CN115010712A - Tdo2抑制剂 - Google Patents
Tdo2抑制剂 Download PDFInfo
- Publication number
- CN115010712A CN115010712A CN202210532542.8A CN202210532542A CN115010712A CN 115010712 A CN115010712 A CN 115010712A CN 202210532542 A CN202210532542 A CN 202210532542A CN 115010712 A CN115010712 A CN 115010712A
- Authority
- CN
- China
- Prior art keywords
- imidazo
- isoindol
- group
- alkyl
- membered heterocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000003112 inhibitor Substances 0.000 title abstract description 17
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 title abstract 3
- 101000892398 Homo sapiens Tryptophan 2,3-dioxygenase Proteins 0.000 title abstract 2
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 claims abstract description 60
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 25
- 206010062016 Immunosuppression Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 266
- 150000001875 compounds Chemical class 0.000 claims description 228
- -1 1- (5H-imidazo [5,1-a ] isoindol-5-yl) ethan-1-ol 2- (5H-imidazo [5,1-a ] isoindol-5-yl) propan-2-ol 1- (5H-imidazo [5,1-a ] isoindol-5-yl) ethane-1, 2-diol Chemical compound 0.000 claims description 199
- 239000000203 mixture Substances 0.000 claims description 132
- 125000000217 alkyl group Chemical group 0.000 claims description 96
- 125000001072 heteroaryl group Chemical group 0.000 claims description 60
- 102000057288 Tryptophan 2,3-dioxygenases Human genes 0.000 claims description 59
- 229910052799 carbon Inorganic materials 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 37
- 125000004043 oxo group Chemical group O=* 0.000 claims description 30
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 10
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 5
- 206010057644 Testis cancer Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000003120 testicular cancer Diseases 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 4
- 210000001072 colon Anatomy 0.000 claims description 3
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- GAXNWWWCUKBUIC-GFCCVEGCSA-N 2-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]propan-2-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2C(C)(C)O GAXNWWWCUKBUIC-GFCCVEGCSA-N 0.000 claims description 2
- GAXNWWWCUKBUIC-LBPRGKRZSA-N 2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]propan-2-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2C(C)(C)O GAXNWWWCUKBUIC-LBPRGKRZSA-N 0.000 claims description 2
- IMCUGBPNZOTWMM-RYUDHWBXSA-N C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@H](CO)O Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@H](CO)O IMCUGBPNZOTWMM-RYUDHWBXSA-N 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
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- TUKBORYXXVUNPN-ZIAGYGMSSA-N (1R)-1-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@H](C(C)C)O TUKBORYXXVUNPN-ZIAGYGMSSA-N 0.000 claims 1
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- OZPZBFLBHBJLPJ-CHWSQXEVSA-N (1R)-1-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]propan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@H](CC)O OZPZBFLBHBJLPJ-CHWSQXEVSA-N 0.000 claims 1
- MYGSWLYTIYRXPI-ZIAGYGMSSA-N (1R)-1-[(5R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound FC1=CC=C2[C@@H](N3C(C2=C1)=CN=C3)[C@@H](C(C)C)O MYGSWLYTIYRXPI-ZIAGYGMSSA-N 0.000 claims 1
- YGWJYVYVHDGOJA-DZGCQCFKSA-N (1R)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-1-(1H-imidazol-2-yl)ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@@](C)(O)C=1NC=CN=1 YGWJYVYVHDGOJA-DZGCQCFKSA-N 0.000 claims 1
- RKAAUKMHFJTFPD-DLBZAZTESA-N (1R)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-1-(oxan-4-yl)ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@](C)(O)C1CCOCC1 RKAAUKMHFJTFPD-DLBZAZTESA-N 0.000 claims 1
- TUKBORYXXVUNPN-UONOGXRCSA-N (1R)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@@H](C(C)C)O TUKBORYXXVUNPN-UONOGXRCSA-N 0.000 claims 1
- UDZRVINHNLAGCI-PRHODGIISA-N (1R)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@@H](C)O UDZRVINHNLAGCI-PRHODGIISA-N 0.000 claims 1
- OZPZBFLBHBJLPJ-OLZOCXBDSA-N (1R)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]propan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@@H](CC)O OZPZBFLBHBJLPJ-OLZOCXBDSA-N 0.000 claims 1
- MYGSWLYTIYRXPI-UONOGXRCSA-N (1R)-1-[(5S)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound FC1=CC=C2[C@H](N3C(C2=C1)=CN=C3)[C@@H](C(C)C)O MYGSWLYTIYRXPI-UONOGXRCSA-N 0.000 claims 1
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- RKAAUKMHFJTFPD-SJORKVTESA-N (1S)-1-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]-1-(oxan-4-yl)ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@](C)(O)C1CCOCC1 RKAAUKMHFJTFPD-SJORKVTESA-N 0.000 claims 1
- TUKBORYXXVUNPN-KGLIPLIRSA-N (1S)-1-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@H](C(C)C)O TUKBORYXXVUNPN-KGLIPLIRSA-N 0.000 claims 1
- OZPZBFLBHBJLPJ-QWHCGFSZSA-N (1S)-1-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]propan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@H](CC)O OZPZBFLBHBJLPJ-QWHCGFSZSA-N 0.000 claims 1
- MYGSWLYTIYRXPI-KGLIPLIRSA-N (1S)-1-[(5R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound FC1=CC=C2[C@@H](N3C(C2=C1)=CN=C3)[C@H](C(C)C)O MYGSWLYTIYRXPI-KGLIPLIRSA-N 0.000 claims 1
- YGWJYVYVHDGOJA-ZFWWWQNUSA-N (1S)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-1-(1H-imidazol-2-yl)ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@](C)(O)C=1NC=CN=1 YGWJYVYVHDGOJA-ZFWWWQNUSA-N 0.000 claims 1
- TUKBORYXXVUNPN-KBPBESRZSA-N (1S)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-2-methylpropan-1-ol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@H](C(C)C)O TUKBORYXXVUNPN-KBPBESRZSA-N 0.000 claims 1
- UDZRVINHNLAGCI-QPUJVOFHSA-N (1S)-1-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]ethanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@H](C)O UDZRVINHNLAGCI-QPUJVOFHSA-N 0.000 claims 1
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- CSZSPTARQFNEKT-CHWSQXEVSA-N (R)-(1-fluorocyclopropyl)-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound FC1(CC1)[C@H](O)[C@@H]1N2C(C3=CC=CC=C13)=CN=C2 CSZSPTARQFNEKT-CHWSQXEVSA-N 0.000 claims 1
- CSZSPTARQFNEKT-QWHCGFSZSA-N (R)-(1-fluorocyclopropyl)-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound FC1(CC1)[C@H](O)[C@H]1N2C(C3=CC=CC=C13)=CN=C2 CSZSPTARQFNEKT-QWHCGFSZSA-N 0.000 claims 1
- KDVNHJBRENYKHK-HZPDHXFCSA-N (R)-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]-(oxan-4-yl)methanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@H](O)C1CCOCC1 KDVNHJBRENYKHK-HZPDHXFCSA-N 0.000 claims 1
- KDVNHJBRENYKHK-JKSUJKDBSA-N (R)-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-(oxan-4-yl)methanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@H]2[C@H](O)C1CCOCC1 KDVNHJBRENYKHK-JKSUJKDBSA-N 0.000 claims 1
- PTJIYOVLLWVTRC-IAGOWNOFSA-N (R)-cyclohexyl-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound C1(CCCCC1)[C@@H](O)[C@@H]1N2C(C3=CC=CC=C13)=CN=C2 PTJIYOVLLWVTRC-IAGOWNOFSA-N 0.000 claims 1
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- AKKWDPIANDTKQB-ZIAGYGMSSA-N (R)-cyclopropyl-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound C1(CC1)[C@@H](O)[C@@H]1N2C(C3=CC=CC=C13)=CN=C2 AKKWDPIANDTKQB-ZIAGYGMSSA-N 0.000 claims 1
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- KDVNHJBRENYKHK-CVEARBPZSA-N (S)-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]-(oxan-4-yl)methanol Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@H](O)C1CCOCC1 KDVNHJBRENYKHK-CVEARBPZSA-N 0.000 claims 1
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- PTJIYOVLLWVTRC-SJORKVTESA-N (S)-cyclohexyl-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound C1(CCCCC1)[C@H](O)[C@@H]1N2C(C3=CC=CC=C13)=CN=C2 PTJIYOVLLWVTRC-SJORKVTESA-N 0.000 claims 1
- PTJIYOVLLWVTRC-IRXDYDNUSA-N (S)-cyclohexyl-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]methanol Chemical compound C1(CCCCC1)[C@H](O)[C@H]1N2C(C3=CC=CC=C13)=CN=C2 PTJIYOVLLWVTRC-IRXDYDNUSA-N 0.000 claims 1
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- SHWGGPRTZMIDFO-CVEARBPZSA-N C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@H](O)C1=CC=NC=C1 Chemical compound C=1N=CN2C=1C1=CC=CC=C1[C@@H]2[C@@H](O)C1=CC=NC=C1 SHWGGPRTZMIDFO-CVEARBPZSA-N 0.000 claims 1
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- KFMOUYRODGSEPU-UKRRQHHQSA-N N-[(R)-hydroxy-[(5R)-5H-imidazo[5,1-a]isoindol-5-yl]methyl]cyclopropanecarboxamide Chemical compound C1(CC1)C(=O)N[C@@H]([C@@H]1N2C(C3=CC=CC=C13)=CN=C2)O KFMOUYRODGSEPU-UKRRQHHQSA-N 0.000 claims 1
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Abstract
本文提供了细胞表达的TDO2的抑制剂及其药物组合物,其可用于调节色氨酸2,3双加氧酶的活性;治疗免疫抑制;治疗受益于抑制色氨酸降解的医学病症;增强包括给予抗癌剂的抗癌治疗的有效性;和治疗与癌症相关的肿瘤‑特异性免疫抑制。
Description
本申请是基于申请日为2016年12月23日,申请号为201680081161.5(PCT/CN2016/111730),发明名称为:“TDO2抑制剂”的专利申请的分案申请。
背景技术
技术领域
本发明涉及用于抑制色氨酸2,3-双加氧酶(TDO2)的化合物和方法;本发明还涉及治疗由色氨酸缺乏介导的疾病和障碍的方法。
相关领域的内容
色氨酸(Trp)是蛋白质、烟酸和神经递质5-羟基色胺(血清素)的生物合成所需的必需氨基酸。酶吲哚胺2,3-双加氧酶1(也称为INDO1或IDO1)、吲哚胺-2,3-双加氧酶2(INDOL1或IDO2)和色氨酸-2,3-双加氧酶(TDO2)在L-色氨酸到N-甲酰基犬尿氨酸的降解中催化第一和限速步骤。尽管这些酶催化相同反应,但认为IDO1与TDO2在不同组织中的不同表达和区别(compartamentalization)导致了它们不同的生物学作用。IDO1通常表达在胃肠和肺上皮细胞、附睾(epididymus)、胎盘、引流淋巴结中的pDC和肿瘤细胞中。IDO2主要表达在脑和胎盘中,但某些拼接变体也在肝脏、小肠(smallintesting)、脾脏、胎盘、胸腺肺、脑、肾脏和结肠中被检测到。TDO2主要表达在肝脏中,并且控制食物Trp向5-羟色胺和犬尿氨酸路径的流量(flux),且也在肿瘤和肿瘤细胞系中表达。
多重证据显示IDO1和TDO2与免疫耐受性的诱导相关。对哺乳动物妊娠、肿瘤耐药性、慢性感染和自身免疫性疾病的研究已显示表达IDO1的细胞可抑制T-细胞应答和促进耐受性。在与细胞免疫活化有关的疾病和障碍(诸如感染、恶性肿瘤、自身免疫性疾病和AIDS)中以及在妊娠期间已观察到加速的Trp分解代谢。有人提出IDO1由HIV感染缓慢诱导并通过机会性感染进一步升高,还提出Trp的慢性流失会启动导致AIDS患者的恶病质、痴呆和腹泻以及可能的免疫抑制的机制(Brown,等人,1991,Adv.Exp.Med.Biol.,294:425-35)。为此,近年来已显示IDO1抑制能在HIV小鼠模型中提高病毒特异性T细胞的水平,并且随之降低受病毒感染的巨噬细胞的数量(Portula等人,2005,Blood,106:2382-90)。
据信IDO1在防止子宫内胎儿排斥的免疫抑制过程中具有重要作用。在40多年以前,在妊娠过程中观察到,遗传学上不同的哺乳动物孕体的存活与通过组织移植免疫学所预测到的无关(Medawar,1953,Symp.Soc.Exp.Biol.7:320-38)。母体和胎儿的解剖学分离(Anatomic separation)以及胎儿的抗原不成熟不能完全解释胎儿同种异体移植存活。近来的关注点已聚焦于母体的免疫耐受性上。由于IDO1通过人合体滋养细胞表达,并且系统性(systemic)色氨酸浓度在正常妊娠期中下降,猜测母胎界面处的IDO1表达对于预防胎儿同种异体移植体的免疫排斥来说是必要的。为测试这种猜测,将怀孕小鼠(携带同基因或同种异体胎儿)暴露于1MT,观察到迅速的、T细胞诱导的所有同种异体孕体(allogeneicconcepti)排斥。因此,通过分解代谢色氨酸,哺乳动物孕体显示抑制T-细胞活性和保护其自身免于排斥,并且在小鼠妊娠期间阻止色氨酸分解代谢允许母体T细胞引起胎儿同种异体移植体排斥(Munn,等人,1998,Science 281:1191-3)。
基于通过IDO1降解色氨酸的肿瘤免疫应答机制的进一步证据来自以下观察:大多数人肿瘤组成性表达IDO,以及免疫原性小鼠肿瘤细胞的IDO1表达通过将小鼠预免疫而阻止其排斥。这种效果伴随着在肿瘤部位处缺乏特异性T细胞的积累,并且可在没有显著毒性的情况下通过用IDO抑制剂系统性治疗小鼠而部分逆转。因此,这暗示了癌症患者的治疗性接种疫苗的功效可通过伴随施用IDO1抑制剂来改进(Uyttenhove等人,2003,Nature Med.,9:1269-74)。这还显示了IDO1抑制剂1-MT可与化疗剂协同作用以降低小鼠中的肿瘤生长,表明IDO1抑制还能增强常规细胞毒性治疗的抗肿瘤活性(Muller等人,2005,Nature Med.,11:312-9)。
对TDO2也观察到类似情况。已显示大部分原发性人肿瘤表达升高水平的TDO2或TDO2+IDO1(Pilotte等,2012,P.N.A.S)。另外,用TDO2抑制剂对TDO2活性的药理学抑制导致过度表达TDO2的肿瘤的免疫介导性排斥,这表示正如在IDO1中所见的那样,TDO2能介导促肿瘤的免疫抑制作用。
IDO1的小分子抑制剂可被开发以治疗或预防IDO1-相关疾病,诸如上面描述的那些。例如,PCT公开WO99/29310报道了改变T细胞介导的免疫的方法,包括使用IDO1抑制剂改变色氨酸和色氨酸代谢物的局部胞外浓度,所述IDO1的抑制剂诸如1-甲基-DL-色氨酸、对-(3-苯并呋喃基)-DL-丙氨酸、对-[3-苯并(b)噻吩基]-DL-丙氨酸和6-硝基-L-色氨酸)(Munn,1999)。在WO03/087347(也公布为欧洲专利1501918)中还报道了制备用于提高或降低T细胞耐受性的抗原呈递细胞的方法(Munn,2003)。具有吲哚胺-2,3-双加氧酶(IDO)抑制活性的化合物还在WO 2004/094409、WO2009/073620、WO2009/132238、WO2011/056652和WO2012/142237中报道。特别是,WO2012/142237的化合物包含一系列具有有效IDO1抑制活性的三环咪唑并异吲哚。
发明内容
我们认识到根据显示IDO1和/或TDO2在免疫抑制、肿瘤耐药性和/或排斥、慢性感染、HIV-感染、AIDS(包括其临床适应症,诸如,恶病质、痴呆和腹泻)、自身免疫性疾病或障碍(诸如类风湿性关节炎)和免疫耐受性以及预防子宫内胎儿排斥中的作用的实验数据,目的在于通过抑制IDO1和/或TDO2活性来抑制色氨酸降解的治疗剂是理想的。IDO1和TDO2的特异性或双重抑制剂可用于在T细胞被妊娠、恶性肿瘤或诸如HIV的病毒所抑制时激活T细胞,由此增强T细胞活化。IDO1和/或TDO2的抑制也可以是对患有神经学或神经精神学疾病或障碍(诸如抑郁)的患者的重要治疗策略。本文的化合物、组合物和方法有助于满足现在对IDO1和TDO2调控剂的需求。
在本发明中,我们描述了与咪唑并异吲哚相关的具有不同电子和血红素结合性质的新型结构,其能特异性地抑制IDO1或TDO2,或能对由这些酶中的任一种介导的色氨酸降解进行组合抑制。
在一方面,本发明包括根据式(I)的化合物,
或其立体异构体,或其药学上可接受的盐,
其中
R1为C1-6烷基、C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),该3-7元杂环基中没有成员为-NH-;
(b)当R1为C1-6烷基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上取代有-NR2或-OH;且
(c)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在一个实施方案中,本发明提供式(I)的化合物,其中
R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)时,该3-7元杂环基中没有成员为-NH-;且
(b)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基时,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在一个实施方案中,本发明提供式(I)的化合物,其中
R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)时,该3-7元杂环基中没有成员为-NH-;且
(b)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)时,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在式(I)化合物的一个实施方案中,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH。在其它实施方案中,本发明包括式(I)的化合物,其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH且n为0。在其它实施方案中,本发明包括式(I)的化合物,其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH且n为1。
在一个实施方案中,本发明包括式(II)的化合物,
其为式(I)的化合物,其中
环A为C3-10环烷基或3-7元杂环基;
m为0、1、2、3或4;且
R4为-NR2或-OR。
在一个实施方案中,本发明包括式(II)的化合物,其中R4为-OH。在其它实施方案中,R4为–OH且n为0。在其它实施方案中,R4为–OH且n为1。
在另一实施方案中,本发明包括式(III)的化合物,
其为式(I)的化合物,其中
环A为C3-8环烷基或3-7元杂环基;
环B为芳基、杂芳基、C3-7环烷基或3-7元杂环基;
m为0、1、2、3或4;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
在一个实施方案中,本发明包括式(III)的化合物,其中n为0。在其它实施方案中,n为1。
在另一实施方案中,本发明包括式(IV)的化合物,
其为式(I)的化合物,其中
环A和环B形成螺环体系,
环A为C3-8环烷基或3-7元杂环基;
环B为C3-7环烷基、3-7元杂环基、芳基或杂芳基;
m为0、1、2、3或4;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
在一个实施方案中,本发明包括式(IV)的化合物,其中n为0。在其它实施方案中,n为1。
在一个实施方案中,本发明包括式(V)的化合物,
其为式(I)的化合物,其中
环A为C3-10环烷基、3-7元杂环基或杂芳基且R4为A环上的取代基或键合至A环的亚甲基;
m为0、1、2、3或4;且
R4为-NR2或-OR。
在一个实施方案中,本发明包括式(V)的化合物,其中R4为-OH。在其它实施方案中,R4为–OH且n为0。在其它实施方案中,R4为–OH且n为1。
在另一方面,提供药物组合物,其包含药学上可接受的赋形剂、稀释剂或载体、和根据式(I)、(II)、(III)、(IV)或(V)的化合物。
在另一方面,提供药物组合物,其包含药学上可接受的赋形剂、稀释剂或载体、根据式(I)、(II)、(III)、(IV)或(V)的化合物和第二治疗剂。
在另一方面,提供试剂盒,其包含药学上可接受的赋形剂、稀释剂或载体、根据式(I)、(II)、(III)、(IV)或(V)的化合物和第二治疗剂。
在另一方面,提供方法,其用于
a)在无细胞系统或细胞中(离体或体内)调节IDO1或TDO2的活性,其包括将IDO1或TDO2与调节有效量的根据式(I)的化合物,或包含根据式(I)的化合物的药物组合物接触;
b)在需要的受试者中治疗IDO1或TDO2介导的免疫抑制,包括给予有效的抑制量的根据式(I)的化合物,或包含根据式(I)的化合物的药物组合物;
c)治疗受益于IDO1和/或TDO2介导的色氨酸降解的抑制的医学病症,包括给予有效量的式(I)的化合物,或包含根据式(I)的化合物的药物组合物;
d)增强抗癌治疗的有效性,包括给予抗癌剂和根据式(I)的化合物,或包含根据式(I)的化合物的药物组合物;和
e)治疗与癌症相关的免疫抑制,包括给予有效量的根据式(I)的化合物,或包含根据式(I)的化合物的药物组合物。
在另一方面,本发明包括本文定义的任何种类化合物或物质在制备用于治疗受益于抑制IDO1或TDO2酶活性的医学病症的药物中的用途。
在另一方面,本发明包括本文定义的任何种类化合物或物质,其用于抑制IDO1或TDO2的酶活性和治疗受益于抑制IDO1或TDO2酶活性的医学病症。
在另一方面,本发明包括本文定义的任何种类化合物或物质用于治疗与癌症相关的免疫抑制、传染病或病毒感染的用途。
发明详述
本发明的目的是开发抑制TDO2的酶活性的小分子。IDO1和IDO2氨基酸序列之间的比对揭示了介导血红素和底物结合的高度保守的特征。尽管IDO1和IDO2或IDO1和TDO2之间的氨基酸序列同一性不是特别高,但是通过IDO1和TDO2诱变以及通过晶体学分析确定对于催化活性重要的显著残基在IDO1、IDO2和TDO2之间高度保守,表明色氨酸(tryophan)双氧化机制中的结构和功能类似性。尽管在活性位点具有这些结构相似性,但IDO1和TDO2具有不同的底物特异性,TDO2几乎专门针对在吲哚基的5-和6-位取代的L-Trp和L-Trp衍生物特异,而IDO1可以接受并且氧化多种底物如D-Trp、色胺、5-羟色胺和1-甲基-L-Trp。IDO1和TDO2活性位点的这些微小结构差异决定了这两种蛋白质对相同的酶抑制剂分子显示出不同的反应,其中一些抑制剂显示出TDO2-特异性反应,另一些显示IDO1-特异性反应并且一些显示双重IDO1和TDO2抑制。此外,特定类别的小分子抑制剂抑制IDO1和TDO2的特异性取决于IDO1和TDO2活性是否使用采用重组纯化的IDO1或TDO2蛋白或细胞内表达的IDO1或TDO2蛋白的生物测定来测量。例如,专利申请WO2012142237和WO2014159248中描述的化合物在针对纯化的重组蛋白和针对细胞表达的IDO1或针对重组纯化的TDO2蛋白进行测试时显示出有效的IDO1抑制。然而,该类化合物在针对在细胞内表达的TDO2进行测试时显示出显著的10-100倍降低的效力。因此,这些化合物不可能有助于体内TDO2的显著抑制。为此,本发明描述了一类在细胞生物测定和体内显示有效的TDO2抑制的新型分子。
在一方面,本发明提供式(I)的化合物,
或其立体异构体,或其药学上可接受的盐,
其中
R1为C1-6烷基、C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),该3-7元杂环基中没有成员为-NH-;
(b)当R1为C1-6烷基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上取代有-NR2或-OH;且
(c)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在一个实施方案中,本发明提供式(I)的化合物,其中
R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、
-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),该3-7元杂环基中没有成员为-NH-;
(b)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在另一实施方案中,本发明提供式(I)的化合物,其中
R1为C3-10环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),该3-7元杂环基中没有成员为-NH-;和
(b)当R1为C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在另一实施方案中,本发明提供式(I)的化合物,
或其立体异构体,或其药学上可接受的盐,
其中
R1为-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,
其中所述C3-10环烷基、3-7元杂环基或杂芳基任选稠合至芳基、杂芳基、C3-8环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
在式(I)化合物的一个实施方案中,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH。在其它实施方案中,本发明包括式(I)的化合物,其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH且n为0。在其它实施方案中,本发明包括式(I)的化合物,其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH且n为1。
本发明进一步包括式(I)的亚类和种类,其为结构式(I)、n、R1和R2的种类和属的任何组合,如下文定义。因此,例如,本发明还包括结构式(I)化合物的亚属,其中n如以下(1c)定义,R1如以下(2h)定义,且R2如以下(3k)定义。
n选自以下组(1a)-(1k)之一:
(1a)n为1、2、3或4.
