,J=17.6,13.8,5.3Hz,1H),2.74–2.67(m,2H),2.63–2.55(m,1H),2.39(ddd,J=17.4,13.1,4.8Hz,1H),2.01–1.88(m,3H),1.79–1.68(m,2H),1.63–1.52(m,2H).
实施例2:3-(1-氧代-4-(3-(喹啉-4-氧)丙基)异吲哚啉-2-)哌啶-2,6-二酮(2)
mg,0.32mmol)加入到100mL圆底烧瓶中,加入20mL四氢呋喃,剧烈搅拌。之后加入偶氮二甲酸二异丙酯(65mg,0.32mmol)。反应完成后,旋走溶剂,HPLC纯化得到产物17.6mg,收率26%;1H NMR(400MHz,DMSO)δ10.96(s,1H),9.10(d,J=6.4Hz,1H),8.26(d,J=7.7Hz,1H),8.13(d,J=8.4Hz,1H),8.08–8.01(m,1H),7.79(t,J=11.3Hz,1H),7.56(t,J=6.4Hz,2H),7.46(dd,J=10.5,4.4Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.52(t,J=5.9Hz,2H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),3.00–2.84(m,3H),2.6(m,1H),2.36-2.14(m,3H),1.97–1.86(m,1H).
实施例3:3-(1-氧代-4-(6-(喹啉-4-氧)己基)异吲哚啉-2-)哌啶-2,6-二酮(3)
3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮,47.2mg,收率50%;1HNMR(400MHz,DMSO)δ11.00(s,1H),8.72(d,J=5.3Hz,1H),8.14(dd,J=8.3,0.9Hz,1H),7.97–7.91(m,1H),7.74(ddd,J=8.4,6.9,1.5Hz,1H),7.56(tdd,J=4.7,3.9,1.2Hz,2H),7.48–7.40(m,2H),7.02(d,J=5.3Hz,1H),5.13(dd,J=13.2,5.2Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.1Hz,1H),4.25(t,J=6.3Hz,2H),2.92(ddd,J=17.5,13.5,5.5Hz,1H),2.70–2.63(m,2H),2.59(dd,J=16.3,2.0Hz,1H),2.41(ddd,J=26.5,13.4,4.6Hz,1H),2.05–1.95(m,1H),1.92–1.83(m,2H),1.71–1.62(m,2H),1.61–1.51(m,2H),1.44(dt,J=15.9,8.0Hz,2H).
实施例4:3-(1-氧代-4-(3-(喹啉-4-氧)丙氧基)异吲哚啉-2-)哌啶-2,6-二酮(4)
拌30分钟。后加入叔丁基二甲基氯硅烷(9.0g,5.97mmol),继续反应1h。反应完成后,加入饱和氯化铵淬灭,乙酸乙酯萃取、饱和氯化钠洗涤、干燥、浓缩、柱层析得到无色油状物(10.06g,90%)1H NMR(400MHz,CDCl3)δ3.87-3.76(m,4H),2.65(t,J=5.2Hz,1H),1.83–1.73(m,2H),0.89(s,9H),0.07(s,6H).
步骤2:将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg,0.34mmol,1.0eq)加入到100ml圆底烧瓶中,加入3-叔丁基二甲基硅氧基-1-丙醇(174mg,0.85mmol,2.5eq),三苯基膦(178mg,0.68mmol,2eq)。反应体系用氮气置换,加入20mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(134μL,0.68mmol,2eq)。室温反应1h。反应完成后旋走溶剂,柱层析得到目标产物。ESI-MS[M+H]+m/z=465.60。
步骤3:将上步所得产物加入到50mL圆底烧瓶中,加入20mL四氢呋喃,加入四丁基氟化铵(0.64ml,0.64mmol)室温反应过夜。反应完成后,减压除去溶剂,柱层析纯化得到产物211mg白的固体,收率78%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.49(t,J=7.8Hz,1H),7.31(d,J=7.2Hz,1H),7.25(d,J=8.0Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.59(t,J=6.0Hz,1H),4.38(d,J=17.4Hz,1H),4.22(d,J=17.3Hz,1H),4.19(t,J=6.2Hz,2H),3.58(dd,J=11.4,6.1Hz,2H),2.97–2.85(m,1H),2.63-2.54(m,1H),2.48–2.38(m,1H),2.05–1.93(m,1H),1.89(p,J=6.1Hz,2H)。ESI-MS[M+H]+m/z=319.26
步骤4:将化合物3-(4-(3-羟基丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(50mg,0.16mmol,1.0eq)加入到100mL圆底烧瓶中,加入4-羟基喹啉(68mg,0.47mmol,3eq),三苯基膦(82mg,0.31mmol,2eq)。抽换N2,加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(62ul,0.31mmol,2eq)。室温反应1h。反应完成后减压除去溶剂,经HPLC纯化得到产物27.6mg,收率39%;1H NMR(400MHz,DMSO)δ11.01(s,1H),9.13(d,J=6.2Hz,1H),8.37(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,1H),8.05(t,J=7.7Hz,1H),7.81(t,J=7.7Hz,1H),7.54(d,J=6.3Hz,1H),7.48(t,J=7.8Hz,1H),7.36–7.28(m,2H),5.10(dd,J=13.3,5.0Hz,1H),4.71(t,J=5.8Hz,2H),4.41(t,J=5.8Hz,2H),4.32(d,J=17.4Hz,1H),4.17(d,J=17.4Hz,1H),2.99–2.84(m,1H),2.62-2.53(m,1H),2.48–2.39(m,2H),2.29(qd,J=13.4,4.4Hz,1H),1.99–1.89(m,1H).ESI-MS[M+H]+m/z=446.33。
实施例5:3-(4-(5-(异吲哚啉-5-氧)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(5)
1H NMR(400MHz,DMSO)δ11.00(s,1H),9.30(s,1H),8.49(d,J=5.9Hz,1H),7.92(d,J=5.9Hz,1H),7.67(d,J=8.2Hz,1H),7.63–7.54(m,2H),7.46(dt,J=14.5,7.2Hz,2H),7.24(d,J=7.6Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),4.20(t,J=6.3Hz,2H),2.92(ddd,J=17.5,13.8,5.5Hz,1H),2.71(t,J=7.6Hz,2H),2.64–2.55(m,1H),2.40(qd,J=13.5,4.5Hz,1H),1.98(ddd,J=10.5,5.0,2.4Hz,1H),1.91(dd,J=14.5,7.0Hz,2H),1.78–1.68(m,2H),1.63–1.53(m,2H).
实施例6:3-(1-氧代-4-(4-(喹啉-4-氧)丁氧基)异吲哚啉-2-)哌啶-2,6-二酮(6)
搅拌30min。后加入叔丁基二甲基氯硅烷(1.52g,10.09mmol,1eq),继续反应1h。反应完成后,加入饱和氯化铵淬灭,乙酸乙酯萃取、饱和氯化钠洗涤、干燥、浓缩、柱层析得到产物1.75g,无色油状物,收率78%;1H NMR(400MHz,CDCl3)δ9.71-3.60(m,4H),2.59(t,J=5.5Hz,1H),1.70–1.58(m,4H),0.90(s,9H),0.07(s,6H).
步骤2:将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg,0.34mmol,1.0eq)加入到100mL圆底烧瓶中,加入4-叔丁基二甲基硅氧基-1-丁醇(174mg,0.85mmol,2.5eq),三苯基膦(178mg,0.68mmol,2eq)。反应tixi用氮气保护,加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(134ul,0.68mmol,2eq)。室温反应1小时。反应完成后旋走溶剂,柱层析纯化得到产物和三苯氧磷的混合物;ESI-MS[M+H]+m/z=479.42。
步骤3:将上步所得混合物加入到50ml圆底烧瓶中,加入20ml四氢呋喃,加入四丁基氟化铵(0.34ml,0.34mmol,1eq)室温反应过夜。反应完成后,旋走溶剂,柱层析纯化得到产物96mg,白的固体,收率85%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.23(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.47(t,J=5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),4.12(t,J=6.4Hz,2H),3.45(dd,J=11.6,6.3Hz,2H),2.96–2.86(m,1H),2.62-2.54(m,1H),2.48–2.39(m,1H),2.03–1.94(m,1H),1.82–1.73(m,2H),1.63-1.53(m,2H)。ESI-MS[M+H]+m/z=333.27。
步骤4:将化合物-(4-(4-羟基丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(50mg,0.15mmol,1.0eq)加入到100mL圆底烧瓶中,加入4-羟基喹啉(65mg,0.45mmol,3eq),三苯基膦(79mg,0.30mmol,2eq)。抽换N2,加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(59ul,0.30mmol,2eq),室温反应1小时。反应完毕减压除去溶剂,残余物经HPLC纯化得到产物9.9mg,收率14%;1H NMR(400MHz,DMSO)δ10.97(s,1H),9.16(d,J=6.4Hz,1H),8.32(d,J=8.3Hz,1H),8.15–8.06(m,2H),7.82(t,J=7.6Hz,1H),7.55(d,J=6.6Hz,1H),7.46(t,J=7.8Hz,1H),7.27(dd,J=14.2,7.8Hz,2H),5.10(dd,J=13.5,5.1Hz,1H),4.63(t,J=5.9Hz,2H),4.33(d,J=17.4Hz,1H),4.27(t,J=5.9Hz,2H),4.19(d,J=17.4Hz,1H),2.97–2.85(m,1H),2.63-2.54(m,1H),2.36(dt,J=13.4,8.7Hz,1H),2.18–2.09(m,2H),2.09–1.92(m,3H)。ESI-MS[M+H]+m/z=460.34。
实施例7:3-(4-(5-((6-甲基-2-(三氟甲基)喹啉-4-)氧)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(7)
率87%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.98(d,J=8.6Hz,1H),7.94(s,1H),7.72(dd,J=8.7,2.0Hz,1H),7.57(dd,J=7.2,1.2Hz,1H),7.46(dt,J=14.7,6.8Hz,2H),7.35(s,1H),5.12(dd,J=13.1,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.38(t,J=6.4Hz,2H),4.32(d,J=17.2Hz,1H),2.91(ddd,J=17.8,13.6,5.2Hz,1H),2.75–2.68(m,2H),2.62–2.55(m,1H),2.52(s,3H),2.39(ddd,J=17.4,12.9,4.0Hz,1H),1.96(ddd,J=18.1,8.7,4.9Hz,3H),1.81–1.71(m,2H),1.64–1.54(m,2H).
实施例8:3-(4-(4-((2-环丙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(8)
9.72mmol,15eq),三苯基膦(2.56g,9.72mmol,15eq),加入四氢呋喃60mL剧烈搅拌。后加入偶氮二甲酸二异丙酯(1.91ml,9.72mmol,15eq)。室温反应1小时。反应完成后,减压除去溶剂,柱层析纯化除去三苯氧磷和1,4-丁二醇。所得混合物无需进一步纯化直接投下一步。ESI-MS[M+H]+m/z=258.57。
步骤2:在氮气保护下,在100mL圆底烧瓶中加入上步所得混合物,5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg,0.7mmol,1eq),三苯基膦(89mg,0.34mmol,2eq),加入四氢呋喃20mL剧烈搅拌。后加入偶氮二甲酸二异丙酯(67ul,0.34mmol,2eq)。室温反应小时。反应完成后,旋走溶剂,柱层析纯化得到产物77mg,淡黄色油状物,收率85%;ESI-MS[M+H]+m/z=532.31。
步骤3:5-胺基-4-(4-(4-((2-环丙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(40mg,0.075mmol,1eq)溶于10mL干燥的四氢呋喃,冰浴条件下加入叔丁醇钾(8.5mg,0.075mmol,1eq),10分钟后开始检测反应。反应完成后,加入5ul甲酸淬灭反应,旋走溶剂,HPLC纯化得到产物21.5mg,白色固体,收率57%。1H NMR(400MHz,DMSO)δ10.97(s,1H),8.20(d,J=8.1Hz,1H),8.08–7.97(m,2H),7.72(t,J=6.9Hz,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.25(d,J=8.2Hz,1H),6.94(s,1H),5.10(dd,J=13.3,5.1Hz,1H),4.57(t,J=6.0Hz,2H),4.33(d,J=17.4Hz,2H),4.26(t,J=6.0Hz,2H),4.17(s,1H),2.99–2.84(m,1H),2.63-2.53(m,1H),2.48-2.42(m,1H),2.41–2.28(m,1H),2.15-2.07(m,2H),2.05–1.94(m,3H),1.48–1.40(m,4H).ESI-MS[M+H]+m/z=500.47。
实施例9:3-(1-氧代-4-(5-(噻吩并[3,2-b]吡啶-7-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(9)
1H NMR(400MHz,DMSO)δ11.00(s,1H),8.52(d,J=5.4Hz,1H),8.04(d,J=5.4Hz,1H),7.56(dd,J=6.9,1.7Hz,1H),7.51(d,J=5.4Hz,1H),7.49–7.40(m,2H),7.00(d,J=5.4Hz,1H),5.13(dd,J=13.4,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.30(dd,J=15.0,8.5Hz,3H),2.92(ddd,J=17.0,13.4,5.3Hz,1H),2.72–2.65(m,2H),2.63–2.56(m,1H),2.40(ddd,J=26.4,13.5,4.7Hz,1H),1.98(ddd,J=8.7,7.3,4.8Hz,1H),1.92–1.81(m,2H),1.71(dt,J=15.5,7.9Hz,2H),1.58–1.46(m,2H).
实施例10:3-(4-(4-((2-乙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(10)
滴加入甲基甲醚(1.69ml,1.79mmol,1eq),室温反应5h。反应完成后,加入饱和氯化铵淬灭,二氯甲烷萃取、干燥、浓缩、柱层析得到1.10g(37%)无色液体。1H NMR(400MHz,CDCl3)δ4.63(s,1H),3.67(s,1H),3.57(t,J=5.9Hz,1H),3.36(s,1H),1.93(s,1H),1.70–1.64(m,2H).
步骤2:将2-乙基喹啉-1-酚(100mg,0.57mmol,1eq),4-甲氧基甲氧基-1-丁醇(1.16g,8.66mmol,15eq),三苯基膦(2.27g,8.66mmol,15eq)溶于40mL四氢呋喃,室温条件下加入偶氮二甲酸二异丙酯(1.75g,8.66mmol,15eq),室温反应2小时。反应完成后旋走溶剂,TLC纯化得到产物147mg,淡黄色油状物,产率90%;1H NMR(400MHz,CDCl3)δ8.16(d,J=8.3Hz,1H),7.96(d,J=8.2Hz,1H),7.65(t,J=6.9Hz,1H),7.45–7.40(m,1H),6.63(s,1H),4.66(s,2H),4.22(t,J=6.3Hz,2H),3.65(t,J=6.3Hz,2H),3.39(s,3H),2.94(q,J=7.6Hz,2H),2.05(d,J=27.7Hz,2H),1.92–1.86(m,2H),1.38(t,J=7.6Hz,3H).ESI-MS[M+H]+m/z=290.61。
步骤3:将化合物2-乙基-4-(4-(甲氧基甲氧基)丁氧基)喹啉(147mg,0.51mmol)转移到100ml圆底烧瓶中,加入10ml盐酸二氧六环和1ml甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后,旋走溶剂,加入少量氨甲醇,旋走溶剂,柱层析纯化得到75mg,白色固体,收率100%;ESI-MS[M+H]+m/z=246.65。
步骤4:将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg,0.17mmol,1eq),2-乙基-4-(4-羟基丁氧基)喹啉(100mg,0.34mmol,2eq),三苯基膦(90mg,0.34mmol,2eq)加入到50mL圆底烧瓶中,加入20mL四氢呋喃,加入偶氮二甲酸二异丙酯(67ul,0.34mmol,2eq)室温反应2h。反应完成后,旋走溶剂,TLC纯化得到产物72mg,白色固体,收率81%;1H NMR(400MHz,CDCl3)δ8.14(d,J=7.3Hz,1H),7.99(d,J=8.4Hz,1H),7.68(t,J=8.4Hz,1H),7.49–7.41(m,1H),7.06(dd,J=6.8,2.1Hz,1H),6.68(s,1H),6.29(s,1H),5.32(s,1H),4.92(dd,J=8.8,6.2Hz,1H),4.44(q,J=17.5Hz,1H),4.32(t,J=5.5Hz,1H),4.23(d,J=5.8Hz,1H),3.67(s,1H),2.98(q,J=7.6Hz,1H),2.50–2.39(m,1H),2.24–2.14(m,2H),1.42(t,J=7.6Hz,1H).ESI-MS[M+H]+m/z=520.35。
步骤5:5-胺基-4-(4-(4-((2-乙基喹啉-4-)氧)丁氧基)-1-氧代异喹啉-2-)-5-氧代戊酸甲酯(72mg,0.14mmol,1.0eq)溶于10mL干燥的四氢呋喃,冰浴条件下加入叔丁醇钾(16mg,0.14mmol,1eq),10分钟后开始检测反应。反应完成后,加入5ul甲酸淬灭反应,旋走溶剂,HPLC纯化得到产物54mg,白色固体,收率79%;1H NMR(400MHz,DMSO)δ10.98(s,1H),8.27(d,J=8.2Hz,1H),8.08(dt,J=8.5,7.6Hz,2H),7.82–7.75(m,1H),7.52(s,1H),7.47(t,J=7.8Hz,1H),7.28(dd,J=17.6,7.8Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.62(t,J=6.0Hz,2H),4.33(d,J=17.4Hz,1H),4.26(t,J=6.0Hz,2H),4.19(d,J=17.4Hz,1H),3.11(q,J=7.6Hz,2H),2.98–2.84(m,1H),2.62-2.53(m,1H),2.35(qd,J=13.3,4.4Hz,1H),2.19-2.09(m,2H),2.08-1.92(m,4H),1.40(t,J=7.6Hz,3H)。ESI-MS[M+H]+m/z=488.43。
实施例11:3-(1-氧代-4-(5-(喹啉-3-氧代)戊基)异吲哚啉-2-)哌啶-2,6-二酮(11)
NMR(400MHz,DMSO)δ11.00(s,1H),8.61(d,J=2.9Hz,1H),7.96–7.91(m,1H),7.89–7.84(m,1H),7.76(d,J=2.9Hz,1H),7.60–7.52(m,3H),7.51–7.43(m,2H),5.13(dd,J=13.3,5.2Hz,1H),4.48(d,J=17.2Hz,1H),4.33(d,J=17.1Hz,1H),4.15(t,J=6.5Hz,2H),2.92(ddd,J=17.6,13.9,5.5Hz,1H),2.73–2.65(m,2H),2.58(ddd,J=16.7,4.2,2.1Hz,1H),2.42(ddd,J=18.3,13.1,4.4Hz,1H),2.03–1.95(m,1H),1.91–1.81(m,2H),1.76–1.66(m,2H),1.53(dt,J=15.3,7.8Hz,2H).
实施例12:3-(1-氧代-4-((5-(喹啉-4-氧)戊基)氧)异吲哚啉-2-)哌啶-2,6-二酮(12)
滴加入溴甲基甲醚(0.75ml,9.6mmol,1eq),室温反应5h。反应完成后,加入饱和氯化铵淬灭,二氯甲烷萃取、干燥、浓缩、柱层析得到产物0.57g,无色液体,产率40%;1H NMR(400MHz,CDCl3)δ4.61(s,1H),3.64(t,J=6.5Hz,1H),3.53(t,J=6.5Hz,1H),3.35(s,1H),1.64–1.58(m,1H),1.54(s,1H),1.47–1.41(m,1H).
步骤2:将5-(甲氧基甲氧基)-1-戊醇(296mg,2.04mmol,3.0eq)加入到100ml圆底烧瓶中,加入4-羟基喹啉(110mg,0.68mmol,1eq),三苯基膦(357mg,1.36mmol,2eq)。抽换N2,加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(268ul,1.36mmol,2eq)。室温反应1h。反应完成后旋走溶剂,柱层析纯化得到产物147mg,无色油状物,收率79%;1HNMR(400MHz,CDCl3)δ8.73(d,J=5.2Hz,1H),8.21(dd,J=8.3,1.0Hz,1H),8.02(d,J=8.4Hz,1H),7.69(ddd,J=8.4,6.9,1.4Hz,1H),7.49(t,J=8.3Hz,1H),6.71(d,J=5.2Hz,1H),4.63(s,2H),4.20(t,J=6.3Hz,2H),3.58(t,J=6.2Hz,2H),3.37(s,3H),2.01–1.96(m,2H),1.76–1.63(m,4H).
步骤3:将化合物4-(5-(甲氧基甲氧基)戊氧基)喹啉(147mg,0.53mmol)转移到100ml圆底烧瓶中,加入10ml盐酸二氧六环和1ml甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后,旋走溶剂,加入少量氨甲醇,旋走溶剂,柱层析纯化得到124mg(100%)白色固体。ESI-MS[M+H]+m/z=276.57。
步骤4:将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg,0.17mmol,1eq),5-(喹啉-4-氧)-1-戊醇(100mg,0.34mmol,2eq),三苯基膦(90mg,0.34mmol,2eq)加入到50ml圆底烧瓶中,加入20ml四氢呋喃,加入偶氮二甲酸二异丙酯(67ul,0.34mmol,2eq)室温反应2h。反应完成后,旋走溶剂,TLC纯化得到产物65mg,白色固体,收率76%;1H NMR(400MHz,CDCl3)δ8.74(d,J=5.2Hz,1H),8.23–8.18(m,1H),8.02(d,J=8.4Hz,1H),7.69(t,J=8.4Hz,1H),7.49(dd,J=11.2,4.0Hz,1H),7.44–7.39(m,2H),7.01(dq,J=7.9,4.1Hz,1H),6.75(d,J=5.2Hz,1H),6.40(s,1H),5.43(s,1H),4.91(dd,J=8.8,6.2Hz,1H),4.41(q,J=17.6Hz,2H),4.25(t,J=6.3Hz,2H),4.11(t,J=10.9,2H),3.63(s,3H),2.42–1.81(m,10H).ESI-MS[M+H]+m/z=506.83。
步骤5:5-胺基-4-(5-(4-((喹啉-4-)氧)戊氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(85mg,0.17mmol,1.0eq)溶于10mL干燥的四氢呋喃,冰浴冷却条件下加入叔丁醇钾(17mg,0.17mmol,1eq),10分钟后开始检测反应。反应完成后,加入5ul甲酸淬灭反应,旋走溶剂,HPLC纯化得到产物29.6mg,白色固体,收率34%;1H NMR(400MHz,DMSO)δ10.98(s,1H),9.14(d,J=6.5Hz,1H),8.33(d,J=8.4Hz,1H),8.14(d,J=8.6Hz,1H),8.07(t,J=8.6Hz,1H),7.82(t,J=7.7Hz,1H),7.53(d,J=6.5Hz,1H),7.46(t,J=7.8Hz,1H),7.30(d,J=7.3Hz,1H),7.24(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.56(t,J=6.3Hz,2H),4.35(d,J=17.4Hz,1H),4.25–4.14(m,3H),3.00–2.84(m,1H),2.56(m,1H),2.38(qd,J=13.1,4.3Hz,1H),2.06–1.80(m,5H),1.78-1.67(m,2H).ESI-MS[M+H]+m/z=506.31。
实施例13:3-(1-氧代-4-(5-((2-(三氟甲基)喹啉-4-)氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(13)
47%;1H NMR(400MHz,DMSO)δ10.99(s,1H),8.19(dd,J=8.3,0.7Hz,1H),8.08(d,J=8.4Hz,1H),7.89(ddd,J=8.4,6.9,1.4Hz,1H),7.75–7.69(m,1H),7.57(dd,J=7.2,1.1Hz,1H),7.50–7.42(m,2H),7.40(s,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.4Hz,1H),4.40(t,J=6.3Hz,2H),4.32(d,J=17.2Hz,1H),2.92(ddd,J=17.4,13.9,5.9Hz,1H),2.76–2.67(m,2H),2.58(ddd,J=6.0,3.3,1.7Hz,1H),2.39(ddd,J=26.7,13.7,5.0Hz,1H),2.02–1.89(m,3H),1.81–1.70(m,2H),1.65–1.53(m,2H).
实施例14:3-(1-氧代-4-((6-(喹啉-4-氧)己基)氧)异吲哚啉-2-)哌啶-2,6-二酮(14)
逐滴加入溴甲基甲醚(1.33ml,16.92mmol,1eq),室温反应5h。反应完成后,加入饱和氯化铵淬灭,二氯甲烷萃取、干燥、浓缩、柱层析得到1.11g,无色液体,收率41%;1H NMR(400MHz,CDCl3)δ4.61(s,2H),3.63(t,J=6.6Hz,1H),3.51(t,J=6.6Hz,1H),3.35(s,1H),1.63-1.53(m,2H),1.51(s,1H),1.43-1.34(m,2H).
步骤2:将6-(甲氧基甲氧基)-1-己醇(180mg,1.24mmol,2.0eq)加入到100mL圆底烧瓶中,加入4-羟基喹啉(100mg,0.62mmol,1eq),三苯基膦(330mg,1.24mmol,2eq)。抽换N2,加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(207ul,1.24mmol,2eq)。室温反应1h。反应完成后旋走溶剂,柱层析纯化得到140mg,无色油状物,收率78%;1H NMR(400MHz,CDCl3)δ8.75(d,J=5.2Hz,1H),8.23(d,J=8.3Hz,1H),8.04(d,J=8.5Hz,1H),7.72(d,J=8.1Hz,1H),7.51(t,J=8.3Hz 1H),6.73(d,J=5.2Hz,1H),4.65(s,2H),4.21(t,J=6.3Hz,2H),3.57(t,J=8.1Hz 2H),3.39(s,3H),2.02–1.93(m,3H),1.71–1.49(m,6H).[M+H]+m/z=290.39。
步骤3:将化合物4-(6-(甲氧基甲氧基)己氧基)喹啉(140mg,0.48mmol)转移到100mL圆底烧瓶中,加入10mL盐酸二氧六环和1mL甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后,旋走溶剂,加入少量氨甲醇,旋走溶剂,柱层析纯化得到118mg,白色固体,收率100%;1H NMR(400MHz,CDCl3)δ8.72(d,J=5.2Hz,1H),8.21(dd,J=8.3,0.8Hz,1H),8.02(d,J=8.4Hz,1H),7.72–7.66(m,1H),7.53–7.47(m,1H),6.71(d,J=5.2Hz,1H),4.18(t,J=6.4Hz,2H),3.69(t,J=6.5Hz,2H),1.95(dd,J=14.5,6.7Hz,2H),1.62(qd,J=14.5,7.0Hz,4H),1.54–1.45(m,2H).[M+H]+m/z=246.72。
步骤4:将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg,0.17mmol,1eq),6-(喹啉-4-氧)-1-己醇(83mg,0.34mmol,2eq),三苯基膦(90mg,0.34mmol,2eq)加入到50ml圆底烧瓶中,加入20ml四氢呋喃,加入偶氮二甲酸二异丙酯(67ul,0.34mmol,2eq)室温反应2h。反应完成后,旋走溶剂,TLC纯化得到63mg,白色固体,收率71%;1H NMR(400MHz,CDCl3)δ8.73(d,J=5.2Hz,1H),8.20(d,J=8.3Hz,1H),8.01(d,J=8.4Hz,1H),7.68(t,J=7.0Hz,1H),7.47(t,J=7.6Hz,1H),7.39(d,J=1.1Hz,1H),6.98(p,J=4.0Hz,1H),6.73(d,J=5.2Hz,1H),6.54(s,1H),5.61(s,1H),4.92(dd,J=8.8,6.1Hz,1H),4.40(dd,J=38.8,17.6Hz,1H),4.22(t,J=6.3Hz,1H),4.11–4.02(m,1H),3.62(s,1H),2.46–2.27(m,1H),2.22-2.12(m,1H),2.05–1.96(m,1H),1.93–1.82(m,1H),1.70-1.66(m,2H).[M+H]+m/z=520.35。
步骤5:5-胺基-5-氧代-4-(1-氧代-4-((6-(喹啉-4-氧)己基)氧)异吲哚啉-2-)戊酸甲酯(63mg,0.19mmol,1.0eq)溶于10ml干燥的四氢呋喃,冰浴条件下加入叔丁醇钾(22mg,0.19mmol,1eq),10分钟后开始检测反应。反应完成后,加入5ul甲酸淬灭反应,旋走溶剂,HPLC纯化得到产物42mg,白色固体,收率45%;1H NMR(400MHz,DMSO)δ10.98(s,1H),9.15(d,J=6.5Hz,1H),8.34(d,J=8.4Hz,1H),8.15(d,J=8.6Hz,1H),8.09(t,J=8.4Hz,1H),7.83(t,J=8.4Hz,1H),7.54(d,J=6.6Hz,1H),7.45(t,J=7.8Hz,1H),7.28(d,J=7.3Hz,1H),7.22(d,J=8.1Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.55(t,J=6.3Hz,2H),4.34(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),4.14(t,J=6.3Hz,2H),2.97–2.84(m,1H),2.61-2.53(m,1H),2.41(qd,J=13.3,4.5Hz,1H),2.03–1.91(m,3H),1.86–1.72(m,2H),1.67-1.52(m,4H).ESI-MS[M+H]+m/z=488.76。
实施例15:3-(1-氧代-4-(4-(喹啉-4-氧)丁基)异吲哚啉-2-)哌啶-2,6-二酮(15)
mmol)加入到100mL圆底烧瓶中,在氮气保护下加入20mL干燥四氢呋喃,搅拌至反应体系成均相,再加入偶氮二甲酸二异丙酯(65mg,0.32mmol),继续于室温下搅拌反应30分钟。反应完成后,减压除去溶剂,残余物经HPLC分离得产物21.7mg,收率31%;1H NMR(400MHz,DMSO)δ11.04(s,1H),9.19(d,J=6.4Hz,1H),8.36(d,J=8.4Hz,1H),8.21–8.06(m,2H),7.88(t,J=7.4Hz,1H),7.60-7.44(m,,4H),5.15(dd,J=13.3,4.9Hz,1H),4.59(t,J=5.8Hz,2H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.00–2.87(m,1H),2.86–2.71(m,2H),2.54(s,2H),2.38–2.26(m,1H),2.05–1.82(m,5H).
实施例16:3-(4-(5-吗啉戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(16)
燥DMF中,室温搅拌下加入碘化钾(50mg,0.297mmol,2eq.),将所得反应液室温下搅拌反应过夜。反应完毕,所得反应液直接用HPLC分离得到3-(4-(5-吗啉戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮13.4mg,白色固体,收率17%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.59–7.53(m,1H),7.45(dd,J=6.2,2.5Hz,2H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),3.59–3.50(m,4H),2.98–2.86(m,1H),2.67–2.56(m,3H),2.42(ddd,J=12.6,9.7,6.9Hz,1H),2.31(s,4H),2.28–2.21(m,2H),2.06–1.96(m,1H),1.61(dt,J=15.3,7.5Hz,2H),1.51–1.39(m,2H),1.32(dt,J=14.9,7.3Hz,2H).
实施例17:3-(1-氧代-4-(5-(2-苯基吡咯啉-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(17)
加入2-苯基吡咯啉(28mg,0.193mmol)和三乙胺(10uL,0.386mmol),室温搅拌24小时,LC-MS跟踪监测反应完毕,产物直接通过HPLC分离得到白色固体30.5mg,收率52%;1H NMR(400MHz,DMSO)δ11.01(s,1H),7.55(d,J=7.3Hz,1H),7.44(t,J=7.4Hz,1H),7.38(d,J=7.4Hz,1H),7.35–7.26(m,4H),7.22(t,J=6.5Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.42(dd,J=17.2,3.9Hz,1H),4.26(d,J=17.1Hz,1H),3.31–3.19(m,2H),2.98–2.87(m,1H),2.69–2.31(m,15H),2.24–1.94(m,4H),1.79(ddd,J=19.8,16.0,8.8Hz,2H),1.61–1.36(m,5H),1.35–1.14(m,2H).