(1b)n为0、1、2或3。
(1c)n为0、1或2。
(1d)n为0或1。
(1e)n为1或2。
(1f)n is 2或3。
(1g)n为1。
(1h)n为2。
(1i)n为3。
(1j)n为4。
(1k)n为0。
R2选自以下组(2a)-(2t)之一:
(2a)R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR,或-NR2。
(2b)R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-OR或-NR2。
(2c)R2独立地为卤素、氰基、C1-6烷基、C3环烷基或-OR。
(2d)R2独立地为卤素、C1-6烷基、C3环烷基或-OR。
(2e)R2独立地为卤素、氰基、C1-6烷基或-OR。
(2f)R2独立地为卤素、C1-6烷基或-OR。
(2g)R2独立地为卤素或-OR。
(2h)R2独立地为C1-6烷基或-OR。
(2i)R2独立地为-OR。
(2j)R2独立地为卤素、甲基或-OR。
(2k)R2独立地为卤素、甲基、-OH或-OMe。
(2l)R2独立地为氯、氟、甲基或-OR。
(2m)R2独立地为氯、氟、甲基、-OH或-OMe.
(2n)R2独立地为氯、氟、甲基或-OH。
(2o)R2独立地为氟、甲基或-OH。
(2p)R2独立地为氟或-OH。
(2q)R2独立地为氟或甲基。
(2r)R2为氟。
(2s)R2为甲基。
(2t)R2为-OH。
R1选自以下组(3a)-(3cccc)之一:
(3a)R1为C3-10环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
(3b)组(3a),其中R1为C4-6环烷基或5-6元杂环基,
其中所述C4-6环烷基或5-6-元杂环基任选稠合至芳基或杂芳基;
或
其中所述C4-6环烷基任选取代有=(螺-C4环烷基)或=(螺-(4-元杂环基))。
(3c)组(3a),其中R1为C4-6环烷基或5-6元杂环基,
其中所述C4-6环烷基或5-6元杂环基任选稠合至芳基或杂芳基;
或
其中所述C4-6环烷基或5-6元杂环基任选取代有=(螺-C4环烷基)或=(螺-(4-元杂环基))。
(3d)组(3a),其中R1为环丁基、环戊基、环己基、吡咯烷基或哌啶基,
其中该环戊基任选稠合至苯基,该环己基任选稠合至吡啶基或苯基,且哌啶基任选稠合至吡咯烷基或苯基;或
其中环丁基任选取代有=(螺-环丁基)或=(螺-氮杂环丁烷基)。
(3e)组(3a),其中R1为C3-10环烷基或3-7元杂环基。
(3f)组(3a),其中R1为C3-10环烷基。
(3g)组(3a),其中R1为C5-8桥接双环。
(3h)组(3a),其中R1为环丁基或环戊基。
(3i)组(3a),其中R1为环丁基。
(3j)组(3a),其中R1为环戊基。
(3k)组(3a),其中R1为3-7元杂环基。
(3l)组(3a),其中R1为吡咯烷基或哌啶基。
(3m)组(3a),其中R1为吡咯烷基。
(3n)组(3a),其中R1为哌啶基。
(3o)组(3a),其中R1为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述C3-8环烷基或3-7元杂环基稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基。
(3p)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基。
(3q)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至杂芳基、C3-7环烷基或3-7元杂环基。
(3r)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至芳基、C3-7环烷基或3-7元杂环基。
(3s)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至芳基、杂芳基、或3-7元杂环基。
(3t)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至芳基、杂芳基或C3-7环烷基。
(3u)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至芳基。
(3v)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至杂芳基。
(3w)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至C3-7环烷基。
(3x)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基稠合至3-7元杂环基。
(3y)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基。
(3z)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至杂芳基、C3-7环烷基或3-7元杂环基。
(3aa)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至芳基、C3-7环烷基或3-7元杂环基。
(3bb)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至芳基、杂芳基、或3-7元杂环基。
(3cc)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至芳基、杂芳基或C3-7环烷基。
(3dd)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至芳基。
(3ee)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至杂芳基。
(3ff)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至C3-7环烷基。
(3gg)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),其中所述3-7元杂环基稠合至3-7元杂环基。
(3hh)组(3a),其中R1为C3-10环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述C3-7环烷基或3-7元杂环基取代有=(螺-C3-8环烷基)或=(螺-(3-7元杂环基))。
(3ii)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基取代有=(螺-C3-7环烷基)。
(3jj)组(3a),其中R1为C3-8环烷基,
其中所述C3-8环烷基取代有=(螺-(3-7元杂环基))。
(3kk)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述3-7元杂环基取代有=(螺-C3-7环烷基)。
(3ll)组(3a),其中R1为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中所述3-7元杂环基取代有=(螺-(3-7元杂环基))。
(3mm)组(3b)-(3ll)的任一个,其中R1取代有至少一个选自-OR和-NR2的Ra基团。
(3nn)组(3b)-(3ll)的任一个,其中R1取代有至少一个选自-OR的Ra基团。
(3oo)组(3b)-(3ll)的任一个,其中R1取代有至少一个选自-NR2的Ra基团。
(3pp)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
(3qq)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
(3rr)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR和-OC(O)N(R)2。
(3ss)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
(3tt)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-S(O)2R、-S(O)2OR和-S(O)2N(R)2。
(3uu)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-S(O)2R、-S(O)2OR和-S(O)2N(R)2。
(3vv)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:C1-6烷基、-OR、-S(O)2R、-S(O)2OR和-S(O)2N(R)2。
(3ww)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-OR、-S(O)2R、-S(O)2OR和-S(O)2N(R)2。
(3xx)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:氧代、卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(3yy)组(3b)-(3oo)的任一个,其中R1取代有1、2或3个独立选自以下的Ra基团:C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(3zz)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(3aaa)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:C1-6烷基、-OR和-S(O)2N(R)2。
(3bbb)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:C1-6烷基、-OR和-S(O)2R。
(3ccc)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:C1-6烷基和-OR。
(3ddd)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:甲基、乙基、丙基、-异丙基、-OMe和-OH。
(3eee)组(3b)-(3oo)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:甲基和乙基。
(3fff)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(3ggg)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:C1-6烷基、-OR和-S(O)2N(R)2。
(3hhh)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:C1-6烷基、-OR和-S(O)2R。
(3iii)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:C1-6烷基和-OR。
(3jjj)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:甲基、乙基、丙基、-异丙基、-OMe和-OH。
(3kkk)组(3b)-(3oo)的任一个,其中R1代有1个独立选自以下的Ra基团:甲基和乙基。
(3lll)组(3b)-(3oo)的任一个,其中R1代有1个甲基基团。
(3mmm)组(3b)-(3oo)的任一个,其中R1代有1个乙基基团。
(3nnn)R1为C1-6烷基、C3-10环烷基、3-7元杂环基(例如,4-6元杂环基或5-6元杂环基)、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基(例如,-C1烷基-4-6元杂环基或-C1烷基-5-6元杂环基)或-C1烷基-杂芳基
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1任选取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
(3ooo)组(3nnn),其中R1为C1-6烷基、C4-6环烷基或5-6元杂环基,
其中所述C4-6环烷基或5-6-元杂环基任选稠合至芳基或杂芳基;
或
其中所述C4环烷基任选取代有=(螺-C4环烷基)或=(螺-(4-元杂环基))。
(3ppp)组(3nnn),其中R1为C1-6烷基、C4-6环烷基或5-6元杂环基,
其中所述C4-6环烷基或5-6元杂环基任选稠合至芳基或杂芳基;
或
其中所述C4-6环烷基或5-6元杂环基任选取代有=(螺-C4环烷基)或=(螺-(4-元杂环基))。
(3qqq)组(3nnn),其中R1为C1-6烷基。
(3rrr)组(3nnn),其中R1为甲基、乙基、丙基、丁基,戊基或己基。
(3sss)组(3nnn),其中R1为甲基、乙基、丙基或丁基。
(3ttt)组(3nnn),其中R1为甲基、乙基或丁基。
(3uuu)组(3nnn),其中R1为甲基或乙基。
(3vvv)组(3nnn),其中R1为甲基。
(3www)组(3nnn),其中R1为乙基。
(3xxx)组(3nnn),其中R1为丁基。
(3yyy)组(3nnn)-(3xxx)的任一个,其中R1取代有1或2个独立选自以下的Ra基团:卤素、C1-6烷基、-C1-6卤代烷基、C3环烷基或-OR。
(3zzz)组(3nnn)-(3xxx)的任一个,其中R1取代有C3环烷基和-OH。
(3aaaa)组(3nnn)-(3xxx)的任一个,其中R1取代有1或2个-OH。
(3bbbb)组(3nnn)-(3xxx)的任一个,其中R1代有1个-OH。
(3cccc)组(3nnn)-(3xxx)的任一个,其中R1代有2个-OH。
本发明进一步包括式(I)的亚类和种类,其为结构式(I)的种类和属的任何组合,可为式(Ia)-(Ii),其中n、R2和R1如上定义。因此,例如,本发明还包括结构式(Ie)化合物的亚属,其中n如以上(1g)定义,且R2如以上(2r)定义。
结构式I为式(Ia)-(Ii)之一:
本发明该方面的具体实施方案包括式(I)和(Ia)–(Ii)任一个的化合物,各自如以下各行定义,其中各条目为如上定义的组号(例如,(2r)是指R2为氟),"X"表示该变量通过实施方案中的另一组定义(例如,在以下实施方案(1)-X中,R1在式(X)中定义)且连接号"-"表示该变量如式(I)或(Ia)–(Ii)定义或根据可适用的变量定义(1a)-(3cccc)中的任一个定义[例如,当R2的条目为连接号,其可如式(I)–(IVi)定义或如定义(2a)-(2t)任一个定义]:
在一个实施方案中,本发明包括式(II)的化合物,
其为式(I)的化合物,其中
环A为C3-10环烷基或3-7元杂环基;
m为0、1、2、3或4;且
R4为-NR2或-OR。
在一个实施方案中,本发明包括式(II)的化合物,其中R4为-OH。在其它实施方案中,R4为–OH且n为0。在其它实施方案中,R4为–OH且n为1。
本发明进一步包括式(II)的亚类,其中所述取代基按照如本文定义的结构式(II)、R2、Ra、m和环A中的一个或多个的任意和全部组合进行选择,包括但不限于,以下:
结构式I为式(IIa)-(IIi)之一:
环A选自以下组(4a)-(4ccc)之一:
(4a)环A为C3-10环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中m为0、1、2或3,各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2,且各个R独立地为氢、C1-6烷基或C1-6卤代烷基。
(4b)R1为:
其中
各个R独立地为氢或C1-6烷基;
R3为甲基、乙基或-O-丁基。
(4c)组(4a),其中环A为C4-6环烷基或4-6元杂环基。
(4d)组(4a),其中环A为C3-8环烷基。
(4e)组(4b),其中环A为环丙基,环丁基,环戊基或环己基。
(4f)组(4b),其中环A为环丁基,环戊基或环己基。
(4g)组(4b),其中环A为环丁基或环己基。
(4h)组(4b),其中环A为环丁基或环戊基。
(4i)组(4b),其中环A为环戊基或环己基。
(4j)组(4b),其中环A为环丙基。
(4k)组(4b),其中环A为环丁基。
(4l)组(4b),其中环A为环戊基。
(4m)组(4b),其中环A为环己基。
(4n)R1为:
(4o)R1为:
(4p)R1为:
(4q)R1为:
(4r)组(4a),其中环A为3-7元杂环基。
(4s)组(4p),其中环A为氮杂环丙烷基,氮杂环丁烷基,吡咯烷基或哌啶基。
(4t)组(4p),其中环A为氮杂环丁烷基,吡咯烷基或哌啶基。
(4u)组(4p),其中环A为氮杂环丁烷基或吡咯烷基。
(4v)组(4p),其中环A为氮杂环丁烷基或哌啶基。
(4w)组(4p),其中环A为吡咯烷基或哌啶基。
(4x)组(4p),其中环A为吡咯烷基。
(4y)组(4p),其中环A为哌啶基。
(4z)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4aa)R1为:
其中
R3为甲基、乙基、丙基或丁基。
(4bb)R1为:
(4cc)R1为:
其中
R3为甲基、乙基、丙基或丁基。
(4dd)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4ee)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4ff)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4gg)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4hh)R1为:
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(4ii)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(4jj)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1、2或3,且各个Ra独立地选自氯、氟、甲基、-OH、-S(O)2乙基、-S(O)2NMe2和-S(O)2NH2。
(4kk)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1或2,且各个Ra独立地选自C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(4ll)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为3,且各个Ra独立地选自卤素、C1-6烷基和-OR。
(4mm)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为3,且各个Ra独立地选自氟、甲基和-OH。
(4nn)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为2,且各个Ra独立地选自C1-6烷基和-OR。
(4oo)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为2,且两个Ra都为甲基。
(4pp)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为2,且两个Ra都为氟。
(4qq)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为2,且各个Ra独立地选自甲基和-OH。
(4rr)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(4ss)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2N(R)2。
(4tt)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2R。
(4uu)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自C1-6烷基和-OR。
(4vv)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自甲基和-OH。
(4ww)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra选自C1-6烷基、-S(O)2R和-S(O)2N(R)2。
(4xx)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra为C1-6烷基。
(4yy)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra为甲基或乙基。
(4zz)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra为甲基。
(4aaa)组(4c)-(4m)或(4r)-(4y)中的任一个,其中m为1,且Ra为-OMe或-OH。
(4bbb)R1为:
其中
各个R独立地为氢或C1-6烷基;
R3为甲基、乙基或-O-丁基。
(4ccc)R1为:
在另一实施方案中,本发明包括式(III)的化合物,
其为式(I)的化合物,其中
环A为C3-8环烷基或3-7元杂环基;
环B为芳基、杂芳基、C3-7环烷基或3-7元杂环基;
m为0、1、2、3或4;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
在一个实施方案中,本发明包括式(III)的化合物,其中n为0。在其它实施方案中,n为1。
本发明进一步包括式(III)的亚类,其中所述取代基按照如本文定义的结构式(III)、R2、Ra、m、环A和环B中的一个或多个的任意和全部组合进行选择,包括但不限于,以下:
结构式I为式(IIIa)-(IIIi)之一:
环A/B选自以下组(5a)-(5yy)之一:
(5a)环A为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为芳基、杂芳基、C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
其中m为0、1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-OR、-C(O)N(R)2、-S(O)2R和-S(O)2N(R)2。
(5b)组(5a),其中环A为C5-6环烷基,且环B为芳基或杂芳基。
(5c)组(5a),其中环A为环戊基或环己基,且环B为芳基或杂芳基。
(5d)组(5a),其中环A为C5-6环烷基,且环B为苯基或吡啶基。
(5e)组(5a),其中环A为环戊基或环己基,且环B为苯基或吡啶基。
(5f)组(5a),其中环A为C3-8环烷基,且环B为芳基、杂芳基、C3-8环烷基或3-7元杂环基。
(5g)组(5a),其中环A为环丙基,且环B为芳基、杂芳基、C3-7环烷基或3-7元杂环基。
(5h)组(5a),其中环A为环丁基,且环B为芳基、杂芳基、C3-8环烷基或3-7元杂环基。
(5i)组(5a),其中环A为环戊基或环己基,且环B为芳基、杂芳基、C3-8环烷基或3-7元杂环基。
(5j)组(5a),其中环A为C3-8环烷基,且环B为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻唑基、三唑基、噁唑基或噁二唑基。
(5k)组(5a),其中环A为环戊基或环己基,且环B为芳基。
(5l)组(5a),其中环A为环戊基或环己基,且环B为苯基。
(5m)组(5a),其中环A为环戊基,且环B为杂芳基。
(5n)组(5a),其中环A为环戊基或环己基,且环B为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻唑基、三唑基、噁唑基或噁二唑基。
(5o)组(5a),其中环A为环戊基,且环B为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻唑基、三唑基、噁唑基或噁二唑基。
(5p)组(5a),其中环A为环己基,且环B为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻唑基、三唑基、噁唑基或噁二唑基。
(5q)组(5a),其中环A为环己基,且环B为吡啶基,吡嗪基,嘧啶基,或哒嗪基。
(5r)组(5a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为芳基、杂芳基、C3-8环烷基或3-7元杂环基。
(5s)组(5a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为芳基或杂芳基。
(5t)组(5a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为芳基。
(5u)组(5a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为杂芳基。
(5v)组(5a),其中环A为哌啶基,且环B为芳基。
(5w)组(5a),其中环A为哌啶基,且环B为杂芳基。
(5x)组(5b)-(5w)中的任一个,其中m为1、2或3,且各个Ra独立地选自C1-6烷基、-OR、-C(O)N(R)2、-S(O)2R和-S(O)2N(R)2。
(5y)组(5b)-(5w)中的任一个,其中m为1、2或3,且各个Ra独立地选自甲基、-OH、-S(O)2乙基、-C(O)NH2、-C(O)N(Me)(H)、-S(O)2NMe2和-S(O)2NH2。
(5z)组(5b)-(5w)中的任一个,其中m为1或2,且各个Ra独立地选自C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(5aa)组(5b)-(5w)中的任一个,其中m为3,且各个Ra独立地选自C1-6烷基和-OR。
(5bb)组(5b)-(5w)中的任一个,其中m为3,且各个Ra独立地选自甲基和-OH。
(5cc)组(5b)-(5w)中的任一个,其中m为2,且各个Ra独立地选自C1-6烷基和-OR。
(5dd)组(5b)-(5w)中的任一个,其中m为2,且各个Ra独立地选自甲基和-OH。
(5ee)组(5b)-(5w)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR、-C(O)N(R)2、-S(O)2R和-S(O)2N(R)2。
(5ff)组(5b)-(5w)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2N(R)2。
(5gg)组(5b)-(5w)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2R。
(5hh)组(5b)-(5w)中的任一个,其中m为1,且Ra选自C1-6烷基和-OR。
(5ii)组(5b)-(5w)中的任一个,其中m为1,且Ra选自甲基、-C(O)NH2、-C(O)N(Me)(H)和-OH。
(5jj)组(5b)-(5w)中的任一个,其中m为1,且Ra选自C1-6烷基、-S(O)2R和-S(O)2N(R)2。
(5kk)组(5b)-(5w)中的任一个,其中m为1,且Ra为C1-6烷基。
(5ll)组(5b)-(5w)中的任一个,其中m为1,且Ra为甲基或乙基。
(5mm)组(5b)-(5w)中的任一个,其中m为1,且Ra为甲基。
(5nn)组(5b)-(5w)中的任一个,其中m为1,且Ra为-OMe或-OH。
(5oo)组(5b)-(5w)中的任一个,其中m为0。
(5pp)R1为
(5qq)R1为
(5rr)R1为
(5ss)R1为
(5tt)R1为
(5uu)R1为
(5vv)R1为
(5ww)R1为
(5xx)R1为
(5yy)R1为
在另一实施方案中,本发明包括式(IV)的化合物,
其为式(I)的化合物,其中
环A和环B形成螺环体系,
环A为C3-8环烷基或3-7元杂环基;
环B为C3-7环烷基、3-7元杂环基、芳基或杂芳基;
m为0、1、2、3或4;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
在一个实施方案中,本发明包括式(IV)的化合物,其中n为0。在其它实施方案中,n为1。
本发明进一步包括式(IV)的亚类,其中所述取代基按照如本文定义的结构式(IV)、R2、Ra、m、环A和环B中的一个或多个的任意和全部组合进行选择,包括但不限于,以下:
结构式I为式(IVa)-(IVi)之一:
环A/B选自以下组(6a)-(6zz)之一:
(6a)环A为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),芳基或杂芳基,
其中m为0、1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(6b)组(6a),其中环A为C4-5环烷基或4-6元杂环基,且环B为C4-6环烷基或4-6元杂环基。
(6c)组(6a),其中环A为C3-8环烷基,且环B为C3-8环烷基或3-7元杂环基。
(6d)组(6a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为C3-7环烷基。
(6e)组(6a),其中环A为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为C3-7环烷基。
(6f)组(6a),其中环A为C3-8环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为3-7元杂环基.