实施例18:3-(1-氧代-4-(5-(4-苯基哌嗪-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(18)
δ10.99(s,1H),7.60–7.54(m,1H),7.50–7.41(m,2H),7.20(dd,J=8.5,7.4Hz,2H),6.91(d,J=8.0Hz,2H),6.76(t,J=7.2Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.15–3.05(m,4H),2.92(ddd,J=17.6,13.7,5.4Hz,1H),2.69–2.57(m,3H),2.57–2.51(m,4H),2.43(dd,J=13.1,4.3Hz,1H),2.38–2.30(m,2H),2.06–1.95(m,1H),1.64(dt,J=15.2,7.6Hz,2H),1.52(dt,J=14.8,7.6Hz,2H),1.41–1.28(m,2H).
实施例19:3-(4-(5-(4-(2-甲氧基苯基)哌嗪-1-)戊基)-1-氧代吲哚啉-2-)哌啶-2,6-二酮(19)
(s,1H),7.56(dt,J=7.8,3.9Hz,1H),7.50–7.42(m,2H),6.97–6.90(m,2H),6.87(d,J=3.8Hz,2H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.76(s,3H),3.03–2.85(m,5H),2.70–2.52(m,5H),2.48–2.24(m,4H),2.05–1.96(m,1H),1.68–1.58(m,2H),1.56–1.46(m,2H),1.40–1.18(m,3H).
实施例20:3-(1-氧代-4-(5-(4-苯基哌啶-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(20)
11.00(s,1H),8.25(s,1H),7.61–7.54(m,1H),7.51–7.42(m,2H),7.33–7.16(m,5H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.09(d,J=11.3Hz,2H),2.99–2.86(m,1H),2.71–2.56(m,3H),2.53–2.36(m,4H),2.22(dd,J=11.5,9.7Hz,2H),2.01(ddd,J=10.2,5.0,3.0Hz,1H),1.83–1.48(m,8H),1.41–1.26(m,2H).
实施例21:3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(21)
δ11.02(s,1H),8.15(s,1H),7.61–7.55(m,1H),7.50–7.45(m,2H),7.34–7.27(m,2H),7.17–7.10(m,1H),5.15(dd,J=13.3,5.2Hz,1H),4.48(d,J=17.2Hz,1H),4.33(d,J=17.2Hz,1H),3.04–2.86(m,5H),2.68(t,J=7.6Hz,2H),2.65–2.53(m,5H),2.47–2.35(m,3H),2.07–1.98(m,1H),1.71–1.59(m,2H),1.52(dt,J=14.2,7.1Hz,2H).
实施例22:3-(4-(5-(4-(6-氟苯并[d]异噁唑-3-)哌啶-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(22)
DMSO)δ10.99(s,1H),8.17(s,1H),8.00(dd,J=8.7,5.3Hz,1H),7.69(dd,J=9.1,2.1Hz,1H),7.56(dt,J=7.7,3.9Hz,1H),7.51–7.43(m,2H),7.28(td,J=9.1,2.1Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.23–3.12(m,1H),3.05(d,J=11.6Hz,2H),2.93(ddd,J=17.7,13.8,5.3Hz,1H),2.71–2.55(m,3H),2.47–2.35(m,3H),2.23(t,J=11.0Hz,2H),2.09–1.97(m,3H),1.93–1.78(m,2H),1.70–1.59(m,2H),1.58–1.48(m,2H),1.41–1.30(m,2H).
实施例23:3-(1-氧代-4-(5-(4-(3-三氟甲基苯基)哌嗪-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(23)
DMSO)δ11.01(s,1H),7.57(dd,J=5.0,2.0Hz,1H),7.49–7.44(m,2H),7.41(t,J=8.1Hz,1H),7.21(dd,J=8.6,2.1Hz,1H),7.15(s,1H),7.06(d,J=7.4Hz,1H),5.14(dd,J=13.2,5.3Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.0Hz,1H),3.28(d,J=48.8Hz,7H),2.98–2.87(m,1H),2.63(dt,J=22.0,15.0Hz,4H),2.46–2.30(m,3H),2.05–1.95(m,1H),1.70–1.58(m,2H),1.52(dt,J=9.8,6.2Hz,2H),1.41–1.28(m,2H).
实施例24:3-(1-氧代-4-(5-(4-(喹啉-4-)哌嗪-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(24)
δ11.03(s,1H),8.69(d,J=4.9Hz,1H),8.16(s,2H),8.01(d,J=8.1Hz,1H),7.95(d,J=8.3Hz,1H),7.73–7.66(m,1H),7.60–7.52(m,2H),7.51–7.44(m,2H),6.98(d,J=5.0Hz,1H),5.15(dd,J=13.3,5.0Hz,1H),4.49(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.24–3.09(m,4H),3.00–2.88(m,1H),2.73–2.57(m,6H),2.48–2.38(m,3H),2.06–1.97(m,1H),1.66(dt,J=15.3,7.7Hz,2H),1.60–1.49(m,2H),1.44–1.32(m,2H).
实施例25:(S)-3-(4-(3-(4-(2,3-二氯苯基)哌嗪-1-)丙氧基)-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(25)
NMR(400MHz,DMSO)δ10.87(s,1H),7.46(t,J=7.8Hz,1H),7.34–7.11(m,5H),4.65(d,J=17.5Hz,1H),4.54(d,J=17.7Hz,1H),4.19(t,J=5.9Hz,2H),3.00(s,3H),2.67(ddd,J=51.9,30.3,22.3Hz,7H),2.00–1.83(m,3H),1.70(s,3H).
实施例26:3-(4-(5-(4-(2,3-二氯苯基)哌嗪-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(26)
DMSO)δ10.99(s,1H),8.16(s,1H),7.60–7.53(m,1H),7.49–7.42(m,2H),7.33–7.26(m,2H),7.16–7.10(m,1H),5.75(s,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.01–2.86(m,5H),2.69–2.63(m,2H),2.58(s,1H),2.53(d,J=6.6Hz,4H),2.47–2.38(m,1H),2.37–2.29(m,2H),2.06–1.96(m,1H),1.63(dt,J=15.3,7.8Hz,2H),1.57–1.43(m,2H),1.40–1.29(m,2H).
实施例27:(S)-4-(3-(4-(2,3-二氯苯基)哌嗪-1-)丙氧基)-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(27)
NMR(400MHz,DMSO)δ11.00(s,1H),7.78(t,J=7.9Hz,1H),7.50(d,J=8.5Hz,1H),7.37(d,J=7.2Hz,1H),7.33–7.27(m,2H),7.14(dd,J=5.8,3.6Hz,1H),4.24(t,J=6.0Hz,2H),2.98(s,4H),2.75–2.51(m,9H),2.08–1.91(m,3H),1.86(d,J=6.1Hz,3H).
实施例28:3-(1-氧代-4-(4-氧代-4-(4-苯基哌嗪-1-)丁氧基)异吲哚啉-2-)哌啶-2,6-二酮(28)
56%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.5Hz,1H),7.23(dd,J=15.1,7.6Hz,3H),6.93(d,J=8.0Hz,2H),6.80(t,J=7.2Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.16(t,J=6.3Hz,2H),3.60(d,J=4.6Hz,4H),3.10(dd,J=9.7,4.7Hz,4H),2.99–2.85(m,1H),2.56(dd,J=16.8,9.9Hz,3H),2.47–2.37(m,1H),2.06–1.93(m,3H).
实施例29:3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(29)
收率为26%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J=7.8Hz,1H),7.37–7.28(m,3H),7.25(d,J=8.1Hz,1H),7.13–7.07(m,1H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.4Hz,1H),4.25(d,J=17.4Hz,1H),4.16(t,J=6.3Hz,2H),3.62(d,J=3.6Hz,4H),2.91(td,J=14.2,7.7Hz,5H),2.64–2.53(m,3H),2.48–2.35(m,1H),2.06–1.94(m,3H).
实施例30:3-(1-氧代-4-((5-氧代-5-(4-苯基哌嗪-1-)戊氧基)异吲哚啉-2-)哌啶-2,6-二酮(30)
37%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J=7.8Hz,1H),7.31(d,J=7.4Hz,1H),7.27–7.16(m,3H),6.95(d,J=7.9Hz,2H),6.81(t,J=7.3Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.15(t,J=6.2Hz,2H),3.65–3.56(m,4H),3.19–3.04(m,4H),2.98–2.85(m,1H),2.57(d,J=18.5Hz,1H),2.50–2.37(m,4H),2.04–1.93(m,1H),1.74(ddd,J=21.7,14.2,6.9Hz,4H).
实施例31:3-(4-((5-(4-(2,3-二氯苯基)哌嗪-1-)-5-氧代戊基)氧)-1-氧代戊基-2-)哌啶-2,6-二酮(31)
收率为25%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J=7.8Hz,1H),7.37–7.27(m,3H),7.25(d,J=8.1Hz,1H),7.12(dd,J=6.3,3.3Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.23(d,J=17.3Hz,1H),4.15(t,J=6.2Hz,2H),3.60(d,J=4.6Hz,4H),3.00–2.81(m,5H),2.56(d,J=18.6Hz,1H),2.49–2.36(m,4H),2.02–1.92(m,1H),1.74(ddd,J=21.8,14.3,7.0Hz,4H).
实施例32:4-(2,3-二氯苯基)-N-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌嗪-1-甲酰胺(32)
温搅拌下加入三乙胺(61μL,0.44mmol)和羰基二咪唑(36mg,0.22mmol),反应液于40℃下搅拌反应0.5小时,待完全生成活性中间体后向反应液中加入4-(2,3-二氯苯基)哌嗪盐酸盐(59mg,0.22mmol),所得反应液继续于40℃下搅拌反应2小时,反应完毕,反应液经HPLC分离得到目标产物39.6mg,收率48%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J=7.8Hz,1H),7.35–7.26(m,3H),7.16–7.09(m,1H),6.81(t,J=5.3Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.25(d,J=17.3Hz,1H),4.17(t,J=5.9Hz,2H),3.58–3.37(m,6H),3.01–2.80(m,5H),2.63–2.55(m,1H),2.41(ddd,J=26.1,13.1,4.4Hz,1H),2.04–1.94(m,1H).
实施例33:4-(2,3-二氯苯基)-N-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌嗪-1-甲酰胺(33)
制备方法同4-(2,3-二氯苯基)-N-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌嗪-1-甲酰胺,白色固体化合物,44.6mg,收率56%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J=7.8Hz,1H),7.31(t,J=5.8Hz,3H),7.24(d,J=8.1Hz,1H),7.16–7.12(m,1H),6.60(t,J=5.4Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.39(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.13(t,J=6.3Hz,2H),3.46–3.39(m,4H),3.12(dd,J=12.7,6.8Hz,2H),2.97–2.85(m,5H),2.58(d,J=18.6Hz,1H),2.50-2.40(m,1H),2.03–1.95(m,1H),1.79-1.72(m,2H),1.64-1.54(m,2H).
实施例34:4-(2,3-二氯苯基)-N-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-1-甲酰胺(34)
率29%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J=8.0Hz,1H),7.34–7.29(m,3H),7.24(d,J=8.1Hz,1H),7.15–7.11(m,1H),6.68(t,J=5.4Hz,1H),5.11(dd,J=13.0,5.0Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.5Hz,1H),4.15(t,J=6.0Hz,2H),3.44(t,4H),3.26-3.19(m,2H),2.90(t,4H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.04–1.86(m,3H).
实施例35:3-(4-(6-(4-(2,3-二氯苯基)哌嗪-1-)己基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(35)
DMSO)δ10.99(s,1H),7.56(dd,J=8.2,4.5Hz,1H),7.46(d,J=3.5Hz,2H),7.30(dd,J=9.1,5.3Hz,2H),7.13(dd,J=6.3,3.1Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.31(d,J=17.2Hz,1H),3.32(s,4H),3.0-2.88(m,5H),2.68-2.56(m,3H),2.47–2.37(m,1H),2.32(s,2H),2.04–1.96(m,1H),1.66–1.56(m,2H),1.50–1.40(m,2H),1.38-1.27(m,4H).
实施例36:4-(4-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌嗪-1-)苯甲腈(36)
DMSO)δ10.99(s,1H),7.60–7.53(m,3H),7.49–7.44(m,2H),7.00(d,J=9.0Hz,2H),5.13(dd,J=13.3,5.2Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.32–3.28(m,4H),2.97–2.86(m,1H),2.67(t,J=7.6Hz,2H),2.58(d,J=16.3Hz,1H),2.47–2.43(m,4H),2.42–2.32(m,3H),2.05–1.96(m,1H),1.69–1.60(m,2H),1.54-1.46(m,2H).
实施例37:3-(4-(4-(4-(3-氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(37)
DMSO)δ10.99(s,1H),7.57(dt,J=7.7,3.9Hz,1H),7.49–7.43(m,2H),7.19(t,J=8.1Hz,1H),6.94–6.84(m,2H),6.77(dd,J=7.8,1.4Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.20–3.10(m,4H),2.98–2.86(m,1H),2.67(t,J=7.5Hz,2H),2.59(d,J=17.0Hz,1H),2.49-2.46(m,4H),2.45–2.35(m,3H),2.05–1.96(m,1H),1.69–1.59(m,2H),1.56–1.46(m,2H).
实施例38:2-(4-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌嗪-1-)苯甲腈(38)
DMSO)δ10.99(s,1H),7.69(dd,J=7.7,1.5Hz,1H),7.62–7.55(m,2H),7.49–7.45(m,2H),7.14(d,J=8.2Hz,1H),7.08(t,J=7.6Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.48(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),3.17–3.10(m,4H),2.97–2.87(m,1H),2.72–2.65(m,2H),2.60(d,J=17.2Hz,1H),2.54(t,4H),2.47–2.36(m,3H),2.06-1.98(m,1H),1.65(dt,J=15.6,6.3Hz,2H),1.52(dt,J=14.8,7.5Hz,2H).
实施例39:3-(4-(4-(4-(4-氟苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(39)
DMSO)δ10.99(s,1H),7.57(dd,J=5.2,3.4Hz,1H),7.49–7.44(m,2H),7.03(t,J=8.9Hz,2H),6.96–6.89(m,2H),5.13(dd,J=13.2,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.08–3.01(m,4H),2.97–2.86(m,1H),2.68(t,J=7.6Hz,2H),2.58(d,J=17.6Hz,1H),2.49-2.46(m,4H),2.44–2.34(m,3H),2.01(dt,J=10.4,5.0Hz,1H),1.69–1.59(m,2H),1.51(dt,J=14.2,7.1Hz,2H).
实施例40:3-(1-氧代-4-(4-(4-(3-甲基苯基)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(40)
MHz,DMSO)δ10.99(s,1H),7.57(dd,J=5.4,3.2Hz,1H),7.50–7.44(m,2H),7.07(t,J=7.8Hz,1H),6.76–6.66(m,2H),6.58(d,J=7.3Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.12–3.07(m,4H),2.97–2.86(m,1H),2.68(t,J=7.5Hz,2H),2.58(d,J=17.4Hz,1H),2.44–2.34(m,3H),2.23(s,3H),2.05–1.96(m,1H),1.69–1.59(m,2H),1.51(dt,J=14.7,7.5Hz,2H).
实施例41:3-(4-(4-(4-(4-氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(41)
MHz,DMSO)δ10.99(s,1H),7.57(dd,J=5.4,3.2Hz,1H),7.49–7.45(m,2H),7.22(d,J=9.0Hz,2H),6.93(d,J=9.0Hz,2H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.2Hz,1H),3.14(s,4H),2.98–2.86(m,1H),2.68(t,J=7.5Hz,2H),2.62-2.53(m,5H),2.48–2.35(m,3H),2.05–1.95(m,1H),1.65(dt,J=15.5,6.9Hz,2H),1.53(dt,J=15.2,7.6Hz,2H).
实施例42:3-(4-(4-(4-(4-硝基苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(42)
MHz,DMSO)δ10.99(s,1H),8.05(d,J=9.4Hz,2H),7.57(dd,J=5.4,3.2Hz,1H),7.50–7.45(m,2H),7.01(d,J=9.5Hz,2H),5.14(dd,J=13.3,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.45–3.41(m,4H),2.97–2.87(m,1H),2.68(t,J=7.6Hz,2H),2.59(d,J=17.2Hz,1H),2.49–2.44(m,4H),2.44–2.33(m,3H),2.06–1.96(m,1H),1.70–1.59(m,2H),1.51(dt,J=15.2,7.7Hz,2H).
实施例43:3-(4-(4-(4-(2,4-二氟苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(43)
MHz,DMSO)δ10.99(s,1H),7.56(dt,J=7.7,3.9Hz,1H),7.49–7.44(m,2H),7.22–7.14(m,1H),7.08–6.94(m,2H),5.14(dd,J=13.2,4.9Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.2Hz,1H),2.98–2.87(m,5H),2.67(t,J=7.6Hz,2H),2.59(d,J=17.6Hz,1H),2.46–2.30(m,7H),2.06–1.97(m,1H),1.68–1.57(m,2H),1.55–1.45(m,2H).
实施例44:3-(4-(4-(4-(3,4-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(44)
制备方法同3-(1-氧代-4-(5-(2-苯基吡咯啉-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮,白色固体45.8mg,收率66.5%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J=8.1,4.8Hz,1H),7.49–7.45(m,2H),7.38(d,J=9.0Hz,1H),7.10(d,J=2.8Hz,1H),6.91(dd,J=9.1,2.9Hz,1H),5.13(dd,J=13.3,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.16(m,4H),2.98–2.86(m,1H),2.67(t,J=7.6Hz,2H),2.59(d,J=16.4Hz,1H),2.48–2.31(m,7H),2.05–1.96(m,1H),1.64(dt,J=15.1,7.2Hz,2H),1.56–1.45(m,2H).
实施例45:3-(1-氧代-4-(4-(4-(4-三氟甲基苯基)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(45)
MHz,DMSO)δ10.99(s,1H),7.58(dd,J=5.5,3.0Hz,1H),7.55–7.46(m,4H),7.07(d,J=7.9Hz,2H),5.14(dd,J=13.4,5.3Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.20-3.10(m.4H),2.99–2.87(m,1H),2.72–2.65(m,2H),2.60(d,J=16.5Hz,1H),2.46–2.30(m,7H),2.05–1.96(m,1H),1.67-1.54(m,4H).
实施例46:3-(4-(4-(4-(4-甲氧基苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(46)
MHz,DMSO)δ11.00(s,1H),7.58(dd,J=5.5,3.2Hz,1H),7.51–7.46(m,2H),6.89(d,J=9.2Hz,2H),6.82(d,J=9.1Hz,2H),5.14(dd,J=13.2,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.33(d,J=17.2Hz,1H),3.69(s,3H),3.08-2.87(m,5H),2.73–2.66(m,2H),2.60(d,J=17.9Hz,1H),2.48–2.31(m,7H),2.06–1.97(m,1H),1.70–1.50(m,4H).
实施例47:2-(2,6-二氧代哌啶-3-)-4-(4-(喹啉-4-氧)丁氧基)异吲哚啉-1,3-二酮(47)
步骤1:将4-羟基喹啉(100mg,0.69mmol,1.0eq)置于50ml圆底烧瓶中,加入4-甲氧基甲氧基-1-丁醇(278mg,2.07mmol,2eq),三苯基膦(543mg,2.07mmol,2eq)。反应体系用氮气置换,加入15mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(408μL,2.07mmol,2eq)。室温反应1h。TLC监测反应完全后减压浓缩,柱层析得到目标产物173mg,收率96%。
步骤2:将4-(4-甲氧基甲氧基丁氧基)喹啉置于50mL圆底烧瓶中,加入10mL 4M盐酸二氧六环和1mL甲醇。室温反应1小时。LC-MS监测反应完全后,减压浓缩,加入饱和碳酸氢钠溶液,乙酸乙酯萃取,分液,有机层用饱和氯化钠洗涤,干燥,柱层析得到白色固体140mg,收率100%。
步骤3:将2-(2,6-二氧代哌啶-3-)-4-羟基异吲哚啉-1,3-二酮(35mg,0.128mmol)置于50ml圆底烧瓶中,加入4-(喹啉-4-氧)-1-丁醇(56mg,0.256mmol,2eq),三苯基膦(67mg,0.256mmol,2eq)。反应体系用氮气置换,加入5mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(51μL,0.256mmol,2eq)。室温反应1h。TLC监测反应完全后减压浓缩,经HPLC得到白色固体20.3mg,收率33.4%;1H NMR(400MHz,DMSO)δ11.11(s,1H),8.75(d,J=5.3Hz,1H),8.16–8.11(m,1H),7.94(d,J=8.4Hz,1H),7.83–7.72(m,2H),7.54(t,J=7.7Hz,2H),7.43(d,J=7.2Hz,1H),7.08(d,J=5.4Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.41(t,J=6.1Hz,2H),4.35(t,J=5.8Hz,2H),2.87(dd,J=8.5,5.3Hz,1H),2.70-2.55(m,1H),2.18–1.95(m,6H).
实施例48:3-(4-(4-(4-(2,6-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(48)
MHz,DMSO)δ10.99(s,1H),7.58(dd,J=5.8,2.7Hz,1H),7.50–7.46(m,2H),7.41(d,J=8.1Hz,2H),7.17–7.12(m,1H),5.14(dd,J=13.5,5.1Hz,1H),4.48(d,J=17.1Hz,1H),4.33(d,J=17.1Hz,1H),3.13(s,4H),2.99–2.87(m,2H),2.72–2.66(m,2H),2.61(d,J=19.2Hz,1H),2.48-2.45(m,4H),2.42-2.33(dd,J=14.2,6.7Hz,3H),2.07-1.99(m,1H),1.70-1.61(m,1H),1.56-1.47(m,1H).
实施例49:4-(4-氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(49)
DMSO)δ11.01(s,1H),7.60–7.54(m,2H),7.54–7.49(m,2H),7.49–7.45(m,2H),5.15(dd,J=13.3,5.4Hz,1H),4.47(d,J=17.0Hz,1H),4.31(d,J=17.2Hz,1H),2.99–2.88(m,1H),2.72–2.56(m,3H),2.48–2.20(m,5H),2.12(d,J=14.0Hz,2H),2.06–1.88(m,3H),1.70–1.59(m,2H),1.52(dt,J=13.4,6.7Hz,2H),1.36(dd,J=14.7,5.1Hz,2H).
实施例50:(S)-4-(2-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(50)
1.22mmol,1.0eq)溶于20ml甲苯。加入三乙胺(136mg,1.34mmol,1.1eq)120℃回流24小时。反应完成后,旋走甲苯,柱层析纯化得到200mg白色固体,收率为57%。1H NMR(400MHz,DMSO)δ11.07(s,1H),10.97(s,1H),7.62(dd,J=8.3,7.3Hz,1H),7.22(dd,J=15.6,7.7Hz,2H),2.75–2.62(m,1H),2.57–2.52(m,1H),2.06–1.97(m,1H),1.86(s,3H),1.29–1.18(m,1H).
步骤2:将(S)-4-羟基-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(200mg,0.69mmol,1.0eq)溶于20mL乙腈,加入1,3-二溴丙烷(681mg,3.54mmol,3.0eq),无水碳酸钾(96mg,0.69mmol,1.0eq)。反应体系50℃反应24小时。反应成后,旋走溶剂。乙酸乙酯稀释,饱和氯化钠洗涤,无水硫酸钠干燥,减压除溶剂,柱层析纯化得到243mg白色固体,收率为86%。1H NMR(400MHz,DMSO)δ10.98(s,1H),7.83–7.78(m,1H),7.52(d,J=8.5Hz,1H),7.40(d,J=7.1Hz,1H),4.29(t,J=5.8Hz,2H),3.72(t,J=6.5Hz,1H),2.68(s,1H),2.31(dd,J=13.8,7.7Hz,1H),2.03(d,J=18.2Hz,1H),1.88(s,1H).
步骤3:将(S)-4-(3-溴丙基)-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(40mg,0.098mmol,1.0eq)溶于3mL DMSO,加入4-(2-氯苯基)哌啶-4-甲腈盐酸盐(38mg,0.147mmol,1.5eq),三乙胺(9.89mg,0.980mmol,10.0eq),40℃反应过夜。反应完成后,用20mL乙酸乙酯稀释,饱和氯化钠洗涤,无水硫酸钠干燥,减压浓缩,薄层色谱纯化和高效液相色谱纯化得到产物23mg,白色固体,收率43%;1H NMR(400MHz,DMSO)δ10.99(d,J=5.1Hz,1H),7.81–7.75(m,1H),7.59–7.51(m,2H),7.49(d,J=8.6Hz,1H),7.47–7.40(m,2H),7.37(d,J=7.2Hz,1H),4.23(t,J=6.0Hz,2H),3.05(d,J=9.4Hz,2H),2.76–2.62(m,1H),2.55(dd,J=12.7,5.3Hz,3H),2.38(dd,J=29.5,18.0Hz,5H),2.00(dd,J=16.1,10.9Hz,5H),1.87(s,3H).
实施例51:4-(3-氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(51)
δ11.01(s,1H),7.60–7.49(m,3H),7.49–7.43(m,3H),5.15(dd,J=13.6,5.2Hz,1H),4.48(d,J=17.1Hz,1H),4.31(d,J=17.2Hz,1H),2.99(d,J=12.2Hz,2H),2.95–2.87(m,1H),2.69–2.64(m,2H),2.64–2.57(m,1H),2.49–2.41(m,1H),2.40–2.32(m,2H),2.24(td,J=11.9,1.3Hz,2H),2.14(dd,J=12.7,1.5Hz,2H),2.06–1.93(m,3H),1.64(dt,J=15.3,7.7Hz,2H),1.56–1.46(m,2H),1.35(dd,J=15.1,7.2Hz,2H).
实施例52:(S)-4-(3-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(52)
14mg,白色固体,收率26%;1H NMR(400MHz,DMSO)δ10.88(s,1H),7.60(s,1H),7.50(dt,J=17.6,7.7Hz,4H),7.24(dd,J=12.5,7.8Hz,2H),4.66(d,J=17.6Hz,1H),4.54(d,J=17.6Hz,1H),4.20(t,J=6.0Hz,2H),3.05(d,J=10.6Hz,2H),2.80–2.52(m,5H),2.35–2.24(m,2H),2.16(d,J=12.4Hz,2H),1.94(ddd,J=23.3,12.4,8.2Hz,5H),1.70(s,3H).
实施例53:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-苯基哌啶-4-甲腈(53)
盐酸盐(0.16mmol,1.5eq),三乙胺(110mg,1.1mmol,10.0eq),40℃反应过夜。反应完毕,反应液用20mL乙酸乙酯稀释,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,浓缩,依次经过薄层色谱纯化、高效液相色谱纯化得到最终产物26.3mg,白色固体,收率41%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.53(dt,J=3.1,2.1Hz,2H),7.46(ddd,J=13.1,11.8,7.1Hz,3H),7.36(ddd,J=8.3,4.3,1.7Hz,1H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.18(t,J=6.2Hz,2H),3.03(d,J=12.2Hz,2H),2.91(ddd,J=17.4,13.7,5.4Hz,1H),2.58(dd,J=12.2,4.8Hz,3H),2.48–2.38(m,1H),2.30(dd,J=12.0,11.3Hz,2H),2.11(d,J=13.0Hz,2H),2.05–1.89(m,5H).ESI-MS[M+H]+m/z=487.65。
实施例54:(S)-4-(3-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(54)
18mg,白色固体,收率34%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.81–7.75(m,1H),7.58(s,1H),7.55–7.41(m,4H),7.37(d,J=7.2Hz,1H),4.24(t,J=6.0Hz,2H),3.02(d,J=11.3Hz,2H),2.74–2.63(m,1H),2.62–2.51(m,4H),2.28(t,J=11.4Hz,2H),2.14(d,J=12.2Hz,2H),2.08–1.93(m,5H),1.87(s,3H).
实施例55:4-(2-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(55)
MHz,DMSO)δ10.99(s,1H),7.61–7.52(m,2H),7.51–7.39(m,3H),7.31(d,J=7.0Hz,1H),7.25(d,J=8.2Hz,1H),5.12(dd,J=13.1,6.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.2Hz,1H),4.20–4.13(m,2H),3.12–3.00(m,2H),2.97–2.85(m,1H),2.68–2.53(m,3H),2.38(ddd,J=16.4,14.0,6.7Hz,5H),1.98(ddd,J=21.0,12.0,4.6Hz,5H).ESI-MS[M+H]+m/z=522.28。
实施例56:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(2-(三氟甲氧基)苯基)哌啶-4-甲腈(56)
制备方法同(S)-4-(2-氯苯基)-1-(3-((2-(3-甲基l-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈,最终得到产物16mg,白色固体,收率30%;1H NMR(400MHz,DMSO)δ10.87(s,1H),7.57(dd,J=18.0,7.6Hz,2H),7.44(dd,J=15.4,7.6Hz,3H),7.22(dd,J=10.7,7.9Hz,2H),4.65(d,J=17.5Hz,1H),4.53(d,J=17.6Hz,1H),4.18(t,J=5.9Hz,2H),3.06(d,J=11.1Hz,2H),2.82–2.52(m,5H),2.41–2.22(m,4H),2.11–1.84(m,5H),1.69(s,3H).
实施例57:4-(3-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(57)
MHz,DMSO)δ11.00(s,1H),7.62–7.58(m,1H),7.56–7.44(m,4H),7.32(d,J=7.2Hz,1H),7.26(d,J=7.9Hz,1H),5.12(dd,J=13.4,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.18(t,J=6.2Hz,2H),3.05(dd,J=10.8,2.7Hz,2H),2.92(ddd,J=17.4,13.3,5.0Hz,1H),2.62–2.55(m,3H),2.49–2.40(m,1H),2.38–2.25(m,2H),2.17(d,J=12.0Hz,2H),1.99(ddd,J=21.0,15.7,9.3Hz,5H).
实施例58:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)-4-(2-(三氟甲氧基)苯基)哌啶-4-甲腈(58)
21mg,白色固体,收率36%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.81–7.74(m,1H),7.56(dd,J=15.7,7.6Hz,2H),7.51–7.40(m,3H),7.37(d,J=7.2Hz,1H),4.23(t,J=6.0Hz,2H),3.04(d,J=11.9Hz,2H),2.68(dd,J=12.5,6.4Hz,1H),2.60–2.51(m,4H),2.43–2.18(m,4H),2.10–1.92(m,5H),1.87(s,3H).
实施例59:4-(4-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(59)
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.60–7.55(m,2H),7.54–7.50(m,2H),7.48(d,J=7.8Hz,1H),7.32(d,J=7.5Hz,1H),7.26(d,J=8.1Hz,1H),5.12(dd,J=13.1,5.0Hz,1H),4.40(d,J=17.4Hz,1H),4.25(d,J=17.4Hz,1H),4.19(t,J=6.0Hz,2H),3.18–3.00(m,2H),2.92(ddd,J=18.5,13.0,4.4Hz,1H),2.59(ddd,J=16.3,3.5,1.3Hz,3H),2.49–2.39(m,2H),2.38–2.32(m,1H),2.16(d,J=15.1Hz,2H),2.09–1.92(m,5H).ESI-MS[M+H]+m/z=522.28。
实施例60:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(60)
18mg,白色固体,收率34%;1H NMR(400MHz,DMSO)δ10.87(s,1H),7.61(d,J=7.0Hz,2H),7.54–7.37(m,3H),7.23(dd,J=12.8,7.8Hz,2H),4.65(d,J=17.6Hz,1H),4.54(d,J=17.6Hz,1H),4.19(t,J=5.9Hz,2H),3.05(d,J=10.4Hz,2H),2.82–2.51(m,5H),2.37–2.24(m,2H),2.17(d,J=12.3Hz,2H),2.11–1.85(m,5H).
实施例61:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(2-氟苯基)哌啶-4-甲腈(61)
制备方法同1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-苯基哌啶-4-甲腈,23.6mg,收率36%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.50(dd,J=15.4,7.3Hz,3H),7.37–7.22(m,4H),5.12(dd,J=13.4,5.2Hz,1H),4.40(d,J=17.4Hz,1H),4.24(d,J=17.8Hz,1H),4.18(t,J=5.8Hz,2H),3.05(ddd,J=12.6,7.5,3.9Hz,2H),2.98–2.86(m,1H),2.65–2.55(m,3H),2.49–2.43(m,1H),2.40–2.20(m,4H),2.10–1.89(m,5H).ESI-MS[M+H]+m/z=505.66。
实施例62:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(62)
物21mg,白色固体,收率36%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.78(t,J=7.9Hz,1H),7.65–7.56(m,2H),7.49(d,J=8.8Hz,2H),7.38(t,J=9.1Hz,2H),4.24(t,J=5.8Hz,2H),3.02(d,J=10.4Hz,2H),2.68(dd,J=12.4,6.5Hz,1H),2.55(dd,J=12.8,4.6Hz,4H),2.29(t,J=11.6Hz,2H),2.16(d,J=12.9Hz,2H),2.08–1.91(m,5H),1.87(s,3H).
实施例63:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-氟苯基)哌啶-4-甲腈(63)
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.54–7.46(m,2H),7.44–7.37(m,2H),7.32(d,J=7.3Hz,1H),7.28–7.19(m,2H),5.12(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.5Hz,1H),4.18(t,J=6.2Hz,2H),3.03(d,J=12.4Hz,2H),2.97–2.86(m,1H),2.63–2.55(m,3H),2.49–2.41(m,1H),2.30(t,J=12.2Hz,2H),2.15(d,J=12.4Hz,2H),2.08–1.89(m,5H).ESI-MS[M+H]+m/z=505.66。
实施例64:4-(2-氯苯基)-1-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌啶-4-甲腈(64)
收率为29%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.59–7.40(m,5H),7.30(dd,J=11.8,7.8Hz,2H),5.11(dd,J=13.3,5.0Hz,1H),4.39(d,J=17.4Hz,1H),4.26(t,J=12.6Hz,3H),3.13(d,J=12.2Hz,2H),3.00–2.79(m,3H),2.57(d,J=22.0Hz,3H),2.46(d,J=13.6Hz,3H),1.98(t,J=9.0Hz,3H),1.23(s,3H).
实施例65:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(4-氟苯基)哌啶-4-甲腈(65)
MHz,DMSO)δ10.99(s,1H),7.58(ddd,J=8.7,5.5,2.8Hz,2H),7.48(t,J=7.8Hz,1H),7.33–7.22(m,4H),5.11(dd,J=13.3,5.2Hz,1H),4.39(d,J=17.5Hz,1H),4.23(d,J=17.5Hz,1H),4.17(t,J=6.2Hz,2H),3.09–2.98(m,2H),2.91(ddd,J=17.7,13.8,5.5Hz,1H),2.64–2.54(m,3H),2.48–2.38(m,1H),2.35–2.23(m,2H),2.18–2.08(m,2H),2.05–1.89(m,5H).ESI-MS[M+H]+m/z=505.61。
实施例66:1-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(66)
为20%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.64–7.56(m,2H),7.53–7.46(m,2H),7.40(d,J=6.2Hz,1H),7.31(dd,J=12.8,7.8Hz,2H),5.11(dd,J=13.3,5.0Hz,1H),4.39(d,J=17.5Hz,1H),4.25(t,J=10.6Hz,3H),3.11(d,J=11.8Hz,2H),2.98–2.80(m,3H),2.61–2.52(m,1H),2.49–2.37(m,3H),2.16(d,J=12.6Hz,2H),2.10–1.91(m,3H).
实施例67:4-(3-氰基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(67)
MHz,DMSO)δ10.99(s,1H),8.03(t,J=1.5Hz,1H),7.93(ddd,J=8.0,2.1,1.1Hz,1H),7.90–7.85(m,1H),7.67(t,J=7.8Hz,1H),7.49(t,J=7.9Hz,1H),7.32(d,J=7.6Hz,1H),7.26(d,J=7.9Hz,1H),5.16–5.08(m,1H),4.40(d,J=17.5Hz,1H),4.24(d,J=17.6Hz,1H),4.18(t,J=6.6Hz,2H),3.04(dt,J=8.5,3.7Hz,2H),2.98–2.86(m,1H),2.63–2.55(m,3H),2.48–2.40(m,1H),2.30(t,J=11.3Hz,2H),2.19(d,J=12.1Hz,2H),2.09–1.90(m,5H).ESI-MS[M+H]+m/z=512.63。
实施例68:4-(2-氯-6-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(68)
NMR(400MHz,DMSO)δ10.98(s,1H),7.52–7.41(m,3H),7.35–7.22(m,3H),5.11(dd,J=13.3,5.0Hz,1H),4.39(d,J=17.4Hz,1H),4.27–4.11(m,3H),3.03(d,J=10.9Hz,2H),2.91(s,2H),2.57(d,J=24.3Hz,4H),2.48–2.22(m,6H),2.03–1.89(m,3H).
实施例69:4-(4-氰基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(69)
MHz,DMSO)δ10.99(s,1H),7.93(d,J=8.5Hz,2H),7.76(d,J=8.6Hz,2H),7.48(t,J=7.8Hz,1H),7.31(d,J=7.3Hz,1H),7.25(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.2Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.18(t,J=6.1Hz,2H),3.15–2.99(m,2H),2.97–2.85(m,1H),2.64–2.55(m,3H),2.48–2.39(m,1H),2.38–2.25(m,2H),2.23–2.11(m,2H),2.09–1.89(m,5H).ESI-MS[M+H]+m/z=512.68。
实施例70:4-(2,4-二氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(70)
46%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.75(d,J=1.9Hz,1H),7.58–7.44(m,3H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.23(d,J=17.5Hz,1H),4.17(t,J=6.1Hz,2H),3.05(d,J=10.6Hz,2H),2.97–2.86(m,1H),2.58(d,J=17.1Hz,3H),2.49–2.26(m,5H),2.04–1.88(m,5H).
实施例71:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(71)
MHz,DMSO)δ10.97(s,1H),7.63–7.56(m,2H),7.51(d,J=2.4Hz,1H),7.47(d,J=7.8Hz,1H),7.42–7.37(m,1H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.18(t,J=6.1Hz,2H),3.05(d,J=9.8Hz,2H),2.91(ddd,J=18.7,13.7,5.4Hz,1H),2.58(dd,J=13.5,2.3Hz,3H),2.49–2.39(m,1H),2.32(t,J=11.7Hz,2H),2.18(d,J=12.8Hz,2H),2.10–1.87(m,5H).ESI-MS[M+H]+m/z=571.66。
实施例72:4-(4-氯-2-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(72)
33%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.59(d,J=11.8Hz,1H),7.56–7.45(m,2H),7.39(d,J=8.6Hz,1H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=6.0Hz,2H),3.20–2.82(m,4H),2.58(d,J=18.6Hz,2H),2.48–2.18(m,5H),2.09–1.89(m,5H).
实施例73:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(4-三氟甲氧基苯基)哌啶-4-甲腈(73)
(400MHz,DMSO)δ10.98(s,1H),7.68(d,J=8.8Hz,2H),7.52–7.41(m,3H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.2Hz,1H),5.11(dd,J=13.5,5.0Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.5Hz,1H),4.18(t,J=6.0Hz,2H),3.03(ddd,J=7.4,4.6,1.9Hz,2H),2.98–2.85(m,1H),2.69–2.52(m,3H),2.48–2.39(m,1H),2.36–2.23(m,2H),2.14(dd,J=13.2,5.0Hz,2H),2.08–1.86(m,5H).ESI-MS[M+H]+m/z=571.66。
实施例74:4-(2-氯-4-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(74)
NMR(400MHz,DMSO)δ10.98(s,1H),7.63–7.54(m,2H),7.48(t,J=7.8Hz,1H),7.32(dd,J=15.2,5.0Hz,2H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=5.9Hz,2H),3.05(d,J=11.7Hz,2H),2.97–2.85(m,1H),2.56(t,J=13.0Hz,3H),2.45(d,J=13.1Hz,3H),2.35(t,J=11.6Hz,2H),2.03–1.88(m,5H).
实施例75:4-(3-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌啶-4-甲腈(75)
(400MHz,DMSO)δ10.99(s,1H),7.57(s,1H),7.55–7.40(m,4H),7.30(d,J=7.5Hz,1H),7.23(d,J=8.2Hz,1H),5.14(dd,J=13.3,5.0Hz,1H),4.40(d,J=17.2Hz,1H),4.24(d,J=17.5Hz,1H),4.17(t,J=5.7Hz,2H),3.02(d,J=12.0Hz,2H),2.98–2.86(m,1H),2.60(dt,J=10.3,5.1Hz,1H),2.45(t,J=6.4Hz,3H),2.27(t,J=12.0Hz,2H),2.12(d,J=12.7Hz,2H),2.02–1.88(m,3H),1.80(dt,J=13.3,6.8Hz,2H),1.70–1.59(m,2H).
实施例76:4-(2,6-二氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(76)
40%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.56(d,J=8.0Hz,2H),7.48(t,J=7.8Hz,1H),7.40(t,J=8.0Hz,1H),7.31(d,J=7.5Hz,1H),7.25(d,J=8.2Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=5.9Hz,2H),3.07(d,J=11.3Hz,2H),2.96–2.86(m,1H),2.56(t,J=12.2Hz,6H),2.39(d,J=11.7Hz,4H),2.04–1.87(m,3H).
实施例77:4-(4-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌啶-4-甲腈(77)
(400MHz,DMSO)δ10.98(s,1H),7.50(dt,J=11.2,8.4Hz,5H),7.30(d,J=7.5Hz,1H),7.25(d,J=8.0Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.38(d,J=17.2Hz,1H),4.22(d,J=17.5Hz,1H),4.15(t,J=5.7Hz,2H),3.00(d,J=12.0Hz,2H),2.96–2.85(m,1H),2.59(dt,J=10.3,5.1Hz,1H),2.43(t,J=6.4Hz,3H),2.24(t,J=12.0Hz,2H),2.10(d,J=12.7Hz,2H),2.02–1.87(m,3H),1.78(dt,J=13.3,6.8Hz,2H),1.69–1.57(m,2H).
实施例78:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丙基)-4-(2-三氟甲氧基苯基)哌啶-4-甲腈(78)
7.51–7.38(m,3H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=6.1Hz,2H),3.04(d,J=12.3Hz,2H),2.96–2.85(m,1H),2.56(t,J=12.2Hz,3H),2.48–2.41(m,1H),2.35(t,J=11.9Hz,2H),2.26(d,J=13.2Hz,2H),2.05–1.88(m,5H).
实施例79:4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈(79)
基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈25mg,白色固体,收率为37%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.58(s,1H),7.54–7.41(m,4H),7.30(d,J=7.5Hz,1H),7.24(d,J=8.2Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.12(t,J=6.3Hz,2H),2.99(d,J=12.2Hz,2H),2.96–2.84(m,1H),2.56(d,J=18.3Hz,2H),2.48–2.35(m,3H),2.25(t,J=11.5Hz,2H),2.13(d,J=12.4Hz,1H),1.98(t,J=11.2Hz,3H),1.82–1.72(m,2H),1.50(dt,J=16.5,10.5Hz,4H).
实施例80:(S)-4-(2-氯苯基)-1-(3-((2-(3-甲基l-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(80)
148.27mmol,1.2eq),后加入MOMCl(11.94g,148.27mmol,1.2eq),室温反应一个小时。反应返程后,加入饱和氯化铵淬灭反应,乙酸乙酯萃取3次,饱和氯化铵洗涤三次,干燥、减压浓缩,柱层析纯化得到25.98g黄色油状物,收率为100%。1H NMR(400MHz,CDCl3)δ7.47(dd,J=7.5,1.4Hz,1H),7.24–7.14(m,2H),5.21(s,2H),3.89(s,3H),3.49(s,3H),2.49–2.41(m,3H).
步骤2:3-甲氧基甲氧基-2-甲基苯甲酸甲酯(25.98g,123.56mmol,1.0eq)溶于200ml四氯化碳中,加入NBS(23.09mmol,129.24mmol,1.05mmol),AIBN(2.03g,12.36mmol,0.1eq),88℃回流6小时。反应完成后,减压旋走溶剂,柱层析纯化得到35.73g棕色固体。收率为100%。1H NMR(400MHz,CDCl3)δ7.58(dd,J=6.5,2.5Hz,1H),7.35–7.27(m,1H),5.30(s,1H),5.10–5.05(m,1H),3.94(s,1H),3.53(s,1H).
步骤3:将2-溴甲基-3-甲氧基甲氧基苯甲酸甲酯(353mg,1.22mmol,1.0eq),(S)-3-胺基o-3-甲基哌啶-2,6-二酮盐酸盐一水合物(294mg,1.22mmol,1.0eq)溶于20ml甲苯。加入三乙胺(136mg,1.34mmol,1.1eq)120℃回流24小时。返佣完成后,旋走甲苯,柱层析纯化得到232mg白色固体,收率为61%。
步骤4:将(S)-3-(4-甲氧基甲氧基-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(232mg,0.73mmol,1.0eq)置于50mL圆底烧瓶中,加入20mL盐酸二氧六环。加入200uL甲醇。室温反应1小时。反应完成后,旋走溶剂,无需进一步纯化,直接投下一步。
步骤5:将(S)-3-(4-羟基-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(200mg,0.73mmol,1.0eq)溶于20mL乙腈。加入1,2-二溴丙烷(736mg,3.65mmol,5.0eq),无水碳酸钾(101mg,0.73mmol,1.0eq),50℃反应24小时。反应完成后,旋走溶剂,乙酸乙酯稀释,饱和氯化钠洗涤,柱层析纯化得到200mg白的固体,收率为69%。
步骤6:(S)-3-(4-(3-溴丙氧基)-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(40mg,0.10mmol,1.0eq)溶于3mL DMSO,加入4-(2-氯苯基)哌啶-4-甲腈盐酸盐(39mg,0.15mmol,1.5eq),三乙胺(102mg,1.01mmol,10.0eq),40℃反应过夜。反应完成后,20mL乙酸乙酯稀释,饱和氯化钠洗涤,薄层色谱和高效液相色谱纯化得产物15mg,白色固体,收率为28%;1H NMR(400MHz,DMSO)δ10.87(s,1H),7.61–7.51(m,2H),7.45(dd,J=12.1,6.3Hz,3H),7.22(dd,J=11.7,7.8Hz,2H),4.65(d,J=17.5Hz,1H),4.54(d,J=17.6Hz,1H),4.18(t,J=6.1Hz,2H),3.07(d,J=11.7Hz,2H),2.80–2.51(m,7H),2.37(t,J=12.3Hz,2H),2.08–1.84(m,5H),1.69(s,3H).
实施例81:4-(4-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈(81)
基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈21mg,白色固体,收率为22%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.55(d,J=8.5Hz,2H),7.52–7.43(m,3H),7.30(d,J=7.5Hz,1H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.12(t,J=6.2Hz,2H),2.98(d,J=11.9Hz,2H),2.94–2.84(m,1H),2.56(d,J=17.6Hz,1H),2.48–2.34(m,3H),2.24(t,J=11.7Hz,2H),2.09(d,J=12.8Hz,2H),1.95(dd,J=17.2,8.5Hz,3H),1.77(dd,J=13.4,6.6Hz,2H),1.58–1.38(m,4H).
实施例82:4-(2-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(82)
66%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.60–7.54(m,1H),7.51–7.40(m,4H),7.30(d,J=7.5Hz,1H),7.24(d,J=8.2Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.64(d,J=13.4Hz,1H),4.39(d,J=17.5Hz,1H),4.25(d,J=17.4Hz,1H),4.13(d,J=16.2Hz,3H),3.37(d,J=12.8Hz,1H),2.89(q,J=13.3Hz,2H),2.64–2.53(m,3H),2.44(dd,J=16.8,8.0Hz,4H),2.05–1.92(m,4H),1.84(d,J=12.5Hz,1H).
实施例83:4-(3-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(83)
率为49%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.61(s,1H),7.56–7.43(m,4H),7.30(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.62(d,J=14.0Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.16(t,J=6.2Hz,2H),4.09(d,J=14.4Hz,1H),3.27(d,J=13.2Hz,1H),2.98–2.74(m,2H),2.56(dd,J=13.3,6.2Hz,3H),2.43(dd,J=13.2,4.4Hz,1H),2.24–1.79(m,7H).
实施例84:4-(4-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(84)
收率为47%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.60–7.43(m,5H),7.27(dd,J=21.4,7.8Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.62(d,J=13.5Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.16(t,J=6.2Hz,2H),4.09(d,J=13.6Hz,1H),3.27(d,J=12.6Hz,1H),2.99–2.75(m,2H),2.56(dd,J=13.2,7.1Hz,3H),2.43(dd,J=13.0,4.4Hz,3H),2.13(d,J=13.3Hz,2H),2.05–1.92(m,4H),1.86(d,J=12.6Hz,1H).
实施例85:4-(2-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(85)
率为33%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.57(dt,J=7.3,3.7Hz,1H),7.54–7.41(m,4H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.63(d,J=14.1Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.13(dd,J=14.7,8.6Hz,3H),3.37(d,J=12.7Hz,1H),2.89(ddd,J=25.1,15.0,8.7Hz,2H),2.59(s,1H),2.51–2.37(m,9H),1.99(dd,J=16.4,8.8Hz,2H),1.91–1.62(m,5H).
实施例86:1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(4-三氟甲氧基苯基哌啶-4-甲腈(86)
1H NMR(400MHz,DMSO)δ10.98(s,1H),7.67(d,J=8.5Hz,2H),7.47(dd,J=15.0,7.9Hz,3H),7.27(dd,J=19.9,7.8Hz,2H),5.11(dd,J=13.4,5.0Hz,1H),4.63(d,J=13.7Hz,1H),4.40(d,J=17.4Hz,1H),4.25(d,J=17.3Hz,1H),4.20–4.06(m,3H),3.28(d,J=13.4Hz,1H),2.99–2.77(m,2H),2.65–2.54(m,3H),2.43(dd,J=13.3,4.4Hz,1H),2.16(d,J=13.0Hz,2H),2.01(dd,J=13.1,6.8Hz,4H),1.92-1.80(m,1H).
实施例87:4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(87)
收率为42%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.62(s,1H),7.56–7.43(m,4H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.61(d,J=13.6Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.15(t,J=6.2Hz,2H),4.09(d,J=14.2Hz,1H),3.27(t,J=9.6Hz,1H),2.97–2.84(m,1H),2.79(t,J=12.6Hz,1H),2.56(d,J=17.9Hz,1H),2.50–2.34(m,6H),2.23–1.60(m,10H).
实施例88:1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(3-三氟甲氧基苯基哌啶-4-甲腈(88)
收率为56%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.67(d,J=8.5Hz,2H),7.47(dd,J=15.0,7.9Hz,3H),7.27(dd,J=19.9,7.8Hz,2H),5.11(dd,J=13.4,5.0Hz,1H),4.63(d,J=13.7Hz,1H),4.40(d,J=17.4Hz,1H),4.25(d,J=17.3Hz,1H),4.20–4.06(m,3H),3.28(d,J=13.4Hz,1H),2.99–2.77(m,2H),2.65–2.54(m,3H),2.43(dd,J=13.3,4.4Hz,1H),2.16(d,J=13.0Hz,2H),2.01(dd,J=13.1,6.8Hz,4H),1.92-1.80(m,1H).
实施例89:4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(89)
收率为82%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.57(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.47(d,J=7.8Hz,1H),7.30(d,J=7.5Hz,1H),7.24(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.61(d,J=12.4Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.15(t,J=6.1Hz,2H),4.08(d,J=14.9Hz,1H),3.28(s,1H),2.88(d,J=12.1Hz,1H),2.79(s,1H),2.56(d,J=18.5Hz,1H),2.45(t,J=7.4Hz,6H),2.14(d,J=12.5Hz,2H),2.10–1.92(m,2H),1.92–1.60(m,6H).
实施例90:1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(2-三氟甲氧基苯基哌啶-4-甲腈(90)
收率为88%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.60–7.40(m,5H),7.30(d,J=7.5Hz,1H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.63(d,J=13.8Hz,1H),4.39(d,J=17.4Hz,1H),4.25(d,J=17.3Hz,1H),4.15(t,J=6.0Hz,3H),3.35(s,1H),2.97–2.82(m,2H),2.56(t,J=10.2Hz,3H),2.45(s,1H),2.28(d,J=13.1Hz,2H),2.07–1.93(m,4H),1.91–1.77(m,1H).
实施例91:4-(2-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(91)
MHz,DMSO)δ10.99(s,1H),7.55(ddd,J=11.7,5.3,2.8Hz,3H),7.44(ddd,J=7.1,5.1,2.8Hz,4H),5.13(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.99(d,J=12.3Hz,2H),2.96–2.85(m,1H),2.67(t,J=7.6Hz,2H),2.58(d,J=17.6Hz,1H),2.48–2.36(m,5H),2.30(t,J=11.9Hz,2H),2.04–1.89(m,3H),1.63(dt,J=15.3,7.7Hz,2H),1.56–1.45(m,2H).
实施例92:4-(2-氯苯基)-1-(5-(2-(2,6-氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(92)
MHz,DMSO)δ11.00(s,1H),7.59–7.51(m,3H),7.44(dt,J=4.4,3.4Hz,4H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.00(d,J=12.0Hz,2H),2.96–2.86(m,1H),2.67-2.56(m,3H),2.44(d,J=12.9Hz,3H),2.39–2.25(m,4H),2.05–1.88(m,3H),1.63(dt,J=15.6,7.9Hz,2H),1.55–1.44(m,2H),1.34(dt,J=14.8,7.5Hz,2H).
实施例93:4-(3-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(93)
10.99(s,1H),7.61–7.41(m,7H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.02–2.84(m,3H),2.67(t,J=7.6Hz,2H),2.59(d,J=16.8Hz,1H),2.46–2.35(m,3H),2.23(t,J=11.3Hz,2H),2.13(d,J=12.6Hz,2H),2.05–1.93(m,3H),1.65(dt,J=16.6,6.8Hz,2H),1.51(dt,J=15.2,7.5Hz,2H).
实施例94:1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(94)
11.00(s,1H),7.62–7.58(m,2H),7.56(dd,J=5.9,2.7Hz,1H),7.50(s,1H),7.48–7.45(m,2H),7.40(d,J=4.1Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.98(d,J=11.5Hz,2H),2.94–2.87(m,1H),2.67-2.56(m,3H),2.45-2.38(m,1H),2.39–2.31(m,2H),2.23(t,J=11.4Hz,2H),2.14(d,J=12.3Hz,2H),2.06–1.93(m,3H),1.63(dt,J=15.1,7.6Hz,2H),1.50(dt,J=14.8,7.6Hz,2H),1.39–1.29(m,2H).
实施例95:4-(4-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(95)
11.00(s,1H),5.13(dd,J=13.3,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.00–2.86(m,3H),2.67(t,J=7.5Hz,2H),2.62–2.55(m,1H),2.47–2.36(m,3H),2.24(t,J=11.9Hz,2H),2.09(d,J=12.9Hz,2H),2.04–1.90(m,3H),1.69–1.58(m,2H),1.51(dt,J=14.1,7.1Hz,2H),1.23–1.23(m,1H).
实施例96:1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)-4-(4-三氟甲氧基苯基)哌啶-4-甲腈(96)
DMSO)δ11.00(s,1H),7.66(dd,J=7.0,4.9Hz,2H),7.56(dt,J=7.7,3.8Hz,1H),7.45(dd,J=8.8,5.8Hz,4H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.98(d,J=11.3Hz,2H),2.94–2.86(m,1H),2.67-2.56(m,3H),2.43(dt,J=13.5,9.1Hz,1H),2.38–2.33(m,2H),2.24(t,J=11.4Hz,2H),2.12(d,J=12.3Hz,2H),2.05–1.90(m,3H),1.63(dt,J=15.2,7.7Hz,2H),1.55–1.45(m,2H),1.34(dt,J=14.9,7.6Hz,2H).
实施例97:1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(97)
δ10.99(s,1H),7.63–7.54(m,3H),7.52–7.44(m,3H),7.39(d,J=6.6Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.02–2.86(m,3H),2.67(t,J=7.6Hz,2H),2.59(d,J=17.1Hz,1H),2.47–2.36(m,3H),2.24(t,J=11.6Hz,2H),2.14(d,J=12.2Hz,2H),2.06–1.94(m,3H),1.64(dt,J=15.7,6.5Hz,2H),1.51(dt,J=14.5,7.2Hz,2H).
实施例98:4-(2-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(98)
δ10.99(s,1H),7.55(dd,J=10.3,6.6Hz,3H),7.48–7.40(m,4H),5.13(dd,J=13.3,5.0Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.1Hz,1H),3.01(d,J=12.2Hz,2H),2.98–2.86(m,1H),2.68-2.56(m,3H),2.47-2.41(m,3H),2.40–2.27(m,4H),2.05–1.90(m,3H),1.65-1.57(m,2H),1.50–1.40(m,2H),1.38-1.27(m,4H).
实施例99:1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)-4-(4-三氟甲氧基苯基)哌啶-4-甲腈(99)
DMSO)δ11.00(s,1H),7.67(d,J=8.9Hz,2H),7.56(dt,J=7.6,3.8Hz,1H),7.46(dt,J=13.1,6.3Hz,4H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),2.97(d,J=12.0Hz,2H),2.94–2.86(m,1H),2.67(t,J=7.6Hz,2H),2.59(d,J=16.8Hz,1H),2.42(dd,J=14.1,7.5Hz,3H),2.25(t,J=11.9Hz,2H),2.12(d,J=12.5Hz,2H),2.01-1.95(m,3H),1.63(dd,J=14.1,6.6Hz,2H),1.52(dd,J=13.9,7.1Hz,2H).
实施例100:4-(3-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(100)
DMSO)δ11.00(s,1H),7.60–7.42(m,7H),5.14(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.1Hz,1H),3.04–2.86(m,3H),2.68-2.56(m,3H),2.47–2.33(m,3H),2.26(t,J=11.5Hz,2H),2.14(d,J=12.3Hz,2H),2.05–1.95(m,3H),1.66–1.56(m,2H),1.51–1.41(m,2H),1.38-1.27(m,4H).
实施例101:4-(2,4-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(101)
δ10.99(s,1H),7.74(d,J=2.0Hz,1H),7.54(qd,J=8.7,3.7Hz,3H),7.48–7.44(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.99(d,J=11.9Hz,2H),2.95–2.86(m,1H),2.67(t,J=7.6Hz,2H),2.62–2.54(m,1H),2.47-2.36(m,5H),2.30(t,J=12.0Hz,2H),2.04-1.91(m,3H),1.69–1.57(m,2H),1.54-1.47(m,2H).
实施例102:4-(4-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(102)
DMSO)δ10.99(s,1H),7.58–7.53(m,3H),7.53–7.48(m,2H),7.47–7.44(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.1Hz,1H),3.02–2.87(m,3H),2.68-2.56(m,3H),2.46–2.31(m,3H),2.24(t,J=11.5Hz,2H),2.10(d,J=12.0Hz,2H),2.05–1.90(m,4H),1.66–1.56(m,2H),1.50–1.40(m,2H),1.38-1.27(m,4H).
实施例103:3-(4-(5-(3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(103)
溶解于5mL干燥DMF中,室温搅拌下加入碘化钠(44mg,0.294mmol,1.5eq.),所得反应液升至80℃反应过夜。反应完毕,所得反应液直接用HPLC分离得到3-(4-(5-(3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮8.5mg,白色固体,收率10%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J=3.9Hz,1H),7.46(dd,J=7.6,4.0Hz,2H),6.95–6.89(m,1H),6.83(dd,J=7.2,1.3Hz,1H),6.54–6.48(m,1H),6.42(td,J=7.2,0.7Hz,1H),5.13(dd,J=13.4,5.2Hz,1H),4.46(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),3.20(dd,J=9.8,4.9Hz,4H),2.92(ddd,J=17.6,13.4,5.2Hz,1H),2.61(ddd,J=8.7,6.6,4.9Hz,5H),2.45–2.31(m,1H),2.04–1.94(m,1H),1.87–1.77(m,2H),1.65(dt,J=8.8,7.0Hz,2H),1.54(dt,J=14.8,7.3Hz,2H),1.36(dd,J=14.4,7.6Hz,2H).
实施例104:3-(4-(5-(6-氟-2-甲基-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(104)
酮,17mg,收率28%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.60–7.53(m,1H),7.45(d,J=4.3Hz,2H),6.76(ddt,J=12.2,5.8,3.0Hz,2H),6.42(dd,J=8.8,4.8Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(dd,J=17.2,1.9Hz,1H),4.30(dd,J=17.2,1.7Hz,1H),3.45–3.37(m,1H),3.31–3.20(m,1H),3.12–3.02(m,1H),2.92(ddd,J=17.1,13.6,5.4Hz,1H),2.75–2.55(m,5H),2.42(ddd,J=26.0,13.1,4.3Hz,1H),2.04–1.94(m,1H),1.66(ddd,J=9.5,8.0,4.6Hz,4H),1.59–1.43(m,2H),1.40–1.28(m,2H),1.03(d,J=6.4Hz,3H).
实施例105:3-(4-(5-(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(105)
25%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J=8.2,4.5Hz,1H),7.49–7.43(m,2H),6.77–6.70(m,1H),6.68–6.61(m,2H),6.47(td,J=7.8,1.4Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),4.15–4.07(m,2H),3.29–3.25(m,2H),3.24–3.18(m,2H),2.92(ddd,J=17.7,13.7,5.4Hz,1H),2.63(dd,J=22.5,14.7Hz,3H),2.42(ddd,J=26.3,13.2,4.4Hz,1H),2.07–1.94(m,1H),1.71–1.61(m,2H),1.60–1.49(m,2H),1.36(dt,J=15.2,7.7Hz,2H).
实施例106:3-(4-(5-(6-溴-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(106)
10%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J=3.9Hz,1H),7.47–7.42(m,2H),7.05(dd,J=8.8,2.5Hz,1H),6.99(d,J=2.5Hz,1H),6.46(d,J=8.9Hz,1H),5.13(dd,J=13.2,5.1Hz,1H),4.46(d,J=17.0Hz,1H),4.30(d,J=17.3Hz,1H),3.26–3.12(m,4H),2.92(ddd,J=17.3,13.3,5.3Hz,1H),2.64(dd,J=9.6,5.9Hz,5H),2.47–2.31(m,2H),2.05–1.95(m,1H),1.83–1.74(m,2H),1.68–1.58(m,2H),1.52(dt,J=14.5,7.4Hz,2H),1.40–1.28(m,2H).
实施例107:3-(4-(5-(吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(107)
收率45%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J=6.1,2.4Hz,1H),7.49–7.43(m,2H),7.03–6.90(m,2H),6.53(t,J=7.2Hz,1H),6.45(d,J=7.8Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.26(t,J=8.4Hz,2H),3.01(t,J=7.2Hz,2H),2.97–2.89(m,1H),2.85(t,J=8.3Hz,2H),2.69–2.64(m,2H),2.63–2.56(m,1H),2.41(ddd,J=17.6,13.5,4.7Hz,1H),2.00(ddd,J=10.5,6.9,3.3Hz,1H),1.73–1.53(m,4H),1.47–1.35(m,2H).