(6g)组(6a),其中环A为C3-8环烷基,且环B为芳基或杂芳基。
(6h)组(6a),其中环A为C3-8环烷基,且环B为3-7元杂环基。
(6i)组(6a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为芳基。
(6j)组(6a),其中环A为3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),且环B为杂芳基。
(6k)组(6a),其中环A为环丁基,且环B为C3-8环烷基或3-7元杂环基。
(6l)组(6a),其中环A为环丁基,且环B为C3-8环烷基。
(6m)组(6a),其中环A为环丁基,且环B为环丁基。
(6n)组(6a),其中环A为环丁基,且环B为3-7元杂环基。
(6o)组(6a),其中环A为环丁基,且环B为4-6元杂环基。
(6p)组(6a),其中环A为环丁基,且环B为4-元杂环基。
(6q)组(6a),其中环A为环丁基,且环B为5-元杂环基。
(6r)组(6a),其中环A为环丁基,且环B为6-元杂环基。
(6s)组(6a),其中环A为环丁基,且环B为氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基或四氢吡喃基。
(6t)组(6a),其中环A为环丁基,且环B为氮杂环丁烷基、氧杂环丁烷基、哌啶基或四氢吡喃基。
(6u)组(6a),其中环A为环丁基,且环B为氮杂环丁烷基或氧杂环丁烷基。
(6v)组(6a),其中环A为环丁基,且环B为哌啶基或四氢吡喃基。
(6w)组(6a),其中环A为环丁基,且环B为氮杂环丁烷基或哌啶基。
(6x)组(6a),其中环A为环丁基,且环B为氧杂环丁烷基或四氢吡喃基。
(6y)组(6b)-(6x)中的任一个,其中m为1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(6z)组(6b)-(6x)中的任一个,其中m为1、2或3,且各个Ra独立地选自氯、氟、甲基、-OH、-S(O)2乙基、-S(O)2NMe2和-S(O)2NH2。
(6aa)组(6b)-(6x)中的任一个,其中m为1或2,且各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(6bb)组(6b)-(6x)中的任一个,其中m为3,且各个Ra独立地选自卤素、C1-6烷基和-OR。
(6cc)组(6b)-(6x)中的任一个,其中m为3,且各个Ra独立地选自氟、甲基和-OH。
(6dd)组(6b)-(6x)中的任一个,其中m为2,且各个Ra独立地选自C1-6烷基和-OR。
(6ee)组(6b)-(6x)中的任一个,其中m为2,且各个Ra独立地选自甲基和-OH。
(6ff)组(6b)-(6x)中的任一个,其中m为2,且两个Ra都为甲基。
(6gg)组(6b)-(6x)中的任一个,其中m为2,且两个Ra都为氟。
(6hh)组(6b)-(6x)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
(6ii)组(6b)-(6x)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2N(R)2。
(6jj)组(6b)-(6x)中的任一个,其中m为1,且Ra选自C1-6烷基、-OR和-S(O)2R。
(6kk)组(6b)-(6x)中的任一个,其中m为1,且Ra选自C1-6烷基和-OR。
(6ll)组(6b)-(6x)中的任一个,其中m为1,且Ra选自甲基和-OH。
(6mm)组(6b)-(6x)中的任一个,其中m为1,且Ra选自C1-6烷基、-S(O)2R和-S(O)2N(R)2。
(6nn)组(6b)-(6x)中的任一个,其中m为1,且Ra为C1-6烷基。
(6oo)组(6b)-(6x)中的任一个,其中m为1,且Ra为甲基或乙基。
(6pp)组(6b)-(6x)中的任一个,其中m为1,且Ra为甲基。
(6qq)组(6b)-(6x)中的任一个,其中m为1,且Ra为-OMe或-OH。
(6rr)组(6b)-(6x)中的任一个,其中m为0。
(6ss)R1为
其中
R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
(6tt)R1为
(6uu)R1为
(6vv)R1为
(6ww)R1为
(6xx)R1为
(6yy)R1为
(6zz)R1为
在另一实施方案中,本发明包括式(V)的化合物,
其中
环A为C3-10环烷基、3-7元杂环基或杂芳基;
m为0、1、2、3或4;且
R4为在A环上取代的-NR2或-OR或键合至A环的亚甲基。
在一个实施方案中,本发明包括式(V)的化合物,其中R4为-OH。在其它实施方案中,R4为–OH且n为0。在其它实施方案中,R4为–OH且n为1。
本发明进一步包括式(V)的亚类,其中所述取代基按照如本文定义的结构式(V)、R4、Ra、m和环A中的一个或多个的任意和全部组合进行选择,包括但不限于,以下:
结构式I为式(Va)-(Vf)之一:
环A选自以下组(7a)-(7cc)之一:
(7a)环A为C3-8环烷基、3-7元杂环基或杂芳基,
其中m为0、1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-S(O)2R、-C(O)N(R)2和C1-6烷基-氰基。
(7b)组(7a),其中环A为C3-6环烷基、4-6元杂环基或杂芳基。
(7c)组(7a),其中环A为
(7e)组(7a),其中环A为C3-8环烷基。
(7f)组(7a),其中环A为C3-6环烷基。
(7g)组(7a),其中环A为环丙基。
(7h)组(7a),其中环A为环己基。
(7i)组(7a),其中环A为3-7元杂环基。
(7j)组(7a),其中环A为4-6元杂环基。
(7k)组(7a),其中环A为4-元杂环基。
(7l)组(7a),其中环A为5-元杂环基。
(7m)组(7a),其中环A为6-元杂环基。
(7n)组(7b)-(7l)中的任一个,其中m为0、1、2或3,且各个Ra独立地选自卤素、C1-6烷基、-S(O)2R、-C(O)N(R)2和C1-6烷基-氰基。
(7o)组(7m),其中各个Ra独立地选自卤素、C1-6烷基、-S(O)2R、-C(O)N(R)2和C1-6烷基-氰基。
(7p)组(7m),其中各个Ra独立地选自卤素、C1-6烷基、-S(O)2R和-C(O)N(R)2。
(7q)组(7m),其中各个Ra独立地选自卤素、C1-6烷基和-S(O)2R。
(7r)组(7m),其中各个Ra独立地选自卤素、C1-6烷基和C1-6烷基-氰基。
(7s)组(7m),其中各个Ra为卤素。
(7t)组(7m),其中各个Ra为C1-6烷基。
(7u)组(7m),其中各个Ra为-S(O)2R。
(7v)组(7m),其中各个Ra为-C(O)N(R)2。
(7w)组(7m),其中各个Ra为C1-6烷基-氰基。
(7x)组(7b)-(7v)中的任一个,其中m为0、1、2或3。
(7y)组(7b)-(7v)中的任一个,其中m为0、1或2。
(7z)组(7b)-(7v)中的任一个,其中m为0或1。
(7aa)组(7b)-(7v)中的任一个,其中m为3。
(7bb)组(7b)-(7v)中的任一个,其中m为2。
(7cc)组(7b)-(7v)中的任一个,其中m为1。
(7dd)组(7b)-(7v)中的任一个,其中m为0。
本发明该方面的具体实施方案包括式(II)、(IIa)–(IIi)、(III)、(IIIa)–(IIIi)、(IV)和(IVa)–(IVi)、(V)和(Va)–(Vf)任一个的化合物,其各自如以下各行定义,其中各条目为如上定义的组号(例如,(2r)是指R2为氟),"X"表示该变量通过实施方案中的另一组定义(例如,在以下实施方案(2)-X中,环A在式(X)中定义)且连接号"-"表示该变量如式(I)–(Vf)定义或根据可适用的变量定义(1a)-(7xx)中的任一个定义[例如,当R2的条目为连接号,其可如式(II)–(Vf)定义或如定义(2a)-(2t)任一个定义]:
在另一实施方案中,各个R独立地为氢或C1-6烷基。在其它实施方案中,R独立地为氢、甲基、乙基或三氟甲基。
在另一实施方案中,本发明的化合物为式(IIk)或(IIl),
其为式(I)的化合物,其中,
环A为C3-10环烷基或3-7元杂环基(例如,4-6元杂环基或5-6元杂环基),
m为0、1、2、3或4;且
R4为-NR2或-OR。
在另一方面,本发明提供化合物,其为:
或其药学上可接受的盐,或其对映异构体或非对映异构体,或其外消旋混合物。
在一个实施方案中,本发明的化合物为
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇;
5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇;
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇;
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇;
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺;和
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇。
在另一实施方案中,本发明的化合物为
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇;
8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇;
3-(-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇;
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺;
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇;和
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇。
在另一实施方案中,本发明的化合物为
4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇;
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇;
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇;
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇;
((5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺;和
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺。
在另一实施方案中,本发明的化合物为
2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇;
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇;
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺;
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺;
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇;和
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇。
在另一实施方案中,本发明的化合物为
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇;
3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇;
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇;
(7S,8S)-7-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇;
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺;和
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-(甲基磺酰基)-3-氮杂双环[3.1.1]庚-6-醇。
本发明进一步包括式(I)的亚类,其中式(I)、(Ia)-(Ii)、(II)、(IIa)-(IIi)、(III)、(IIIa)-(IIIi)、(IV)、(IVa)-(IVi)、(V)或(Va)-(Vf)任一个的结构包括结构元素
其具有以下构型1–27任一个的立体异构体构型,其中各立体异构体碳原子(上述标记的“a,”“b,”和“c”)的立体化学指定为外消旋(“-”)、“S”或“R”:
结构式I为立体异构体构型(1)-(27)之一:
在一个实施方案中,本发明的化合物在上述标记为“a”的位置为S立体构型。例如,该化合物具有的立体构型为构型1、7、8、15、16或19-22。
在另一实施方案中,本发明的化合物在上述标记为“a”的位置为R立体构型。例如,该化合物具有的立体构型为构型2、9、10、17、18或23-26。
在一个实施方案中,本发明的化合物为构型20的立体构型。
在另一实施方案中,本发明的化合物为构型19的立体构型。
在另一方面,本发明提供以立体异构体构型1-27中每一种的化合物1-41和56-115、117-126、130、133、136、139、139-1、142、146、146-1、149-151、156-163、166-176和178-183的每一个。例如:
本发明进一步包括式(I)的亚类,其中式(I)、(I)或(IIj)-(IIo)任一个的结构包含结构元素,
其具有以下构型28-36任一个的立体异构体构型,其中各立体异构体碳原子(如上标记为“d”和“e”)的立体化学指定为外消旋(“-”)、“S”或“R”:
结构式I为立体异构体构型(28)-(36)之一:
在另一方面,本发明提供化合物42-55、116、127-129、131-132、134-135、137-138、140-141、143-145、147-148、152-155、164-165和177,它们以立体异构体构型28-36的每一个。例如:
在另一方面,本发明提供根据上述任一方面的化合物,其包含一个或多个稳定的同位素。该稳定的同位素可替代任何原子,例如,氢,且可包括任何稳定的同位素,例如,氘。
在另一方面,本发明提供了化合物和包括本发明前述方面中任一个或其任何实施方式的化合物以及可药用的赋形剂、稀释剂或载体的药物组合物。
在另一方面,本发明提供了在有此需要的受试对象中治疗色氨酸2,3-双加氧酶(TDO2)介导的免疫抑制的方法,包括施用有效的色氨酸2,3-双加氧酶抑制量的根据本发明前述方面中任一个或其任何实施方式的化合物或药物组合物。
在一个实施方案中,所述免疫抑制与癌症相关。
在一个实施方案中,所述免疫抑制为与癌症相关的肿瘤-特异性免疫抑制。
在另一实施方案中,所述免疫抑制与癌症相关,其中所述癌症为结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头癌、或颈癌、或淋巴瘤、白血病、或黑素瘤。
在另一方面,本发明提供了如上所定义的前述方面中任一个(及其任何实施方式)所述的化合物用于制备治疗受益于IDO1或TDO2的酶活性的抑制的医学病症的药物中的用途。在该方面中所考虑的医学病症包括本文所述的所有病症。
在另一方面,本发明提供了如上所定义的前述方面中任一个(及其任何实施方式)所述的化合物用于制备刺激T-细胞增殖或逆转无应答或免疫抑制的免疫状态的药物中的用途。
在另一方面,本发明提供了如上所定义的前述方面中任一个(及其任何实施方式)中所述的化合物用于制备治疗与癌症或病毒感染相关的免疫抑制的药物中的用途。
在一个实施方式中,本发明提供了如上所定义的前述方面中任一个(及其任何实施方式)中所述的化合物用于制备治疗与癌症相关的肿瘤特异性免疫抑制的药物中的用途。优选地,所述癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌或头颈部癌、淋巴瘤、白血病、黑素瘤等。
定义
本文所用术语可前缀或后缀于单线“-”或双线“=”,以表示所命名的取代基及其母体部分之间的键的键级;单线表示单键,双线表示双键或在螺-取代基的情况下表示两个单键。在没有单线或双线的情况下,应理解为在取代基及其母体部分之间形成单键;此外,除非短线以其它方式表现,取代基意欲“从左到右”阅读。例如,C1-C6烷氧基羰基氧基和-OC(O)C1-C6烷基表示相同的官能团;类似地,芳基烷基、芳基烷基-和-烷基芳基表示相同的官能团。
此外,如同本领域技术人员所熟悉的那样,且通过其在两个其它部分之间连接的表达,本文中的某些术语可同时作为一价和二价连接基团施用。例如,烷基基团可同时作为一价基团和二价基团;在后一种情况中,本领域技术人员应清楚理解从一价烷基基团上去除额外的氢原子以提供合适的二价部分。
除非另外指明,本文所用的术语“烯基”表示包含2~10个碳并包含至少一个碳-碳双键的直链或支链烃。烯基的代表性例子包括但不限于乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基、3-癸烯基和3,7-二甲基辛-2,6-二烯基。
本文所用的术语“烷氧基”表示如本文所定义的烷基基团通过氧原子附着在母体分子部分上。烷氧基的代表性例子包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基和己氧基。
除非另外指明,本文所用的术语“烷基”是指包含1~10个碳原子的直链或支链烃。烷基的代表性例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。当“烷基”基团为两个其它部分之间的连接基团时,则其也可为直连或支链;例子包括但不限于-CH2-、-CH2CH2-、-CH2CH2CHC(CH3)-、-CH2CH(CH2CH3)CH2-。
本文所用的术语“芳基”是指苯基(即,单环芳基)或包含至少一个苯环的二环体系或在芳香性二环体系中仅包含碳原子的芳香性二环。所述二环芳基可为薁基,萘基,或与单环环烷基、单环环烯基或单环杂环基稠合的苯基。所述二环芳基通过该二环体系的苯基部分中所含的任何碳原子或者萘环或薁环的任何碳原子连接到母体分子部分。所述二环芳基的稠合单环环烷基或单环杂环基部分任选被一个或两个氧代和/或硫代基团取代。二环芳基的代表性例子包括但不限于薁基、萘基、二氢茚-1-基、二氢茚-2-基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2,3-二氢吲哚-6-基、2,3-二氢吲哚-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2-基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢萘-1-基、5,6,7,8-四氢萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]二氧杂环戊烯-4-基、苯并[d][1,3]二氧杂环戊烯-5-基、2H-色烯-2-酮-5-基、2H-色烯-2-酮-6-基、2H-色烯-2-酮-7-基、2H-色烯-2-酮-8-基、异二氢吲哚-1,3-二酮-4-基、异二氢吲哚-1,3-二酮-5-基、茚-1-酮-4-基、茚-1-酮-5-基、茚-1-酮-6-基、茚-1-酮-7-基、2,3-二氢苯并[b][1,4]二噁烷-5-基、2,3-二氢苯并[b][1,4]二噁烷-6-基、2H-苯并[b][1,4]噁嗪3(4H)-酮-5-基、2H-苯并[b][1,4]噁嗪3(4H)-酮-6-基、2H-苯并[b][1,4]噁嗪3(4H)-酮-7-基、2H-苯并[b][1,4]噁嗪3(4H)-酮-8-基、苯并[d]噁嗪-2(3H)-酮-5-基、苯并[d]噁嗪-2(3H)-酮-6-基、苯并[d]噁嗪-2(3H)-酮-7-基、苯并[d]噁嗪-2(3H)-酮-8-基、喹唑啉-4(3H)-酮-5-基、喹唑啉-4(3H)-酮-6-基、喹唑啉-4(3H)-酮-7-基、喹唑啉-4(3H)-酮-8-基、喹喔啉-2(1H)-酮-5-基、喹喔啉-2(1H)-酮-6-基、喹喔啉-2(1H)-酮-7-基、喹喔啉-2(1H)-酮-8-基、苯并[d]噻唑-2(3H)-酮-4-基、苯并[d]噻唑-2(3H)-酮-5-基、苯并[d]噻唑-2(3H)-酮-6-基和苯并[d]噻唑-2(3H)-酮-7-基。在某些实施方式中,所述二环芳基是(i)萘基或(ii)与5或6元单环环烷基、5或6元单环环烯基或5或6元单环杂环基稠合的苯环,其中所述稠合环烷基、环烯基和杂环基基团任选被一个或两个独立为氧代或硫代的基团取代。
本文所用的术语“芳基烷基”、“烷基芳基”和“芳基烷基-”是指如本文所定义的芳基基团通过如本文所定义的烷基基团附着到母体分子部分。芳基烷基的代表性例子包括但不限于苄基、2-苯乙基、3-苯丙基和2-萘-2-基乙基。
本文所用的术语“氰基”和“腈”是指-CN基团。