实施例108:2-(2,6-二氧代哌啶-3-)-4-(4-((2-甲基喹啉-4-)氧)丁氧基)异吲哚啉-1,3-二酮(108)
DMSO)δ11.10(s,1H),8.15(d,J=9.0Hz,1H),7.92(d,J=8.1Hz,1H),7.88–7.78(m,2H),7.55(t,J=11.0Hz,2H),7.44(d,J=7.2Hz,1H),7.20(s,1H),5.07(dd,J=12.8,5.4Hz,1H),4.49(s,2H),4.35(t,J=5.9Hz,2H),2.88(ddd,J=16.8,14.0,5.4Hz,1H),2.69(s,3H),2.63–2.55(m,1H),2.18–1.95(m,6H).
实施例109:3-(4-(5-(7-氯-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(109)
率5%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.56(dt,J=7.7,3.9Hz,1H),7.47–7.43(m,2H),6.83(d,J=7.9Hz,1H),6.48(d,J=1.9Hz,1H),6.42(dd,J=7.9,1.9Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.21(dd,J=9.3,5.6Hz,4H),2.98–2.86(m,1H),2.72–2.56(m,5H),2.47–2.35(m,1H),2.01(ddd,J=10.7,5.0,2.7Hz,1H),1.83–1.73(m,2H),1.71–1.60(m,2H),1.59–1.49(m,2H),1.35(dt,J=15.4,7.7Hz,2H).
实施例110:3-(4-(5-(7-溴-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(110)
收率28%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(t,J=4.3Hz,1H),7.45(d,J=4.3Hz,2H),6.87(dd,J=8.6,2.3Hz,1H),6.80(d,J=2.3Hz,1H),6.61(d,J=8.7Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),4.20–4.05(m,2H),3.30–3.25(m,2H),3.24–3.17(m,2H),2.99–2.85(m,1H),2.63(dd,J=20.5,12.8Hz,3H),2.47–2.35(m,1H),2.07–1.93(m,1H),1.64(dt,J=15.1,7.7Hz,2H),1.54(dt,J=14.9,7.6Hz,2H),1.41–1.27(m,2H).
实施例111:3-(1-氧代-4-(5-(2,3,4,5-四氢-1H-苯并[b]氮杂卓-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(111)
25%;1H NMR(400MHz,DMSO)δ10.98(d,J=5.3Hz,1H),7.55(dd,J=8.2,4.2Hz,1H),7.43(dd,J=11.7,8.0Hz,2H),7.11–6.98(m,2H),6.88(t,J=6.9Hz,1H),6.77(dd,J=13.5,6.7Hz,1H),5.17–5.04(m,1H),4.43(dd,J=16.7,6.2Hz,1H),4.28(dd,J=17.0,6.2Hz,1H),3.07(dd,J=12.5,6.2Hz,2H),2.98–2.76(m,3H),2.60(d,J=18.9Hz,4H),2.45–2.34(m,1H),1.99(dd,J=12.1,4.6Hz,1H),1.68–1.44(m,7H),1.43–1.32(m,2H).
实施例112:3-(4-(5-(6-溴吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(112)
收率46%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dt,J=7.7,3.8Hz,1H),7.49–7.44(m,2H),7.12(d,J=1.7Hz,1H),7.08(dd,J=8.3,2.0Hz,1H),6.39(d,J=8.3Hz,1H),5.75(s,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),3.30(t,J=8.5Hz,2H),3.01(t,J=7.3Hz,2H),2.98–2.91(m,1H),2.87(t,J=8.2Hz,2H),2.70–2.56(m,3H),2.42(ddd,J=26.6,13.4,4.5Hz,1H),2.00(dtd,J=6.8,4.9,1.8Hz,1H),1.65(dt,J=15.5,7.8Hz,2H),1.56(dt,J=14.8,7.5Hz,2H),1.38(dt,J=15.0,7.7Hz,2H).
实施例113:3-(4-(5-(3,4-二氢异喹啉-2(1H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(113)
率35%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.50(dt,J=20.8,6.9Hz,3H),7.23–7.03(m,4H),5.14(dd,J=13.1,4.7Hz,1H),4.49(d,J=17.3Hz,1H),4.32(d,J=17.1Hz,1H),3.46–3.16(m,6H),3.07–2.76(m,5H),2.74–2.65(m,2H),2.60(dd,J=18.5,1.8Hz,1H),2.48–2.37(m,1H),2.09–1.96(m,1H),1.79–1.58(m,4H),1.39(dd,J=14.9,7.9Hz,2H).
实施例114:3-(4-(5-(5-溴吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(114)
收率39%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.60–7.53(m,1H),7.48–7.41(m,2H),6.90(d,J=7.6Hz,1H),6.63(dd,J=7.6,1.7Hz,1H),6.59(d,J=1.6Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.37–3.31(m,2H),3.04(t,J=7.2Hz,2H),2.92(ddd,J=17.6,13.7,5.4Hz,1H),2.83(t,J=8.4Hz,2H),2.71–2.57(m,3H),2.42(ddd,J=26.5,13.3,4.5Hz,1H),2.01(ddd,J=12.3,6.2,4.0Hz,1H),1.66(dt,J=15.5,7.7Hz,2H),1.56(dt,J=14.8,7.5Hz,2H),1.38(dt,J=14.8,7.6Hz,2H).
实施例115:3-(4-(5-(6-氯-3,4-二氢异喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(115)
31%;1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J=3.8Hz,1H),7.45(d,J=4.4Hz,2H),6.93(dd,J=8.8,2.7Hz,1H),6.88(d,J=2.6Hz,1H),6.50(d,J=8.9Hz,1H),5.13(dd,J=13.4,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),3.19(dd,J=9.8,5.4Hz,4H),2.92(ddd,J=17.2,12.9,5.5Hz,1H),2.69–2.56(m,5H),2.48–2.32(m,1H),2.05–1.96(m,1H),1.84–1.74(m,2H),1.64(dt,J=16.2,8.0Hz,2H),1.53(dt,J=14.3,7.3Hz,2H),1.34(dt,J=14.2,7.0Hz,2H).
实施例116:3-(4-(4-(吲哚啉-1-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(116)
1H NMR(400MHz,DMSO)δ10.96(s,1H),8.10(d,J=8.0Hz,1H),7.48(t,J=7.8Hz,1H),7.34–7.16(m,3H),7.13(t,J=7.6Hz,1H),6.96(t,J=7.4Hz,1H),5.07(dd,J=13.4,5.0Hz,1H),4.31(d,J=17.3Hz,1H),4.18(dd,J=15.4,11.7Hz,3H),4.09(t,J=8.5Hz,2H),3.13(t,J=8.4Hz,2H),2.95–2.82(m,1H),2.64(t,J=6.7Hz,2H),2.55(d,J=10.6Hz,1H),2.30–2.04(m,3H),1.97–1.87(m,1H).
实施例117:3-(4-(4-(3,4-二氢喹啉-1(2H)-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(117)
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.46(t,J=7.8Hz,2H),7.29(d,J=7.5Hz,1H),7.21(d,J=8.1Hz,1H),7.18–7.10(m,2H),7.06(t,J=7.3Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.25–4.02(m,4H),3.68(td,J=12.6,6.2Hz,2H),3.29(s,1H),2.99–2.86(m,1H),2.77–2.55(m,5H),2.34(dd,J=13.1,4.2Hz,1H),2.09–1.94(m,3H),1.86–1.77(m,2H).
实施例118:3-(4-((5-(吲哚啉-1-)-5-氧戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(118)
39%;1H NMR(400MHz,DMSO)δ10.96(s,1H),8.07(d,J=8.0Hz,1H),7.48(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),7.21(d,J=7.3Hz,1H),7.13(t,J=7.7Hz,1H),6.96(t,J=7.4Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.27–4.13(m,3H),4.08(t,J=8.5Hz,2H),3.12(t,J=8.4Hz,2H),2.96–2.84(m,1H),2.55(dd,J=12.5,7.6Hz,3H),2.44–2.31(m,1H),2.02–1.92(m,1H),1.90–1.71(m,4H).
实施例119:3-(4-((5-(3,4-二氢喹啉-1(2H)-)-5-氧戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(119)
1H NMR(400MHz,DMSO)δ10.97(s,1H),7.45(d,J=7.7Hz,2H),7.30(d,J=7.5Hz,1H),7.23–7.01(m,4H),5.10(dd,J=13.3,5.1Hz,1H),4.31(s,1H),4.21(s,1H),4.08(s,2H),3.67(t,J=6.4Hz,2H),2.96–2.84(m,1H),2.66(d,J=6.5Hz,2H),2.55(d,J=7.0Hz,3H),2.40(ddd,J=35.4,17.8,9.0Hz,1H),2.05–1.93(m,1H),1.89–1.80(m,2H),1.72(s,4H).
实施例120:3-(4-(6-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)己基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(120)
DMSO)δ10.99(s,1H),7.56(dd,J=8.2,4.5Hz,1H),7.46(d,J=3.7Hz,2H),7.36(s,1H),7.34–7.27(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.94(s,2H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),2.99–2.86(m,2H),2.79(d,J=10.0Hz,2H),2.68-2.56(m,3H),2.46–2.23(m,5H),2.05–1.97(m,1H),1.92(dd,J=12.7,9.1Hz,2H),1.61(d,J=11.7Hz,4H),1.46(s,2H),1.38-1.27(m,4H).
实施例121:3-(1-氧代-4-(5-(2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)吲哚啉-2-)哌啶-2,6-二酮(121)
(s,1H),10.40(s,1H),8.19(s,1H),7.58(dd,J=6.2,2.4Hz,1H),7.52–7.42(m,3H),7.19(t,J=7.5Hz,1H),6.96(t,J=7.5Hz,1H),6.85(d,J=7.7Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.49(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.99–2.85(m,3H),2.73–2.57(m,5H),2.48–2.37(m,1H),2.07–1.97(m,1H),1.88–1.76(m,2H),1.73–1.49(m,6H),1.37(dt,J=14.4,7.4Hz,2H).
实施例122:3-(4-(4-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(122)
11.01(s,1H),8.17(s,1H),7.61–7.54(m,1H),7.50–7.44(m,2H),7.19(dd,J=7.4,0.9Hz,1H),7.10(td,J=7.9,1.3Hz,1H),6.84(dd,J=7.8,7.0Hz,1H),6.75(d,J=7.9Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=16.4Hz,3H),2.93(ddd,J=17.5,14.0,5.5Hz,1H),2.84(d,J=11.8Hz,2H),2.67(t,J=7.5Hz,2H),2.65–2.57(m,1H),2.48–2.30(m,3H),2.01(dd,J=17.2,6.7Hz,3H),1.84(td,J=12.8,3.7Hz,2H),1.69–1.57(m,4H),1.57–1.45(m,2H).
实施例123:3-(4-(5-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(123)
10.99(s,1H),8.19(s,1H),7.60–7.55(m,1H),7.49–7.44(m,2H),7.30–7.20(m,3H),5.14(dd,J=13.3,5.1Hz,1H),4.97(s,2H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.92(ddd,J=17.9,11.8,4.6Hz,3H),2.71–2.56(m,3H),2.43(dd,J=21.2,8.6Hz,5H),1.98(dddd,J=26.0,16.8,8.7,2.8Hz,3H),1.65(t,J=12.0Hz,4H),1.54(dd,J=14.6,7.7Hz,2H),1.40–1.29(m,2H).
实施例124:3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(124)
MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.35–7.23(m,5H),5.11(dd,J=13.3,5.1Hz,1H),4.93(s,2H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.16(t,J=6.3Hz,2H),2.97–2.85(m,1H),2.79(d,J=10.7Hz,2H),2.58(d,J=18.2Hz,1H),2.48–2.36(m,3H),2.26(t,J=10.9Hz,2H),2.03–1.94(m,1H),1.88(dd,J=17.6,7.6Hz,2H),1.83–1.72(m,2H),1.63(dd,J=21.1,9.9Hz,4H).
实施例125:3-(1-氧代-4-(5-(2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(125)
10.99(s,1H),10.18(s,1H),8.18(s,1H),7.59–7.54(m,1H),7.50–7.43(m,2H),7.30–7.19(m,2H),7.05–6.98(m,1H),6.91–6.85(m,1H),5.13(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),2.98–2.86(m,1H),2.75(d,J=10.6Hz,2H),2.70–2.56(m,3H),2.40(ddd,J=24.4,15.6,7.6Hz,5H),1.98(ddd,J=39.2,21.1,8.9Hz,5H),1.64(dt,J=15.3,7.6Hz,2H),1.57–1.45(m,2H),1.35(dt,J=14.8,7.5Hz,2H).
实施例126:3-(4-(4-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(126)
MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.1Hz,1H),7.18(d,J=7.1Hz,1H),7.14–7.05(m,1H),6.84(t,J=7.4Hz,1H),6.75(d,J=7.9Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.4Hz,1H),4.34(s,2H),4.23(d,J=17.4Hz,1H),4.15(t,J=6.2Hz,2H),2.92(dd,J=22.7,8.6Hz,3H),2.60(s,1H),2.48–2.39(m,3H),2.00(ddd,J=13.9,10.4,7.6Hz,3H),1.89–1.73(m,4H),1.65(t,J=11.5Hz,4H).
实施例127:3-(4-(5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(127)
10.99(s,1H),7.56(dt,J=7.6,3.9Hz,1H),7.49–7.43(m,2H),7.39–7.25(m,3H),5.14(dd,J=13.3,5.1Hz,1H),4.93(s,2H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.99–2.86(m,1H),2.82–2.53(m,5H),2.48–2.37(m,1H),2.35–2.27(m,2H),2.26–2.15(m,2H),2.02(ddd,J=9.9,4.9,2.9Hz,1H),1.94–1.81(m,2H),1.69–1.55(m,4H),1.54–1.43(m,2H),1.34(dt,J=14.8,7.3Hz,2H).
实施例128:3-(4-(4-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(128)
MHz,DMSO)δ10.98(s,1H),7.48(t,J=7.8Hz,1H),7.33–7.22(m,3H),7.14(dd,J=8.9,2.2Hz,1H),7.12–7.05(m,1H),5.11(dd,J=13.3,5.0Hz,1H),4.93(s,2H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.15(t,J=6.2Hz,2H),2.97–2.85(m,1H),2.81(d,J=11.0Hz,2H),2.57(d,J=18.0Hz,1H),2.47–2.38(m,3H),2.29(t,J=11.5Hz,2H),2.02–1.95(m,1H),1.95–1.85(m,2H),1.83–1.73(m,2H),1.64(dd,J=19.0,10.7Hz,4H).
实施例129:3-(4-(5-(5-氯-3-氧代-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(129)
10.99(s,1H),8.15(s,1H),7.87(d,J=1.4Hz,1H),7.82(dt,J=13.8,5.0Hz,2H),7.57(dt,J=7.7,3.8Hz,1H),7.51–7.41(m,2H),5.75(s,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),2.99–2.85(m,3H),2.71–2.56(m,3H),2.47–2.37(m,3H),2.36–2.27(m,2H),2.21(t,J=12.1Hz,2H),2.07–1.95(m,1H),1.64(dd,J=13.9,8.5Hz,4H),1.58–1.48(m,2H),1.36(dt,J=14.8,7.5Hz,2H).
实施例130:3-(4-(4-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(130)
制备方法同1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-苯基哌啶-4-甲腈,16.2mg,白色固体,收率29%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.31(d,J=7.5Hz,1H),7.25(d,J=8.1Hz,1H),7.13(d,J=7.6Hz,1H),7.07(d,J=7.7Hz,1H),7.00(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.90(s,2H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.16(t,J=6.3Hz,2H),2.98–2.85(m,1H),2.80(d,J=11.0Hz,2H),2.57(d,J=18.4Hz,1H),2.48–2.38(m,3H),2.35–2.23(m,5H),2.03–1.93(m,1H),1.90–1.73(m,4H),1.63(dt,J=20.6,10.0Hz,4H).
实施例131:3-(1-氧代-4-(5-(2'-氧代-1',2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(131)
7.72(dd,J=7.6,1.1Hz,1H),7.59–7.54(m,1H),7.50–7.43(m,2H),7.07(dd,J=7.6,5.0Hz,1H),5.75(s,1H),5.13(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.99–2.86(m,1H),2.78(d,J=10.6Hz,2H),2.64(dd,J=22.3,14.4Hz,3H),2.47–2.29(m,5H),2.09–1.88(m,5H),1.64(dt,J=15.4,7.7Hz,2H),1.56–1.44(m,2H),1.41–1.29(m,2H).
实施例132:3-(4-((5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(132)
率为48%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J=7.8Hz,1H),7.36(s,1H),7.33–7.27(m,3H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.93(s,2H),4.37(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.13(t,J=6.3Hz,2H),2.97–2.84(m,1H),2.78(d,J=10.5Hz,2H),2.56(d,J=18.0Hz,1H),2.45(dd,J=13.1,4.4Hz,1H),2.37(t,J=7.0Hz,2H),2.27(t,J=11.5Hz,2H),2.02–1.85(m,3H),1.82–1.71(m,2H),1.61(d,J=12.4Hz,2H),1.48(ddd,J=22.2,14.8,9.1Hz,4H).
实施例133:3-(4-(5-(5-氯-2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(133)
DMSO)δ10.99(s,1H),10.51(s,1H),8.18(s,1H),7.57(dd,J=6.0,2.6Hz,1H),7.53–7.43(m,3H),7.24(dd,J=8.3,2.1Hz,1H),6.85(d,J=8.3Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.01–2.84(m,3H),2.63(ddd,J=21.4,16.7,4.4Hz,5H),2.53(d,J=6.9Hz,2H),2.48–2.36(m,1H),2.02(ddd,J=10.2,5.0,3.1Hz,1H),1.86–1.70(m,4H),1.69–1.61(m,2H),1.60–1.50(m,2H),1.37(dt,J=14.7,7.5Hz,2H).
实施例134:3-(4-((5-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(134)
3-(4-((5-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮35mg,白色固体,收率为37%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.49(t,J=7.8Hz,1H),7.31(d,J=7.5Hz,1H),7.25(d,J=8.1Hz,1H),7.19(d,J=7.3Hz,1H),7.11(td,J=7.8,1.2Hz,1H),6.85(t,J=7.4Hz,1H),6.76(d,J=7.9Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.42–4.31(m,3H),4.24(d,J=17.4Hz,1H),4.14(t,J=6.3Hz,2H),2.91(ddd,J=13.4,11.9,5.7Hz,3H),2.59(s,1H),2.45(dd,J=13.1,4.3Hz,1H),2.38(t,J=6.8Hz,2H),2.10–1.94(m,3H),1.91–1.72(m,4H),1.63(d,J=13.0Hz,2H),1.59–1.39(m,4H).
实施例135:3-(4-(5-(5-甲氧基-2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(135)
DMSO)δ10.99(s,1H),10.19(s,1H),8.18(s,1H),7.56(dt,J=7.9,3.9Hz,1H),7.51–7.43(m,2H),7.02(s,1H),6.75(s,2H),5.75(s,2H),5.14(dd,J=13.2,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.71(s,3H),2.92(ddd,J=13.0,12.2,5.1Hz,3H),2.71–2.57(m,5H),2.54(s,2H),2.47–2.37(m,1H),2.02(ddd,J=10.4,5.0,3.6Hz,1H),1.90–1.47(m,8H),1.44–1.28(m,2H).
实施例136:3-(4-(3-(2H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(136)
MHz,DMSO)δ10.98(s,1H),7.49(t,J=7.8Hz,1H),7.32(d,J=7.5Hz,1H),7.26(d,J=8.1Hz,1H),7.20(d,J=6.9Hz,1H),7.11(t,J=7.7Hz,1H),6.86(t,J=7.4Hz,1H),6.76(d,J=8.0Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.39(d,J=14.5Hz,3H),4.29–4.13(m,3H),3.57–3.12(m,4H),3.07–2.83(m,3H),2.63–2.55(m,1H),2.47–2.37(m,1H),2.09–1.81(m,5H),1.69(d,J=12.4Hz,2H).
实施例137:3-(1-氧代-4-(5-(螺[异色满-1,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(137)
10.99(s,1H),7.57(dt,J=7.5,3.8Hz,1H),7.51–7.40(m,2H),7.21–7.05(m,4H),5.14(dd,J=13.2,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.81(t,J=5.4Hz,2H),2.99–2.86(m,1H),2.74(dd,J=14.1,8.6Hz,4H),2.69–2.57(m,3H),2.46–2.31(m,5H),2.06–1.87(m,3H),1.78(d,J=13.1Hz,2H),1.70–1.59(m,2H),1.53(dd,J=12.4,6.0Hz,2H),1.36(dd,J=13.7,7.5Hz,2H).
实施例138:3-(4-(3-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(138)
MHz,DMSO)δ10.99(s,1H),7.50(t,J=7.8Hz,1H),7.40–7.30(m,3H),7.27(t,J=7.0Hz,2H),5.12(dd,J=13.3,5.1Hz,1H),4.99(s,2H),4.41(d,J=17.4Hz,1H),4.24(dd,J=17.8,11.6Hz,3H),3.47–3.16(m,6H),2.97–2.87(m,1H),2.59(dd,J=17.2,1.0Hz,1H),2.47–2.37(m,1H),2.36–2.05(m,4H),2.04–1.97(m,1H),1.85–1.67(m,2H).
实施例139:3-(1-氧代-4-(5-(2-氧代螺[吲哚啉-3,3'-吡咯啉]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(139)
10.98(s,1H),10.35(s,1H),8.15(s,1H),7.56(dt,J=7.8,3.9Hz,1H),7.49–7.40(m,2H),7.27(dd,J=7.1,4.0Hz,1H),7.15(td,J=7.6,0.6Hz,1H),6.94(tdd,J=7.6,2.6,0.8Hz,1H),6.81(d,J=7.7Hz,1H),5.75(s,2H),5.13(dd,J=13.3,5.1Hz,1H),4.46(dd,J=17.2,2.9Hz,1H),4.30(d,J=17.1Hz,1H),3.09(td,J=8.1,4.7Hz,1H),2.98–2.85(m,1H),2.81(dd,J=9.0,2.0Hz,1H),2.70–2.52(m,6H),2.39(ddd,J=25.6,12.8,4.3Hz,1H),2.16(ddd,J=12.1,7.9,4.1Hz,1H),1.99(dd,J=11.5,5.5Hz,1H),1.88(dt,J=12.5,7.6Hz,1H),1.64(dt,J=14.9,7.4Hz,2H),1.57–1.46(m,2H),1.45–1.33(m,2H).
实施例140:3-(4-(3-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(140)
DMSO)δ11.00(s,1H),7.50(t,J=7.8Hz,1H),7.33(d,J=7.5Hz,1H),7.27(d,J=8.1Hz,1H),7.18(d,J=7.6Hz,1H),7.12(d,J=7.6Hz,1H),6.98(s,1H),5.13(dd,J=13.3,5.0Hz,1H),4.96(s,2H),4.41(d,J=17.4Hz,1H),4.31–4.17(m,3H),3.37(dd,J=17.2,16.7Hz,6H),2.97–2.88(m,1H),2.59(d,J=17.2Hz,1H),2.46–2.37(m,1H),2.33(s,3H),2.17(dt,J=36.9,32.7Hz,4H),2.01(dd,J=8.9,3.3Hz,1H),1.83–1.63(m,2H).
实施例141:3-(1-氧代-4-(5-(螺[茚-1,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(141)
制备方法同3-(1-氧代-4-(5-(2-苯基吡咯啉-1-)戊基)吲哚啉-2-)
(m,2H),7.39(d,J=7.0Hz,1H),7.33(d,J=7.0Hz,1H),7.26–7.15(m,2H),6.97(d,J=5.6Hz,1H),6.80(d,J=5.6Hz,1H),5.75(s,2H),5.14(dd,J=13.3,5.0Hz,1H),4.47(dd,J=17.1,8.0Hz,1H),4.31(dd,J=17.1,7.9Hz,1H),3.06(d,J=11.6Hz,2H),2.99–2.87(m,1H),2.72–2.53(m,5H),2.46–2.35(m,2H),2.19–2.07(m,2H),2.06–1.94(m,1H),1.63(qd,J=14.8,8.1Hz,4H),1.43–1.31(m,2H),1.23(d,J=12.9Hz,2H).
实施例142:3-(4-(3-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(142)
MHz,DMSO)δ10.99(s,1H),7.49(t,J=7.8Hz,1H),7.34–7.22(m,3H),7.17(dd,J=8.9,2.2Hz,1H),7.08(td,J=9.4,2.3Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.93(s,2H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.18(t,J=6.1Hz,2H),2.97–2.86(m,1H),2.82(d,J=10.2Hz,2H),2.63–2.52(m,3H),2.48–2.39(m,1H),2.31(t,J=11.1Hz,2H),2.04–1.86(m,5H),1.62(d,J=12.5Hz,2H).
实施例143:3-(4-(5-(2,3-二氢螺[茚-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(143)
11.00(s,1H),7.57(dt,J=7.7,3.9Hz,1H),7.50–7.43(m,2H),7.23–7.09(m,4H),5.75(s,1H),5.14(dd,J=13.2,5.0Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.03–2.88(m,3H),2.84(t,J=7.3Hz,2H),2.71–2.57(m,4H),2.47–2.37(m,2H),2.35–2.20(m,2H),2.06–1.92(m,3H),1.90–1.78(m,2H),1.69–1.60(m,2H),1.55(dd,J=13.9,7.3Hz,2H),1.47(d,J=12.6Hz,2H),1.39–1.30(m,2H).
实施例144:3-(4-((5-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(144)
为40%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J=7.7Hz,1H),7.35–7.21(m,3H),7.19–7.13(m,1H),7.09(dd,J=12.5,5.1Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.93(s,2H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.12(t,J=6.1Hz,2H),2.98–2.85(m,1H),2.80(d,J=9.9Hz,2H),2.58(s,1H),2.48–2.35(m,3H),2.29(t,J=11.4Hz,2H),2.04–1.85(m,3H),1.82–1.71(m,2H),1.61(d,J=12.7Hz,2H),1.57–1.39(m,4H).
实施例145:3-(4-(5-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)戊基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(145)
11.00(s,1H),7.63–7.53(m,1H),7.45(dd,J=7.1,5.7Hz,2H),7.19(d,J=7.1Hz,1H),7.11(dd,J=11.2,4.2Hz,1H),6.85(t,J=7.3Hz,1H),6.75(d,J=7.9Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.36–4.28(m,3H),3.00–2.82(m,3H),2.73–2.57(m,3H),2.49–2.30(m,3H),2.12–1.96(m,3H),1.86(td,J=12.8,3.1Hz,2H),1.63(d,J=13.2Hz,4H),1.57–1.44(m,2H),1.41–1.28(m,2H).
实施例146:3-(4-((5-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(146)
为20%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J=7.8Hz,1H),7.31(d,J=7.5Hz,1H),7.25(d,J=8.2Hz,1H),7.14(d,J=7.6Hz,1H),7.07(d,J=7.8Hz,1H),7.02(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.91(s,2H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.13(t,J=6.2Hz,2H),2.97–2.74(m,3H),2.56(d,J=16.4Hz,1H),2.47–2.25(m,8H),2.03–1.94(m,1H),1.93–1.83(m,2H),1.77(dd,J=13.5,6.5Hz,2H),1.64–1.40(m,6H).
实施例147:3-(1-氧代-4-(5-(4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-8-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(147)
11.00(s,1H),8.73(s,1H),8.28(s,1H),7.57(dd,J=6.3,2.2Hz,1H),7.52–7.42(m,2H),7.22(t,J=7.9Hz,2H),6.87(d,J=8.2Hz,2H),6.75(t,J=7.3Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.58(s,2H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.20–2.73(m,5H),2.71–2.52(m,7H),2.40(ddd,J=26.3,13.2,4.3Hz,1H),2.07–1.95(m,1H),1.75–1.60(m,4H),1.56(dd,J=14.2,7.6Hz,2H),1.42–1.28(m,2H).
实施例148:3-(4-((6-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)己基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(148)
收率为22%;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.48(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),7.18(d,J=7.2Hz,1H),7.10(td,J=7.9,1.2Hz,1H),6.84(t,J=7.4Hz,1H),6.75(d,J=7.9Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.33(s,2H),4.22(d,J=17.4Hz,1H),4.12(t,J=6.3Hz,2H),2.97–2.87(m,1H),2.83(d,J=11.7Hz,2H),2.57(d,J=17.9Hz,1H),2.48–2.38(m,1H),2.36–2.25(m,2H),1.97(t,J=10.8Hz,3H),1.83(td,J=12.8,3.6Hz,2H),1.79–1.68(m,2H),1.61(d,J=12.4Hz,2H),1.53–1.40(m,4H),1.39–1.30(m,2H).
实施例149:3-(4-(4-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(149)
11.02(s,1H),7.62–7.56(m,1H),7.51–7.45(m,2H),7.31–7.21(m,4H),5.15(dd,J=13.3,5.1Hz,1H),4.96(s,2H),4.49(d,J=17.2Hz,1H),4.33(d,J=17.1Hz,1H),2.94(ddd,J=17.6,13.9,5.5Hz,1H),2.84–2.75(m,2H),2.69(t,J=7.5Hz,2H),2.65–2.57(m,1H),2.47–2.37(m,3H),2.31(t,J=10.9Hz,2H),2.03(dtd,J=12.6,5.1,2.0Hz,1H),1.90(td,J=13.1,4.3Hz,2H),1.65(ddd,J=21.1,10.2,4.5Hz,4H),1.53(dt,J=14.9,7.6Hz,2H).
实施例150:3-(4-((6-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)己基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(150)
收率为26%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J=7.8Hz,1H),7.35(s,1H),7.33–7.27(m,3H),7.24(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.93(s,2H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.12(t,J=6.3Hz,2H),3.00–2.85(m,1H),2.78(d,J=10.6Hz,2H),2.63–2.54(m,1H),2.48–2.39(m,1H),2.38–2.31(m,2H),2.27(t,J=11.3Hz,2H),2.04–1.83(m,3H),1.80–1.68(m,2H),1.60(d,J=12.6Hz,2H),1.47(q,J=16.3Hz,4H),1.35(dd,J=13.0,6.3Hz,2H).
实施例151:3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(151)
11.01(s,1H),8.18(s,1H),7.60–7.54(m,1H),7.50–7.44(m,2H),7.37(d,J=1.4Hz,1H),7.35–7.27(m,2H),5.14(dd,J=13.3,5.1Hz,1H),4.94(s,2H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.99–2.88(m,1H),2.82(d,J=11.0Hz,2H),2.68(t,J=7.5Hz,2H),2.60(dd,J=17.0,2.8Hz,1H),2.48–2.41(m,3H),2.34(t,J=10.8Hz,2H),2.02(ddd,J=9.6,5.5,2.0Hz,1H),1.94(ddd,J=14.4,10.7,3.8Hz,2H),1.70–1.59(m,4H),1.57–1.47(m,2H).
实施例152:3-(4-((5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)-5-氧代戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(152)
收率为39%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J=7.8Hz,1H),7.42(s,1H),7.32(q,J=8.1Hz,3H),7.25(d,J=8.1Hz,1H),5.10(dd,J=13.0,4.7Hz,1H),4.47–4.34(m,2H),4.22(d,J=17.4Hz,1H),4.15(t,J=6.1Hz,2H),3.87(d,J=12.3Hz,1H),3.27(s,1H),2.87(ddd,J=31.9,19.7,9.4Hz,2H),2.62–2.53(m,1H),2.45(d,J=6.8Hz,5H),1.94(dd,J=23.7,11.7Hz,2H),1.87–1.57(m,7H).
实施例153:3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)-4-氧代丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(153)
23%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.39(s,1H),7.35–7.24(m,4H),5.11(dd,J=13.3,5.1Hz,1H),4.99(s,2H),4.48–4.36(m,2H),4.24(d,J=17.4Hz,1H),4.17(t,J=6.3Hz,2H),3.87(d,J=11.9Hz,1H),3.27(s,1H),2.99–2.79(m,2H),2.65–2.52(m,3H),2.48–2.35(m,1H),2.01(dt,J=14.6,7.3Hz,3H),1.82(ddd,J=19.2,17.3,8.8Hz,2H),1.63(d,J=13.0Hz,2H).
实施例154:6-氯-N-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁基)-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-甲酰胺(154)
50.6mg,收率65%;1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J=7.8Hz,1H),7.38(s,1H),7.35–7.28(m,3H),7.24(d,J=8.1Hz,1H),6.54(t,J=5.2Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.97(s,2H),4.39(d,J=17.5Hz,1H),4.23(d,J=17.4Hz,1H),4.14(t,J=6.3Hz,2H),3.95(d,J=11.5Hz,2H),3.12(dd,J=12.4,6.7Hz,2H),2.99-2.85(m,3H),2.60-2.52(m,1H),2.44(dd,J=17.5,8.9Hz,1H),2.04–1.92(m,1H),1.83-1.72(m,4H),1.62-1.55(m,4H).
实施例155:6-氯-N-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-甲酰胺(155)
率60%;1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J=7.8Hz,1H),7.37(s,1H),7.34–7.28(m,4H),6.76(t,J=5.3Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.97(s,2H),4.39(d,J=17.4Hz,1H),4.25(d,J=17.4Hz,1H),4.17(t,J=6.1Hz,2H),3.96(d,J=12.7Hz,2H),3.43(dd,J=11.5,5.8Hz,2H),3.02-2.95(m,2H),2.94–2.86(m,1H),2.58(d,J=18.0Hz,1H),2.46–2.34(m,1H),2.04–1.94(m,1H),1.79(td,J=13.0,4.5Hz,2H),1.58(d,J=12.8Hz,2H).
实施例156:3-(4-(5-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(156)
11.00(s,1H),7.60–7.54(m,1H),7.49–7.44(m,2H),7.29(dd,J=8.0,4.9Hz,1H),7.18–7.06(m,2H),5.14(dd,J=13.2,5.2Hz,1H),4.93(s,2H),4.47(d,J=17.4Hz,1H),4.31(d,J=17.2Hz,1H),3.00–2.79(m,3H),2.68-2.56(m,3H),2.38(dt,J=26.6,15.4Hz,5H),2.05-1.91(m,3H),1.63(d,J=11.3Hz,4H),1.58–1.48(m,2H),1.35(dd,J=15.8,6.9Hz,2H).
实施例157:3-(4-(5-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(157)
11.00(s,1H),7.57(dd,J=5.4,3.1Hz,1H),7.51–7.41(m,2H),7.13(d,J=7.6Hz,1H),7.07(d,J=7.7Hz,1H),7.02(s,1H),5.14(dd,J=13.3,5.1Hz,1H),4.91(s,2H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),2.98–2.87(m,1H),2.80(d,J=10.8Hz,2H),2.70–2.56(m,3H),2.47–2.27(m,8H),2.03-1.98(m,1H),1.92–1.81(m,2H),1.69–1.47(m,6H),1.40–1.30(m,2H).
实施例158:N-(3-氯-4-甲基苯基)-4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰胺(158)
33.14mmol,2.0eq),-40℃搅拌30分钟,加入叔丁醇(9.83g,132.56mmol,8.0eq)逐渐升值室温,反应过夜。反应完成后,将反应体系倒入饱和碳酸氢钠溶液中,乙酸乙酯萃取,饱和氯化钠洗涤,减压浓缩得到3.75g淡黄色油状物,收率为95%。1H NMR(400MHz,CDCl3)δ3.41(t,J=6.7Hz,2H),2.25(t,J=7.3Hz,2H),1.94–1.85(m,2H),1.79–1.68(m,2H),1.44(s,9H).
步骤2:将5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(400mg,1.37mmol,1.0eq),4-溴丁酸叔丁酯(1.62g,6.85mmol,5.0eq)溶于20mL DMSO中,加入无水碳酸钾(379mg,2.74mmol,2.0eq),50℃反应24小时。反应完成后,乙酸乙酯稀释,饱和氯化钠洗涤,干燥,减压浓缩,柱层析纯化得到530mg无色油状物,收率为86%。1H NMR(400MHz,DMSO)δ7.61(s,1H),7.44(t,J=7.8Hz,1H),7.27(d,J=7.4Hz,1H),7.20(d,J=8.3Hz,1H),4.72(dd,J=10.4,4.8Hz,1H),4.50(d,J=17.6Hz,1H),4.35(d,J=17.6Hz,1H),4.11(t,J=6.0Hz,1H),3.50(s,1H),2.31–2.14(m,2H),2.06(ddd,J=13.7,10.3,6.5Hz,1H),1.79–1.62(m,2H),1.38(s,3H).
步骤3:将5-胺基-4-(4-(4-(叔丁氧基)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(530mg,1.18mmol,1.0eq)溶于20mg无水四氢呋喃中,冰浴15分钟。加入叔丁醇钾(146mg,1.30mmol,1.1eq),冰浴下继续反应90分钟。反应完成后,加入50uL甲酸淬灭反应。减压旋走溶剂,柱层析纯化得到463mg黄色固体,收率为94%;1H NMR(400MHz,DMSO)δ10.98(s,1H),7.46(d,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.23(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.37(d,J=17.3Hz,1H),4.21(d,J=17.2Hz,1H),4.12(t,J=5.9Hz,2H),2.98–2.83(m,1H),2.58(d,J=18.0Hz,1H),2.44(dd,J=17.9,8.8Hz,2H),2.27(t,J=7.1Hz,3H),2.03–1.92(m,1H),1.85–1.54(m,6H),1.40–1.36(m,13H).
步骤4:将4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酸叔丁酯(463mg,1.11mmol)置于100mL圆底烧瓶中,加入20mL盐酸二氧六环溶液,室温反应30分钟。反应完成后,旋走溶剂,无需进一步纯化直接投下一步;1H NMR(400MHz,DMSO)δ10.99(s,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.23(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.41–4.32(m,1H),4.23(t,J=12.9Hz,1H),4.12(t,J=6.0Hz,2H),3.59–3.54(m,1H),2.90(ddd,J=13.6,11.9,5.4Hz,1H),2.57(d,J=17.8Hz,1H),2.47–2.35(m,1H),2.33–2.25(m,2H),2.02–1.92(m,1H),1.71(ddd,J=19.0,13.1,5.6Hz,4H).
步骤5:将4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酸(50mg,0.139mmol,1.0eq)溶于3mL二甲基亚砜中,加入3-氯-4-甲基苯胺(0.208mmol,1.5eq),O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(79mg,0.208mmol,1.5eq),1-羟基苯并三唑(28mg,0.208mmol,1.5eq),三乙胺(141mg,1.39mmol,10eq)室温反应小时。反应完成后,乙酸乙酯稀释,饱和氯化钠洗涤,薄层色谱和高效液相色谱纯化得到产物18mg,白色固体,收率为26%;1H NMR(400MHz,DMSO)δ10.96(s,1H),10.03(s,1H),7.83(d,J=1.8Hz,1H),7.48(t,J=7.8Hz,1H),7.35–7.28(m,2H),7.24(dd,J=8.2,3.6Hz,2H),5.07(dd,J=13.4,5.0Hz,1H),4.27(d,J=17.4Hz,1H),4.14(d,J=17.1Hz,3H),2.96–2.84(m,1H),2.59–2.52(m,1H),2.25(s,3H),2.21–1.87(m,4H),1.24(s,2H).
实施例159:N-(3-氯-4-甲基苯基)-5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰胺(159)
1H NMR(400MHz,DMSO)δ10.96(s,1H),10.00(s,1H),7.80(d,J=1.9Hz,1H),7.47(t,J=7.8Hz,1H),7.36–7.28(m,2H),7.24(d,J=8.4Hz,2H),5.10(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.14(d,J=5.4Hz,2H),2.98–2.85(m,1H),2.56(d,J=19.3Hz,1H),2.46–2.32(m,3H),2.25(s,3H),2.03–1.93(m,1H),1.78(d,J=3.5Hz,4H).
实施例160:1-(3-氯-4-甲基苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲(160)
以及三苯基膦(672mg,2.56mmol)溶解于干燥的四氢呋喃(30mL)中,室温搅拌下加入DIAD(504μL,2.56mmol),所得反应液室温下搅拌反应30分钟,反应完毕,减压除去溶剂,所得残余物经硅胶柱层析得到5-胺基-4-(4-(2-(叔丁氧羰基胺基)乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯468mg,63%。
步骤2:将5-胺基-4-(4-(2-(叔丁氧羰基胺基)乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(468mg,1.07mmol)溶解于干燥的四氢呋喃中(40mL),将反应液冷却至0℃,搅拌条件下加入叔丁醇钾(133mg,1.18mmol),继续于冰浴冷却条件下搅拌反应10分钟,反应完毕,反应液用60μL甲酸淬灭,减压除去溶剂,残余物经硅胶柱层析得到目标产物350mg,81%。
步骤3:将步骤2所得产物溶解于20mL氯化氢的1,4-二氧六环溶液中,室温下搅拌反应2小时,反应完毕,减压除去溶剂得到目标产物为白色粉末固体。
步骤4:3-(4-(2-胺基乙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮盐酸盐(50mg,0.147mmol)溶解于3mL干燥DMSO中,向反应液中依次加入三乙胺(61μL,0.44mmol)和3-氯-4-甲基苯基异氰酸酯(37mg,0.22mmol),所得反应液40℃加热条件下反应3小时,反应完毕,所得反应液经HPLC分离得到目标产物1-(3-氯-4-甲基苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲48mg,收率69%;1H NMR(400MHz,DMSO)δ10.96(s,1H),8.78(s,1H),7.66(d,J=2.0Hz,1H),7.48(t,J=7.8Hz,1H),7.32(d,J=7.4Hz,1H),7.27(d,J=8.1Hz,1H),7.21–7.00(m,4H),6.46(t,J=5.6Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.3Hz,1H),4.17(t,J=5.5Hz,2H),3.49(dd,J=5.4,1.9Hz,2H),2.91(ddd,J=17.6,13.7,5.4Hz,1H),2.58(dt,J=6.8,3.3Hz,1H),2.33(ddd,J=26.6,13.4,4.5Hz,1H),2.22(s,3H),2.03–1.91(m,1H).
实施例161:1-(4-氯-3-甲基苯基)-3-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)脲(161)
收率31%;1H NMR(400MHz,DMSO)δ10.96(s,1H),8.64–8.55(m,1H),7.64(d,J=2.1Hz,1H),7.48(t,J=7.8Hz,1H),7.31(d,J=7.4Hz,1H),7.25(d,J=8.0Hz,1H),7.15(d,J=8.5Hz,1H),7.08(dd,J=8.3,2.1Hz,1H),6.32(s,1H),5.09(dd,J=13.3,5.2Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=5.9Hz,2H),3.33-3.24(m,2H),2.95–2.85(m,1H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.22(s,3H),2.01-1.88(m,3H).
实施例162:1-(3-氯-4-甲基苯基)-3-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)脲(162)
收率65%;1H NMR(400MHz,DMSO)δ10.96(s,1H),8.52(s,1H),7.63(d,J=2.0Hz,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.4Hz,1H),7.24(d,J=8.1Hz,1H),7.16(d,J=8.4Hz,1H),7.09(dd,J=8.3,2.1Hz,1H),6.22(t,J=5.8Hz,1H),5.10(dd,J=13.3,5.0Hz,1H),4.38(d,J=17.4Hz,1H),4.22(d,J=17.3Hz,1H),4.15(t,J=6.2Hz,2H),3.15(dd,J=12.8,6.6Hz,2H),2.96–2.85(m,1H),2.56(d,J=17.6Hz,1H),2.47–2.36(m,1H),2.22(s,3H),2.03–1.94(m,1H),1.76(dd,J=14.3,6.4Hz,2H),1.61(dd,J=14.4,6.9Hz,2H).
实施例163:1-(3,4-二氯苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-氧乙基)脲(163)
制备方法同1-(3-氯-4-甲基苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲,白色固体化合物,50mg,收率69%;1H NMR(400MHz,DMSO)δ10.97(s,1H),8.96(s,1H),7.85(d,J=2.5Hz,1H),7.65-7.54(m,H),7.59–7.52(m,1H),7.52–7.42(m,2H),7.27(ddd,J=13.5,11.3,5.0Hz,3H),6.56(t,J=5.7Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.4Hz,1H),4.25(d,J=17.3Hz,1H),4.18(t,J=5.5Hz,2H),3.55–3.47(m,1H),2.91(ddd,J=18.6,13.6,5.2Hz,1H),2.57(d,J=17.0Hz,2H),2.41–2.28(m,2H),2.02-1.93(m,1H).
实施例164:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-苯基戊酰胺(164)
0.109mmol)溶解于10mL二氯甲烷中,室温搅拌条件下依次加入三乙胺(46μL,0.326mmol)、HOBt(mg,mmol)以及HATU(62mg,0.163mmol),反应液室温下搅拌反应2小时,LC-MS监测反应完毕,将反应液用乙酸乙酯稀释,饱和氯化钠溶液洗涤,乙酸乙酯层经无水硫酸钠干燥,过滤,减压除去溶剂,所得粗品直接用于下一步。
步骤2:将步骤1得到的反应粗品溶解于10mL氯化氢的1,4-二氧六环饱和溶液,反应液在室温下反应2小时,LC-MS监测反应完毕,减压除去溶剂,残余物用乙酸乙酯稀释,依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,乙酸乙酯层用无水硫酸钠干燥,过滤,减压干燥得到反应粗品直接用于下一步反应。
步骤3:将步骤2中的反应粗品溶解于10mL干燥的二氯甲烷中,室温搅拌下依次加入三乙胺(152μL,1.09mmol)和乙酰氯(16μL,0.218mmol),反应液继续于室温下搅拌反应过夜,LC-MS监测反应完毕,减压除去溶剂,残余物溶解于乙酸乙酯中,依次用饱和碳酸氢钠和饱和氯化钠溶液洗涤。乙酸乙酯层用无水硫酸钠干燥,过滤,滤液减压干燥,所得粗品经反相HPLC分离得到(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-苯基戊酰胺10.2mg,收率19%;1H NMR(400MHz,DMSO)δ10.95(s,1H),10.08(d,J=5.3Hz,1H),8.18(d,J=7.8Hz,1H),7.63–7.51(m,3H),7.48–7.40(m,2H),7.29(t,J=7.8Hz,2H),7.04(t,J=7.3Hz,1H),5.12(dd,J=13.3,5.0Hz,1H),4.47(dd,J=12.1,6.8Hz,1H),4.39(d,J=17.3Hz,1H),4.26(dd,J=17.1,6.3Hz,1H),2.99–2.85(m,1H),2.73–2.56(m,3H),2.30(dtd,J=16.3,12.3,3.0Hz,1H),2.05–1.92(m,1H),1.86(s,3H),1.80–1.50(m,4H).
实施例165:N-((2S)-1-(苄氨基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丙基甲酰胺(165)
Hz,1H),7.57(d,J=7.3Hz,1H),7.46(t,J=7.5Hz,1H),7.40(d,J=7.2Hz,1H),7.29(dd,J=10.4,4.2Hz,2H),7.24–7.18(m,3H),5.75(s,2H),5.14(ddd,J=8.5,4.9,4.1Hz,1H),4.48–4.34(m,2H),4.33–4.20(m,3H),2.99–2.86(m,1H),2.63(dd,J=19.4,12.7Hz,3H),2.46–2.29(m,1H),2.06–1.95(m,1H),1.79–1.49(m,5H),0.73–0.57(m,4H).
实施例166:(2S)-2-乙酰氨基-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(166)
DMSO)δ11.00(s,1H),8.46(td,J=5.7,2.6Hz,1H),8.04(d,J=7.9Hz,1H),7.57(d,J=7.1Hz,1H),7.49–7.37(m,2H),7.33–7.17(m,3H),5.14(ddd,J=13.0,5.7,1.1Hz,1H),4.43(dd,J=17.4,7.0Hz,1H),4.36–4.23(m,3H),2.99–2.87(m,1H),2.69–2.57(m,3H),2.37(ddd,J=18.1,10.9,5.9Hz,1H),2.05–1.94(m,1H),1.85(s,3H),1.63(ddd,J=35.4,18.8,7.9Hz,4H).
实施例167:(2S)-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-异丁酰胺基戊酰胺(167)
MHz,DMSO)δ11.00(s,1H),8.42(dd,J=9.5,5.9Hz,1H),7.89(d,J=8.2Hz,1H),7.57(d,J=7.4Hz,1H),7.46(t,J=7.5Hz,1H),7.40(d,J=7.0Hz,1H),7.29(dd,J=10.2,4.3Hz,2H),7.22(dd,J=6.9,3.5Hz,3H),5.14(ddd,J=13.2,5.0,3.1Hz,1H),4.43(dd,J=17.1,6.0Hz,1H),4.38–4.31(m,1H),4.31–4.20(m,3H),2.99–2.87(m,1H),2.69–2.56(m,3H),2.49–2.43(m,1H),2.37(ddd,J=17.8,11.3,4.4Hz,1H),2.05–1.95(m,1H),1.72(dt,J=8.9,5.6Hz,1H),1.66–1.45(m,3H),0.98(dd,J=6.8,3.2Hz,6H).
实施例168:(2S)-2-乙酰氨基-N-叔丁基-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(168)
DMSO)δ10.99(s,1H),7.86(d,J=8.4Hz,1H),7.59–7.51(m,2H),7.45(dt,J=7.4,6.9Hz,2H),5.15(dd,J=13.2,5.1Hz,1H),4.44(dd,J=17.1,7.2Hz,1H),4.28(dd,J=18.7,8.9Hz,2H),3.00–2.86(m,1H),2.70–2.56(m,3H),2.40(ddd,J=28.4,14.4,5.0Hz,1H),2.02(dt,J=12.1,4.9Hz,1H),1.82(s,3H),1.66–1.43(m,4H),1.23(d,J=0.8Hz,9H).
实施例169:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((R)-1-苯乙基)戊酰胺(169)
合成方法同(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-苯基戊酰胺,17.3mg,收率53%;1H NMR(400MHz,DMSO)δ11.01(s,1H),8.37(dd,J=8.0,5.0Hz,1H),7.97(d,J=8.3Hz,1H),7.58(dd,J=6.9,1.6Hz,1H),7.50–7.42(m,2H),7.30(d,J=4.3Hz,4H),7.26–7.18(m,1H),5.15(dd,J=13.3,5.1Hz,1H),4.95–4.85(m,1H),4.45(dd,J=17.2,6.5Hz,1H),4.36(dd,J=14.4,6.6Hz,1H),4.29(d,J=17.0Hz,1H),2.94(ddd,J=17.5,13.8,5.4Hz,1H),2.74–2.58(m,3H),2.41(ddd,J=16.8,13.5,4.2Hz,1H),2.02(ddd,J=9.6,4.7,2.2Hz,1H),1.81(s,3H),1.75–1.51(m,4H),1.32(d,J=7.0Hz,3H).
实施例170:(2S)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-2-)苯基)戊酰胺(170)
离,37mg,收率66%;1H NMR(400MHz,DMSO)δ10.99(s,1H),8.63(t,J=6.1Hz,1H),8.29(dd,J=8.2,1.3Hz,1H),7.90(tt,J=7.8,1.9Hz,1H),7.81(d,J=7.8Hz,1H),7.73(dt,J=7.8,1.6Hz,1H),7.56(d,J=7.4Hz,1H),7.48–7.40(m,2H),7.39–7.32(m,2H),7.23(td,J=7.7,1.1Hz,1H),5.12(dd,J=13.2,4.8Hz,1H),4.40(d,J=17.0Hz,1H),4.25(d,J=17.1Hz,1H),3.66(d,J=4.6Hz,1H),2.99–2.84(m,1H),2.69–2.55(m,3H),2.39–2.22(m,1H),1.98(dd,J=11.4,6.1Hz,1H),1.87–1.72(m,1H),1.63(s,3H).
实施例171:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((S)-1-苯乙基)戊酰胺(171)
49%;1H NMR(400MHz,DMSO)δ11.00(d,J=2.7Hz,1H),8.46(d,J=8.0Hz,1H),7.97(d,J=8.3Hz,1H),7.57(dd,J=7.5,1.0Hz,1H),7.44(td,J=7.5,1.6Hz,1H),7.33(d,J=7.5Hz,1H),7.31–7.15(m,5H),5.13(ddd,J=13.2,5.0,2.4Hz,1H),4.96–4.85(m,1H),4.44–4.33(m,2H),4.23(dd,J=17.1,9.9Hz,1H),2.99–2.86(m,1H),2.64(ddd,J=13.5,7.7,4.6Hz,3H),2.45–2.31(m,1H),1.99(ddd,J=6.8,5.2,2.2Hz,1H),1.84(d,J=1.8Hz,3H),1.69–1.41(m,4H),1.34(dd,J=7.0,2.7Hz,3H).
实施例172:(2S)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-3-)苯基)戊酰胺(172)
38mg,收率68%;1H NMR(400MHz,DMSO)δ11.00(s,1H),8.58(s,1H),8.54(dd,J=4.8,1.5Hz,1H),8.23(s,1H),7.85(d,J=7.9Hz,1H),7.80(d,J=7.8Hz,1H),7.58(dd,J=7.0,1.2Hz,1H),7.51–7.38(m,4H),7.34(dd,J=7.5,1.4Hz,1H),7.28(t,J=7.4Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.45(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),3.41(dd,J=6.8,5.2Hz,1H),2.99–2.85(m,1H),2.66–2.54(m,3H),2.45–2.31(m,1H),2.05–1.95(m,1H),1.73–1.62(m,1H),1.57(dt,J=14.8,7.4Hz,2H),1.51–1.40(m,1H).
实施例173:N-((2S)-1-(苄胺)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丁基甲酰胺(173)
Hz,1H),7.57(d,J=7.3Hz,1H),7.45(t,J=7.5Hz,1H),7.39(d,J=7.3Hz,1H),7.28(dd,J=10.3,4.3Hz,2H),7.24–7.17(m,3H),5.75(s,2H),5.18–5.10(m,1H),4.43(dd,J=17.2,6.3Hz,1H),4.35(dd,J=13.7,7.9Hz,1H),4.30–4.20(m,3H),3.09(p,J=8.2Hz,1H),3.00–2.85(m,1H),2.71–2.56(m,3H),2.39(tdd,J=16.9,8.3,3.8Hz,1H),2.18–1.93(m,5H),1.87(dt,J=17.6,8.7Hz,1H),1.74(ddd,J=14.4,9.0,3.5Hz,2H),1.63–1.49(m,3H).
实施例174:(2S)-N-((3R,5R,7R)-金刚烷-1-)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(174)
离,51mg,收率94%;1H NMR(400MHz,DMSO)δ11.04(s,1H),8.10(d,J=7.5Hz,1H),7.58(d,J=7.1Hz,1H),7.50–7.40(m,2H),5.75(s,1H),5.15(dd,J=13.2,5.0Hz,1H),4.45(d,J=17.1Hz,1H),4.29(dd,J=17.0,4.2Hz,1H),3.85(d,J=6.5Hz,1H),3.71–3.64(m,1H),3.00–2.87(m,1H),2.71–2.56(m,3H),2.39(ddd,J=26.3,13.2,4.3Hz,1H),2.06–1.90(m,2H),1.63(ddd,J=68.6,36.4,13.9Hz,17H).
实施例175:(2S)-2-乙酰氨基-N-((S)-2,3-二氢-1H-茚-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(175)
DMSO)δ10.99(s,1H),8.32(d,J=8.3Hz,1H),8.01(dd,J=8.2,3.7Hz,1H),7.57(d,J=6.9Hz,1H),7.44(dt,J=7.4,6.9Hz,2H),7.26–7.09(m,3H),7.05(d,J=6.9Hz,1H),5.27(q,J=8.1Hz,1H),5.13(ddd,J=13.3,4.8,3.8Hz,1H),4.36(ddd,J=32.6,31.1,17.1Hz,3H),2.99–2.85(m,2H),2.84–2.73(m,1H),2.72–2.55(m,3H),2.45–2.29(m,2H),1.98(dddd,J=15.4,9.8,4.8,2.6Hz,1H),1.84(s,3H),1.82–1.68(m,2H),1.63(dd,J=18.5,6.0Hz,3H).
实施例176:(2S)-N-((1S,3S,5S,7S)-金刚烷-2-)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(176)
离,47mg,收率87%;1H NMR(400MHz,DMSO)δ11.01(s,1H),7.72(s,1H),7.59(d,J=7.1Hz,1H),7.51–7.42(m,2H),5.75(s,1H),5.15(dd,J=13.3,4.9Hz,1H),4.45(d,J=17.1Hz,1H),4.30(dd,J=17.1,3.2Hz,1H),3.51(s,1H),3.02–2.87(m,1H),2.70–2.57(m,3H),2.46–2.31(m,1H),2.01(s,4H),1.89(s,6H),1.73–1.48(m,10H).
实施例177:(2S)-2-乙酰氨基-N-((R)-2,3-二氢-1H-茚-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(177)
NMR(400MHz,DMSO)δ11.01(s,1H),8.33(d,J=8.0Hz,1H),8.01(d,J=7.8Hz,1H),7.58(d,J=6.6Hz,1H),7.51–7.41(m,2H),7.29–7.12(m,4H),5.33–5.21(m,1H),5.15(dd,J=13.0,4.4Hz,1H),4.45(dd,J=17.4,6.7Hz,1H),4.30(t,J=11.8Hz,2H),2.92(ddd,J=13.1,10.9,3.5Hz,2H),2.83–2.73(m,1H),2.72–2.57(m,3H),2.46–2.29(m,2H),2.02(dd,J=8.8,4.7Hz,1H),1.85(s,3H),1.79–1.68(m,2H),1.68–1.51(m,3H).
实施例178:(2S)-2-乙酰氨基-N-(2,4-二氟苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(178)
DMSO)δ11.01(s,1H),8.48(td,J=5.7,1.8Hz,1H),8.06(dd,J=7.9,1.4Hz,1H),7.57(d,J=7.2Hz,1H),7.45(t,J=7.5Hz,1H),7.39(d,J=7.2Hz,1H),7.32(td,J=8.6,6.8Hz,1H),7.23–7.15(m,1H),7.02(td,J=8.6,2.5Hz,1H),5.14(dd,J=13.4,5.2Hz,1H),4.43(dd,J=17.0,4.8Hz,1H),4.34–4.23(m,4H),2.99–2.87(m,1H),2.68–2.55(m,3H),2.40(ddd,J=16.7,13.2,5.1Hz,1H),2.06–1.96(m,1H),1.84(s,3H),1.73–1.64(m,1H),1.62–1.48(m,3H).
实施例179:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((S)-1,2,3,4-四氢萘基-1-)戊酰胺(179)
δ10.99(s,1H),8.26(dd,J=8.6,1.2Hz,1H),7.97(dd,J=8.1,2.6Hz,1H),7.57(d,J=6.2Hz,1H),7.44(dt,J=7.5,6.9Hz,2H),7.17–7.10(m,1H),7.06(dt,J=12.5,5.3Hz,3H),5.13(ddd,J=13.2,4.9,3.3Hz,1H),4.95(t,J=7.5Hz,1H),4.36(ddd,J=37.5,31.1,17.1Hz,3H),2.92(tdd,J=17.3,5.1,1.6Hz,1H),2.80–2.55(m,5H),2.46–2.30(m,1H),2.04–1.94(m,1H),1.91–1.80(m,5H),1.77–1.55(m,6H).
实施例180:(2S)-2-乙酰氨基-N-(2,4-二甲氧基苄基)-5-(2-(2,6-二哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(180)
DMSO)δ11.03(s,1H),8.20(td,J=5.9,1.9Hz,1H),8.04(dd,J=8.2,2.0Hz,1H),7.58(d,J=7.3Hz,1H),7.46(t,J=7.4Hz,1H),7.41(d,J=7.5Hz,1H),7.03(d,J=8.4Hz,1H),6.52(d,J=2.4Hz,1H),6.42(dd,J=8.3,2.4Hz,1H),5.15(dd,J=12.9,4.9Hz,1H),4.44(dd,J=17.0,6.9Hz,1H),4.38–4.32(m,1H),4.28(dd,J=17.1,3.9Hz,1H),4.17(dd,J=15.2,5.8Hz,1H),4.10(ddd,J=15.4,5.7,1.6Hz,1H),3.74(s,3H),3.73(s,3H),3.01–2.87(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.06–1.94(m,1H),1.84(s,3H),1.75–1.47(m,4H).
实施例181:(2S)-2-乙酰氨基-N-二苯甲基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(181)
MHz,DMSO)δ11.00(d,J=3.3Hz,1H),8.92(dd,J=8.5,5.9Hz,1H),8.03(d,J=8.2Hz,1H),7.57(d,J=7.5Hz,1H),7.44(t,J=7.5Hz,1H),7.38–7.18(m,10H),6.10(d,J=8.7Hz,1H),5.13(dd,J=12.9,5.2Hz,1H),4.49(dt,J=7.8,5.2Hz,1H),4.39(dd,J=17.1,2.3Hz,1H),4.24(dd,J=17.1,7.2Hz,1H),3.00–2.86(m,1H),2.69–2.56(m,3H),2.45–2.29(m,1H),2.07–1.94(m,1H),1.83(d,J=1.5Hz,3H),1.74–1.44(m,4H).
实施例182:(2S)-2-乙酰氨基-N-(3-溴苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(182)
MHz,DMSO)δ11.03(s,1H),8.54(td,J=6.1,2.3Hz,1H),8.10(dd,J=8.0,1.0Hz,1H),7.57(d,J=7.2Hz,1H),7.49–7.38(m,4H),7.29–7.19(m,2H),5.14(ddd,J=13.3,4.9,1.2Hz,1H),4.43(dd,J=17.2,7.6Hz,1H),4.30(ddd,J=17.4,11.1,4.4Hz,4H),3.00–2.87(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.05–1.95(m,1H),1.85(s,3H),1.71(dt,J=11.5,7.0Hz,1H),1.64–1.51(m,3H).
实施例183:(2S)-N-(3-氯-4-甲基苯基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-异丁酰氨基戊酰胺(183)
DMSO)δ11.00(d,J=4.2Hz,1H),10.17(d,J=2.4Hz,1H),8.03(d,J=7.7Hz,1H),7.83–7.77(m,1H),7.57(dd,J=6.6,1.8Hz,1H),7.50–7.40(m,2H),7.36(dd,J=8.3,2.1Hz,1H),7.26(d,J=8.4Hz,1H),5.13(dd,J=13.7,5.7Hz,1H),4.42(dd,J=17.0,11.7Hz,2H),4.28(dd,J=17.1,5.4Hz,1H),2.99–2.87(m,1H),2.68(t,J=7.1Hz,2H),2.65–2.55(m,2H),2.34(ddd,J=15.4,13.2,5.0Hz,1H),2.26(s,3H),2.05–1.94(m,1H),1.82–1.53(m,4H),1.05–0.93(m,6H).
实施例184:(2S)-2-乙酰氨基-N-(3-氯苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(184)
DMSO)δ11.03(s,1H),8.54(td,J=5.9,2.4Hz,1H),8.10(d,J=8.1Hz,1H),7.57(d,J=7.1Hz,1H),7.45(t,J=7.4Hz,1H),7.40(d,J=7.4Hz,1H),7.35–7.25(m,3H),7.18(d,J=7.3Hz,1H),5.14(ddd,J=13.5,4.8,1.0Hz,1H),4.43(dd,J=17.2,7.3Hz,1H),4.35–4.22(m,4H),3.00–2.86(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.00(dd,J=10.4,5.7Hz,1H),1.85(s,3H),1.77–1.65(m,1H),1.65–1.49(m,3H).