本文所用的术语“环烷基”是指单环或二环的环烷基环体系。单环环体系是包含3~10个碳原子的环状烃基团,其中这样的基团可以是饱和或不饱和的,但不是芳香性的。在某些实施方式中,环烷基基团是完全饱和的。单环环烷基的例子包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。二环环烷基环体系是桥接单环或稠合二环。桥接单环包含如下单环环烷基环:其中所述单环的两个不相邻碳原子通过具有1~3个其它碳原子的亚烷基桥(即,-(CH2)w-形式的桥接基团,其中w是1、2、3或4)连接。二环环体系的代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷、双环[4.2.1]壬烷和金刚烷。稠合二环环烷基环体系包含与苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基稠合的单环环烷基环。桥接或稠合二环环烷基通过单环环烷基环中所含的任何碳原子连接到母体分子部分。环烷基基团任选被一个或两个独立为氧代或硫代的基团取代。在某些实施方式中,所述稠合二环环烷基是与苯环、5或6元单环环烷基、5或6元单环环烯基、5或6元单环杂环基或5或6元单环杂芳基稠合的5或6元单环环烷基环,其中所述稠合二环环烷基任选被一个或两个独立为氧代或硫代的基团取代。
本文所用的“环烯基”是指单环或二环环烯基环系统。所述单环环系统是指包含3~10个碳原子的环状烃基团,其中这样的基团是不饱和(即,包含至少一个环碳-碳双键),但不是芳香性的。单环环系统的例子包括环戊烯基和环己烯基。二环环烯基环是桥接单环或稠合二环。桥接单环包含如下单环环烯基环:其中所述单环的两个不相邻碳原子通过具有1~3个其它碳原子的亚烷基桥(即,-(CH2)w-形式的桥接基团,其中w是1、2、3或4)相连。二环环烯基的代表性例子包括但不限于降冰片烯基和二环[2.2.2]辛-2-烯基。稠合二环环烯基环系统包含与苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基稠合的单环环烯基环。所述桥接或稠合二环环烯基通过所述单环环烯基环中所含的任何碳原子连接到母体分子部分。环烯基基团任选被一个或两个独立为氧代或硫代的基团取代。
本文所用的术语“卤”或“卤素”是指-Cl、-Br、-I或-F。
本文所用的术语“卤代烷基”是指如本文所述的至少一个卤素通过如本文所定义的烷基基团附着到母体分子部分上。卤代烷基的代表性例子包括但不限于氯甲基、2-氟乙基、三氟甲基、五氟乙基和2-氯-3-氟戊基。
本文所用的术语“杂芳基”是指单环杂芳基环系统或包含至少一个杂芳环的二环环系统。所述单环杂芳基可以是5或6元环。所述5元环由两个双键和一个、两个、三个或四个氮原子以及任选的一个氧或硫原子组成。所述六元环由三个双键和一个、两个、三个或四个氮原子组成。所述5或6元杂芳基通过杂芳基中所含的任何碳原子或任何氮原子连接到母体分子部分。单环杂芳基的代表性例子包括但不限于呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基和三嗪基。所述二环杂芳基由与苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基稠合的单环杂芳基组成。所述二环杂芳基基团的稠合环烷基或杂环基部分任选被一个或两个独立为氧代或硫代的基团取代。当所述二环杂芳基包含稠合环烷基、环烯基或杂环基环时,则所述二环杂芳基基团通过该二环环系统的单环杂芳基部分中所含的任何碳或氮原子连接到母体分子部分。当所述二环杂芳基是与苯环或单环杂芳基稠合的单环杂芳基时,则所述二环杂芳基基团通过所述二环环系统中的任何碳原子或氮原子与母体分子部分相连。二环杂芳基的代表性例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并氧杂噻二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢异喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异喹啉基、萘啶基、喹啉基、嘌呤基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉-3-基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢苯并[c][1,2,5]噁二唑基和6,7-二氢苯并[c][1,2,5]噁二唑-4(5H)-酮基。在某些实施方式中,所述稠合二环杂芳基是与苯环、5或6元单环环烷基、5或6元单环环烯基、5或6元单环杂环基或5或6元单环杂芳基稠合的5或6元单环杂芳基环,其中所述稠合环烷基、环烯基和杂环基基团任选被一个或两个独立为氧代或硫代的基团取代。
本文所用的术语“杂芳基烷基”和“-烷基杂芳基”是指如本文所定义的杂芳基通过如本文所定义的烷基基团附着到母体分子部分。杂芳基烷基的代表性例子包括但不限于呋喃-3-基甲基、1H-咪唑-2-基甲基、1H-咪唑-4-基甲基、1-(吡啶-4-基)乙基、吡啶-3-基甲基、吡啶-4-基甲基、嘧啶-5-基甲基、2-(嘧啶-2-基)丙基、噻吩-2-基甲基和噻吩-3-基甲基。
本文所用的术语“杂环基”是指单环杂环或二环杂环。所述单环杂环是包含至少一个独立选自O、N和S的杂原子的3、4、5、6或7元环,其中所述环是饱和或不饱和的,但不是芳香性的。所述3或4元环包含1个选自O、N和S的杂原子。所述5元环可包含零个或一个双键以及一个、两个或三个选自O、N和S的杂原子。所述6或7元环包含零个、一个或两个双键以及一个、两个或三个选自O、N和S的杂原子。所述单环杂环通过该单环杂环中所含的任何碳原子或任何氮原子连接到母体分子部分。单环杂环的代表性例子包括但不限于氮杂环丁烷基、氮杂环庚烷基、氮杂环丙烷基、二氮杂环庚烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,3-二硫杂环戊烷基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑啉基、异噻唑烷基、异噁唑啉基、异噁唑烷基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧化硫代吗啉基(硫代吗啉砜)、硫代吡喃基和三噻烷基。所述二环杂环是与苯基、单环环烷基、单环环烯基、单环杂环或单环杂芳基稠合的单环杂环。通过杂原子稠合的双环杂环可如同杂原子在环A或环B中那样根据本发明的环A/B规定进行分类。例如,6,7,8,9-四氢-4H-喹嗪-4-酮-基:
可被分类为环A=C6环烷基且环B=取代有氧代基团的6-元杂环基,或A=6-元杂环基且环B=取代有氧代基团的C6环烯基。所述二环杂环通过该二环环系统的单环杂环部分中所含的任何碳原子或任何氮原子连接到母体分子部分。二环杂环基的代表性例子包括但不限于2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚-3-基、2,3-二氢苯并噻吩-2-基、十氢喹啉基、十氢异喹啉基、八氢-1H-吲哚基和八氢苯并呋喃基。所述杂环基基团任选被一个或两个独立为氧代或硫代的基团取代。在某些实施方式中,所述二环杂环基是与苯环、5或6元单环环烷基、5或6元单环环烯基、5或6元单环杂环基或5或6元单环杂芳基稠合的5或6元单环杂环基环,其中所述二环杂环基任选被一个或两个独立为氧代或硫代的基团取代。
本文所用的术语“羟基”是指-OH基团。
本文所用的术语“硝基”是指-NO2基团。
本文所用的术语“氧代”是指=O基团。
本文所用的术语“饱和”是指所提及的化学结构不包含任何多重碳-碳键。例如,本文所定义的饱和环烷基基团包括环己基、环丙基等。
本文所用的术语“螺”是指由取代原子与在该同一原子上的两个可用的可取代部位形成的环状部分。例如,诸如的部分,当R是螺-环烷基=基团时,其包括诸如的化合物,其中所述螺-环戊基基团是通过两个单键与母体环己基环相连的R基团。类似地,当R是螺-杂环基基团时,这样的化合物包括其中所述螺-1,3-二氧杂环戊烷基环是通过两个单键与母体环己基环相连的R基团。
本文所用的术语“硫代”是指=S基团。
本文所用的术语“不饱和”是指所提及的化学结构包含至少一个多重碳-碳键,但不是芳香性的。例如,本文所定义的不饱和环烷基基团包括环己烯基、环戊烯基、环己二烯基等。
本文所用的术语“细胞”意图指代体外、离体或体内的细胞。在一些实施方式中,离体细胞可以是从诸如哺乳动物的有机体上切除的组织样品的一部分。在一些实施方式中,体外细胞可以是细胞培养中的细胞。在一些实施方式中,体内细胞是存活于诸如哺乳动物的有机体中的细胞。
本文所用的术语“接触”是指将所指出的部分在体外系统或体内系统中放在一起。例如,将TDO2酶与化合物“接触”包括将本文所述的化合物施用于具有TDO2的个体或患者(诸如人),以及,例如,将化合物引入包含含有TDO2酶的细胞或纯化试剂的样品中。
可互换使用的术语“个体”或“患者”是指任何动物,包括哺乳动物。优选小鼠、大鼠、其它啮齿动物、兔、犬、猫、猪、牛、羊、马或灵长类动物,最优选人。
本文所用的短语“治疗有效量”是指活性化合物或药物剂的量,其引发了研究员、兽医、医师或其它临床医生要在组织、系统、动物、个体或人中寻求的生物反应或药物反应。
在某些实施方式中,治疗有效量可为适合于以下的量:
(1)预防疾病;例如,在可能易于罹患疾病、病症或障碍但尚未经历或显示疾病的病理学或症候学的个体中预防疾病、病症或障碍;
(2)抑制疾病;例如,在经历或显示疾病、病症或障碍的病理学或症候学的个体中抑制疾病、病症或障碍;或
(3)减轻疾病;例如,在经历或显示疾病、病症或障碍的病理学或症候学的个体中减轻疾病、病症或障碍(即,逆转病理学和/或症候学),诸如降低疾病的严重程度。
如本文所用的,术语“治疗(treatment和treating)”是指(i)减轻所提及的疾病状态,例如,在经历或显示疾病、病症或障碍的病理学或症候学的个体中减轻疾病、病症或障碍(即,逆转病理学和/或症候学),诸如降低疾病的严重程度;或(ii)引发所提及的生理效果(例如,TDO2调控或色氨酸降解抑制)。
伴有潜在TDO2-介导的免疫抑制的疾病病症的减轻的表现可能需要伴随或顺序施用其它治疗剂,诸如,在癌症的情况下的抗肿瘤剂或在病毒性疾病的情况下的抗逆转录病毒剂。例如,当作为单一药剂使用时,施用TDO2抑制剂以治疗癌症并非总是产生直接的抗肿瘤效果。然而,当与化疗药物(抗肿瘤药)组合时,观察到的抗肿瘤效果高于单独每种药剂的效果之和。
本文所用的术语“催化口袋(catalytic pocket)”、“催化位点”、“活性位点”共同和不区分地指代如下酶区域:其包含负责底物结合(电荷、疏水性、空间位阻)的氨基酸残基以及用作质子供体或受体或者负责结合辅因子并参与化学反应的催化的催化性氨基酸残基。
本文所用的短语“可药用盐”是指可药用的酸和碱的加成盐和溶剂化物。这样的可药用盐包括诸如以下的酸的盐:盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH2)n-COOH(其中n是0~4))等。无毒的药物碱加成盐包括诸如以下的碱的盐:钠、钾、钙、铵等。本领域技术人员知晓多种无毒的可药用加成盐。
使用方法
本文所述的化合物和药物组合物能调控酶色氨酸-2,3-双加氧酶(TDO2)的活性。本文所用的术语“调控”意图指代降低酶或受体活性的能力。因此,本文所述的化合物可用于通过将酶与本文所述的化合物或组合物中的任何一种或多种接触来调控TDO2的方法。在一些实施方式中,本文所述的化合物可用作TDO2的抑制剂。在其它实施方式中,本文所述的化合物可用于通过施用调控(例如,抑制)量的本文所述的化合物而在细胞中或在需要对酶进行调控的个体中调控TDO2的活性。
还提供了在包含表达TDO2的细胞的系统(诸如,组织、活的有机体或细胞培养物)中抑制色氨酸降解和预防N-甲酰犬尿氨酸产生的方法。在一些实施方式中,在哺乳动物中改变(例如,升高)胞外色氨酸水平的方法包括施用有效量的本文所提供的化合物或药物组合物。测量色氨酸水平和色氨酸降解的方法在本领域中是惯常所知的。
还提供了通过对患者施用有效量的本文所述的化合物或组合物而在患者中抑制免疫抑制(诸如TDO2-介导的免疫抑制)的方法。TDO2-介导的免疫抑制已与,例如,癌症、肿瘤生长、转移、传染病(例如,病毒感染)、病毒复制等相关联。
还提供了通过对患者施用有效量的本文所述的化合物或组合物而在患者中治疗与癌症相关的肿瘤特异性免疫抑制的方法。可通过本文所述方法治疗的与癌症相关的肿瘤特异性免疫抑制的例子包括与以下癌症相关的免疫抑制:结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头颈部癌、淋巴瘤、白血病、黑素瘤等。
例如,正在经历或已完成用于治疗诸如癌症的疾病状态的化疗和/或放射治疗疗程的患者可受益于对该患者施用治疗有效量的本文所述用于抑制源自疾病状态和/或其治疗的免疫抑制的化合物或组合物。
还提供了通过对需要此治疗的个体施用治疗有效量或剂量的本文所述的化合物或其药物组合物而在个体(例如,患者)中治疗与TDO2活性或表达(例如,异常活性和/或过度表达)相关的疾病的方法。疾病的例子可包括与TDO2酶的表达或活性(诸如过度表达或异常活性)直接或间接关联的任何疾病、障碍或病症。TDO2-相关的疾病还可包括能通过调控酶活性而预防、减轻或治愈的任何疾病、障碍或病症。
TDO2-相关的疾病的例子包括癌症、病毒感染诸如HIV感染、抑郁、神经退行性障碍诸如阿耳茨海默病和亨廷顿舞蹈病、创伤、年龄相关性白内障、器官移植(例如,器官移植排斥)和自身免疫性疾病(包括哮喘、类风湿性关节炎、多发性硬化、炎性肠病、牛皮癣和系统性红斑狼疮)。可通过本文所述方法治疗的癌症的例子包括结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头颈部癌、淋巴瘤、白血病、黑素瘤等。
组合治疗
用于治疗方法的一种或多种其它药物剂(诸如,例如,抗病毒剂、化疗剂或其它抗癌剂、免疫增强剂、免疫抑制剂、放射疗法、抗肿瘤和抗病毒疫苗、细胞因子疗法(例如,IL2、GM-CSF等)和/或吲哚胺2,3-双加氧酶(IDO)抑制剂)可与本文所述用于治疗TDO2-相关性疾病、障碍或病症(如上所述)或用于增强疾病状态或病症(诸如癌症)的治疗效力的化合物和药物组合物组合使用。所述药剂可与本发明化合物组合在单一剂型中,或者所述药剂可作为单独剂型同时或顺序施用。
当与本发明的TDO2抑制剂组合时,构成针对特定癌症类型或传染病的治疗标准的治疗剂被预期是有益的。例如,对于肿瘤的情况,优选所述肿瘤对化疗剂的细胞毒性作用敏感以便刺激最终将介导免疫应答的抗原的释放,所述免疫应答将通过向组合治疗中添加TDO2抑制剂而被增强。本领域技术人员知晓如何根据每种肿瘤对不同抗肿瘤剂的临床特性和已知敏感性来选择这样的化疗剂。
设想与本文所述化合物组合使用的合适的抗病毒剂可包括核苷和核苷酸逆转录酶抑制剂(NRTIs)、非核苷类逆转录酶抑制剂(NNRTIs)、蛋白酶抑制剂和其它抗病毒药物。
合适的NRTI的例子包括齐多夫定(AZT);地达诺新(ddI);扎西他滨(ddC);司他夫定(d4T);拉米夫定(3TC);阿巴卡韦(1592U89);阿德福韦酯[二(POM)-PMEA];洛布卡韦(BMS-180194);BCH-10652;恩曲他滨[(-)-FTC];β-L-FD4(也称为β-L-D4C,并且命名为β-L-2',3'-二去氧(dicleoxy)-5-氟-胞啶(cytidene));DAPD,((-)-β-D-2,6-二氨基-嘌呤二氧戊环);和洛德腺苷(FddA)。典型合适的NNRTI包括奈韦拉平(BI-RG-587);地拉韦啶(BHAP,U-90152);依法韦仑(DMP-266);PNU-142721;AG-1549;MKC-442(1-(乙氧基-甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶-二酮);和(+)-胡桐素A(NSC-675451)和B。典型合适的蛋白酶抑制剂包括沙奎那韦(Ro31-8959);利托那韦(ABT-538);茚地那韦(MK-639);奈非那韦(nelfnavir)(AG-1343);安普那韦(141W94);拉西那韦(lasinavir)(BMS-234475);DMP-450;BMS-2322623;ABT-378;和AG-1549。其它抗病毒剂包括羟基脲、病毒唑、IL-2、IL-12、喷他夫西(pentafuside)和YissumProjectNo.11607。
合适的化疗剂或其它抗癌剂包括,例如,烷基化试剂(包括但不限于,氮芥、乙烯亚胺衍生物、烷基磺酸盐、亚硝基脲和三嗪),诸如乌拉莫司汀、氮芥(chlormethine)、环磷酰胺(CytoxanTM)、异环磷酰胺、美法仑、苯丁酸氮芥、胍血生、三亚乙基-三聚氰胺(triethylene-melamine)、三亚乙基硫代磷胺(triethylenethiophosphoramine)、白消安、卡莫司汀、洛莫司汀、链脲菌素、达卡巴嗪和替莫唑胺。
合适的化疗或其它抗癌剂包括,例如,抗代谢物(包括但不限于叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂),诸如甲氨蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯嘌呤、6-硫鸟嘌呤、磷酸氟达他滨、喷司他丁和吉西他滨。
合适的化疗或其它抗癌剂还包括,例如,某些天然产物及其衍生物(例如,长春花生物碱、抗肿瘤抗体、酶、淋巴因子和表鬼臼毒素),诸如长春花碱、长春新碱、长春地辛、博莱霉素、放线菌素D、道诺霉素、阿霉素、表柔比星、伊达比星、阿糖胞苷、紫杉醇(TaxolTM))、多西他赛、光神霉素、脱氧助间霉素、丝裂霉素-C、L-天冬酰胺酶、干扰素(尤其是IFN-a)、依托泊苷和替尼泊苷。
其它细胞毒性剂包括诺维本(navelbene)、CPT-11、阿那曲替、四唑、卡培他滨、雷洛昔芬、环磷酰胺、异环磷酰胺和曲洛昔芬(droloxafine)。
合适的还有细胞毒性剂:诸如表鬼臼毒素(epidophyllotoxin);抗肿瘤酶;拓扑异构酶抑制剂;甲基苄肼;米托蒽醌;铂配合物,诸如顺铂和卡铂;生物应答改性剂;生长抑制剂;抗激素治疗剂;甲酰四氢叶酸;喃氟啶;和造血生长因子。
其它抗癌剂包括抗体治疗剂,诸如曲妥单抗(赫赛汀),针对共调节分子(诸如CTLA-4,4-1BB)的抗体,或针对细胞因子(IL-10,TGF-β等)的抗体。
其它抗癌剂还包括阻止免疫细胞迁移的那些,诸如趋化因子受体拮抗剂,包括CCR2、CCR4和CCR6。
其它抗癌剂还包括提高免疫系统的那些,诸如继承性T细胞转移。
抗-癌疫苗包括树突状细胞、合成肽、DNA疫苗和重组病毒。
本申请化合物还可以用于遏制或抑制由PD-1(程序性细胞死亡蛋白1)或其配体PD-L1调节的生物途径的治疗性治疗的组合疗法。此类治疗性治疗包括遏制或抑制PD-1或PD-L1表达的那些治疗性治疗,以及抑制或遏制PD-1或PD-L1蛋白本身活性的治疗性治疗。抗PD-1化合物的例子包括,例如,派姆单抗、纳武单抗、皮地利珠单抗和BMS 936559。抗PD-L1的实例包括例如阿特珠单抗和阿维单抗。
安全有效施用大部分这些化疗剂的方法对本领域技术人员来说是已知的。另外,其施用在标准文献中描述。例如,许多化疗剂的施用在“Physicians'Desk Reference”(PDR,e.g.,1996edition,Medical Economics Company,Montvale,N.J.)中描述,其公开内容通过引用并入本文,如同以其整体阐述一样。
药物制剂和剂型
本文所述的药物组合物大体上包括本文所述的化合物与可药用的载体、稀释剂或赋形剂的组合。这样的组合物基本不含非-可药用性组分,即,所含的非-可药用性组分的量低于本申请提交时美国监督要求所允许的量。在该方面的一些实施方式中,如果化合物被溶解或悬浮在水中,则组合物还任选包括其它可药用的载体、稀释剂或赋形剂。在其它实施方式中,本文所述的药物组合物是固体药物组合物(例如,片剂、胶囊等)。
这些组合物可以药物领域熟知的方式制备,并且可通过多种途径施用,这取决于希望局部或全身性治疗和取决于待治疗的区域。施用可以是局部(包括眼部和粘膜,包括鼻、阴道和直肠递送)、经肺部(例如,通过吸入或吹入粉末或气溶胶,包括通过雾化器;气管内、鼻内、表皮和透皮)、经眼部、口服或肠胃外的。经眼部递送的方法可包括局部施用(眼部滴剂)、结膜下、眼周或玻璃体内注射或者通过气囊导管或通过外科手术放置在结膜囊中的眼部插入物来引入。肠胃外施用包括静脉内、动脉内、皮下、腹膜内或肌内注射或输液;或者颅内,例如,囊内或心室内施用。肠胃外施用可为单个单次计量形式,或者例如可通过连续灌注泵。用于局部施用的药物组合物和制剂可包括透皮贴、油膏、乳液、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体剂和粉末剂。常规药物载体、水溶液、粉末或油性基底、增稠剂等可以是必要或理想的。
另外,药物组合物可包含作为活性成分的一种或多种如上所述的本文的化合物与一种或多种可药用载体的组合。在制备本文所述组合物时,活性成分通常与赋形剂混合,用赋形剂稀释或包封在诸如胶囊、药袋(sachet)或其它容器形式的载体中。当赋形剂用作稀释剂时,其可以是用作活性成分媒介物(vehicle)、载体(carrier)或介质(medium)的固体、半固体或液体材料。因此,所述组合物可为片剂、丸剂、粉末、锭剂、药包、扁囊剂(cachet)、酏剂、悬浮剂、乳液、溶液、糖浆、气溶胶(作为固体或在液体介质中)、包含例如至多10wt%活性化合物的油膏、软和硬明胶胶囊、栓剂、无菌注射液和无菌包装粉末。