实施例185:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丙基甲酰胺(185)
MHz,DMSO)δ11.00(d,J=3.7Hz,1H),10.22(d,J=4.1Hz,1H),8.43(d,J=7.9Hz,1H),7.82(dd,J=3.5,2.2Hz,1H),7.58(dd,J=5.9,2.6Hz,1H),7.49–7.42(m,2H),7.36(dd,J=8.3,2.0Hz,1H),7.27(d,J=8.3Hz,1H),5.13(dd,J=14.0,4.9Hz,1H),4.50–4.37(m,2H),4.28(dd,J=17.1,7.1Hz,1H),3.00–2.87(m,1H),2.69(t,J=7.1Hz,2H),2.65–2.56(m,1H),2.44–2.29(m,1H),2.27(s,3H),2.00(tdd,J=9.9,6.2,3.9Hz,1H),1.83–1.55(m,5H),0.65(dd,J=6.1,2.6Hz,4H).
实施例186:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(4-(吡咯烷-1-)苄基)戊酰胺(186)
MHz,DMSO)δ11.02(s,1H),8.31(td,J=5.8,1.6Hz,1H),8.01(dd,J=8.3,2.0Hz,1H),7.56(d,J=7.3Hz,1H),7.44(t,J=7.5Hz,1H),7.38(d,J=7.3Hz,1H),7.01(d,J=8.3Hz,2H),6.43(dd,J=8.7,2.4Hz,2H),5.14(dd,J=13.5,5.2Hz,1H),4.42(dd,J=17.1,10.4Hz,1H),4.29(ddd,J=22.5,11.9,4.6Hz,2H),4.20–4.04(m,2H),3.16(td,J=6.4,2.2Hz,4H),2.99–2.87(m,1H),2.60(dt,J=5.9,4.6Hz,3H),2.46–2.31(m,1H),2.04–1.96(m,1H),1.96–1.90(m,4H),1.83(s,3H),1.73–1.64(m,1H),1.61–1.49(m,3H).
实施例187:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丁基甲酰胺(187)
7.95(d,J=7.9Hz,1H),7.80(dd,J=3.2,2.3Hz,1H),7.57(dd,J=6.6,1.7Hz,1H),7.49–7.40(m,2H),7.36(dd,J=8.3,2.1Hz,1H),7.26(d,J=8.3Hz,1H),5.12(ddd,J=13.3,5.0,1.5Hz,1H),4.47–4.35(m,2H),4.27(dd,J=17.1,5.2Hz,1H),3.11(p,J=8.3Hz,1H),3.01–2.87(m,1H),2.67(t,J=7.2Hz,2H),2.64–2.56(m,1H),2.42–2.29(m,1H),2.26(s,3H),2.17–2.05(m,2H),2.04–1.95(m,3H),1.87(dt,J=17.7,8.7Hz,1H),1.79–1.71(m,2H),1.70–1.53(m,3H).
实施例188:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-苯基丙基-2-)戊酰胺(188)
DMSO)δ11.02(s,1H),8.16(d,J=3.4Hz,1H),7.89(d,J=8.1Hz,1H),7.60–7.56(m,1H),7.47(ddd,J=13.4,9.8,4.2Hz,2H),7.29(dd,J=5.7,4.2Hz,2H),7.23(td,J=7.6,1.8Hz,2H),7.18–7.11(m,1H),5.15(ddd,J=13.1,5.1,1.3Hz,1H),4.49–4.36(m,2H),4.28(dd,J=17.3,6.2Hz,1H),3.00–2.88(m,1H),2.71–2.57(m,3H),2.45–2.31(m,1H),2.06–1.96(m,1H),1.83(s,3H),1.72–1.45(m,10H).
实施例189:6-胺基-N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)己酰胺(189)
DMSO)δ11.00(d,J=3.2Hz,1H),10.29(s,1H),8.20(d,J=6.9Hz,1H),7.83(dd,J=8.8,6.4Hz,4H),7.57(dd,J=6.6,1.9Hz,1H),7.42(ddd,J=11.3,10.3,4.7Hz,3H),7.26(d,J=8.4Hz,1H),5.13(dd,J=13.3,5.0Hz,1H),4.43(dd,J=17.1,11.9Hz,2H),4.28(dd,J=17.1,4.6Hz,1H),2.93(ddd,J=17.6,11.8,4.9Hz,1H),2.70(dt,J=19.6,6.6Hz,4H),2.60(d,J=17.0Hz,1H),2.43–2.30(m,1H),2.26(s,3H),2.15(t,J=7.4Hz,2H),1.99(dd,J=10.8,5.2Hz,1H),1.84–1.57(m,4H),1.51(tt,J=15.6,7.7Hz,4H),1.26(dt,J=13.7,6.9Hz,2H).
实施例190:(2S)-2-乙酰氨基-N-(4-(2-(二甲氨基)乙氧基)苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(190)
(400MHz,DMSO)δ11.03(s,1H),8.42(t,J=5.2Hz,1H),8.16(s,1H),8.04(d,J=8.4Hz,1H),7.57(d,J=7.3Hz,1H),7.45(t,J=7.5Hz,1H),7.39(d,J=7.3Hz,1H),7.13(d,J=8.4Hz,2H),6.85(d,J=8.3Hz,2H),5.14(dd,J=13.6,4.8Hz,1H),4.43(dd,J=16.8,7.5Hz,1H),4.34–4.23(m,2H),4.22–4.14(m,2H),4.04(t,J=5.5Hz,2H),3.00–2.87(m,1H),2.76(t,J=5.4Hz,2H),2.61(dd,J=25.9,7.7Hz,3H),2.43–2.36(m,1H),2.32(s,6H),2.05–1.95(m,1H),1.84(s,3H),1.73–1.64(m,1H),1.63–1.49(m,3H).
实施例191:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)哌啶-4-甲酰胺(191)
9.3Hz,1H),8.67–8.49(m,1H),8.31(d,J=7.8Hz,1H),7.82(t,J=2.3Hz,1H),7.57(dd,J=6.6,1.8Hz,1H),7.48–7.41(m,2H),7.38(dd,J=8.3,2.0Hz,1H),7.26(d,J=8.4Hz,1H),5.13(dd,J=13.2,4.9Hz,1H),4.49–4.38(m,2H),4.28(dt,J=5.9,3.5Hz,1H),3.30–3.17(m,2H),3.01–2.76(m,3H),2.68(t,J=6.9Hz,2H),2.65–2.52(m,2H),2.37(ddd,J=26.3,13.1,4.2Hz,1H),2.26(s,3H),2.00(td,J=10.3,5.1Hz,1H),1.91–1.53(m,8H).
实施例192:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(4-苯氧基苄基)戊酰胺(192)
MHz,DMSO)δ11.02(s,1H),8.49(td,J=5.9,2.1Hz,1H),8.06(dd,J=8.0,1.2Hz,1H),7.56(dd,J=7.0,1.5Hz,1H),7.45–7.34(m,4H),7.24(d,J=8.6Hz,2H),7.13(td,J=7.4,0.5Hz,1H),6.99–6.91(m,4H),5.14(dd,J=13.2,5.0Hz,1H),4.43(dd,J=17.2,7.4Hz,1H),4.32(ddd,J=13.6,8.5,3.6Hz,2H),4.25(d,J=6.1Hz,2H),2.99–2.86(m,1H),2.71–2.55(m,3H),2.40(ddd,J=17.5,13.8,5.6Hz,1H),2.00(ddd,J=8.4,5.8,3.2Hz,1H),1.84(s,3H),1.75–1.66(m,1H),1.65–1.47(m,3H).
实施例193:N-((2S)-1-(3-氯-4-甲基苯胺)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)-6-羟基己酰胺(193)
1H NMR(400MHz,DMSO)δ10.98(s,1H),10.16(d,J=3.4Hz,1H),8.11(d,J=7.8Hz,1H),7.83–7.76(m,1H),7.57(dd,J=6.4,2.0Hz,1H),7.49–7.41(m,2H),7.36(dd,J=8.3,2.0Hz,1H),7.26(d,J=8.3Hz,1H),5.12(dd,J=13.3,3.5Hz,1H),4.47–4.37(m,2H),4.29(dt,J=17.1,5.6Hz,2H),3.37–3.33(m,2H),2.93(t,J=13.9Hz,1H),2.68(t,J=7.0Hz,2H),2.59(d,J=17.3Hz,1H),2.43–2.29(m,1H),2.26(s,3H),2.13(t,J=7.2Hz,2H),1.99(dd,J=12.0,5.2Hz,1H),1.78–1.56(m,4H),1.48(dt,J=15.1,7.5Hz,2H),1.43–1.34(m,2H),1.30–1.19(m,2H).
实施例194:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-2-)苯基)戊酰胺(194)
DMSO)δ12.17(s,1H),11.01(s,1H),8.72–8.68(m,1H),8.43(dd,J=7.2,1.9Hz,1H),8.37(dd,J=8.2,0.6Hz,1H),7.99–7.93(m,1H),7.89(d,J=8.3Hz,1H),7.78(dd,J=8.0,1.3Hz,1H),7.56(dd,J=7.2,1.2Hz,1H),7.42(ddd,J=12.4,9.6,4.5Hz,3H),7.21(td,J=7.9,1.3Hz,1H),5.13(dd,J=13.3,5.2Hz,1H),4.43(d,J=17.2Hz,1H),4.33–4.22(m,2H),3.00–2.86(m,1H),2.71–2.56(m,3H),2.44–2.27(m,1H),1.99(dtd,J=12.5,5.1,2.4Hz,1H),1.95–1.76(m,4H),1.75–1.55(m,3H).
实施例195:3-(4-((S)-4-胺基-4-(7-溴-1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(195)
室温搅拌下加入三乙胺(84μL,0.6mmol)和HATU(152mg,0.4mmol),所得反应液继续于室温下搅拌反应4小时,LC-MS监测缩合反应完毕。减压除去溶剂,向所得残余物中加入乙酸5mL,将反应液温度升温至110℃回流反应2小时,LC-MS监测反应完毕。减压除去溶剂,残余物经HPLC分离得到目标产物3-(4-((S)-4-胺基-4-(7-溴-1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮84mg,白色固体,收率82%;1H NMR(400MHz,DMSO)δ7.56(dd,J=8.2,3.0Hz,2H),7.43(q,J=7.6Hz,3H),7.14(t,J=7.9Hz,1H),5.12(dd,J=13.2,4.9Hz,1H),4.50(t,J=6.5Hz,1H),4.31(ddd,J=24.0,19.8,12.0Hz,3H),3.00–2.86(m,1H),2.64(dd,J=19.6,12.5Hz,3H),2.54(s,2H),2.41–2.22(m,1H),2.01(dd,J=14.6,8.4Hz,3H),1.75–1.54(m,2H).
实施例196:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-3-)苯基)戊酰胺(196)
DMSO)δ11.02(d,J=3.0Hz,1H),9.53(d,J=3.8Hz,1H),8.55–8.52(m,1H),8.49(dt,J=4.8,1.6Hz,1H),8.04(dd,J=7.7,1.7Hz,1H),7.74(ddd,J=7.7,3.8,1.8Hz,1H),7.58(d,J=7.4Hz,1H),7.52–7.40(m,4H),7.40–7.30(m,3H),5.14(dd,J=12.5,5.2Hz,1H),4.43(dd,J=17.3,9.0Hz,1H),4.30(ddd,J=18.9,13.1,3.5Hz,2H),2.93(t,J=14.7Hz,1H),2.60(t,J=7.1Hz,3H),2.38(ddd,J=20.5,14.9,4.7Hz,1H),2.05–1.93(m,1H),1.81(s,3H),1.66–1.40(m,4H).
实施例197:N-((1S)-1-(7-溴-1H-苯并[d]咪唑-2-)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)乙酰胺(197)
室温搅拌下依次加入三乙胺(85μL,0.61mmol)和乙酰氯(5μL,0.072mmol),反应液继续于室温下搅拌反应2小时。反应完毕,反应液用乙酸乙酯萃取,有机相经无水硫酸钠干燥,过滤,减压干燥,所得粗品经HPLC分离得到产物15.5mg,收率46%;1H NMR(400MHz,DMSO)δ12.63(d,J=14.9Hz,1H),11.00(s,1H),8.51(d,J=8.0Hz,1H),7.56(dd,J=5.3,3.2Hz,1H),7.45(dd,J=8.1,5.2Hz,3H),7.36(dd,J=7.6,4.4Hz,1H),7.09(td,J=7.5,3.0Hz,1H),5.26–5.07(m,2H),4.50–4.18(m,2H),3.00–2.87(m,1H),2.71(dd,J=16.9,8.1Hz,2H),2.65–2.56(m,1H),2.35(ddd,J=12.5,10.5,4.4Hz,1H),2.13–1.96(m,2H),1.95–1.82(m,4H),1.76–1.52(m,2H).
实施例198:(2S)-2-乙酰氨基-N-((3R,5R,7R)-金刚烷-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(198)
DMSO)δ11.01(s,1H),7.85(d,J=8.3Hz,1H),7.57(dd,J=7.1,1.1Hz,1H),7.44(ddd,J=13.0,10.7,6.4Hz,3H),5.15(dd,J=13.4,5.3Hz,1H),4.43(dd,J=16.9,6.6Hz,1H),4.33–4.23(m,2H),3.00–2.87(m,1H),2.62(ddd,J=19.9,7.6,3.5Hz,3H),2.46–2.32(m,1H),2.07–1.94(m,4H),1.81(d,J=2.1Hz,9H),1.67–1.43(m,10H).
实施例199:3-(4-((S)-4-胺基-4-(1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(199)
DMSO)δ10.99(s,1H),8.24(s,1H),7.55(dd,J=5.6,2.9Hz,1H),7.53–7.47(m,2H),7.46–7.40(m,2H),7.17–7.09(m,2H),5.11(dd,J=13.3,5.1Hz,1H),4.37(dd,J=21.6,17.2Hz,1H),4.23(dd,J=14.5,7.8Hz,2H),2.98–2.85(m,1H),2.70–2.56(m,3H),2.30(tdd,J=26.1,13.0,4.4Hz,2H),1.96(ddd,J=17.0,12.2,6.0Hz,2H),1.89–1.78(m,1H),1.73–1.55(m,2H).
实施例200:(2S)-2-乙酰氨基-N-((1S,3S,5S,7S)-金刚烷-2-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(200)
DMSO)δ10.99(s,1H),7.96(d,J=8.4Hz,1H),7.76(dd,J=7.3,2.7Hz,1H),7.57(dd,J=6.9,1.4Hz,1H),7.49–7.39(m,2H),5.14(dd,J=13.2,5.1Hz,1H),4.46(ddd,J=19.3,15.4,4.6Hz,2H),4.27(d,J=17.1Hz,1H),3.80(d,J=6.8Hz,1H),3.01–2.85(m,1H),2.73–2.57(m,3H),2.40(ddd,J=22.7,13.5,4.5Hz,1H),2.11–1.92(m,2H),1.91–1.38(m,20H).
实施例201:3-(4-((S)-4-胺基-4-(3H-咪唑[4,5-c]吡啶-2-)丁基)-1-氧代吲哚啉-2-)哌啶-2,6-二酮(201)
DMSO)δ11.00(s,1H),9.50(s,1H),9.04(d,J=53.3Hz,2H),8.58(dd,J=29.1,6.2Hz,1H),8.13(dd,J=51.3,6.3Hz,1H),7.63–7.51(m,1H),7.43(d,J=4.0Hz,2H),5.12(d,J=11.0Hz,1H),4.88(s,1H),4.55–4.39(m,1H),4.34–4.21(m,1H),3.00–2.85(m,1H),2.76–2.58(m,3H),2.44–2.30(m,1H),2.18(d,J=6.0Hz,2H),2.05–1.87(m,1H),1.78–1.61(m,2H).
实施例202:(2S)-2-乙酰氨基-N-(3-氯-4-甲基苯基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(202)
DMSO)δ10.99(s,1H),10.17(d,J=3.8Hz,1H),8.20(d,J=7.8Hz,1H),7.81(dd,J=3.3,2.2Hz,1H),7.57(dd,J=5.9,2.6Hz,1H),7.49–7.41(m,2H),7.37(dd,J=8.3,2.0Hz,1H),7.26(d,J=8.4Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.42(dd,J=16.9,13.3Hz,2H),4.27(dd,J=17.1,4.5Hz,1H),3.00–2.86(m,1H),2.68(t,J=6.8Hz,2H),2.59(ddd,J=7.4,6.7,2.4Hz,1H),2.42–2.29(m,1H),2.26(s,3H),1.99(dd,J=12.4,5.2Hz,1H),1.86(s,3H),1.80–1.53(m,4H).
实施例203:N-((1S)-1-(1H-苯并[d]咪唑-2-)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)酰胺(203)
NMR(400MHz,DMSO)δ10.99(s,1H),8.24(s,1H),7.55(dd,J=5.6,2.9Hz,1H),7.53–7.47(m,2H),7.46–7.40(m,2H),7.17–7.09(m,2H),5.11(dd,J=13.3,5.1Hz,1H),4.37(dd,J=21.6,17.2Hz,1H),4.23(dd,J=14.5,7.8Hz,2H),2.98–2.85(m,1H),2.70–2.56(m,3H),2.30(tdd,J=26.1,13.0,4.4Hz,2H),1.96(ddd,J=17.0,12.2,6.0Hz,2H),1.91(s,3H),1.89–1.78(m,1H),1.73–1.55(m,2H).
实施例204:(2S)-2-乙酰氨基-N-苄基-5-(2-(2,6-氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-甲基戊酰胺(204)
DMSO)δ11.00(s,1H),8.20(ddd,J=9.9,9.0,1.7Hz,1H),7.56(t,J=6.4Hz,1H),7.49–7.40(m,2H),7.39–7.29(m,2H),7.28–7.20(m,2H),7.18(d,J=7.2Hz,1H),5.17–5.09(m,1H),4.79(s,1H),4.64–4.18(m,4H),2.99–2.75(m,4H),2.64(ddd,J=20.4,15.7,4.6Hz,3H),2.39(ddd,J=22.0,16.2,7.2Hz,1H),2.01(dd,J=10.9,5.0Hz,1H),1.80(d,J=34.8Hz,3H),1.73–1.40(m,4H).
实施例205:N-((1S)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-(3H-咪唑[4,5-c]吡啶-2-)丁基)乙酰胺(205)
8.52(d,J=8.0Hz,1H),8.26(d,J=5.5Hz,1H),8.17(s,1H),7.60–7.54(m,1H),7.52–7.48(m,1H),7.47–7.42(m,2H),5.21–5.09(m,2H),4.43(t,J=16.5Hz,1H),4.28(d,J=17.1Hz,1H),3.01–2.88(m,1H),2.76–2.57(m,3H),2.45–2.29(m,1H),2.13–1.96(m,2H),1.91(s,3H),1.76–1.59(m,2H).
实施例206:(2S)-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-丙酰胺基戊酰胺(206)
DMSO)δ11.00(s,1H),8.44(d,J=1.9Hz,1H),7.94(d,J=7.8Hz,1H),7.57(d,J=7.2Hz,1H),7.46(t,J=7.3Hz,1H),7.40(d,J=7.4Hz,1H),7.32–7.25(m,2H),7.22(d,J=7.1Hz,3H),5.75(d,J=2.3Hz,1H),5.14(dd,J=11.8,3.1Hz,1H),4.43(dd,J=17.0,6.9Hz,1H),4.38–4.20(m,4H),3.01–2.85(m,1H),2.61(d,J=19.4Hz,3H),2.39(dd,J=27.6,13.5Hz,1H),2.14(dd,J=14.8,7.2Hz,2H),2.05–1.94(m,1H),1.77–1.46(m,4H),0.98(t,J=7.5Hz,3H).
实施例207:N-((2S)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧-1-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基-2-)乙酰胺(207)
MHz,DMSO)δ11.01(s,1H),8.17(dd,J=18.4,7.4Hz,1H),7.64–7.54(m,1H),7.47(dd,J=6.9,3.2Hz,2H),7.29(d,J=8.5Hz,3H),7.24–7.06(m,1H),5.15(dd,J=13.2,4.3Hz,1H),5.01(d,J=3.8Hz,2H),4.81(dd,J=7.5,4.3Hz,1H),4.55–4.23(m,3H),3.88(d,J=9.4Hz,1H),3.32–3.24(m,1H),3.04–2.82(m,2H),2.80–2.55(m,3H),2.41(ddd,J=22.3,15.0,9.5Hz,1H),2.02(dd,J=14.8,5.4Hz,1H),1.85(d,J=5.0Hz,3H),1.78–1.48(m,7H).
实施例208:3-(1-氧代-4-(4-(4-(苯基-d5)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(208)
10.99(s,1H),7.57(dd,J=5.5,3.1Hz,1H),7.48–7.44(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),3.14–3.06(m,4H),2.97–2.85(m,1H),2.68(t,J=7.6Hz,2H),2.59-2.53(m,1H),2.49–2.38(m,5H),2.35(t,J=7.1Hz,2H),2.05–1.96(m,1H),1.64(dt,J=15.1,7.5Hz,2H),1.51(dt,J=14.3,7.3Hz,2H).
实施例209:3-(1-氧-4-(6-(4-(苯基-d5)哌嗪-1-)己基)异吲哚啉-2-)哌啶-2,6-二酮(209)
DMSO)δ10.99(s,1H),7.56(dd,J=8.1,4.6Hz,1H),7.48–7.42(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.30(d,J=17.1Hz,1H),3.32(s,4H),3.14–3.06(m,4H),2.98–2.85(m,1H),2.69–2.56(m,3H),2.46–2.37(m,1H),2.32(t,J=7.2Hz,2H),2.05–1.98(m,1H),1.66-1.58(m,2H),1.52–1.41(m,2H),1.38-1.32(m,4H).
实施例210:3-(1-氧代-4-(5-(4-(苯基-d5)哌嗪-1-)戊基)异吲哚啉-2-)哌嗪-2,6-二酮(210)
5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.32(s,4H),3.10(s,4H),2.99–2.86(m,1H),2.69–2.55(m,3H),2.46–2.27(m,3H),2.05–1.95(m,1H),1.63(dd,J=15.1,7.7Hz,2H),1.56–1.46(m,2H),1.36(dd,J=13.8,6.9Hz,2H).
实施例211:3-(6-氟-1-氧-4-(4-(喹啉-4-氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(211)
率43.2%;1H NMR(400MHz,DMSO)δ10.97(s,1H),8.73(d,J=5.2Hz,1H),8.12(d,J=7.2Hz,1H),7.93(d,J=8.5Hz,1H),7.74(t,J=7.0Hz,1H),7.53(t,J=7.5Hz,1H),7.20(dd,J=11.5,2.0Hz,1H),7.11–7.02(m,2H),5.08(dd,J=13.4,5.1Hz,1H),4.35(t,J=5.8Hz,2H),4.27(dd,J=11.5,5.3Hz,3H),4.14(d,J=17.4Hz,1H),2.95–2.85(m,1H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.11–1.91(m,5H).
实施例212:3-(6-氟-4-(4-((2-甲基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(212)
步骤2:将5-氟-2-甲基-3-硝基苯甲酸甲酯(1.02g,4.8mmol)溶于20ml甲醇中,加入10%Pd/C(110mg),氢气常压室温反应过夜,TLC监测反应完全后,反应液抽滤,固体用甲醇洗涤(20ml×1),滤液浓缩,得到无色液体3-氨基-5-氟-2-甲基-苯甲酸甲酯918mg,直接投下一步。
步骤3:3-氨基-5-氟-2-甲基-苯甲酸甲酯(918mg,粗品)和10%H2SO4(1.54ml,28.71mmol),0℃条件下逐滴加入亚硝酸钠(505mg,7.32mmol)的水溶液(5ml),相同温度反应1h后,加入50%H2SO4(7.65ml,143.55mmol),升温至100℃反应1h,TLC监测反应完全后,反应液浓缩,加入水20ml和乙酸乙酯100ml,摇匀分液,水相用乙酸乙酯萃取(50ml×2),合并有机相,无水硫酸钠干燥,减压浓缩,柱层析得到产物415mg,两步收率47%。
步骤4:将5-氟-3羟基-2-甲基-苯甲酸甲酯(410mg,2.23mmol)溶于20ml DMF,0℃条件下,加入60%氢化钠(107mg,2.67mmol),反应1h后,相同温度逐滴加入氯甲基甲醚(203ul,2.67mmol),滴加完后升至室温反应2h,TLC监测反应完全后,加水淬灭,乙酸乙酯萃取,分液,有机相依次用水和饱和氯化钠溶液洗涤,干燥,柱层析,得到产物430mg,收率84%.
步骤5:将5-氟-3-甲氧基甲氧基-2-甲基苯甲酸甲酯(425mg,1.86mmol)NBS(398mg,2.23mmol)溶于15ml四氯化碳,然后加入70%的过氧化苯甲酰(65mg,0.186mmol),升温回流3h,减压浓缩,经快速分离柱层析得到黄色固体545mg,收率95.4%.
步骤6:将2-溴甲基-5-氟-3-甲氧基甲氧基苯甲酸甲酯(540mg,1.76mmol)和4,5-二氨基-5-氧代戊酸甲酯盐酸盐.(413mg,2.11mmol)的乙腈悬浊液(20ml)中,加入N,N-二异丙基乙胺(873ul,5.28mmol),40℃反应过夜,反应完全后,减压浓缩,乙酸乙酯稀释,依次用水用和饱和氯化钠洗涤,干燥,浓缩直接投下一步。
步骤7:将上一步的粗品置于50ml圆底烧瓶中,加入10ml 4M的盐酸二氧六环和1ml甲醇,室温反应1h后,旋干,柱层析得到目标产物300mg,两步收率55%。
步骤8:将5-胺基-4-(6-氟-4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(35mg,0.11mmol)置于50ml圆底烧瓶中,加入4-((2-甲基喹啉-4-)氧)-1-丁醇(51mg,0.22mmol,2eq),三苯基膦(58mg,0.22mmol,2eq)。反应体系用氮气置换,加入5mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(43μL,0.22mmol,2eq)。室温反应1h。TLC监测反应完全后减压浓缩,柱层析得到产物56.8mg,收率98%。
步骤9:将上一步得到的产物(56.8mg,0.108mmol)溶于干燥的THF中,℃条件下加入叔丁醇钾(13mg,0.12mmol),相同温度反应30min,加入1N HCl淬灭,乙酯乙酯稀释,饱和氯化钠洗涤,干燥,HPLC纯化,得到白色固体20.1mg,收率37.9%;1H NMR(400MHz,DMSO)δ10.97(s,1H),8.04(d,J=8.3Hz,1H),7.82(d,J=8.5Hz,1H),7.67(t,J=7.0Hz,1H),7.43(t,J=7.6Hz,1H),7.20(d,J=11.6Hz,1H),7.08(dd,J=7.4,1.8Hz,1H),6.93(s,1H),5.08(dd,J=13.5,4.9Hz,1H),4.36–4.23(m,5H),4.14(d,J=17.3Hz,1H),2.95–2.85(m,1H),2.62–2.54(m,4H),2.36–2.25(m,1H),2.10–1.91(m,5H).
实施例213:3-(4-(4-((2-甲基喹啉-4-)甲氧基)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(213)
步骤2:将喹啉-4-甲酸(665mg,3.55mmol)溶于25ml干燥的THF,加入三乙胺(598ul,4.62mmol),冰浴下滴加氯甲酸异丙酯(635ul,4.62mmol),0.5h后,加入硼氢化钠(403mg,10.65mmol)水溶液(5ml),相同温度反应2h,反应完全后,旋干,乙酸乙酯稀释,饱和氯化钠洗涤,干燥,柱层析得到产物390mg,收率63%。
步骤3:将喹啉-4-甲醇(100mg,0.577mmol)溶于6ml干燥的THF,0℃充分冷却,加入60%氢化钠(35mg,0.87mmol),相同温度反应0.5h,加入1,4-二溴丁烷(206ul,0.866mmol)升温回流过夜,反应完全后,加水淬灭,乙酸乙酯萃取,有机层用饱和氯化钠洗涤,干燥,柱层析得到83mg,收率47%。
步骤4:4-((4-溴丁氧基)甲基)-2-甲基喹啉(44.7mg,0.145mmol)和5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(42mg,0.145mmol)溶于6ml乙腈中,加入无水碳酸钾(20mg,0.145mmol)升温至80℃反应48h,反应完全后过滤旋干,柱层析纯化得到产物38.3mg,收率51%
步骤5:将上一步得到产物(38.3mg,0.074mmol)溶于6mlTHF中,0℃条件下,加入叔丁醇钾(9mg,0.081mmol)相同温度反应0.5h,加入1NHCl淬灭,乙酸乙酯稀释,饱和氯化钠洗涤,干燥,旋干,HPLC纯化得到白色固体17.7mg,收率49%
1H NMR(400MHz,DMSO)δ10.96(s,1H),8.00(d,J=8.2Hz,1H),7.93(d,J=8.3Hz,1H),7.70(t,J=7.3Hz,1H),7.53(t,J=7.4Hz,1H),7.46(t,J=7.8Hz,1H),7.40(s,1H),7.30(d,J=7.4Hz,1H),7.20(d,J=8.1Hz,1H),5.09(dd,J=13.3,5.0Hz,1H),4.96(s,2H),4.36(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),4.14(t,J=5.9Hz,2H),3.65(t,J=5.9Hz,2H),2.96–2.83(m,1H),2.63(s,3H),2.56(d,J=17.5Hz,1H),2.45–2.32(m,1H),2.02–1.92(m,1H),1.89–1.74(m,4H).
实施例214:3-(4-(4-((2-乙基喹啉-4-)甲氧基)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(214)
NMR(400MHz,DMSO)δ10.96(s,1H),8.01(d,J=8.4Hz,1H),7.95(d,J=8.3Hz,1H),7.70(t,J=7.7Hz,1H),7.53(t,J=7.6Hz,1H),7.45(dd,J=13.6,5.7Hz,2H),7.30(d,J=7.4Hz,1H),7.20(d,J=8.2Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.97(s,2H),4.35(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),4.14(t,J=5.9Hz,2H),3.66(t,J=5.9Hz,2H),2.91(q,J=7.5Hz,2H),2.56(d,J=18.5Hz,1H),2.44–2.31(m,1H),2.01–1.91(m,1H),1.89–1.74(m,4H),1.29(t,J=7.6Hz,3H).
实施例215:3-(4-(4-(4-(2-氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(215)
2H),7.39(dd,J=7.9,1.4Hz,1H),7.32–7.26(m,1H),7.14(dd,J=8.1,1.3Hz,1H),7.03(td,J=7.7,1.4Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),3.02–2.84(m,5H),2.68(t,J=7.6Hz,2H),2.59(d,J=20.8Hz,5H),2.48–2.36(m,3H),2.06–1.97(m,1H).1.70–1.60(m,2H),1.57–1.47(m,2H).UPLC-MS(ESI)理论值为C27H31ClN4O3[M+H]+:495.21,实测值为495.52.
实施例216:3-(4-(4-(4-(2-硝基苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(216)
7.4,4.3,1.6Hz,2H),7.50–7.44(m,2H),7.30(d,J=7.7Hz,1H),7.11(t,J=7.2Hz,1H),5.14(dd,J=13.2,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.00–2.87(m,5H),2.67(t,J=7.6Hz,2H),2.62–2.53(m,1H),2.48–2.43(m,4H),2.43–2.34(m,3H),2.02(ddd,J=12.1,7.1,5.1Hz,1H),1.63(dt,J=14.7,7.5Hz,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C27H31N5O5[M+H]+:506.23,实测值为506.44.
实施例217:3-(1-氧代-4-(4-(4-(邻甲苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(217)
(m,2H),7.13(t,J=7.7Hz,2H),6.99(d,J=7.7Hz,1H),6.94(t,J=7.3Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.1Hz,1H),2.93(ddd,J=17.3,13.7,5.4Hz,1H),2.83(t,4H),2.68(t,J=7.5Hz,2H),2.64–2.53(m,5H),2.48–2.38(m,3H),2.22(s,3H),2.06–1.96(m,1H),1.70–1.59(m,2H),1.52(dt,J=15.5,7.8Hz,2H).UPLC-MS(ESI)理论值为C28H34N4O3[M+H]+:475.26,实测值为475.49.
实施例218:3-(4-(4-(4-(2-氟苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(218)
(m,2H),7.15–7.06(m,2H),7.05–6.92(m,2H),5.14(dd,J=13.4,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.05–2.98(m,4H),2.92(ddd,J=17.6,13.7,5.5Hz,1H),2.68(t,J=7.5Hz,2H),2.67-2.52(m,5H),2.46–2.35(m,3H),2.06–1.97(m,1H),1.70–1.58(m,2H),1.57–1.47(m,2H).UPLC-MS(ESI)理论值为C27H31FN4O3[M+H]+:479.24,实测值为479.47.
实施例219:3-(1-氧代-4-(4-(4-(2-(三氟甲基)苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(219)
2H),7.50–7.45(m,2H),7.33(t,J=7.6Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.00–2.85(m,5H),2.68(t,J=7.6Hz,2H),2.65–2.53(m,5H),2.48–2.36(m,3H),2.07–1.98(m,1H),1.70–1.58(m,2H),1.58–1.48(m,2H).UPLC-MS(ESI)理论值为C28H31F3N4O3[M+H]+:529.23,实测值为529.39.
实施例220:3-(1-氧代-4-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(220)
(m,2H),7.42(dd,J=14.7,6.4Hz,1H),7.21(dd,J=8.4,1.8Hz,1H),7.15(s,1H),7.06(d,J=7.7Hz,1H),5.14(dd,J=13.3,4.9Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.22(t,4H),2.97–2.86(m,1H),2.68(t,J=7.5Hz,2H),2.65–2.53(m,5H),2.45–2.35(m,3H),2.06–1.96(m,1H),1.70–1.58(m,2H),1.57–1.48(m,2H).UPLC-MS(ESI)理论值为C28H31F3N4O3[M+H]+:529.23,实测值为529.41.
实施例221:3-(4-(4-(4-(苯并噻吩-7-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(221)
1H),7.57(dd,J=6.1,2.5Hz,1H),7.51–7.44(m,2H),7.39(d,J=5.5Hz,1H),7.27(t,J=7.8Hz,1H),6.88(d,J=7.5Hz,1H),5.14(dd,J=13.2,5.0Hz,1H),4.49(d,J=17.2Hz,1H),4.33(d,J=17.2Hz,1H),3.06(s,4H),2.98–2.87(m,1H),2.69(t,J=7.5Hz,2H),2.64-2.54(m,5H),2.47–2.38(m,3H),2.06–1.98(m,1H),1.72-1.62(m,2H),1.58-1.48(m,2H).UPLC-MS(ESI)理论值为C29H32N4O3S[M+H]+:519.22,实测值为517.47.
实施例222:3-(4-(4-(4-(2,4-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(222)
7.14(d,J=8.7Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),2.99–2.87(m,5H),2.67(t,J=7.5Hz,2H),2.64–2.56(m,1H),2.46–2.34(m,3H),2.08–1.95(m,1H),1.70–1.58(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C27H30Cl2N4O3[M+H]+:529.17,实测值为529.35.
实施例223:3-(4-(4-(4-(3,5-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(223)
6.91(d,J=1.6Hz,2H),6.84(t,J=1.5Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.22–3.15(m,4H),2.98–2.86(m,1H),2.67(t,J=7.5Hz,2H),2.63–2.56(m,1H),2.47–2.38(m,5H),2.33(t,J=7.0Hz,2H),2.08–1.95(m,1H),1.69–1.57(m,2H),1.55–1.42(m,2H).UPLC-MS(ESI)理论值为C27H30Cl2N4O3[M+H]+:529.17,实测值为529.53.
实施例224:3-(4-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(224)
=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.98-2.87(m,5H),2.68(t,J=7.5Hz,2H),2.64–2.55(m,1H),2.48-2.42(m,2H),2.39–2.34(m,2H),2.06–1.97(m,1H),1.69–1.58(m,2H),1.55–1.44(m,2H).UPLC-MS(ESI)理论值为C28H34N4O4[M+H]+:491.26,实测值为491.53.
实施例225:3-(4-(5-(4-(苯并噻吩-7-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(225)
5.5Hz,1H),7.27(t,J=7.9Hz,1H),6.89(d,J=7.6Hz,1H),5.14(dd,J=13.3,5.0Hz,1H),4.48(d,J=17.1Hz,1H),4.32(d,J=17.2Hz,1H),3.10-3.01(m,4H),2.98–2.87(m,1H),2.73–2.56(m,5H),2.44(dd,J=13.3,4.4Hz,3H),2.06–1.96(m,1H),1.72–1.59(m,2H),1.59–1.47(m,2H),1.36(dt,J=8.6,5.6Hz,2H),1.28–1.18(m,2H).UPLC-MS(ESI)理论值为C30H34N4O3S[M+H]+:531.24,实测值为531.47.
实施例226:3-(4-(5-(4-(6-氟苯并异唑-3-基)哌啶-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(226)
7.28(td,J=9.2,2.0Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.20-3.08(m,1H),3.04–2.87(m,3H),2.70–2.64(m,2H),2.60(d,J=17.8Hz,1H),2.47–2.30(m,3H),2.17–1.95(m,5H),1.83(dd,J=22.7,12.1Hz,2H),1.64(dt,J=15.2,7.6Hz,2H),1.51(dd,J=13.1,6.9Hz,2H),1.36(dd,J=13.4,6.3Hz,2H).UPLC-MS(ESI)理论值为C30H33FN4O4[M+H]+:533.25,实测值为533.51.
实施例227:3-(4-(4-(4-(6-氟苯并异恶唑-3-基)哌啶-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(227)
7.28(td,J=9.2,2.2Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.20-3.08(m,1H),3.04–2.96(m,2H),2.96–2.86(m,1H),2.68(t,J=7.5Hz,2H),2.60(d,J=16.8Hz,1H),2.47-2.38(m,3H),2.17(t,J=10.2Hz,2H),2.04(dd,J=13.4,9.5Hz,3H),1.84(dd,J=24.4,11.9Hz,2H),1.64(dt,J=15.3,7.8Hz,2H),1.53(dt,J=14.7,7.5Hz,2H).UPLC-MS(ESI)理论值为C29H31FN4O4[M+H]+:519.23,实测值为519.53.
实施例228:3-(4-(4-(4-(苯并异唑-3-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(228)
3H),7.50–7.43(m,2H),7.29(dt,J=8.0,4.0Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.46(t,J=4.1Hz,4H),2.97–2.87(m,1H),2.68(t,J=7.5Hz,2H),2.62–2.56(m,1H),2.54(t,J=4.1Hz,4H),2.47–2.41(m,1H),2.38(t,J=6.8Hz,2H),2.05–1.97(m,1H),1.68–1.61(m,2H),1.56–1.47(m,2H).UPLC-MS(ESI)理论值为C28H31N5O4[M+H]+:502.24,实测值为502.53.
实施例229:3-(4-(4-(4-(2,5-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(229)
7.42(d,J=8.5Hz,1H),7.14(d,J=2.4Hz,1H),7.09(dd,J=8.5,2.4Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.97(t,J=5.6Hz,4H),2.94–2.87(m,1H),2.67(t,J=7.5Hz,2H),2.64–2.56(m,1H),2.48(t,J=5.6Hz,4H),2.46–2.41(m,1H),2.36(t,J=7.5Hz,2H),2.05–1.98(m,1H),1.69–1.58(m,2H),1.46–1.53(m,2H).UPLC-MS(ESI)理论值为C27H30Cl2N4O3[M+H]+:529.17,实测值为529.45.
实施例230:3-(4-(4-(4-(苯并异噻唑-3-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(230)
7.51–7.40(m,3H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.2Hz,1H),4.33(d,J=17.1Hz,1H),3.48–3.38(m,4H),2.99–2.86(m,1H),2.69(t,J=7.6Hz,2H),2.65–2.54(m,5H),2.47–2.35(m,3H),2.07–1.96(m,1H),1.71–1.60(m,2H),1.60–1.48(m,2H).UPLC-MS(ESI)理论值为C28H31N5O3S[M+H]+:518.21,实测值为518.45.
实施例231:3-(4-(5-(4-(苯并异唑-3-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(231)
1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.53–3.39(m,4H),2.92(ddd,J=18.4,13.6,5.2Hz,1H),2.66(t,J=7.7Hz,2H),2.59(dd,J=11.2,8.5Hz,1H),2.55–2.51(m,4H),2.46–2.38(m,1H),2.33(t,J=7.0Hz,2H),2.04–1.97(m,1H),1.64(dt,J=15.3,7.8Hz,2H),1.57–1.44(m,2H),1.41–1.30(m,2H).UPLC-MS(ESI)理论值为C29H33N5O4[M+H]+:516.25,实测值为516.51.
实施例232:3-(4-(5-(4-(苯并异噻唑-3-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(232)
17.2Hz,1H),4.32(d,J=17.3Hz,1H),3.47-3.37(m,4H),2.92-2.86(m,1H),2.70–2.54(m,7H),2.48–2.40(m,1H),2.34(d,J=8.1Hz,2H),2.06-1.97(m,1H),1.70–1.60(m,2H),1.53(dt,J=10.4,5.1Hz,2H),1.41–1.30(m,2H).UPLC-MS(ESI)理论值为C29H33N5O3S[M+H]+:532.23,实测值为532.53.
实施例233:3-(4-(5-(4-(2,5-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(233)
=8.5,2.4Hz,1H),5.14(dd,J=13.4,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),2.99–2.95(m,4H),2.94–2.87(m,1H),2.70–2.63(m,2H),2.61–2.57(m,1H),2.49–2.47(m,4H),2.45–2.38(m,1H),2.49–2.47(m,2H),2.01–1.98(m,1H),1.67–1.59(m,2H),1.54–1.46(m,2H),1.39–1.31(m,2H).UPLC-MS(ESI)理论值为C28H32Cl2N4O3[M+H]+:543.19,实测值为543.47.
实施例234:3-(4-(5-(4-(3,4-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(234)
2.4Hz,1H),5.13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),3.14(t,J=2.4Hz,4H),2.97–2.88(m,1H),2.65(t,J=8.0Hz,2H),2.62–2.57(m,1H),2.45(t,J=8.0Hz,4H),2.42–2.37(m,1H),2.29(t,J=8.0Hz,2H),2.04–1.96(m,1H),1.66–1.58(m,2H),1.53–1.45(m,2H),1.37–1.29(m,2H).UPLC-MS(ESI)理论值为C28H32Cl2N4O3[M+H]+:543.19,实测值为543.42.
实施例235:3-(4-(5-(4-(2,6-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(235)
=13.3,5.2Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.12(t,J=3.2Hz,4H),2.98–2.88(m,1H),2.71–2.63(m,2H),2.62–2.56(m,1H),2.49–2.43(m,4H),2.42–2.37(m,1H),2.35–2.27(m,2H),2.05–1.98(m,1H),1.69–1.59(m,2H),1.54–1.45(m,2H),1.39–1.32(m,2H).UPLC-MS(ESI)理论值为C28H32Cl2N4O3[M+H]+:543.19,实测值为543.51
实施例236:3-(4-(5-(4-(2,4-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(236)
8.7Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),2.97–2.92(m,4H),2.90–2.88(m,1H),2.65(t,J=4.0Hz,2H),2.62–2.56(m,1H),2.48–2.47(m,4H),2.45–2.38(m,1H),2.32(t,J=5.6Hz,2H),2.06–1.97(m,1H),1.67–1.59(m,2H),1.54–1.44(m,2H),1.38–1.30(m,2H).UPLC-MS(ESI)理论值为C28H32Cl2N4O3[M+H]+:543.19,实测值为543.42.
实施例237:3-(4-(5-(4-(3,5-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(237)
制备方法参考合成方法1及实施例22.1H NMR(400MHz,
5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.19(t,J=4.0Hz,4H),2.97–2.88(m,1H),2.65(t,J=8Hz,2H),2.62–2.57(m,1H),2.43(t,J=4.0Hz,4H),2.40–2.36(m,1H),2.29(t,J=6.6Hz,2H),2.04–1.97(m,1H),1.67–1.59(m,2H),1.53–1.46(m,2H),1.38–1.30(m,2H).UPLC-MS(ESI)理论值为C28H32Cl2N4O3[M+H]+:543.19,实测值为543.43.
实施例238:3-(4-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(238)
3H),7.25(d,J=8.1Hz,1H),7.14(dd,J=6.4,3.2Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.4Hz,1H),4.18(t,J=6.2Hz,2H),3.02–2.86(m,5H),2.63–2.52(m,7H),2.48–2.38(m,1H),2.03–1.90(m,3H).UPLC-MS(ESI)理论值为C26H28Cl2N4O4[M+H]+:531.15,实测值为531.35.
实施例239:3-(4-(4-(4-(苯并噻吩-7-基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(239)
3H),6.89(d,J=7.5Hz,1H),5.10(dd,J=13.4,5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.24(d,J=17.4Hz,1H),4.17(t,J=6.2Hz,2H),3.11-2.99(m,4H),2.96-2.84(m,1H),2.69–2.53(m,5H),2.46-2.42(m,3H),2.03–1.95(m,1H),1.86–1.73(m,2H),1.72–1.59(m,2H).UPLC-MS(ESI)理论值为C29H32N4O4S[M+H]+:533.21,实测值为533.51.
实施例240:3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(240)
制备方法参考合成方法6及实施例21.1H NMR(400MHz,
13.3,5.1Hz,1H),4.39(d,J=17.5Hz,1H),4.24(d,J=17.5Hz,1H),4.16(t,J=6.3Hz,2H),3.06–2.85(m,5H),2.71–2.52(m,5H),2.49–2.38(m,3H),1.99(td,J=5.5,2.7Hz,1H),1.85–1.74(m,2H),1.69–1.59(m,2H).UPLC-MS(ESI)理论值为C27H30Cl2N4O4[M+H]+:545.16,实测值为545.37.
实施例241:3-(4-(4-(4-(6-氟苯并异恶唑-3-基)哌啶-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(241)
(dd,J=13.3,5.0Hz,1H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.16(t,J=6.2Hz,2H),3.23–3.12(m,2H),3.05(d,J=11.0Hz,2H),2.95–2.86(m,1H),2.62–2.50(m,2H),2.47–2.40(m,1H),2.30–2.14(m,2H),2.10–2.01(m,2H),1.98(ddd,J=12.3,5.4,2.1Hz,1H),1.92–1.82(m,2H),1.78(dd,J=13.9,6.3Hz,2H),1.72–1.60(m,2H).UPLC-MS(ESI)理论值为C29H31FN4O5[M+H]+:535.23,实测值为535.49.
实施例242:3-(4-(4-(4-(苯并异唑-3-基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(242)
5.1Hz,1H),4.39(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.16(t,J=6.3Hz,2H),3.56–3.38(m,4H),2.96–2.84(m,1H),2.58(d,J=13.0Hz,5H),2.47–2.34(m,3H),2.03–1.94(m,1H),1.85–1.73(m,2H),1.70–1.60(m,2H).UPLC-MS(ESI)理论值为C28H31N5O5[M+H]+:518.23,实测值为518.47.
实施例243:3-(4-(4-(4-(3,4-二氯苯基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(243)
=2.8Hz,1H),6.92(dd,J=9.0,2.8Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.15(t,J=6.3Hz,2H),3.15(t,J=4.0Hz,4H),2.96–2.87(m,1H),2.61–2.55(m,1H),2.47(t,J=4.0Hz,4H),2.40–2.44(m,1H),2.37(t,J=6.4Hz,2H),2.03–1.95(m,1H),1.82–1.73(m,2H),1.67–1.58(m,2H).UPLC-MS(ESI)理论值为C27H30Cl2N4O4[M+H]+:545.16,实测值为545.49.
实施例244:4-(3,5-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(244)
(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.14–2.86(m,3H),2.68(t,J=7.0Hz,2H),2.60(dd,J=17.2,1.6Hz,1H),2.47–2.36(m,3H),2.30–2.10(m,4H),2.10–1.87(m,3H),1.74–1.42(m,4H).UPLC-MS(ESI)理论值为C29H30Cl2N4O3[M+H]+:553.17,实测值为553.49.
实施例245:4-(2-氯-4-甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(245)
7.45(m,2H),7.42(d,J=9.0Hz,1H),7.13(d,J=2.7Hz,1H),6.98(dd,J=8.9,2.7Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),3.79(s,3H),2.98(d,J=11.1Hz,2H),2.94–2.86(m,1H),2.67(t,J=7.7Hz,2H),2.58(d,J=17.0Hz,1H),2.44-2.37(m,5H),2.30(t,J=11.9Hz,2H),2.03–1.97(m,1H),1.91(t,J=14.0Hz,2H),1.63(d,J=7.9Hz,2H),1.56–1.46(m,2H).UPLC-MS(ESI)理论值为C30H33ClN4O4[M+H]+:549.22,实测值为549.43.
实施例246:4-(2,5-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(246)
=2.9Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.80(s,3H),3.72(s,3H),2.90(dd,J=22.3,8.8Hz,3H),2.67(t,J=7.6Hz,2H),2.58(d,J=17.6Hz,1H),2.41(dd,J=17.8,4.7Hz,3H),2.27(d,J=11.5Hz,4H),2.04–1.96(m,1H),1.90(d,J=13.3Hz,2H),1.62(dd,J=13.9,6.7Hz,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C31H36N4O5[M+H]+:545.27,实测值为545.56.
实施例247:4-(2,5-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(247)
(d,J=2.9Hz,1H),5.13(dd,J=13.2,5.0Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.80(s,3H),3.73(s,3H),3.04–2.82(m,3H),2.72–2.55(m,3H),2.45–2.40(m,1H),2.39–2.30(m,2H),2.25(t,J=3.6Hz,4H),2.04–1.97(m,1H),1.88(t,J=12.2,10.8Hz,2H),1.68–1.59(m,2H),1.53–1.45(m,2H),1.39–1.28(m,2H).UPLC-MS(ESI)理论值为C32H38N4O5[M+H]+:559.28,实测值为559.51.
实施例248:4-(2,5-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(248)
=17.2Hz,1H),4.30(d,J=17.2Hz,1H),3.00(d,J=12.5Hz,2H),2.95–2.87(m,1H),2.69–2.62(m,2H),2.60–2.56(m,1H),2.45–2.41(m,3H),2.39–2.32(m,2H),2.32–2.20(m,2H),2.05–1.89(m,3H),1.66–1.59(m,2H),1.56–1.44(m,2H),1.41–1.28(m,2H).UPLC-MS(ESI)理论值为C30H32Cl2N4O3[M+H]+:567.19,实测值为567.48.
实施例249:4-(3,4-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(249)
J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.78(s,3H),3.75(s,3H),3.00–2.93(m,2H),2.92–2.88(m,1H),2.65(t,J=7.2Hz,2H),2.61–2.56(m,1H),2.45–2.41(m,1H),2.34(t,J=7.2Hz,2H),2.22(t,J=11.4Hz,2H),2.09(d,J=13.4Hz,2H),2.05–1.89(m,3H),1.67–1.59(m,2H),1.53–1.46(m,2H),1.37–1.30(m,2H).UPLC-MS(ESI)理论值为C32H38N4O5[M+H]+:559.28,实测值为559.59.
实施例250:4-(2,6-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(250)
J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.11–3.03(m,2H),2.97–2.88(m,1H),2.70–2.63(m,2H),2.61–2.57(m,1H),2.55–2.52(m,4H),2.47–2.43(m,1H),2.42–2.31(m,4H),2.04–1.98(m,1H),1.67–1.59(m,2H),1.55–1.47(m,2H),1.37–1.30(m,2H).UPLC-MS(ESI)理论值为C30H32Cl2N4O3[M+H]+:567.19,实测值为567.48.
实施例251:4-(3,5-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(251)
(dd,J=13.3,5.0Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.04–2.87(m,3H),2.70–2.63(m,2H),2.60–2.56(m,1H),2.45–2.41(m,1H),2.40–2.29(m,2H),2.29–2.09(m,4H),2.06–1.91(m,3H),1.69–1.58(m,2H),1.57–1.43(m,2H),1.37–1.29(m,2H).UPLC-MS(ESI)理论值为C30H32Cl2N4O3[M+H]+:567.19,实测值为567.52.
实施例252:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(((S)-四氢呋喃-3-基)氧基)苯基)哌啶-4-甲腈(252)
(m,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.92–3.71(m,4H),3.00–2.86(m,3H),2.71–2.54(m,3H),2.47–2.30(m,3H),2.27–2.16(m,3H),2.11–1.84(m,6H),1.65–1.57(m,2H),1.55–1.44(m,2H),1.38–1.29(m,2H).UPLC-MS(ESI)理论值为C34H40N4O5[M+H]+:585.30.,实测值为585.56.
实施例253:1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)-4-(2,3,4-三甲氧基苯基)哌啶-4-甲腈(253)
17.2Hz,1H),4.32(d,J=17.1Hz,1H),3.92(s,3H),3.80(s,3H),3.76(s,3H),3.03–2.84(m,3H),2.67(t,J=7.4Hz,2H),2.62–2.53(m,1H),2.48–2.12(m,7H),2.06–1.95(m,1H),1.91–1.74(m,2H),1.70–1.56(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C32H38N4O6[M+H]+:575.28,实测值为575.57.
实施例254:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(2,3,4-三甲氧基苯基)哌啶-4-甲腈(254)
制备方法参考合成方法1及实施例51.1H NMR(400MHz,
3.76(s,3H),3.06–2.85(m,3H),2.71–2.54(m,3H),2.46–2.12(m,7H),2.05–1.96(m,1H),1.91–1.73(m,2H),1.70–1.57(m,2H),1.56–1.41(m,3H),1.38–1.27(m,2H).UPLC-MS(ESI)理论值为C33H40N4O6[M+H]+:589.30,实测值为589.58.
实施例255:4-(2,4-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(255)
5.14(dd,J=13.2,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.84(s,3H),3.77(s,3H),3.05–2.82(m,3H),2.70–2.54(m,3H),2.46–2.13(m,7H),2.06–1.95(m,1H),1.92–1.76(m,2H),1.68–1.57(m,2H),1.56–1.42(m,2H),1.38–1.26(m,2H).UPLC-MS(ESI)理论值为C32H38N4O5[M+H]+:559.28,实测值为559.54.
实施例256:4-(2,4-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(256)
7.19(d,J=8.7Hz,1H),6.69–6.30(m,1H),6.57–6.51(m,1H),5.13(dd,J=13.2,5.0Hz,1H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),3.84(s,3H),3.77(s,3H),2.99–2.82(m,3H),2.67(t,J=7.3Hz,2H),2.62–2.53(m,1H),2.46–2.11(m,8H),2.05–1.94(m,1H),1.89–1.77(m,2H),1.69–1.56(m,2H),2.46–2.11(m,2H).UPLC-MS(ESI)理论值为C31H36N4O5[M+H]+:545.27,实测值为545.53.
实施例257:4-(2-氯-4-(三氟甲氧基)苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(257)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
17.1Hz,1H),4.31(d,J=17.1Hz,1H),3.06–2.84(m,3H),2.73–2.54(m,3H),2.47–2.23(m,7H),2.04–1.90(m,3H),1.67–1.58(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C30H30ClF3N4O4[M+H]+:603.19,实测值为603.51.
实施例258:4-(2-氯-4-(三氟甲氧基)苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(258)
制备方法参考合成方法1及实施例51.1H NMR(400MHz,DMSO)δ10.99(s,1H),7.23–7.64(m,2H),7.58–7.63(m,1H),7.52–7.41(m,3H),5.14(dd,J=13.3,5.0Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.05–2.87(m,3H),2.69–2.56(m,3H),2.47–2.22(m,7H),2.06–1.89(m,3H),1.69–1.57(m,2H),1.55–1.43(m,2H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C31H32ClF3N4O4[M+H]+:617.21,实测值为617.58.
实施例259:4-(2,3-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(259)
(m,2H),7.13–7.04(m,2H),6.90(dd,J=7.4,1.9Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.87(s,3H),3.83(s,3H),2.98–2.85(m,3H),2.67(t,J=7.6Hz,2H),2.62–2.55(m,1H),2.47–2.33(m,3H),2.33–2.16(m,4H),2.04–1.95(m,1H),1.84(t,J=12.3Hz,2H),1.68–1.56(m,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C31H36N4O5[M+H]+:545.27,实测值为545.49.
实施例260:4-(2,3-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(260)
(s,3H),3.84(s,3H),3.14–3.05(m,2H),2.99–2.89(m,1H),2.68–2.57(m,3H),2.49–2.36(m,3H),2.36–2.07(m,4H),2.04–1.98(m,1H),1.88–1.84(m,2H),1.68–1.58(m,2H),1.53–1.46(m,2H),1.27–1.20(m,2H).UPLC-MS(ESI)理论值为C32H38N4O5[M+H]+:559.28,实测值为559.56.
实施例261:1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)-4-均三甲基苯基哌啶-4-甲腈(261)
制备方法参考合成方法1及实施例51.1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.57(dd,J=5.6,2.7Hz,1H),7.51–7.42(m,2H),6.86(s,2H),5.13(dd,J=13.1,4.9Hz,1H),4.47(d,J=17.0Hz,1H),4.32(d,J=17.1Hz,1H),3.01–2.86(m,3H),2.73–2.64(m,2H),2.63–2.56(m,1H),2.51(s,6H),2.49–2.39(m,3H),2.39–2.21(m,6H),2.17(s,3H),2.09–2.03(m,1H),1.69–1.58(m,2H),1.56–1.43(m,2H).UPLC-MS(ESI)理论值为C32H38N4O3[M+H]+:527.29,实测值为527.56.
实施例262:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-均三甲基苯基哌啶-4-甲腈(262)
制备方法参考合成方法1及实施例51.1H NMR(400MHz,
4.47(d,J=17.2Hz,1H),4.31(d,J=17.3Hz,1H),3.00–2.86(m,3H),2.69–2.56(m,3H),2.51(s,6H),2.49–2.36(m,3H),2.36–2.20(m,6H),2.18(s,3H),2.05–1.97(m,1H),1.70–1.58(m,2H),1.56–1.44(m,2H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C33H40N4O3[M+H]+:541.31,实测值为541.45.
实施例263:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(((S)-四氢呋喃-3-基)氧基)苯基)哌啶-4-甲腈(263)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
2H),5.14(dd,J=13.4,5.1Hz,1H),5.08–4.97(m,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.89(dd,J=10.1,4.6Hz,1H),3.86–3.80(m,1H),3.76(ddd,J=16.5,8.7,4.9Hz,2H),3.07–2.84(m,3H),2.68–2.56(m,3H),2.43–2.36(m,3H),2.29–2.15(m,3H),2.14–1.80(m,6H),1.70–1.56(m,2H),1.56–1.42(m,2H),1.33(p,J=8.7,8.3Hz,2H).UPLC-MS(ESI)理论值为C34H40N4O5[M+H]+:585.30,实测值为585.53.
实施例264:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(2-甲氧基乙氧基)苯基)哌啶-4-甲腈(264)
5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),4.12–4.07(m,2H),3.68–3.61(m,2H),3.47-3.35(m,3H),3.30(s,3H),3.23-3.04(m,2H),2.99–2.87(m,1H),2.70-2.56(m,3H),2.46–2.35(m,2H),2.27-2.12(m,2H),2.09–1.94(m,3H),1.69–1.52(m,4H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C33H40N4O5[M+H]+:573.30,实测值为573.53.
实施例265:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-甲氧基苯基)哌啶-4-甲腈(265)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
17.2Hz,1H),4.32(d,J=17.0Hz,1H),3.77(s,3H),3.44-3.23(m,6H),3.01–2.87(m,1H),2.70-2.56(m,3H),2.46–2.35(m,1H),2.29–2.14(m,2H),2.07–1.94(m,3H),1.70–1.50(m,4H),1.40-1.27(m,2H).UPLC-MS(ESI)理论值为C31H36N4O4[M+H]+:529.27,实测值为529.58.
实施例266:4-(2,6-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(266)
制备方法参考合成方法1及实施例51.1H NMR(400MHz,
(d,J=17.1Hz,1H),4.33(d,J=17.1Hz,1H),3.52-3.17(m,4H),2.99–2.88(m,1H),2.80–2.58(m,9H),2.46–2.35(m,1H),2.08–1.98(m,1H),1.72–1.50(m,4H).UPLC-MS(ESI)理论值为C29H30Cl2N4O3[M+H]+:553.17,实测值为553.50.
实施例267:4-(2-氯-4-甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(267)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
5.1Hzz,1H),4.46(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.79(s,3H),3.07–2.86(m,3H),2.68-2.56(m,3H),2.46-2.36(m,3H),2.37–2.32(m,2H),2.28(t,J=11.7Hz,2H),2.05–1.95(m,1H),1.89(t,J=11.1Hz,2H),1.68–1.56(m,2H),1.50(dt,J=14.8,7.6Hz,2H),1.34(dd,J=14.1,7.2Hz,2H).UPLC-MS(ESI)理论值为C31H35ClN4O4[M+H]+:563.23,实测值为563.52.
实施例268:4-(4-氰基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(268)
(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.1Hz,1H),3.12–2.86(m,3H),2.70-2.56(m,3H),2.46-2.38(m,3H),2.35-2.20(m,2H),2.19–2.09(m,2H),2.08–1.94(m,3H),1.63(dt,J=15.5,7.7Hz,2H),1.53(dd,J=12.5,7.1Hz,2H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C31H33N5O3[M+H]+:524.26,实测值为524.55.
实施例269:4-(2,5-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(269)
7.49–7.43(m,2H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.1Hz,1H),4.31(d,J=17.2Hz,1H),3.08–2.86(m,3H),2.66(t,J=7.6Hz,2H),2.59(d,J=17.1Hz,1H),2.47–2.23(m,7H),2.05–1.93(m,3H),1.63(dd,J=15.5,7.8Hz,2H),1.58–1.45(m,2H).UPLC-MS(ESI)理论值为C29H30Cl2N4O3[M+H]+:553.17,实测值为553.52.
实施例270:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(氧杂环丁烷-3-基氧基)苯基)哌啶-4-甲腈(270)
13.3,5.0Hz,1H),4.93(t,J=6.7Hz,2H),4.54(dd,J=7.4,5.1Hz,2H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.24–3.05(m,2H),3.04–2.83(m,3H),2.72–2.64(m,2H),2.60–2.56(m,1H),2.48–2.31(m,3H),2.23–2.09(m,2H),2.04–1.98(m,3H),1.70–1.47(m,4H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C33H38N4O5[M+H]+:571.28,实测值为571.53.
实施例271:1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(三氟甲基)苯基)哌啶-4-甲腈(271)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
4.47(dd,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.03-2.95(m,2H),2.94–2.86(m,1H),2.69-2.54(m,3H),2.43(dd,J=13.2,4.5Hz,1H),2.39–2.33(m,2H),2.24(t,J=11.4Hz,2H),2.12(d,J=12.3Hz,2H),2.06-1.95(m,3H),1.68–1.58(m,2H),1.55–1.46(m,2H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C31H33F3N4O3[M+H]+:567.25,实测值为567.53.