在制剂的制备中,活性化合物可在与其它成分结合之前被研磨以提供合适的粒径。如果活性化合物是基本不溶的,则其可被研磨至小于200目的粒径。如果活性化合物是基本可溶于水的,则粒径可通过研磨调整为在制剂中提供基本均匀的分布,例如,约40目。
合适赋形剂的一些例子包括乳糖、右旋糖、蔗糖、山梨糖醇、木糖醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆(syrup)和甲基纤维素。所述制剂还可包含:润滑剂,诸如滑石、硬脂酸镁和矿物油;湿润剂;乳化和悬浮剂;防腐剂,诸如甲基-和丙基羟基-苯甲酸盐;增甜剂;和香味剂。本文所述的组合物可配制为在通过本领域已知程序施用于患者之后提供迅速、持续或延迟的活性成分释放。
组合物可配制为单位剂型,每剂包含约5~约100mg、更经常为约10~约30mg的活性成分。术语“单位剂型”是指适合用于人受试对象和其它哺乳动物的单一剂量的物理上独立的单元,每个单元包含计算为产生理想疗效的预定量的活性物质以及合适的药物赋形剂。
活性化合物可在广泛的剂量范围上有效,并且通常以药学有效量施用。然而,应理解实际上施用的化合物的量通常将由医师根据相关情况来确定,包括待治疗的病症,所选择的施用途径,所施用的实际化合物,个体患者年龄、重量和反应、患者症状的严重程度等。
对于固体组合物诸如片剂的制备,将主要的活性成分与药物赋形剂混合以形成包含本文所述化合物的均匀混合物的固体制剂组合物。当提及这些制剂组合物是均匀的时候,活性成分通常在整体组合物中均匀分布,因此该组合物可容易地再细分为同等有效的单位剂型,诸如片剂、丸剂和胶囊。这样的固体制剂随后被再细分为上面所述形式的单位剂型,其包含,例如,0.1~约500mg的本文所述化合物的活性成分。
片剂或丸剂可被包衣或以其它方式复合(compounded)以提供能给予持续作用(prolonged action)优势的剂型。例如,片剂或丸剂可包括内部剂量和外部剂量组分,后者为位于前者之上的包层(envelope)形式。这两种组分可通过惰性层分离,所述惰性层用于阻止在胃里崩解和允许内部组分完整地进入十二指肠或者延迟释放。多种物质可用于这样的惰性层或包衣。这样的材料包括多种聚合酸及聚合酸与诸如虫胶、鲸蜡醇和醋酸纤维素的材料的混合物。
其中包含所述化合物和组合物的用于口服或注射施用的液体形式可包括水溶液、适当调味的糖浆、水或油悬浮液和用食用油(诸如棉籽油、芝麻油、椰子油或花生油)调味的乳液以及酏剂和类似药物媒介物。
用于吸入或吹入的组合物包括在可药用的水溶剂或有机溶剂或其混合物中的溶液和悬浮液以及粉末。液体或固体组合物可包含如上所述的合适的可药用赋形剂。在一些实施方式中,组合物通过经口或经鼻吸入途径施用以产生局部或全身性作用。组合物可通过使用惰性气体来雾化。雾化的溶液可从雾化设备直接呼吸,或者雾化设备可被连接到面罩幕(face mask stent)或间歇式正压呼吸机上。溶液、悬浮剂或粉末组合物可以合适方式从递送制剂的设备口服施用或经鼻施用。
施用给患者的化合物或组合物的量将取决于所施用的物质、施用目的(诸如预防或治疗)、患者状态、施用方式而改变。在治疗用途中,组合物可以足以治愈或至少部分阻止疾病及其并发症的症状的量而施用于已患病的患者。有效剂量将取决于待治疗的疾病状态以及主治临床医师根据多种因素(诸如疾病严重程度,患者年龄、体重和一般状况等)的判断。
施用于患者的组合物可为上面所述的药物组合物的形式。这些组合物可通过常规灭菌技术灭菌,或者可进行无菌过滤。水溶液可被包装以照原样施用,或者可被冻干,冻干制剂在施用前与无菌水性载体组合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。应理解前述赋形剂、载体或稳定剂的施用将导致形成药物的盐。
化合物的治疗剂量将根据,例如,进行治疗的具体用途、化合物的施用方式、患者的健康和病症以及处方医师的判断而变。本文所述化合物在药物组合物中的比例或浓度可根据多种因素而变,包括剂型、化学特性(例如,疏水性)和施用途径。例如,本文所述的化合物可在包含约0.1~约10%w/v的化合物的水性生理缓冲溶液中提供以用于肠胃外施用。一些典型的剂量范围是约1μg/kg~约1g/kg体重/天。在一些实施方式中,剂量范围是约0.01mg/kg~约100mg/kg体重/天。该剂量很可能取决于诸如以下的变量:疾病或障碍的类型或进展程度,具体患者的总体健康状态,所选化合物的相对生物功效,赋形剂的配方及其施用路径。有效剂量可从来自体外或动物模型测试系统的剂量-应答曲线推测。
本文所述的化合物还可配制为与一种或多种其它活性成分组合,所述其它活性成分可包括任何药物剂,诸如抗病毒剂、疫苗、抗体、免疫增强剂、免疫抑制剂、抗炎剂等。
以下实施例提供用于说明目的,而不是意图以任何方式限制公开内容。本领域技术人员将容易地意识到多个非关键参数可被改变或修改以得到基本相同的结果。根据本文所述的一个或多个试验发现下面的实施例化合物是TDO2的抑制剂。
试剂盒
还包括可用于例如治疗或预防与TDO2相关的疾病或病症、肥胖症、糖尿病和其它本文涉及的疾病的药物试剂盒,其包含一个或多个含有药物组合物的容器,所述药物组合物包含治疗有效量的本文所述的化合物。如果需要,这样的试剂盒还可以包括各种常规药物试剂盒组分中的一种或多种,例如,具有一种或多种药学上可接受的载体的容器、额外的容器等,这对于本领域技术人员来说是显而易见的。试剂盒中还可以包含说明书,可以作为插页或标签说明要施用的组分的量,施用指导和/或混合组分的指南。
以下实施例是为了说明的目的而提供的,并且不旨在以任何方式限制本发明。本领域技术人员将容易地认识到可以改变或修改多种非关键参数以产生基本上相同的结果。根据本文所述的一种或多种测定,发现下面的实施例化合物是TDO2的抑制剂。
实施例
所有试剂和溶剂购自商业来源。所有商业试剂和溶剂按照收到时使用而不经进一步纯化。使用分析薄层色谱(TLC)用0.25mm EM Science硅胶板(60F-254)监控反应。显影的TLC板通过短波UV光(254nm)或者浸泡在高锰酸钾溶液中随后在热板上加热而视觉观察。用32-63μm粒径的Selecto Scientific硅胶进行快速色谱。所有反应在氮气下在烤干或烘干的玻璃器皿中进行。除非另外指明,所有反应在环境温度下机械搅拌。1H NMR谱使用以下得到:Bruker DRX400,Varian VXR400或VXR300。1H NMR谱以相对于TMS(0.0)、DMSO-d6(2.50)或CD3OD(4.80)作为内部参比的百万分之份数(parts per million)来报告。除非另外表明,所有1H NMR谱在CDCl3中获取。磷酸盐根据以下文献方法制备:(专利:US5807892 A1,1998;专利:US2012/033245;专利:US2008/306084A1,2008)。1-(叠氮基甲基)-2,4-二甲氧基苯根据ChemMedChem,2011,vol.6,#5,840-847合成。
合成途径IA
合成Int-2的通用步骤:
将碱(1当量)添加至酮(1当量)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1当量)在MeOH(15mL)中的搅拌混合物中。反应混合物在50℃加热2小时直到TLC显示SM消失。冷却至室温后,反应混合物用DCM(50mL)稀释且用水洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过combi-flash纯化,使用EtOAc/己烷作为洗脱液。
表1
合成Int-3和Int-4的通用步骤:
Int-2(1当量)在MeOH和AcOH(5:1)在80℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3添加至残余物直到其为中性。水层用DCM萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗物质通过combi-flash纯化,使用EtOAc/DCM作为洗脱液以将四种非对映异构体的混合物分离为Int-3和Int-4表示的对映异构体的两种混合物。
合成5和6的通用步骤:
将Int-3或Int-4(1当量)溶于MeOH(6mL)且添加NaBH4(3当量),将反应混合物搅拌2h。将NH4Cl(5mL)添加至反应混合物且搅拌5分钟。将溶液倒入包含水(10mL)的分液漏斗。水层用DCM萃取(2x20mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过Combi-Flash使用甲醇/dcm梯度液纯化。
C10-OH类似物的合成途径
醛或酮加成的通用步骤
在–40℃向5H-咪唑并[5,1-a]异吲哚(650mg,4.16mmol)在无水THF(10mL)中的溶液中添加n-BuLi(1.66mL,4.16mmol)且溶液在–40℃搅拌1h。添加醛或酮(6.24mmol)且将反应温热至室温且搅拌过夜。反应通过添加饱和氯化铵(10mL)溶液和水(15mL)淬灭,产物用CH2Cl2(3x30mL)萃取。溶剂在减压下蒸馏以得到粗产物。粗产物通过combi-flash纯化以得到所需产物。
手性分离立体异构体和分析的通用步骤
最终产物的立体异构体通过色谱法分离。除非另有所述,使用以下通用条件:
A.开发/顺序筛选14个手性柱的方法
常规地在Waters UPC2 HPLC系统上在以下条件下筛选14个手性柱:流动相A:二氧化碳,流动相B:甲醇w/0.1%NH4OH,或乙醇,IPA,或混合物,5-60%B在1.8分钟内,流速为4ml/min,运行时间:2.5分钟,压力:120bar,温度:40℃。常规筛选的14个柱(4.6x50mm,3um)为:Chiral Technologies的Chiralpak AD、Chiralpak AS、Chiralpak IA、Chiralpak IB、Chiralpak IC、Chiralpak ID、Chiralpak IE、Chiralpak OJ、ChiralpakOX,Phenomenex的Lux Cellulose-1、LuxCellulose-2、Lux Cellulose-3、Lux Cellulose-4和Regis的WhelkO-1(s,s)。
B.在制备型SFC上的纯化
挑选提供分辨率值Rs>0.5的柱以进行制备型分离。制备型运行在PIC 100SFC仪器上进行,使用显示来自步骤A的对映异构体的最佳拆分的相应柱子(150×20mm,5μm),其中具有步骤A中鉴定的等度流动相B,流动相A:二氧化碳,流动相B:甲醇w/0.1%NH4OH,流速:70ml/min,压力:100bar,温度:40℃
C.分离具有2个手性中心的化合物的典型条件为:
柱:Chiralpak AD(250x20mm,5um)
方法:在25%B的等度洗脱
MP A:二氧化碳
MP B:乙醇w/0.1%NH4OH
Flow:70ml/min
压力:100bar
温度:4040℃
D.分离具有3个手性中心的化合物的典型条件为:
阶段1:
柱:Chiralpak OX(250x20mm,5um)
方法:在20%B的等度洗脱
MP A:二氧化碳
MP B:乙醇w/0.1%NH4OH
Flow:70ml/min
压力:100bar
温度:4040℃
阶段2:
柱:Cellulose-1(250x20mm,5um)
方法:在15%B的等度洗脱
MP A:二氧化碳
MP B:甲醇w/0.1%NH4OH
Flow:70ml/min
压力:100bar
温度:40degC
阶段3:
柱:Chiralcel OX(250x20mm,5um)
方法:在15%B的等度洗脱
MP A:二氧化碳
MP B:甲醇w/0.1%NH4OH
Flow:70ml/min
压力:100bar
温度:40℃
E.最终产物的QC以得到%ee
上述步骤B中分离出的各个异构体的纯度使用以下手性分析SFC分析:
仪器:Waters UPC2;柱:用于纯化的柱(50x4.6mm,3um);方法:流动相A:二氧化碳,等度洗脱流动相B具有与步骤B中使用的相同百分比的流动相B,流速:4ml/min,运行时间:2.5分钟,压力:120bar,温度:40℃。
表2
实施例1:2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
步骤1:
(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮
向2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(2.0g,4.82mmol,1.00当量)和环丁酮(0.72mL,9.65mmol,2.00当量)在无水乙醇(100mL)中的溶液中添加NaOH(0.192g,4.82mmol,1.00当量)且所得混合物在50℃搅拌1小时。反应通过30mL水淬灭且混合物通过二氯甲烷(3x50mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。产物通过CombiFlash纯化以得到(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮,其为黄色油状物:LCMS(ESI,m/z):466[M+H]+
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(顺)
向(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮添加MeOH(16mL)和AcOH(4mL)。所得混合物在90℃搅拌2小时。反应通过30mL饱和NaHCO3溶液淬灭且混合物通过二氯甲烷(3x20mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。非对映异构体的混合物在CombiFlash上分离以得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-(顺),其为淡黄色油状物:LCMS(ESI,m/z):225[M+H]+.
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(反)
向(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮添加MeOH(16mL)和AcOH(4mL)。所得混合物在90℃搅拌2小时。反应通过30mL饱和NaHCO3溶液淬灭且混合物通过二氯甲烷(3x20mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。非对映异构体的混合物在CombiFlash上分离以得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-(反),其为淡黄色固体:LCMS(ESI,m/z):225[M+H]+.
步骤3:
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(顺)(275mg,1.23mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(93mg,2.45mmol)且溶液在0℃搅拌30分钟。将溶剂蒸馏掉且添加饱和氯化铵(10mL)。水层用5%CF3CH2OH在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。异构体1a、1b、1c、1d、1e的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例1a:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.57(dd,J=13.5,7.7Hz,2H),7.36(t,J=7.5Hz,1H),7.25(td,J=7.4,1.1Hz,1H),7.14(s,1H),5.74(d,J=4.5Hz,1H),5.49(d,J=6.2Hz,1H),4.59–4.48(m,1H),2.88–2.75(m,1H),2.24–2.10(m,1H),1.85–1.52(m,3H)。
实施例1b:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.57(dd,J=13.3,7.6Hz,2H),7.36(t,J=7.5Hz,1H),7.29–7.20(m,1H),7.14(s,1H),5.74(d,J=4.0Hz,1H),5.49(d,J=6.3Hz,1H),4.52(d,J=11.3Hz,1H),2.82(p,J=6.3Hz,1H),2.24–2.09(m,1H),1.85–1.52(m,3H)。
实施例1c:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.61–7.54(m,2H),7.36(t,J=7.6Hz,1H),7.30–7.21(m,1H),7.13(s,1H),5.34(dd,J=15.3,7.4Hz,2H),4.25(p,J=7.8Hz,1H),3.44–3.21(m,2H),2.41(dq,J=9.7,7.8Hz,1H),2.15–2.03(m,1H),1.73–1.50(m,2H),1.12(qd,J=10.2,8.1Hz,1H)。
实施例1d:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.61–7.54(m,2H),7.36(t,J=7.6Hz,1H),7.31–7.21(m,1H),7.13(s,1H),5.34(dd,J=15.4,6.8Hz,2H),4.25(p,J=7.5Hz,1H),2.41(dq,J=9.6,7.7Hz,1H),2.15–2.03(m,1H),1.73–1.50(m,2H),1.12(qd,J=10.2,8.1Hz,1H)。
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(反)(178mg,0.79mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(60mg,1.59mmol)且溶液在0℃搅拌30分钟。将溶剂蒸馏掉且添加饱和氯化铵(10mL)。水层用5%CF3CH2OH在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。
实施例1e:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.60(d,J=7.5Hz,1H),7.49(d,J=7.5Hz,1H),7.38(t,J=7.6Hz,1H),7.28–7.19(m,1H),7.10(s,1H),5.72(d,J=3.7Hz,1H),5.45(d,J=9.6Hz,1H),4.42(s,1H),2.39(tt,J=10.2,7.7Hz,2H),2.24(ddt,J=14.9,12.1,7.4Hz,1H),2.01–1.81(m,2H)。
实施例1f:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.89(s,1H),7.58(d,J=7.5Hz,1H),7.42–7.31(m,2H),7.29–7.20(m,1H),7.10(s,1H),5.30(dd,J=25.5,8.2Hz,2H),4.14(p,J=7.6Hz,1H),2.33–2.05(m,2H),1.84–1.50(m,3H)。
实施例1g:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.63–7.45(m,2H),7.37(q,J=7.4Hz,1H),7.24(q,J=7.1Hz,1H),7.12(d,J=13.9Hz,1H),5.73(dd,J=9.0,5.1Hz,1H),5.47(dd,J=14.1,7.9Hz,1H),4.42(tp,J=5.6,2.5Hz,1H),2.48–2.12(m,3H),2.01–1.81(m,2H)。
实施例1h:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):227.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.60(d,J=7.5Hz,1H),7.49(d,J=7.5Hz,1H),7.38(t,J=7.6Hz,1H),7.28–7.19(m,1H),7.10(s,1H),5.72(d,J=3.7Hz,1H),5.45(d,J=9.6Hz,1H),4.42(s,1H),2.39(tt,J=10.2,7.7Hz,2H),2.24(ddt,J=14.9,12.1,7.4Hz,1H),2.01–1.81(m,2H)。
实施例2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
步骤1:
(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环戊烷-1-酮
将吡咯烷(0.22mL,2.65mmol)添加至环戊酮(0.24mL,2.65mmol)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.1g,2.65mmol)在MeOH(15mL)中的搅拌混合物中。反应混合物在50℃加热2小时直到TLC显示SM消失。冷却至室温后,反应混合物用DCM(50mL)稀释且用水洗涤且用Na2SO4干燥。粗产物直接用于下一步:LCMS(ESI,m/z):481.4[M+H]+.
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-酮
该标题化合物通过合成Int-3的通用步骤合成。
两种非对映异构体对通过combin-flash分离,使用EtOAc/DCM作为洗脱液:LCMS(ESI,m/z):+239.2
步骤3a:
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为四种非对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):241.3
异构体2a、2b、2c、2d的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例2a:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.61(dd,J=22.5,7.6Hz,2H),7.37(t,J=7.5Hz,1H),7.31–7.23(m,1H),5.39(d,J=6.8Hz,1H),5.16(d,J=3.8Hz,1H),4.37(q,J=4.7Hz,1H),2.14–2.01(m,1H),1.84–1.39(m,7H)。
实施例2b:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇。LCMS(ESI,m/z):241.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.67–7.54(m,2H),7.37(t,J=7.5Hz,1H),7.31–7.22(m,1H),5.39(d,J=6.9Hz,1H),5.16(d,J=3.9Hz,1H),4.38(qd,J=4.6,2.6Hz,1H),2.08(p,J=8.4Hz,1H),1.84–1.37(m,7H)。
实施例2f:5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):..241.3[M+H]+;1HNMR由于样品量少未获得。实施例2h:-5H.咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR由于样品量少未获得。
步骤3b:
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为四种非对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):241.3
实施例2c:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.60(d,J=7.5Hz,1H),7.50(d,J=7.9Hz,1H),7.37(t,J=7.5Hz,1H),7.24(td,J=7.7,1.3Hz,1H),7.12(s,1H),5.26(d,J=10.2Hz,1H),5.07(d,J=4.1Hz,1H),4.30(p,J=3.7Hz,1H),2.03–1.82(m,3H),1.76–1.55(m,4H)。
实施例2d:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.60(d,J=7.5Hz,1H),7.50(d,J=7.7Hz,1H),7.37(t,J=7.5Hz,1H),7.24(td,J=7.4,1.2Hz,1H),7.12(s,1H),5.26(d,J=10.2Hz,1H),5.06(d,J=4.2Hz,1H),4.30(q,J=3.5Hz,1H),2.02–1.82(m,3H),1.76–1.58(m,4H)。
实施例2e:5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR由于样品量少未获得。
实施例2g:5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241.3[M+H]+;1HNMR由于样品量少未获得。
实施例3:2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
步骤1:
(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环己烷-1-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):495.4[M+H]+
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-酮
该标题化合物通过合成Int-3的通用步骤合成。
两种非对映异构体对通过combin-flash分离,使用EtOAc/DCM作为洗脱液:LCMS(ESI,m/z):253.2
步骤3a:
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为4种对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):255.3.异构体3a、3b、3g和3h的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例3a:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.57–7.51(m,2H),7.40–7.31(m,1H),7.30–7.21(m,1H),7.08(s,1H),5.23(d,J=2.7Hz,1H),4.94–4.89(m,1H),4.27–4.22(m,1H),2.03–1.93(m,1H),1.83–1.75(m,1H),1.65–1.43(m,3H),1.39–1.30(m,1H),1.22–0.98(m,2H),0.79–0.71(m,1H)。
实施例3b:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.66(d,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.40–7.32(m,1H),7.27–7.18(m,1H),7.10(s,1H),5.16(d,J=5.4Hz,1H),4.69(d,J=4.0Hz,1H),4.09–4.04(m,1H),1.82–1.30(m,7H),1.18–1.10(m,1H)。
实施例3c:5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.60(d,J=7.5Hz,1H),7.51(d,1H),7.41–7.34(m,1H),7.30–7.23(m,1H),7.11(s,1H),5.73(d,J=3.9Hz,1H),5.20(d,J=5.2Hz,1H),3.69–3.57(m,1H),2.20–1.92(m,2H),1.65–1.54(m,1H),1.42–1.20(m,2H),1.12–0.89(m,1H),0.62–0.51(m,1H),0.26–0.12(m,1H)。
实施例3d:5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.61–7.55(m,1H),7.50–7.41(m,1H),7.41–7.33(m,1H),7.33–7.25(m,1H),7.14(s,1H),5.73(d,J=2.2Hz,1H),5.24(d,J=5.7Hz,1H),3.70–3.58(m,1H),2.05–1.90(m,2H),1.66–1.56(m,1H),1.41–1.21(m,2H),1.20–0.89(m,2H),0.75–0.64(m,1H),0.26–0.10(m,1H)。
步骤3b:
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。
产物分离为4种对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):255.3
实施例3e:5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.61–7.56(m,1H),7.47–7.41(m,1H),7.41–7.33(m,1H),7.33–7.25(m,1H),7.14(s,1H),5.73(d,J=2.3Hz,1H),5.25(d,J=5.7Hz,1H),3.69–3.59(m,1H),2.05–1.90(m,2H),1.66–1.55(m,1H),1.41–1.26(m,2H),1.20–0.89(m,2H),0.74–0.66(m,1H),0.26–0.10(m,1H)。
实施例3f:5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.60(d,J=7.5Hz,1H),7.50(d,J=7.7,1.1Hz,1H),7.42–7.33(m,1H),7.31–7.22(m,1H),7.11(s,1H),5.73(d,J=3.7Hz,1H),5.20(d,J=5.2Hz,1H),3.68–3.56(m,1H),2.18–2.08(m,1H),2.00–1.91(m,1H),1.63–1.55(m,1H),1.42–1.21(m,2H),1.12–0.89(m,1H),0.60–0.52(m,1H),0.27–0.12(m,1H)。
实施例3g:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.66(d,J=7.7,0.9Hz,1H),7.57(d,1H),7.40–7.31(m,1H),7.27–7.18(m,1H),7.10(s,1H),5.16(d,J=5.4Hz,1H),4.69(d,J=3.9Hz,1H),4.09–4.04(m,1H),1.79–1.31(m,7H),1.21–1.08(m,1H)
实施例3h:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇LCMS(ESI,m/z):255.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.58–7.51(m,2H),7.40–7.31(m,1H),7.30–7.21(m,1H),7.08(s,1H),5.23(d,J=2.7Hz,1H),4.94–4.89(m,1H),4.27–4.22(m,1H),2.03–1.93(m,1H),1.83–1.74(m,1H),1.61–1.46(m,2H),1.39–1.30(m,1H),1.21–1.02(m,2H),0.79–0.71(m,1H)。
实施例4:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
合成途径IC[方案改变]
步骤1:7-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)-5,6,7,8-四氢异喹啉-8-酮
向5,6,7,8-四氢异喹啉-8-酮盐酸盐(2.01g,10.946mmol,1.000当量)在四氢呋喃(100mL)中的溶液中添加2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(9.07g,21.88mmol)和氢氧化钠(1.74g,43.50mmol)。将反应在室温搅拌6h且所得混合物用水(50mL)稀释。所得溶液用二氯甲烷(3x200mL)萃取且将有机相合并,用无水硫酸钠干燥且真空浓缩。残余物用二氯甲烷(30mL)稀释且固体通过过滤收集以得到7-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)-5,6,7,8-四氢异喹啉-8-酮(2.55g,39%),其为淡黄色固体:LCMS(ESI,m/z):544[M+H]+.1HNMR(300MHz,CDCl3)δ9.27(s,1H),8.68(s,1H),8.05(d,J=9.0Hz,1H),7.88(s,1H),7.57(s,1H),7.56-7.09(m,18H),7.10(d,J=9.0Hz,1H),6.85(s,1H),2.89(t,J=3.0Hz,2H),2.73(t,J=3.0Hz,2H)。
步骤2:7-[5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-酮
向(2E)-2-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)-1,2,3,4-四氢萘-1-酮(2.4g,4.42mmol)在甲醇(60mL)中的溶液中添加乙酸(2.6mL,45.37mmol)。将反应在80℃搅拌16h,然后真空浓缩以得到7-[5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-酮(2.0g,粗物质),其为淡黄色油状物:LCMS(ESI,m/z):302[M+H]+
步骤3:
(7S,8S)-7-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇
(7R,8R)-7-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇
(7S,8R)-7-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇
(7R,8S)-7-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
向7-[5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-酮(2.0g,6.64mmol)在甲醇(100mL)中的溶液中添加硼氢化钠(2.5g,67.89mmol)。将反应在室温搅拌6h。所得混合物真空浓缩,然后用二氯甲烷(200mL)稀释。将固体过滤出且将滤液真空浓缩。粗产物通过prep-HPLC纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。各异构体的立体化学任意指定。
1.柱:Chiralpak IB,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:40B至40B在12min内;254/220nm;
2.柱:Chiralpak IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:40B至40B在32min内;254/220nm;
3.柱:lux-4,2.12x20cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:50B至50B在20min内;254/220nm;
所有异构体的绝对构型任意指定。
实施例4a:5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇(47.3mg,2%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.74(s,1H),8.25(d,J=5.4Hz,1H),7.91(s,1H),7.68-7.62(m,2H),7.46-7.41(m,1H),7.34-7.29(m,1H),7.11(s,1H),7.10(d,J=5.4Hz,1H),5.89(d,J=3.0Hz,1H),5.09(d,J=10.5Hz,1H),2.71-2.62(m,3H),1.09-1.04(m,2H);tR=1.309分钟(Chiralpak IB-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。4b和4a为对映异构体。
实施例4b:5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇(28.5mg,1%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.74(s,1H),8.25(d,J=5.4Hz,1H),7.91(s,1H),7.68-7.62(m,2H),7.46-7.41(m,1H),7.34-7.29(m,1H),7.11(s,1H),7.10(d,J=5.4Hz,1H),5.89(d,J=3.0Hz,1H),5.09(d,J=10.5Hz,1H),2.71-2.62(m,3H),1.09-1.04(m,2H);tR=2.147分钟(Chiralpak IB-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。
实施例4c:5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇(47.2mg,2%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.42(s,1H),8.27(d,J=5.1Hz,1H),8.04(s,1H),7.73-7.70(m,1H),7.64-7.61(m,1H),7.43-7.38(m,1H),7.31-7.26(m,1H),7.18(d,J=5.1Hz,1H),7.15(s,1H),5.50(d,J=3.0Hz,1H),4.88(d,J=10.5Hz,1H),3.06-2.93(m,1H),2.82-2.70(m,1H),2.26-1.97(m,3H);tR=1.505分钟,(Chiralpak IB-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。4d和4c为对映异构体。
实施例4d:5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇(32.1mg,2%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.42(s,1H),8.27(d,J=5.1Hz,1H),8.04(s,1H),7.73-7.70(m,1H),7.64-7.61(m,1H),7.43-7.38(m,1H),7.31-7.26(m,1H),7.18(d,J=5.1Hz,1H),7.15(s,1H),5.50(d,J=3.0Hz,1H),4.88(d,J=10.5Hz,1H),3.06-2.93(m,1H),2.82-2.70(m,1H),2.26-1.97(m,3H);tR=2.147分钟,(Chiralpak IB-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。
实施例4e:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(30.3mg,2%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.79(s,1H),8.27(d,J=5.1Hz,1H),7.99(s,1H),7.66-7.64(m,1H),7.50-7.32(m,3H),7.20(s,1H),7.18(d,J=5.1Hz,1H),5.89(d,J=3.0Hz,1H),5.10(d,J=10.5Hz,1H),2.70-2.68(m,2H),2.50-2.42(m,1H),1.14-0.98(m,2H);tR=2.893分钟,(Chiralpak IC-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。4e和4f为对映异构体。
实施例4f:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(79.2mg,5%):LCMS(ESI,m/z):304[M+H]+;1HNMR(400MHz,CD3OD)δ8.79(s,1H),8.27(d,J=5.6Hz,1H),7.99(s,1H),7.66-7.64(m,1H),7.50-7.32(m,3H),7.20(s,1H),7.18(d,J=5.6Hz,1H),5.89(d,J=3.0Hz,1H),5.10(d,J=10.4Hz,1H),2.70-2.68(m,2H),2.50-2.42(m,1H),1.14-0.98(m,2H);tR=5.240分钟,(Chiralpak IC-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。
实施例4g:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(35.9mg,2%):LCMS(ESI,m/z):304[M+H]+;1HNMR(400MHz,CD3OD)δ8.56(s,1H),8.30(d,J=5.6Hz,1H),8.11(s,1H),7.62-7.56(m,2H),7.43-7.39(m,1H),7.34-7.30(m,1H),7.16(d,J=5.6Hz,1H),7.14(s,1H),5.92(d,J=4.0Hz,1H),5.12(d,J=10.4Hz,1H),2.84-2.78(m,1H),2.66-2.54(m,2H),1.61-1.57(m,1H),1.10-1.05(m,1H);tR=4.569分钟,(ChiralpakIC-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。4h和4g为对映异构体。
实施例4h:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(74.7mg,5%):LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.56(s,1H),8.30(d,J=5.2Hz,1H),8.11(s,1H),7.62-7.56(m,2H),7.43-7.39(m,1H),7.34-7.30(m,1H),7.16(d,J=5.4Hz,1H),7.14(s,1H),5.92(d,J=3.0Hz,1H),5.12(d,J=10.5Hz,1H),2.84-2.78(m,1H),2.66-2.54(m,2H),1.61-1.57(m,1H),1.10-1.05(m,1H);tR=6.44分钟,(ChiralpakIC-3,0.46x5cm,3um,乙醇:己烷(0.1%DEA)=40:60,1.0mL/min)。
实施例5和6:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇和4-(5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
合成途径IIA
步骤1:1-(2-溴苄基)-1H-咪唑
在0℃向1H-咪唑(40g,0.587mol)在四氢呋喃(1L)中的溶液中添加氢化钠(20g,0.833mol),且将混合物在室温搅拌1小时。然后添加1-溴-2-(溴甲基)苯(90g,0.36mol)且在室温再搅拌1小时。该反应然后通过饱和氯化铵(200mL)淬灭且所得溶液用乙酸乙酯(3x500mL)萃取。将有机相合并,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱色谱法纯化且用二氯甲烷/乙酸乙酯(1:1)洗脱以得到1-[(2-溴苯基)甲基]-1H-咪唑(90g,65%),其为黄色油状物:LCMS(ESI,m/z):237,239[M+H]+;
步骤2:5H-咪唑并[5,1-a]异吲哚
将1-[(2-溴苯基)甲基]-1H-咪唑(90g,0.379mol)、乙酸钯(II)(3.5g,0.015mol)/三苯基磷烷(8.1g,0.030mol)和碳酸钾(81g,0.586mol)在DMSO(1L)中的溶液在130℃搅拌1h,然后用水(100mL)稀释。所得溶液用乙酸乙酯(3x200mL)萃取。将有机相合并,用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱色谱法纯化且用二氯甲烷/乙酸乙酯(1:1)洗脱以得到5H-咪唑并[4,3-a]异吲哚,其为黄色固体(20g,34%):LCMS(ESI,m/z):157[M+H]+.
步骤3:
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
在-40℃向5H-咪唑并[4,3-a]异吲哚(1.6g,10.25mmol)在四氢呋喃(25mL)中的溶液中滴加n-BuLi(6.5mL,2.5M在正己烷中)。将反应在-30℃搅拌1小时后,在-40℃滴加3,7-二氧杂双环[4.1.0]庚烷(1.4g,13mmol)在四氢呋喃(3mL)中的溶液,然后缓慢升高至室温且在室温再搅拌1小时。该反应然后通过饱和氯化铵(20mL)淬灭且所得溶液用乙酸乙酯(3x50mL)萃取。将有机相合并,用无水硫酸钠干燥且真空浓缩。粗产物通过prep-HPLC纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。异构体5a-5d的绝对构型通过X-射线晶体学指定。异构体6a-6d的绝对构型通过X-射线晶体学指定。
实施例5a:(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇(65.3mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.80(s,1H),7.53-7.50(m,1H),7.39-7.24(m,3H),7.17(s,1H),5.82(d,J=2.1Hz,1H),4.14-4.06(m,1H),3.94-3.89(m,1H),3.31-3.21(m,2H),2.57-2.49(m,1H),2.42-2.33(m,1H),2.11-2.05(m,1H),1.90-1.77(m,1H);tR=3.537分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.0ml/min)。
实施例5b:(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇(70.5mg,2%)。LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.98(s,1H),7.55-7.53(m,1H),7.41-7.29(m,3H),7.20(s,1H),5.82(d,J=2.1Hz,1H),4.16-4.09(m,1H),3.95-3.89(m,1H),3.32-3.21(m,2H),2.57-2.50(m,1H),2.41-2.33(m,1H),2.11-2.05(m,1H),1.88-1.79(m,1H);tR=4.966分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.0ml/min)。
实施例5c:(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇(62.7mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.82(s,1H),7.57-7.48(m,2H),7.42-7.37(m,1H),7.29-7.24(m,1H),7.20(s,1H),5.70(d,J=3.3Hz,1H),4.07-3.90(m,2H),3.32-3.23(m,2H),2.81-2.73(m,1H),2.50-2.43(m,1H),2.00-1.96(m,1H),1.77-1.72(m,1H);tR=4.866分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.0ml/min)。
实施例5d:(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇(63.3mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.98(m,1H),7.58-7.48(m,2H),7.43-7.38(m,1H),7.31-7.24(m,1H),7.20(s,1H),5.73(d,J=2.7Hz,1H),4.07-3.90(m,2H),3.32-3.23(m,2H),2.78(t,J=11.1Hz,1H),2.54-2.47(m,1H),2.02-1.96(m,1H),1.82-1.73(m,1H);tR=7.967分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.0ml/min)。
实施例6a:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(53.6mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ8.02(s,1H),7.55-7.53(m,1H),7.40-7.28(m,3H),7.20(s,1H),5.85(d,J=2.1Hz,1H),4.16-4.11(m,1H),4.07-3.97(m,1H),3.75-3.69(m,1H),3.27-3.12(m,2H),2.40-2.30(m,1H),0.92-0.72(m,2H);tR=2.442分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.5ml/min)。
实施例6b:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(52.0mg,1%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.92(s,1H),7.55-7.52(m,1H),7.39-7.25(m,3H),7.19(s,1H),5.83(d,J=1.8Hz,1H),4.16-4.11(m,1H),4.06-3.95(m,1H),3.76-3.70(m,1H),3.27-3.18(m,2H),2.29-2.19(m,1H),0.91-0.72(m,2H);tR=3.200分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.5ml/min)。
实施例6c:(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(120.7mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.72(s,1H),7.58-7.55(m,1H),7.49-7.46(m,1H),7.42-7.37(m,1H),7.27-7.19(m,2H),5.79(d,J=3.3Hz,1H),4.13-3.96(m,2H),3.78-3.73(m,1H),3.28-3.15(m,2H),2.39-2.29(m,1H),0.94-0.85(m,2H);tR=4.117分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.5ml/min)。
实施例6d:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(23.9mg,2%):LCMS(ESI,m/z):257[M+H]+;1HNMR(300MHz,CDCl3)δ7.78(s,1H),7.62-7.57(m,1H),7.55-7.49(m,1H),7.41-7.36(m,1H),7.27-7.18(m,2H),5.80(d,J=3.0Hz,1H),4.11-3.97(m,2H),3.76-3.72(m,1H),3.28-3.15(m,2H),2.40-2.30(m,1H),0.97-0.84(m,2H);tR=9.372分钟(CHIRALCEL OJ-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=85:15,1.5ml/min)。
实施例6:4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
步骤1:4-硝基苯甲酸(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-基酯
在氮气下,在0℃向(3R,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环己烷-3-醇(256mg,1.00mmol)和4-硝基苯甲酸(200mg,1.20mmol)在THF(50mL)中的溶液中添加PPh3(801mg,3.05mmol)和DIAD(606mg,3.00mmol)。在室温所得溶液搅拌4h。该反应然后通过添加水淬灭。所得溶液用EtOAc萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物通过combi-flash纯化,用DCM/MeOH(20:1)洗脱以得到300mg(74%)的4-硝基苯甲酸(3S,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环己烷-3-基酯,其为黄色固体:LCMS(ESI,m/z):406[M+H]+.