实施例272:4-(3,4-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(272)
制备方法参考合成方法1及实施例51.1H NMR(400MHz
13.2,5.0Hz,1H),4.47(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),3.40-3.28(m,4H),3.10-2.86(m,3H),2.68(t,J=7.0Hz,2H),2.59(d,J=16.6Hz,1H),2.42(dd,J=13.2,4.3Hz,1H),2.29–2.10(m,3H),2.05-1.94(m,2H),1.69-1.40(m,4H).UPLC-MS(ESI)理论值为C29H30Cl2N4O3[M+H]+:553.17,实测值为553.52.
实施例273:3-(4-(5-(5-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(273)
J=13.3,5.0Hz,1H),5.02(s,2H),4.48(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.50(d,J=6.9Hz,2H),3.20-3.06(m,2H),3.00–2.88(m,1H),2.68(t,J=7.4Hz,2H),2.64-2.56(m,1H),2.44-2.34(m,3H),2.19(t,J=13.5Hz,2H),2.06–1.97(m,1H),1.86(d,J=13.6Hz,2H),1.78-1.62(m,4H),1.41-1.33(m,2H).UPLC-MS(ESI)理论值为C30H34FN3O4[M+H]+:520.25,实测值为520.53.
实施例274:3-(4-(5-(5-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(274)
13.3,5.1Hz,1H),5.03(s,2H),4.48(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),3.51(d,J=12.2Hz,2H),3.20-3.08(m,2H),3.00-2.87(m,1H),2.72–2.57(m,3H),2.41(dd,J=17.7,8.7Hz,1H),2.14(t,J=12.0Hz,2H),2.07–1.95(m,2H),1.88(d,J=13.2Hz,2H),1.80–1.60(m,5H),1.42-1.32(m,2H).UPLC-MS(ESI)理论值为C30H34ClN3O4[M+H]+:536.22,实测值为536.52.
实施例275:3-(4-(5-(6-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(275)
1.9Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.1Hz,1H),4.31(d,J=17.1Hz,1H),2.99-2.85(m,3H),2.70-2.60(m,4H),2.59-2.52(m,3H),2.47–2.37(m,1H),2.06–1.97(m,1H),1.87-1.77(m,2H),1.72-1.61(m,4H),1.55(dd,J=14.3,7.0Hz,2H),1.43–1.29(m,2H).UPLC-MS(ESI)理论值为C30H33ClN4O4[M+H]+:549.22,实测值为549.53.
实施例276:3-(4-(5-(4-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(276)
6.82(d,J=7.6Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.49(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.15–2.88(m,5H),2.75–2.57(m,6H),2.47–2.38(m,2H),2.07–1.98(m,3H),1.76–1.58(m,6H),1.42-1.32(m,2H).UPLC-MS(ESI)理论值为C30H33ClN4O4[M+H]+:549.22,实测值为549.49.
实施例277:3-(4-(5-(6-氯-2-氧代-1,2-二氢螺[苯并[1,3]恶嗪-4,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(277)
Hz,1H),6.89(d,J=8.5Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),2.98–2.87(m,1H),2.75(d,J=10.3Hz,2H),2.68-2.54(m,3H),2.43(dd,J=13.1,4.4Hz,1H),2.39–2.28(m,4H),2.07-1.98(m,3H),1.90(d,J=13.0Hz,2H),1.68–1.58(m,2H),1.56–1.45(m,2H),1.39-1.32(m,2H).UPLC-MS(ESI)理论值为C30H33ClN4O5[M+H]+:565.21,实测值为565.53.
实施例278:3-(4-(5-(5-氟-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(278)
=9.5,2.4Hz,1H),6.82(dd,J=8.6,4.6Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4.48(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),2.99–2.81(m,3H),2.67(t,J=7.8Hz,2H),2.65–2.55(m,3H),2.46–2.40(m,3H),2.06–1.98(m,1H),1.86–1.75(m,2H),1.74–1.59(m,4H),1.59–1.50(m,2H),1.42–1.32(m,2H).UPLC-MS(ESI)理论值为C30H33FN4O4[M+H]+:533.25,实测值为533.52.
实施例279:3-(4-(5-(7-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(279)
1H),7.02(t,J=7.8Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.0Hz,1H),4.32(d,J=17.1Hz,1H),3.22–3.14(m,2H),3.05–2.88(m,3H),2.87-2.76(m,2H),2.72–2.64(m,2H),2.64–2.57(m,1H),2.46–2.36(m,1H),2.06–1.98(m,1H),1.97-1.84(m,4H),1.73-1.58(m,4H),1.44-1.33(m,2H).UPLC-MS(ESI)理论值为C30H33ClN4O4[M+H]+:549.22,实测值为549.48.
实施例280:3-(4-(5-(4-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(280)
=13.4,5.1Hz,1H),5.08(s,2H),4.48(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.53(d,J=11.8Hz,2H),3.23-3.10(m,4H),3.01–2.85(m,1H),2.73–2.65(m,2H),2.61(d,J=18.7Hz,1H),2.44-2.36(m,1H),2.20–2.08(m,2H),2.07–1.99(m,2H),1.98-1.91(m,1H),1.77–1.63(m,4H),1.42-1.30(m,2H).UPLC-MS(ESI)理论值为C30H34ClN3O4[M+H]+:536.22,实测值为536.53.
二、实验实施例:
肿瘤细胞增殖抑制实验方法:本专利发明人测试了所有实施例化合物对血液瘤细胞,多发性骨髓瘤MM1s细胞系和部分实施例化合物对急性白血病细胞MV-4-11细胞系,其活性测试方法和结果如下。
1.化合物对MM.1S细胞增殖的抑制作用MTS细胞活力检测实验:
1).实验方法:
MM.1S细胞用1640加10%胎牛血清培养并收集,按7天的作用时间稀释细胞浓度,在96孔细胞板中每孔加入180ul细胞悬液,使其细胞数为20000个。对照细胞孔加入20ul终浓度为0.2%的DMSO,化合物由10mM母液5倍梯度稀释,同样加20ul到化合物细胞孔(DMSO终浓度为0.2%)。细胞放入37℃,5%CO2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后,每孔加入20μL,37℃,5%CO2培养箱孵育3-4小时。用酶标板读取490nm吸收光值,并以690nm吸收光值作为背景值,以OD490-OD690为最终原始数据。化合物的抑制率计算公式为:抑制率=(ODDMSO-OD化合物)/(ODDMSO-O空白)×100%。化合物的增殖抑制IC50由Graph PadPrism 5.0拟合。实验重复三次,每次用三个平行实验计算计算平均数和标准差。
细胞活性测试结果:****表示细胞活性IC50>20μM,***表示细胞活性1μM<IC50<20μM,**表示细胞活性100nM<IC50<1μM,*表示细胞活性IC50<100nM。2).实验结果:
基于以上化合物细胞生长抑制活性测试结果,本发明的一些实施例化合物对多发性骨髓瘤MM1s细胞生长具有很好的抑制活性,部分化合物的活性与阳性化合物相当或优于阳性化合物。另一方面,这些结构多样性化合物的开发,未获得更高活性的药物分子和药学性质更佳的分子,提供可选择的分子来源。因此,本发明的化合物可以用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病,如多发性骨髓瘤或非限制性的包括其他潜在的肿瘤疾病、疼痛、神经系统疾病和免疫系统疾病。
2.化合物对MV-4-11细胞增殖的抑制作用,MTS细胞活力检测实验:
1).实验方法:
MV-4-11细胞用IMDM加10%胎牛血清培养并收集,按7天的作用时间稀释细胞浓度,在96孔细胞板中每孔加入180ul细胞悬液,使其细胞数为2000个。对照细胞孔加入20ul终浓度为0.2%的DMSO,化合物由10mM母液5倍梯度稀释,同样加20ul到化合物细胞孔(DMSO终浓度为0.2%)。细胞放入37℃,5%CO2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后,每孔加入20μL,37℃,5%CO2培养箱孵育3-4小时。用酶标板读取490nm吸收光值,并以690nm吸收光值作为背景值,以OD490-OD690为最终原始数据。化合物的抑制率计算公式为:抑制率=(ODDMSO-OD化合物)/(ODDMSO-O空白)×100%。化合物的增殖抑制IC50由GraphPad Prism 5.0拟合。实验重复三次,每次用三个平行实验计算计算平均数和标准差。
2).实验结果:
基于以上化合物细胞生长抑制活性测试结果,本发明的一些实施例化合物对急性白血病细胞MV-4-11细胞具有非常好的抑制活性。多个化合物的IC50处于纳摩尔级别,表中测试的化合物最好的活性可以达到17nM;然而阳性化合物无论是已经上市的药物来那度胺(Lenalidomide)或泊马度胺,还是目前在临床的化合物CC-122或者CC-220在急性白血病细胞MV-4-11细胞上的细胞抑制活性(IC50)都是大于20μM。从上述表中测试结果发现,本发明的部分化合物对急性白血病细胞MV-4-11细胞增殖的抑制抑制活性强于相关阳性化合物的,最好的化合物活性是阳性化合物的1000倍以上。因此,本发明的化合物拓宽了度胺类药物在血液瘤疾病治疗中的应用范围,可以用于拓展到血液肿瘤的其他适应症,比如作为急性白血病的抑制剂,作为制备治疗该类疾病的药物。因此本发明的化合物可以作为强效新型的CRBN调节剂,用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病,如多发性骨髓瘤或非限制性的包括其他潜在的肿瘤疾病、炎症、疼痛、神经系统疾病和免疫系统疾病。
综上所述,本发明提供了一类结构新颖的取代异吲哚啉类化合物,其中部分代表性化合物对测试的血液瘤细胞表现出非常强的增殖抑制活性。此外,本发明提供的部分代表性化合物能有效克服现有度胺药物的应用局限,此项特征不仅可以有效弥补现有度胺药物的不足,更能将其适应症拓展到新的领域,因此具有非常强的研究潜力和应用前景。
Claims (32)
1.如下通式(I)表示的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘、氟或C1-C6直链或支链烃基;
R2、R4各自独立地为氢或氘;
R3为氢、氘或卤素;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羟基、氨基、氰基、C1-C6烷基、卤素取代的C1-C6烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代或未取代的C1-6烷基、由卤素、羟基、氰基、硝基取代或未取代的C3-6环烷基;
Y不存在,或为–CO–、–CO–NH–;
Y与A、L形成的连接方式分别为A–L–、A–CO–L–、A–CO–NH–L–,A为:i)选自以下的杂环基:
X3为C、N或O;
n4为0、1、或2;
n5为0、1、或2,
Y1为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
Y2为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
Y3不存在,或为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
条件是:当Y3不存在时,并且Y不存在时,X1不为-O-;
Y4、Y5为不存在或其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、C1-C3烷基、C3环烷基、卤素取代的C1-C3烷基或苯基;
ii)选自以下的稠杂环基:
X4为C、N或O;
n6为0、1、或2;
n7为0、1、或2;
n8为0、1、2、3或4;
为6-10元芳基环或5-10元杂芳基环;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基卤素取代C1-C3烷氧基;
条件是:当上述R8各自独立地选自下列任意取代基:氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为不存在或其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、C1-C3烷基、卤素取代的C1-C3烷基;
或者iii)选自以下的螺杂环基:
nc1为0、1、或2;
nc2为0、1、或2;
nc3为1、或2;
n9为0、1、2、3或4;
为6-10元芳基环或5-10杂芳基环;
R9独立选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基;
R10、R11独立选自为氢、取代或未取代6-10元芳基、取代或未取代5-10元杂芳基,所述取代类型与上述环上取代基R9相同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8选自:氘、卤素、C1-C3烷基、卤素取代的C1-C3烷基。
2.如下通式(I)表示的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘、氟或C1-C6直链或支链烃基;
R2、R4各自独立地为氢或氘;
R3为氢、氘或卤素;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羟基、氨基、氰基、C1-C6烷基、卤素取代的C1-C6烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代或未取代的C1-6烷基、由卤素、羟基、氰基、硝基取代或未取代的C3-6环烷基;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–,Y与A、L形成的连接方式为A–NH–CO–L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHRa9)–L–或A–CH(NHRa9)–L–,其中A为:
6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH2–、(5-10元杂芳基)–CH2–,所述芳基或杂芳基可选地由一个或多个R5取代基所取代,
或者A为选自以下基团:
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C3-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
3.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,
其中,R1为氢、氘、氟或C1-C3直链或支链烃基;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羟基、氨基、氰基、C1-C3烷基、卤素取代的C1-C3烷基-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代的C1-6烷基、由卤素、羟基、氰基、硝基取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–,Y与A、L所形成的连接方式为A–L–、A–CO–L–或A–CO–NH–L–,A为:
i)选自以下的杂环基:
其中,Y1为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、氨基羰基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
Y2为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
Y3不存在,或为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代:氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基;
条件是:当Y3为Y3不存在时,并且Y不存在时,X1不为-O-;
Y4、Y5为不存在或其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、C1-C3烷基、或苯基;
ii)选自以下的稠杂环基:
n8为0、1、2、3或4;
X4为C、N或O;
为6-10元芳基环或5-10元杂芳基环;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、卤素取代C1-C3烷氧基;
条件是:当上述R8各自独立地选自下列任意取代基:氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y为不存在时,X1不为-O-;
Y6、Y7为不存在或其所在杂环上的一个或多个取代基,且各自独立选自氘、卤素、C1-C3烷基、卤素取代的C1-C3烷基;
或者iii)选自以下的螺杂环基:
其中,n9为0、1、2、3或4;
为6-10元芳基环或5-10杂芳基环;
R9独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8选自:氘、卤素、C1-C3烷基、卤素取代的C1-C3烷基。
4.根据权利要求2所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中,
R1为氢、氘、氟或C1-C3直链或支链烃基;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、羟基、氨基、氰基、C1-C3烷基、卤素取代的C1-C3烷基-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代的C1-6烷基、由卤素、羟基、氰基、硝基取代的C3-6环烷基。
5.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,
其中,
R1为氢、氘或氟;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或者由一个或多个卤素取代或未取代的C3-6环烷基;
Y为不存在,或为–CO–或–CO–NH–,Y与A、L所形成的连接方式为–A–CO–L–、–A–CO–NH–L–、–A–L–、A部分至少含有一个氮原子且Y与氮原子连接,A为:
i)选自以下的杂环基:
n10为0、1、2、3、4或5;
Y1选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基;
R10各自独立地为氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
Y4、Y5为不存在或其所在杂环上的一个或多个取代基,Y4、Y5各自独立地为氘、卤素、甲基、乙基或苯基;
ii)选自以下的稠杂环基:
n8为0、1、2、3或4;
X4为C、N或O;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、卤素取代C1-C3烷氧基,其中当n8>1时,各个R8可以相同或不同;
条件是:当上述R8各自独立地选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为不存在或其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、甲基、乙基、三氟甲基;
或者iii)选自以下的螺杂环基:
其中,n9为0、1、2、3或4;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8选自:氘、卤素、甲基、乙基、三氟甲基。
6.根据权利要求2所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,
其中,
R1为氢、氘或氟;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或者由一个或多个卤素取代或未取代的C3-6环烷基;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–,Y与A、L所形成的连接方式为A–NH–CO–L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHRa9)–L–或A–CH(NHRa9)–L–,其中A为:
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C3-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
7.根据权利要求1所述的化合物以及、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-1)至(I-8)中任意一个表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地选自为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或者由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或者为–CO–或–CO–NH–;
n9为0、1、2、3或4;
为6-10元芳基环或5-10杂芳基环,与螺环母核稠合形成螺杂环基;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8选自:氘、卤素、甲基、乙基、三氟甲基取代基所取代;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,其中当n9>1时,各个R9可以相同或不同。
8.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-9)至(I-16)中任意一个表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢、氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n9为0、1、2、3或4;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,其中当n9>1时,各个R9可以相同或不同;
Y8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基,Y8选自:氘、卤素、甲基、乙基、三氟甲基。
9.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,
其中通式(I)表示的化合物为通式(I-17)或(I-18)表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3选自为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基;
Y不存在,或为–CO–或–CO–NH–;
n10为0、1、2、3、4或5;
Y1选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,并且所述6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同。
10.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-19)至(I-23)中任意一个表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n8为0、1、2、3或4;
X4为C、N或O;
R8各自独立地为氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、卤素取代C1-C3烷氧基,其中当n8>1时,各个R8可以相同或不同;
当R8选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-;
Y6、Y7为不存在或其所在杂环上的一个或多个取代基,且各自独立地选自氘、卤素、甲基、乙基、三氟甲基。
11.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-24)至(I-32)中任意一个表示的化合物:
其中,X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3选自为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–或–CO–NH–;
n8、n9、n10各自独立地选自0、1、2、3或4;
Y1为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
X4为C、N或O;
R9选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,其中当n9>1时,各个R9可以相同或不同;
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,并且所述6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、卤素取代C1-C3烷氧基,当n8>1时,各个R8可以相同或不同。
12.根据权利要求1所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-33)至(I-40)中任意一个表示的化合物:
其中,X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地为氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基或由一个或多个卤素取代或未取代的C3-6环烷基;
Y不存在,或为–CO–、–CO–NH–;
n8、n9、n10各自独立地为0、1、2、3或4;
Y1为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6烷基、卤素取代的C1-C6烷氧基;
X4选自C、N或O;
R9各自独立地选自以下取代基:氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C3-C6环烷基氧基、C1-C3烷基磺酰基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基,当n9>1时,各个R9可以相同或不同;
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基,并且所述6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基;
R10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、C1-C3酰基氨基、卤素取代C1-C3烷基、卤素取代的C1-C3烷氧基,当n10>1时,各个R10可以相同或不同;
R8各自独立地选自氢、氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基、C1-C3烷基氨基、C1-C3酰基氨基、氨基羰基、卤素取代C1-C3烷氧基,其中当n8>1时,各个R8可以相同或不同;
条件是:当R8选自下列任意取代基:氘、C1-C3烷氧基、卤素、C1-C3烷基、羧基、C1-C3烷基氨基羰基、硝基、氨基、氰基、卤素取代C1-C3烷基、羟基、C1-C3烷基磺酰基时,并且Y不存在时,X1不为-O-。
13.根据权利要求2所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中通式(I)表示的化合物为通式(I-49)至(I-53)中任意一个表示的化合物:
其中,X1为-CH2-或-O-;
X2为-CH2-或-CO-;
R1为氢、氘或氟;
R2、R4各自独立地选自氢或氘;
R3为氢、氘或氟;
L为含有2-8个碳原子的取代或未取代的直链亚烷基,所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代:氘、卤素、氰基、C1-C3烷基、卤素取代的C1-C3烷基、-NHC(O)Ra1、-NRa3Ra4,其中Ra1、Ra3和Ra4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C1-6烷基、或由一个或多个卤素取代或未取代的C3-6环烷基;
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa9)–或–CH(NHRa9)–;
n1为0、1、2、3或4;
R5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C1-C6烷基、直链或支链C1-C6烷氧基、C1-C3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C3-C6环烷基、C3-C6环烷基氧基、C1-C3烷基磺酰基、苯基氧基或5-6元杂芳基氧基,当n1>1时,各个R5可以相同或不同;
Ra9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C3-C8环烷基羰基、C3-C8的杂环烷基羰基,其中所述取代是指碳链末端被羟基、氨基所取代。
14.根据权利要求1或3所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中,为苯环或吡啶环和/或为苯环或吡啶环。
15.根据权利要求3所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中,所述6-10元芳基选自苯基、萘基,所述5-10元杂芳基选自噻吩基、吡啶基、苯并噻吩基、苯并咪唑基、吲哚基、喹啉基、异喹啉基。
16.根据权利要求5所述的化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,其中,选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基。
17.一种化合物、其对映体、其消旋体、其同位素化合物、或其可药用的盐,所述的化合物为下列化合物之一:
18.一种制备根据权利要求1或2所述通式(I)所示的化合物的方法,所述方法选自如下方法之一:
合成方法1:
其中,R1、R2、R3、R4和X2的定义与权利要求1中定义相同;
m1为1~7的整数;
与权利要求1中A定义中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同;
步骤1-1:化合物1A与1B在以DMF或DMA偶极有机溶剂为溶剂,Pd催化剂、一价铜催化剂和碱的存在下,在室温或加热条件通过Sonogashira偶联反应得到化合物1C;
步骤1-2:化合物1C在Pd/C、兰尼镍或威尔金森催化剂催化条件下被氢气还原为化合物1D;
步骤1-4:化合物1D在三苯基膦和四溴化碳存在下,反应得到化合物1G;
步骤1-5:化合物1G和含氮杂环化合物1H在碘化钠存在下反应得到化合物1I;
合成方法2:
其中,R1、R2、R3、R4和X2的定义与权利要求1中的定义相同;
m1为1~7的整数;
定义与权利要求1中A中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同;
G2为保护基,选自TBS、Trit、苄基;
步骤2-1:化合物2A与2B在非质子溶剂为反应溶剂,Pd催化剂、膦配体、有机碱存在下加热反应生成多取代烯烃衍生物2C;
步骤2-2:化合物2C在Pd/C或威尔金森催化剂催化条件下被氢气还原为化合物2D;
步骤2-3:以干燥四氢呋喃为溶剂,在叔丁醇钾存在条件下关环得到哌啶酮衍生物2E;
步骤2-4:化合物2E在酸性条件下或者在TBAF存在条件下,脱除保护基得到化合物2F;
步骤2-5:化合物2F在三苯基膦和四溴化碳存在下,反应得到化合物2G;
步骤2-6:化合物2G和含氮杂环化合物2H在碘化钠存在下反应得到化合物2I;
合成方法3:
其中,R1、R2、R3、R4、和X2的定义与权利要求1中的定义相同;
m2为1~7的整数;
与权利要求1中A中i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同;
G3-NH2为本发明实施例中使用的芳香胺或脂肪胺化合物;
步骤3-1:化合物3A与3B在三氟乙酸酐和叔丁醇存在下,反应得到化合物3C;
步骤3-2:化合物3C和3D在碳酸钾存在的条件下,反应得到化合物3E;
步骤3-3:化合物3E叔丁醇钾存在条件下关环得到哌啶酮衍生物3F;
步骤3-4:化合物3F在盐酸条件下,脱除保护基获得化合物3G;
步骤3-5:化合物3G和含氮杂环化合物3H在缩合剂及碱存在下,缩合获得化合物3I;
步骤3-6:化合物3G和化合物3J在缩合剂及碱存在下,缩合获得化合物3K;
合成方法4:
其中,R1、R2、R3、R4、X2、Ra9的定义与权利要求2中的定义相同;
R11的定义与权利要求2中R5的定义相同;
n11的定义与权利要求2中n1的定义相同;
G4、G5为保护基,选自叔丁氧羰基或苄基;
G6-NH2为芳香胺或脂肪胺化合物;
步骤4-1:化合物4A与4B在Pd催化剂、一价铜催化剂和碱的存在下,在室温或加热条件、一价铜催化剂和碱的存在下,通过Sonogashira偶联反应得到化合物4C;
步骤4-2:化合物4C在Pd/C、兰尼镍或威尔金森催化剂催化条件下被氢气还原为化合物4D;
步骤4-3:化合物4D在胺类衍生物4E和缩合剂HATU及HOBt条件下缩合得到化合物4F;
步骤4-4:化合物4F在盐酸条件下脱除保护基,反应后旋干与相应的酰氯或羧酸反应获得化合物4G;
步骤4-5:化合物4D和邻苯二胺衍生物4H在缩合剂HATU及HOBt条件下反应后,在酸性条件下加热条件下获得化合物4I;
步骤4-6:化合物4I在盐酸条件下脱除保护基,反应后旋干与相应的酰氯或羧酸反应获得化合物4J;
合成方法5:
其中,R1、R2、R3、R4、和X2的定义与权利要求2中的定义相同;
m3为1~7的整数;
与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同;
Ar为6-10元芳基、5-10元杂芳基,所述芳基或杂芳基可选地被一个或多个R5取代基所取代,R5定义与权利要求2中的定义相同;
步骤5-1:化合物5A与5B在三苯基膦和偶氮二甲酸二异丙酯条件下,反应得到化合物5C;
步骤5-2:化合物5C在碳酸钾存在的条件下,反应得到化合物5D;
步骤5-3:化合物5D在盐酸条件下脱除保护基,得到化合物5E;
步骤5-4:化合物5E和化合物5F在碱性条件下反应得到化合物5G;
步骤5-5:化合物5E和含氮杂环化合物5H在N,N'-羰基二咪唑和碱性条件下,反应得到化合物5I;
合成方法6:
其中,R1、R2、R3、R4、和X2的定义与权利要求1中定义相同;
m4为1~7的整数;
与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同;
步骤6-1:化合物6A与6B在碳酸钾存在条件下,反应得到化合物6C;
步骤6-2:化合物6C在叔丁醇钾存在的条件下,反应得到化合物6D;
步骤6-3:化合物6D和含氮杂环化合物6E在碱性条件下,反应得到化合物6F;
合成方法7
其中,R1、R2、R3、和R4的定义与权利要求1中的定义相同;
m4为1~7的整数;
与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同;
步骤7-1:化合物7A与7B氯甲基甲醚在氢化钠存在的条件下反应,得到化合物7C;
步骤7-2:化合物7C在7D和偶氮二异丁腈存在的条件下反应,得到化合物7E;
步骤7-3:化合物7E在7F在碱性条件下反应,得到化合物7G;
步骤7-4:化合物7G在酸性条件下反应,得到化合物7H;
步骤7-5:化合物7I和7F在碱性条件下反应,得到化合物7H;
步骤7-6:化合物7H与6B在碳酸钾存在条件下,反应得到化合物7J;
步骤7-7:化合物7J和含氮杂环化合物7K在碱性条件下,反应得到化合物7L。
19.根据权利要求18所述的方法,其中,步骤1-1中,Pd催化剂选自:Pd(PPh3)4、Pd(PPh3)2Cl2,一价铜催化剂为碘化亚酮,碱为三乙胺或二异丙基乙基胺。
20.根据权利要求18所述的方法,其中,步骤2-1中,非质子溶剂选自:乙腈、DMF;Pd催化剂选自:乙酸钯(II)、Pd(PPh3)4;膦配体选自:三苯基膦、s-Phos;有机碱选自:三乙胺或二异丙基乙基胺。
21.根据权利要求18所述的方法,其中,合成方法3中,缩合剂选自:HATU、HOBt;碱为三乙胺。
22.根据权利要求18所述的方法,其中,步骤4-1中,Pd催化剂选自:Pd(PPh3)4、Pd(PPh3)2Cl2,一价铜催化剂为碘化亚酮,碱为三乙胺或二异丙基乙基胺。
23.根据权利要求18所述的方法,其中,步骤5-4中,所述碱选自:三乙胺或而二异丙基乙基胺。
24.根据权利要求18所述的方法,其中,合成方法7中,碱选自:三乙胺或二异丙基乙基胺。
25.根据权利要求18所述的方法,其中,步骤7-4中,酸选自:盐酸、二氧六环。
26.一种药物组合物,其特征在于,包含治疗有效剂量的权利要求1至17中任意一项所述的化合物,其对映体、其消旋体、其同位素化合物、或其可药用的盐,和至少一种其它药学上可接受的载体。
27.根据权利要求1或2所述的通式(I)所示的化合物,其对映体、其消旋体、其同位素化合物、或其可药用的盐在制备治疗与CRL4CRBNE3泛素连接酶相关的疾病的药物中的用途。
28.如权利要求27所述的用途,其中,所述的疾病选自下组:癌症、炎症、疼痛、神经系统疾病和免疫系统疾病。
29.如权利要求27所述的用途,其中,所述的癌症选自:皮肤癌症、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌,喉癌以及与艾滋病相关的癌症。
30.如权利要求27所述的用途,其中,所述疾病选自:血液瘤或骨髓瘤。
31.如权利要求27所述的用途,其中,所述疾病选自:多发性骨髓瘤、淋巴瘤或急慢性白血病。
32.如权利要求27所述的用途,其中,所述疾病选自:原发肿瘤和转移性肿瘤。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679380A (zh) * | 2007-03-20 | 2010-03-24 | 细胞基因公司 | 4’-o-取代的异吲哚啉衍生物和包含它的组合物及使用方法 |
CN107257800A (zh) * | 2014-12-23 | 2017-10-17 | 达纳-法伯癌症研究所股份有限公司 | 通过双功能分子诱导靶蛋白降解的方法 |
WO2017180417A1 (en) * | 2016-04-12 | 2017-10-19 | The Regents Of The University Of Michigan | Bet protein degraders |
WO2017223452A1 (en) * | 2016-06-23 | 2017-12-28 | Dana-Farber Cancer Institute, Inc. | Degradation of bromodomain-containing protein 9 (brd9) by conjugation of brd9 inhibitors with e3 ligase ligand and methods of use |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2620085C (en) * | 2005-08-31 | 2016-07-12 | Celgene Corporation | Isoindole-imide compounds and compositions comprising and methods of using the same |
BRPI0716092A2 (pt) | 2006-08-30 | 2013-09-17 | Celgene Corp | composto ou um sal, solvato, ou estereoisâmero do mesmo, composiÇço farmacÊutica, mÉtodo para tratar, controlar ou prevenir uma doenÇa ou distérbio, e, forma de dosagem de unidade simples. |
US8877780B2 (en) | 2006-08-30 | 2014-11-04 | Celgene Corporation | 5-substituted isoindoline compounds |
LT3202460T (lt) | 2010-02-11 | 2019-10-10 | Celgene Corporation | Arilmetoksi izoindolino dariniai ir kompozicijos, apimantys ir jų panaudojimo būdus |
PL3214081T3 (pl) * | 2014-10-30 | 2021-04-06 | Kangpu Biopharmaceuticals, Ltd. | Pochodna izoindoliny, półprodukt, sposób wytwarzania, kompozycja farmaceutyczna i ich zastosowanie |
WO2017176958A1 (en) * | 2016-04-06 | 2017-10-12 | The Regents Of The University Of Michigan | Monofunctional intermediates for ligand-dependent target protein degradation |
GB201610156D0 (en) * | 2016-06-10 | 2016-07-27 | Otsuka Pharma Co Ltd | Cliptac compositions |
BR112019012878A2 (pt) * | 2016-12-23 | 2019-11-26 | Arvinas Operations Inc | compostos e métodos para a degradação alvo de polipeptídos de fibrossarcoma rapidamente acelerados |
JP2021508703A (ja) * | 2017-12-26 | 2021-03-11 | カイメラ セラピューティクス, インコーポレイテッド | Irak分解剤およびそれらの使用 |
CN117050002A (zh) * | 2018-11-21 | 2023-11-14 | 冰洲石生物科技公司 | 具有雌激素受体α降解活性的新型化合物及其用途 |
CN111285850B (zh) * | 2018-12-06 | 2022-04-22 | 中国科学院上海药物研究所 | 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679380A (zh) * | 2007-03-20 | 2010-03-24 | 细胞基因公司 | 4’-o-取代的异吲哚啉衍生物和包含它的组合物及使用方法 |
CN107257800A (zh) * | 2014-12-23 | 2017-10-17 | 达纳-法伯癌症研究所股份有限公司 | 通过双功能分子诱导靶蛋白降解的方法 |
WO2017180417A1 (en) * | 2016-04-12 | 2017-10-19 | The Regents Of The University Of Michigan | Bet protein degraders |
WO2017223452A1 (en) * | 2016-06-23 | 2017-12-28 | Dana-Farber Cancer Institute, Inc. | Degradation of bromodomain-containing protein 9 (brd9) by conjugation of brd9 inhibitors with e3 ligase ligand and methods of use |
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