步骤2:(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
将4-硝基苯甲酸(3S,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环己烷-3-基酯(300mg,0.74mmol)、LiOH(88mg,3.68mmol)在THF(10mL)和水(10mL)中的混合物在室温搅拌4h。该反应然后通过添加水淬灭。所得溶液用EtOAc萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物通过combi-flash纯化,用DCM/MeOH(10:1)洗脱。
实施例006e:(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇(73.1mg,39%),其为白色固体:LCMS(ESI,m/z):257.3[M+H]+.1HNMR(300MHz,CDCl3)δ8.09(s,1H),7.58-7.15(m,5H),5.27(d,J=4.3Hz,1H),4.16(s,1H),4.10-3.90(m,2H),3.58(dd,J=12.2,1.2Hz,1H),3.42-3.26(m,2H),2.16-1.98(m,1H),1.79-1.60(m,1H),1.19(d,J=12.6Hz,1H)。
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
该标题化合物通过与实施例006e相同的方法合成。
实施例006f:(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇(77.5mg,41%),其为白色固体:LCMS(ESI,m/z):257.2[M+H]+.1HNMR(300MHz,CDCl3)δ8.42(s,1H),7.58(d,J=7.5Hz,1H),7.53-7.23(m,4H),5.42(d,J=3.6Hz,1H),4.23(s,1H),4.07(d,J=12.1Hz,1H),3.94(dd,J=11.5,4.8Hz,1H),3.64-3.53(m,1H),3.32(td,J=12.1,2.3Hz,1H),2.19(dd,J=12.2,3.1Hz,1H),1.66(td,J=12.9,4.9Hz,1H),1.26(s,1H),1.09(d,J=13.1Hz,1H)。
4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
该标题化合物通过与实施例006e相同的方法合成。006g和006h的绝对构型任意指定。
实施例006g:(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(25.3mg,21%),其为白色固体:LCMS(ESI,m/z):257.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ8.53(s,1H),7.61(d,J=7.6Hz,1H),7.50-7.40(m,2H),7.31-7.29(m,2H),5.30(d,J=9.0Hz,1H),4.14-4.03(m,3H),3.49-3.31(m,2H),2.19(qd,J=12.6,4.7Hz,1H),1.90(d,J=13.3Hz,1H),1.80-1.71(m,1H)。
实施例006h:(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇(24.0mg,21%),其为白色固体:LCMS(ESI,m/z):257.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ8.11(s,1H),7.60(d,J=7.6Hz,1H),7.56-7.37(m,2H),7.26-7.24(m,2H),5.20(d,J=8.9Hz,1H),4.12-4.01(m,3H),3.47-3.31(m,2H),2.15(qd,J=12.7,4.9Hz,1H),1.89(d,d,J=13.3Hz,1H),1.78-1.69(m,1H)。
实施例7:7-(5H-咪唑并[4,3-a]异吲哚-5-基)-5H,6H,7H,8H-咪唑并[1,5-a]吡啶-8-醇
该标题化合物通过与实施例4相同的方法合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱:CHIRALPAK AD-H-TC001 SFC,20x250mm,5um;流动相A:Hex(0.1%DEA)--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:25B至25B在34min内;254/220nm;
2.柱:CHIRALPAK ID,2.0cm I.Dx25cm L;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:40B至40B在23min内;254/220nm;
3.柱:CHIRALPAK ID,2.0cm I.Dx25cm L;流动相A:CO2:60,流动相B:IPA(0.2%DEA):40;流速:40mL/min;220nm;
异构体7c、7d、7g和7h的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例7a:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(38.3mg,4%);LCMS(ESI,m/z):293.1[M+H]+;1HNMR(300MHz,DMSO-d6)δ7.92(s,1H),7.62(m,2H),7.45-7.35(m,2H),7.28-7.23(m,1H),7.17(s,1H),6.90(s,1H),6.06(d,J=6.6Hz,1H),5.76(d,J=3.0Hz,1H),4.98-4.93(m,1H),3.96-3.90(m,1H),3.70-3.61(m,1H),2.67-2.57(m,1H),1.16-0.92(m,2H);tR=2.538分钟,(Chiralpak AD-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=75:25;1.0mL/min)。7a和7b为对映异构体。
实施例7b:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(41.0mg,4%);LCMS(ESI,m/z):293.1[M+H]+;tR=3.257分钟,(Chiralpak AD-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=75:25;1.0mL/min)。7a和7b为对映异构体。
实施例7c:(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(35.8mg,4%);LCMS(ESI,m/z):293.1[M+H]+;1HNMR(300MHz,DMSO-d6)δ7.97(s,1H),7.65-7.62(m,1H),7.51-7.39(m,3H),7.35-7.29(m,1H),7.18(s,1H),6.93(s,1H),7.78-7.75(m,1H),5.05-4.99(m,1H),3.95-3.89(m,1H),3.58-3.68(m,1H),2.49-2.40(m,1H),1.04-0.95(m,2H);tR=4.012分钟,(Chiralpak AD-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=75:25;1.0mL/min)。7c和7d为对映异构体。
实施例7d:(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(35.6mg,4%):LCMS(ESI,m/z):293.1[M+H]+;tR=5.054分钟,(Chiralpak AD-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=75:25;1.0mL/min)。7c和7d为对映异构体。
实施例7e:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(37.7mg,4%):LCMS(ESI,m/z):293.1[M+H]+;1HNMR(300MHz,DMSO-d6)δ7.97(s,1H),7.74-7.72(m,1H),7.63-7.60(m,1H),7.50(s,1H),7.42-7.37(t,1H),7.27-7.21(m,1H),7.14(s,1H),6.87(s,1H),5.62-5.60(m,1H),5.45-5.44(m,1H),5.02-4.96(m,1H),4.21-4.16(m,1H),3.77-3.68(m,1H),2.23-2.17(m,2H),1.82-1.78(m,1H);tR=4.468分钟,(Chiralpak ID-3,0.46x10cm,3um;Hex(0.1%DEA):IPA=60:40;1.0mL/min)。7e和7f为对映异构体。
实施例7f:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(29.3mg,3%):LCMS(ESI,m/z):293.1[M+H]+;tR=6.020分钟,(Chiralpak ID-3,0.46x10cm,3um;Hex(0.1%DEA):IPA=60:40;1.0mL/min)。7e和7f为对映异构体。
实施例7g:(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(30.5mg,4%):LCMS(ESI,m/z):293.1[M+H]+;1HNMR(300MHz,DMSO-d6)δ7.95(s,1H),7.65-7.57(m,2H),7.49(s,1H),7.42-7.36(m,1H),7.31-7.26(m,1H),7.12(s,1H),6.92(s,1H),5.90-5.86(m,1H),5.53-5.50(m,1H),5.21-5.18(m,1H),4.09-4.03(m,1H),3.67-3.57(m,1H),2.56-2.51(m,1H),1.86-1.71(m,1H),1.15-1.07(m,1H)。tR=2.18分钟,(Chiralpak ID,4.6x100mm,3um;IPA(0.1%DEA)=40%;4mL/min)。7g和7h为对映异构体。
实施例7h:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,为白色固体(30.6mg,4%):LCMS(ESI,m/z):293.1[M+H]+;tR=2.92分钟,(Chiralpak ID,4.6x100mm,3um;IPA(0.1%DEA)=40%;4mL/min)。7g和7h为对映异构体。
实施例8:6-(5H-咪唑并[4,3-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇
该标题化合物通过与实施例4相同的方法合成:
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱:Chiralpak IC,2x25cm,5um;流动相A:CO2:50,流动相B:MeOH:50;流速:40mL/min;220nm;
2.柱:CHIRALCEL OD-H,20x250mm;流动相A:CO2:70,流动相B:MeOH:30;流速:40mL/min;260nm;
3.柱:CHIRALPAK AD-H,20x250mm;流动相A:CO2:60,流动相B:MeOH:40;流速:40mL/min;220nm;
所有异构体的绝对构型通过X-射线晶体学指定。
实施例8a:(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(23.9mg,1%);LCMS(ESI,m/z):304[M+H]+.1HNMR(300MHz,CD3OD)δ8.39-8.37(m,1H),8.23(s,1H),8.04(s,1H),7.72-7.66(m,2H),7.51-7.35(m,3H),7.24(s,1H),5.91(s,1H),5.04(d,J=5.4Hz,1H),2.71-2.68(m,2H),2.53-2.46(m,1H),1.20-1.17(m,1H),1.08-0.94(m,1H)。tR=1.393分钟,(CHIRALPAK AS-3 100x3mm,3um;CO2:MeOH(20mM NH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0分钟;220nm;2mL/min)。8a和8b为对映异构体。
实施例8b:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(22.1mg,1%);LCMS(ESI,m/z):304[M+H]+.1HNMR(300MHz,CD3OD)δ8.39-8.37(m,1H),8.23(s,1H),8.04(s,1H),7.72-7.66(m,2H),7.51-7.35(m,3H),7.24(s,1H),5.91(s,1H),5.04(d,J=5.4Hz,1H),2.71-2.68(m,2H),2.53-2.46(m,1H),1.20-1.17(m,1H),1.08-0.94(m,1H);tR=1.524分钟,(CHIRALPAK AS-3 100x3mm,3um;CO2:MeOH(20mM NH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0分钟;220nm;2mL/min)。8a和8b为对映异构体。
实施例8c:(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(101.8mg,3%);LCMS(ESI,m/z):304[M+H]+.1HNMR(300MHz,CD3OD)δ8.31(s,2H),8.06(s,1H),8.04(s,1H),7.70-7.62(m,2H),7.43-7.24(m,3H),7.17(s,1H),5.54-5.52(m,1H),4.79-4.78(m,1H),3.00-2.92(m,1H),2.78-2.68(m,1H),2.32-2.25(m,1H),2.10-1.99(m,2H);tR=1.632分钟,(CHIRALPAK AS-3 100x3mm,3um;CO2:MeOH(20mMNH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0分钟;220nm;2mL/min)。8c和8d为对映异构体。
实施例8d:(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(75.7mg,3%);LCMS(ESI,m/z):304[M+H]+.1HNMR(300MHz,CD3OD)δ8.31(s,2H),8.06(s,1H),8.04(s,1H),7.70-7.62(m,2H),7.43-7.24(m,3H),7.17(s,1H),5.54-5.52(m,1H),4.79-4.78(m,1H),3.00-2.92(m,1H),2.78-2.68(m,1H),2.32-2.25(m,1H),2.10-1.99(m,2H);tR=1.914分钟,(CHIRALPAK AS-3 100x3mm,3um;CO2:MeOH(20mMNH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0分钟;220nm;2mL/min)。8c和8d为对映异构体。
实施例8e:(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(18.8mg,1%);LCMS(ESI,m/z):304[M+H]+ ; 1HNMR(300MHz,CD3OD)δ8.38-8.36(m,1H),8.23(s,1H),7.92(s,1H),7.69-7.61(m,3H),7.46-7.42(m,1H),7.35-7.29(m,1H),7.20(s,1H),5.90-5.89(m,1H),4.98(d,J=5.1Hz,1H),2.71-2.68(m,2H),2.72-2.58(m,3H),1.14-0.97(m,2H);tR=1.403分钟,(CHIRALPAK AS-3 100x3mm,3um流动相:CO2:MeOH(20mMNH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0min;2ml/min;220nm)。8e和8f为对映异构体。
实施例8f:(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(19.9mg,1%);LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.38-8.36(m,1H),8.23(s,1H),7.92(s,1H),7.69-7.61(m,3H),7.46-7.42(m,1H),7.35-7.29(m,1H),7.20(s,1H),5.90-5.89(m,1H),4.98(d,J=5.1Hz,1H),2.71-2.68(m,2H),2.72-2.58(m,3H),1.14-0.97(m,2H);tR=1.701分钟,(CHIRALPAK AS-3 100x3mm,3um流动相:CO2:MeOH(20mMNH3),梯度(B%):10%至50%在4.0分钟内,在50%保持2.0min;2ml/min;220nm)。8e和8f为对映异构体。
实施例8g:(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(239.8mg,6%);LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.39-8.38(m,1H),8.30(s,1H),8.07(s,1H),7.63-7.57(m,2H),7.54-7.49(m,1H),7.45-7.41(m,1H),7.36-7.32(m,1H),7.14(s,1H),5.63-5.61(m,1H),5.12-5.11(m,1H),2.82-2.77(m,1H),2.64-2.53(m,2H),1.58-1.48(m,1H),1.15-1.13(m,1H);tR=2.563分钟,(CHIRALPAK AD-3 100x3mm,3um;流动相:CO2:MeOH(20mM NH3),MeOH(20mMNH3);梯度(B%):10%至50%在4.0分钟内,在50%保持2.0min;220nm)。8g和8h为对映异构体。
实施例8h:(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,为灰白色固体(70.3mg,2%);LCMS(ESI,m/z):304[M+H]+;1HNMR(300MHz,CD3OD)δ8.39-8.38(m,1H),8.30(s,1H),8.07(s,1H),7.63-7.57(m,2H),7.54-7.49(m,1H),7.45-7.41(m,1H),7.36-7.32(m,1H),7.14(s,1H),5.63-5.61(m,1H),5.12-5.11(m,1H),2.82-2.77(m,1H),2.64-2.53(m,2H),1.58-1.48(m,1H),1.15-1.13(m,1H);tR=2.776分钟,(CHIRALPAK AD-3 100x3mm,3um;流动相:CO2:MeOH(20mM NH3),MeOH(20mMNH3);梯度(B%):10%至50%在4.0分钟内,在50%保持2.0min;220nm)。8g和8h为对映异构体。
所有异构体的绝对构型任意指定。
实施例9:1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮
该标题化合物通过与实施例27相同的方法合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.CHIRALCEL OD-H,20x250mm;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:10B至10B在24min内;254/220nm;
2.CHIRALPAK-AD-H-SL002,20x250mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:30B至30B在15min内;254/220nm;
实施例9a:1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮(10.0mg,11%),其为白色固体:LCMS(ESI,m/z):298.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.95-7.90(m,1H),7.64-7.62(m,1H),7.52-7.36(m,3H),7.20(s,1H),5.84-5.83(m,1H),4.88-3.67(m,3H),3.06-2.85(m,1H),2.55-2.28(m,2H),2.14-1.98(m,3H),1.00-0.85(m,1H),0.59-0.58(m,1H);tR=9.351分钟,(ChiralCELOD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=7:93;1.0mL/min)。9a和9b为对映异构体。
实施例9b:1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮(31.5mg,33%),为白色固体:LCMS(ESI,m/z):298.2[M+H]+;tR=10.852分钟,(ChiralCELOD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=7:93;1.0mL/min)。9a和9b为对映异构体。
实施例9c:1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮(3.2mg,3%),为白色固体:LCMS(ESI,m/z):298.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.91(s,1H),7.63-7.62(m,1H),7.53-7.50(m,1H),7.43-7.39(m,1H),7.32-7.28(m,1H),7.15(s,1H),5.82-5.80(m,1H),4.86-3.65(m,3H),3.00-2.93(m,1H),2.49-2.35(m,2H),2.09-1.94(m,3H),0.84-0.71(m,1H),0.63-0.42(m,1H);tR=13.717分钟,(ChiralCELOD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=7:93;1.0mL/min)。9c和9d为对映异构体。
实施例9d:1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮(7.0mg,7%),为白色固体:LCMS(ESI,m/z):298.2[M+H]+;tR=16.140分钟,(ChiralCELOD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=7:93;1.0mL/min)。9c和9d为对映异构体。
实施例10和11:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
和4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
以下异构体使用inter-6通过Chiral-HPLC分离。
inter-6的混合物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.Chiralpak IA,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在10min内;254/220nm;
2.Phenomenex Lux 5u Cellulose-4,AXIA Packed,250x21.2mm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在26min内;254/220nm;
3.CHIRALPAK ID,2.0cm I.Dx25cm L;流动相A:Hex--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:15B至15B在18min内;254/220nm;
4.CHIRALPAK ID,2.0cm I.Dx25cm L;流动相A:Hex--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:30B至30B在13min内;254/220nm;
5.所有异构体的绝对构型任意指定。
实施例10a:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(38.7mg,1%),为白色固体:LCMS(ESI,m/z):356.2[M+H]+;.1HNMR(400MHz,CD3OD)δ7.89(s,1H),7.64(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.45-7.34(m,2H),7.20(s,1H),5.82(d,J=4.0Hz,1H),4.37-4.33(m,1H),3.86-3.71(m,2H),2.62-2.50(m,2H),2.27-2.20(m,1H),1.43(s,9H),0.87-0.83(m,1H),0.47-0.42(m,1H);tR=1.323分钟,(Chiralpak IA,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。10a和10b为对映异构体。
实施例10b:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(39.9mg,1%),为白色固体:LCMS(ESI,m/z):356.2[M+H]+;tR=1.866分钟。(ChiralpakIA,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。10a和10b为对映异构体。
实施例10c:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(16.1mg,1%),其为白色固体:LCMS(ESI,m/z):356.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.93(s,1H),7.65(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.46-7.42(m,1H),7.35-7.31(m,1H),7.17(s,1H),5.82(d,J=4.0Hz,1H),4.31-4.28(m,1H),3.87-3.74(m,2H),2.61-2.50(m,2H),2.40-2.34(m,1H),1.41(s,9H),0.73-0.70(m,1H),0.56-0.46(m,1H)。tR=2.348分钟(Lux Cellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。10c和10d为对映异构体。
实施例10d 3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(16.0mg,1%),其为白色固体:LCMS(ESI,m/z):356.2[M+H]+;tR=2.841分钟,(LuxCellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。10c和10d为对映异构体。
异构体11a&11b的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例11a:(3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(36.1mg,1%),其为白色固体:LCMS(ESI,m/z):356.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.96(s,1H),7.66(d,J=7.2Hz,1H),7.54(d,J=7.2Hz,1H),7.46-7.38(m,2H),7.21(s,1H),5.83(d,J=4.0Hz,1H),4.07-4.00(m,2H),3.34-3.32(m,1H),2.79-2.65(m,1H),2.21-2.07(m,2H),1.84-1.77(m,1H),1.60-1.49(m,1H),1.27(s,9H);tR=2.511分钟,(Chiralpak ID-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=15:85;1.0mL/min)。11a和11b为对映异构体。
实施例11b:(3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(30.1mg,1%),其为白色固体:LCMS(ESI,m/z):356.2[M+H]+.tR=3.240分钟。(Chiralpak ID-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=15:85;1.0mL/min)。11a和11b为对映异构体。
实施例11c:4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(10.6mg,1%),其为白色固体:LCMS(ESI,m/z):356.2[M+H]+.1HNMR(400MHz,CD3OD)δ7.98(s,1H),7.67(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.47-7.33(m,2H),7.21(s,1H),5.84(d,J=4.0Hz,1H),4.06-4.00(m,2H),3.18-3.11(m,1H),2.71-2.55(m,1H),2.35-2.21(m,1H),2.11-2.04(m,1H),1.95-1.85(s,1H),1.61-1.49(m,1H),1.37(s,9H);tR=2.130min(Chiralpak ID-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。11c和11d为对映异构体。
实施例11d:4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(11.4mg,1%),为白色固体:LCMS(ESI,m/z):356.3[M+H]+;tR=2.788min,(Chiralpak ID-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。11c和11d为对映异构体。
实施例12:1-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮
所有异构体的绝对构型任意指定。
实施例12a:1-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮(16.4mg,4%),为白色固体:LCMS(ESI):M+H+=298.2;1HNMR(400MHz,CD3OD)δ7.95-7.90(m,1H),7.69-7.60(m,1H),7.50-7.37(m,3H),7.21(s,1H),5.84-5.82(m,1H),4.55-4.45(m,0.5H),4.08-4.07(m,1H),3.88-3.84(m,1H),3.05-2.98(m,1H),2.55-2.53(m,0.5H),2.27-2.03(m,4H),1.72-1.48(m,3H);tR=3.477分钟,(柱,Lux Cellulose-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=25:75;1.0mL/min)。12a和12b为对映异构体。
实施例12b:1-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮(13.8mg,4%),为白色固体:LCMS(ESI,m/z):298.2[M+H]+;tR=4.190分钟(柱,Lux Cellulose-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=25:75;1.0mL/min)。12a和12b为对映异构体。
实施例12c:1-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮(8.6mg,2%),为白色固体:LCMS(ESI,m/z):298.2[M+H]+.1HNMR(400MHz,CD3OD)δ8.05-7.92(m,1H),7.70-7.62(m,2H),7.49-7.35(m,2H),7.24-7.20(m,1H),5.87-5.82(m,1H),4.55-4.45(m,0.5H),4.12-4.05(m,1H),3.94-3.71(m,1H),3.55-3.53(m,0.5H),3.01-2.75(m,1H),2.51-2.04(m,4H),1.82-1.75(m,3H);tR=5121分钟,(柱,Lux Cellulose-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=25:75;1.0mL/min)。12c和12d为对映异构体。
实施例12d:1-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮(10.2mg,2%),为白色固体。LCMS(ESI,m/z):298.2[M+H]+;tR=10.013min(柱,Lux Cellulose-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=25:75;1.0mL/min)。12c和12d为对映异构体。
实施例13:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
该标题化合物通过与实施例3相同的方法合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,ChiralpakOJ-H,2x25cm;流动相:Hex(0.1%DEA):IPA=12:12;检测器,uv254nm;流速,20mL/min.
2.柱,ChiralpakChiralpak IA,2x25cm,5um;;流动相:Hex(0.1%DEA):IPA=30:30;检测器,uv 254nm;流速,20mL/min
3.柱,ChiralpakOJ-H,2x25cm;流动相:Hex(0.1%DEA):IPA=15:15;检测器,uv254nm;流速,20mL/min
4.柱,ChiralpakIA,2x25cm,5um,3um;流动相:Hex(0.1%DEA):IPA=10:10;检测器,uv 254nm;流速,20mL/min.
异构体13c和13d的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例13a:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2.1HNMR(300MHz,CD3OD)δ7.93(s,1H),7.63-7.59(m,1H),7.40-7.37(m,1H),7.23(s,1H),7.08-7.02(m,1H),5.37(d,J=9Hz,1H),4.34-4.30(m,1H),2.62-2.46(m,1H),2.32-2.14(m,1H),1.88-1.67(m,2H),1.38-1.20(m,2H)。tR=6.997分钟(Chiralpak OJ-3,0.46x15cm,3um;Hex(0.1%DEA):IPA=88:12;1.0mL/min)。13a和13b为对映异构体。
实施例13b:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2;tR=8.947分钟(Chiralpak OJ-3,0.46x15cm,3um;Hex(0.1%DEA):IPA=88:12;1.0mL/min)。13a和13b为对映异构体。
实施例13c:(1R,2S)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2.1HNMR(300MHz,CD3OD)δ8.01(s,1H),7.46-7.37(m,2H),7.19(s,1H),7.10-6.95(m,1H),5.33(d,J=6Hz,1H),4.22-4.18(m,1H),2.52-2.34(m,1H),2.36-2.23(m,1H),2.01-1.79(m,2H),1.78-1.59(m,1H)。tR=1.347分钟(Chiralpak IA-3,0.46x5cm,3um;流动相:Hex(0.1%DEA):IPA=70:30;检测器,uv 254nm;流速,1.0mL/min)。13c和13d为对映异构体。
实施例13d:(1S,2R)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2[M+H]+;tR=2.379分钟(Chiralpak IA-3,0.46x5cm,3um;流动相:Hex(0.1%DEA):IPA=70:30;检测器,uv 254nm;流速,1.0mL/min)。13c和13d为对映异构体。
实施例13e:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2[M+H]+;1HNMR(300MHz,CD3OD)δ8.19(s,1H),7.58-7.53(m,1H),7.39-7.36(m,1H),7.23(s,1H),7.09-6.96(m,1H),5.55(d,J=5.9Hz,1H),4.68-4.64(m,1H),3.05-2.87(m,1H),2.41-2.20(m,1H),1.97-1.76(m,2H),1.59-1.50(m,1H)。tR=4.185分钟(ChiralpakOJ-3,0.46x15cm,3um;Hex(0.1%DEA):IPA=85:15;1.0mL/min)。
实施例13f:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2[M+H]+;tR=5.659分钟(Chiralpak OJ-3,0.46x15cm,3um;Hex(0.1%DEA):IPA=85:15;1.0mL/min)。13e和13f为对映异构体。
实施例13g:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.98(s,1H),7.53-7.48(m,1H),7.40-7.36(m,1H),7.19(s,1H),7.01-6.93(m,1H),5.51(d,J=9.0Hz,1H),4.56-4.51(m,1H),2.60-2.31(m,3H),2.21-1.90(m,2H)。tR=2.293分钟(Chiralpak IA-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=90:10;1.0mL/min)。13g和13h为对映异构体。
实施例13h:8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇:LCMS(ESI,m/z):245.2[M+H]+;tR=3.120分钟(Chiralpak IA-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=90:10;1.0mL/min)。13g和13h为对映异构体。
实施例15和16:1-(乙基磺酰基)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
和1-(乙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
该标题化合物通过与实施例27相同的方法合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.Chiralpak IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:15mL/min;梯度:50B至50B在18min内;254/220nm;
2.Phenomenex Lux 5u Cellulose-4,AXIA Packed,250X21.2mm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:40B至40B在38min内;254/220nm;
3.CHIRALPAK IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在20min内;254/220nm;
异构体16a-16d的绝对构型通过X-射线晶体学指定。
实施例16a:(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇:LCMS(ESI,m/z):348.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.95(s,1H),7.65(d,J=7.6Hz,1H),7.55(d,J=7.6Hz,1H),7.46-7.32(m,2H),7.17(s,1H),5.83(d,J=3.6Hz,1H),4.01-3.90(m,2H),3.53-4.90(m,1H),3.00(q,J=7.2Hz,2H),2.74-2.65(m,2H),2.42-2.30(m,1H),1.30(t,J=7.2Hz,3H),0.85-0.79(m,1H),0.75-0.60(m,1H);tR=2.844分钟,(LuxCellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.5mL/min)。16a和16b为对映异构体。
实施例16b:(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇:LCMS(ESI,m/z):348.2[M+H]+;tR=6.072分钟,(Lu Cellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.5mL/min)。16a和16b为对映异构体。
实施例16c:(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇:LCMS(ESI,m/z):348.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.93(s,1H),7.64(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.46-7.35(m,2H),7.21(s,1H),5.84(d,J=3.6Hz,1H),4.03-3.83(m,2H),3.54-3.51(m,1H),3.03(q,J=7.2Hz,2H),2.78-2.67(m,2H),2.25-2.19(m,1H),1.30(t,J=7.2Hz,3H),0.98-0.94(m,1H),0.69-0.55(m,1H);tR=1.519分钟(Chiralpak IC-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。16c和16d为对映异构体。
实施例16d:(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇:LCMS(ESI,m/z):348.2[M+H]+;tR=2.357分钟(Chiralpak IC-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。16c和16d为对映异构体。
所有异构体15a-d的绝对构型任意指定。
实施例15a:(3S,4R)-1-(乙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇:LCMS(ESI,m/z):348.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.98(s,1H),7.66(d,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),7.48-7.34(m,2H),7.21(s,1H),5.85(d,J=4.0Hz,1H),4.01-3.98(m,1H),3.74-3.70(m,1H),2.90-2.76(m,4H),2.55-2.45(m,1H),2.13-2.05(m,2H),1.80-1.68(m,1H),1.16(t,J=7.2Hz,3H);tR=2.495(Chiralpak IC-3,0.46x5cm,3um;己烷(0.1%DEA)=30:70;1.0mL/min)。15a和15b为对映异构体。
实施例15b:(3R,4S)-1-(乙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇:LCMS(ESI,m/z):348.2[M+H]+;tR=3.738,(Chiralpak IC-3,0.46x5cm,3um;己烷(0.1%DEA)=30:70;1.0mL/min)。15a和15b为对映异构体。
实施例15c:(3R,4S)-1-(乙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇:LCMS(ESI,m/z):348.2[M+H]+;1HNMR(400MHz,CD3OD)δ7.93(s,1H),7.64(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.45-7.37(m,2H),7.19(s,1H),5.83(d,J=3.6Hz,1H),4.03-3.92(m,1H),3.75-3.65(m,1H),3.02-2.98(m,1H),2.85-2.70(m,3H),2.40-2.30(m,1H),2.20-2.15(m,1H),2.00-1.90(m,1H),1.79-1.65(m,1H),1.12(t,J=7.2Hz,3H);tR=2.240分钟(Lux Cellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.5mL/min)。15c和15d为对映异构体。
实施例15d:(3S,4R)-1-(乙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇:LCMS(ESI,m/z):348.2[M+H]+;tR=3.661分钟(Lux Cellulose-4,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.5mL/min)。15c和15d为对映异构体。
实施例17:2-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
实施例17a-e都使用制备实施例1a-h的反应条件合成,其中试剂环丁酮替代为螺[3.3]庚-1-酮。各实施例为具有未确定绝对构型的单一非对映异构体。
所有异构体17a-e的绝对构型任意指定。
实施例17a:2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇:LCMS(ESI,m/z):267[M+H]+;1HNMR:no NMR;tR=0.45分钟(Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例17b:2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇:LCMS(ESI,m/z):267[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.65–7.46(m,1H),7.44–7.29(m,2H),7.23(td,J=7.5,1.1Hz,1H),7.09(s,1H),5.30(d,J=7.6Hz,2H),3.86(t,J=7.5Hz,1H),2.42–2.23(m,1H),2.09–1.69(m,5H),1.69–1.45(m,2H)。;tR=0.89分钟(ChiralpakAD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例17c:2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇:LCMS(ESI,m/z):267[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),δ7.59(t,J=8.0Hz,2H),7.36(dd,J=7.9,6.8Hz,1H),7.25(td,J=7.5,1.0Hz,1H),7.09(s,1H),5.75(d,J=4.9Hz,1H),5.35(d,J=8.3Hz,1H),4.18(s,1H),2.42(d,J=8.3Hz,1H),2.35–2.18(m,1H),2.04(t,J=9.9Hz,1H),1.90(q,J=6.6Hz,3H),1.76(q,J=7.3Hz,2H),1.56(d,J=10.0Hz,1H)。;tR=0.79分钟(Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例17d:2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇:LCMS(ESI,m/z):267[M+H]+;1HNMR:no NMR;tR=1.15分钟(Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例17e(实施例17b的对映异构体):2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇:LCMS(ESI,m/z):267[M+H]+;无分析SFC,Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例18:4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2S)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇(18a)
(1S,2S)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇(18f)
(1S,2R)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,2R)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2S)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,2R)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇(18b)
(1R,2R)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇(18e)
步骤1:
(E)-4,4-二氟-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环己烷-1-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):531.3[M+H]+
步骤2:
4,4-二氟-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):289.27[M+H]+
步骤3:
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):291.26
异构体18a和18e的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例18a:(1S,2S)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;(1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.61-7.55(m,2H),7.39(d,J=1.1Hz,1H),7.32-7.32(m,1H),5.45(s,1H),7.11(s,1H),5.32(d,J=3.1Hz,1H),4.29(s,1H),2.38-2.31(m,1H),2.15-1.95(m,1H),1.94-1.78(m,2H),1.77-1.67(m,1H),1.65-1.46(m,1H),1.15-1.03(m,1H)
实施例18b:(1R,2R)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;(1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.69(d,J=7.6Hz,1H),7.60(d,J=7.4Hz,1H),7.39(t,J=7.5Hz,1H),7.27(dd,J=7.5,1.4Hz,1H),7.12(s,1H),5.33(d,J=6.2Hz,1H),5.09–5.05(s,1H),4.07(s,1H),2.22–1.96(m,3H),1.91-1.79(m,3H),1.65-1.54(m,1H)
实施例18c:4,4-二氟-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.63(d,J=7.8Hz,1H),7.54(d,J=7.6Hz,1H),7.42(t,J=1.0Hz,1H),7.31(dd,J=7.6,1.4Hz,1H),7.15(s,1H),5.72(t,J=3.2Hz,1H)5.52(s,1H),3.87-3.76(m,1H),2.04-1.70(m,3H),1.58-1.45(m,1H),0.90-0.73(m,2H)
实施例18d:4,4-二氟-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.63(d,J=7.8Hz,1H),7.54(d,J=7.6Hz,1H),7.42(t,J=1.0Hz,1H),7.31(dd,J=7.6,1.4Hz,1H),7.15(s,1H),5.72(t,J=3.2Hz,1H)5.52(s,1H),3.87-3.76(m,1H),2.04-1.70(m,3H),1.58-1.45(m,1H),0.9-0.73(m,2H)。
实施例18e:(1R,2R)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;(1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.61-7.55(m,2H),7.39(d,J=1.1Hz,1H),7.32-7.25(m,1H),5.45(s,1H),7.11(s,1H),5.32(d,J=3.1Hz,1H),4.29(s,1H),2.38-2.31(m,1H),2.15-1.95(m,1H),1.94-1.78(m,2H),1.77-1.67(m,1H),1.65-1.46(m,1H),1.15-1.03(m,1H)
实施例18f:(1S,2S)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;(1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.69(d,J=7.6Hz,1H),7.60(d,J=7.4Hz,1H),7.39(t,J=7.5Hz,1H),7.27(dd,J=7.5,1.4Hz,1H),7.12(s,1H),5.33(d,J=6.2Hz,1H),5.09–5.05(s,1H),4.07(s,1H),2.22-1.96(m,3H),1.91-1.79(m,3H),1.65-1.54(m,1H)
实施例18g:4,4-二氟-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.62(d,J=7.4Hz,1H),7.48(d,J=7.4Hz,1H),7.41(t,J=7.5Hz,1H),7.35–7.29(m,1H),7.18(s,1H),5.74(s,1H),5.55(d,J=5.8Hz,1H),3.86(dt,J=10.8,5.8Hz,1H),2.34–2.22(m,1H),2.08–1.77(m,2H),1.48–1.61(m,1H),0.99(d,J=5.4Hz,1H),0.90–0.70(m,1H)。
实施例18h:4,4-二氟-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.26[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.62(d,J=7.4Hz,1H),7.48(d,J=7.4Hz,1H),7.41(t,J=7.5Hz,1H),7.35–7.29(m,1H),7.18(s,1H),5.74(s,1H),5.55(d,J=5.8Hz,1H),3.86(dt,J=10.8,5.8Hz,1H),2.34–2.22(m,1H),2.08–1.77(m,2H),1.48–1.61(m,1H),0.99(d,J=5.4Hz,1H),0.90–0.70(m,1H)。
实施例19:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
步骤1:
(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-2,3-二氢-1H-茚-1-酮
向2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(2.0g,4.82mmol)和1-2,3-二氢-1-茚酮(1.28g,9.65mmol)在无水甲醇(40mL)中的溶液中添加哌啶(0.48mL,4.82mmol)且所得混合物在90℃搅拌6小时。产物从溶液沉淀。混合物在冰浴上冷却且将沉淀过滤且用冷甲醇(15mL)洗涤以得到粗(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-2,3-二氢-1H-茚-1-酮,其为淡黄色固体。产物直接使用而不用进一步纯化:LCMS(ESI,m/z):529.3[M+H]+.
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-酮
向(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-2,3-二氢-1H-茚-1-酮(2.20g,4.16mmol)添加MeOH(56mL)和AcOH(14mL)。所得混合物在90℃搅拌2小时。溶剂在减压下去除。反应通过30mL饱和NaHCO3溶液(30mL)淬灭且将混合物用二氯甲烷(3x20mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。产物通过CombiFlash分离以得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-酮,其为淡黄色固体:LCMS(ESI,m/z):287.3[M+H]+.
步骤3:
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-酮(1.06g,3.70mmol)在MeOH(25mL)中的溶液中分批添加NaBH4(280mg,7.40mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵(20mL)。水层用DCM萃取(3x20mL)。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到6种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例19a:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.62(d,J=7.4Hz,1H),7.53(d,J=7.7Hz,1H),7.37(d,J=7.5Hz,1H),7.27(d,J=5.5Hz,1H),7.25–7.21(m,1H),7.20–7.14(m,2H),7.12(s,2H),5.70(d,J=4.9Hz,1H),5.57(d,J=6.5Hz,1H),5.09(s,1H),2.95(dd,J=7.3,4.9Hz,1H),2.78(dd,J=15.9,8.6Hz,1H)。
实施例19b:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.62(d,J=7.6Hz,1H),7.53(d,J=7.5Hz,1H),7.38(t,J=7.6Hz,1H),7.29–7.25(m,1H),7.25–7.20(m,1H),7.19–7.15(m,2H),7.11(d,J=6.1Hz,2H),5.70(d,J=4.9Hz,1H),5.57(d,J=6.5Hz,1H),5.09(t,J=6.7Hz,1H),2.95(tdd,J=8.6,7.0,5.0Hz,1H),2.78(dd,J=15.9,8.6Hz,1H),2.48–2.39(m,1H)。
实施例19c:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.62(d,J=7.8Hz,1H),7.55(d,J=7.7Hz,1H),7.49–7.42(m,1H),7.38(t,J=7.4Hz,1H),7.26–7.18(m,4H),7.16(s,1H),5.77(d,J=6.2Hz,1H),5.53(d,J=9.8Hz,1H),5.17(t,J=6.0Hz,1H),3.28–3.20(m,1H),2.97(dd,J=15.5,7.8Hz,1H),2.40(tdd,J=9.5,7.7,5.9Hz,1H)。
实施例19d:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.72(d,J=7.5Hz,1H),7.60(d,J=7.2Hz,1H),7.51(s,1H),7.46–7.37(m,2H),7.32(dd,J=7.5,1.4Hz,1H),7.26–7.19(m,1H),7.17(dd,J=7.4,1.4Hz,1H),7.07–7.01(m,2H),6.04(d,J=5.1Hz,1H),5.63(d,J=5.4Hz,1H),5.39(dd,J=7.1,5.2Hz,1H),2.99(dtd,J=8.3,6.6,5.1Hz,1H),2.73(dd,J=16.1,8.4Hz,1H),2.45(dd,J=16.0,6.4Hz,1H)。
实施例19e:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.72(d,J=7.4Hz,1H),7.60(d,J=7.4Hz,1H),7.51(s,1H),7.41(q,J=7.2Hz,2H),7.35–7.28(m,1H),7.25–7.19(m,1H),7.16(td,J=7.3,1.4Hz,1H),7.06–7.00(m,2H),6.04(d,J=5.1Hz,1H),5.63(d,J=5.4Hz,1H),5.39(dd,J=7.0,5.2Hz,1H),3.04–2.92(m,1H),2.73(dd,J=16.1,8.3Hz,1H),2.45(dd,J=16.1,6.5Hz,1H)。
实施例19f:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇:LCMS(ESI,m/z):289.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.62(d,J=7.4Hz,1H),7.55(d,J=7.7Hz,1H),7.47–7.41(m,1H),7.38(t,J=7.5Hz,1H),7.27–7.19(m,4H),7.16(s,1H),5.77(d,J=6.1Hz,1H),5.53(d,J=10.0Hz,1H),5.17(t,J=6.1Hz,1H),3.29–3.22(m,1H),2.97(dd,J=15.5,7.7Hz,1H),2.40(tdd,J=9.5,7.9,6.0Hz,1H)。
实施例20:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
该标题化合物通过实施例5和6合成
粗产物通过prep-HPLC纯化且进一步通过SFC分离使用以下条件分离:
条件1:柱:CHIRALPAK AD-H-TC001 SFC,20x250mm,5um;流动相A:CO2:50,流动相B:IPA(0.2%DEA):50;流速:40mL/min;220nm;
条件2:柱:Chiralpak AD-H,2x25cm;流动相A:CO2:60,流动相B:IPA(0.2%DEA):40;流速:40mL/min;220nm;
所有异构体的绝对构型任意指定。
实施例20a:(1S,2R)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇:LCMS(ESI,m/z):259.2[M+H]+;1H NMR(300MHz,CD3OD)δ8.11(s,1H),7.45(dd,J=8.5,4.8Hz,1H),7.34(dd,J=8.6,2.5Hz,1H),7.21(s,1H),7.01-6.95(m,1H),5.46(d,J=4.4Hz,1H),3.97-3.94(m,1H),2.48-2.38(m,1H),1.67-1.56(m,3H),1.54-1.42(m,2H),1.16-1.10(m,1H)。tR=1.11分钟(Chiralpak AD-H,4.6x100mm,5um;IPA(0.1%DEA)=35%;4mL/min)。20a和20b为对映异构体。
实施例20b:(1S,2R)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇:LCMS(ESI,m/z):259.2[M+H]+;tR=2.17分钟(Chiralpak AD-H,4.6x100mm,5um;IPA(0.1%DEA)=35%;4mL/min)。20a和20b为对映异构体。
实施例20c:(1R,2S)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇:LCMS(ESI,m/z):259.2[M+H]+;1H NMR(300MHz,CD3OD)δ7.83(s,1H),7.37(dd,J=8.4,4.8Hz,1H),7.26(dd,J=8.7,2.5Hz,1H),7.12(s,1H),6.98-6.91(m,1H),5.45-5.44(m,1H),4.16(q,J=7.0Hz,1H),2.43-2.39(m,1H),1.80-1.75(m,1H),1.55-1.48(m,2H),1.34-1.18(m,2H),0.62-0.55(m,1H)。tR=1.002分钟(Chiralpak AD-3,3x100mm,3um;MEOH(0.1%DEA)=15%;2mL/min)。20c和20d为对映异构体。
实施例20d:(1R,2S)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇。LCMS(ESI,m/z):259.2[M+H]+;tR=1.186分钟(Chiralpak AD-3,3x100mm,3um;MEOH(0.1%DEA)=15%;2mL/min)。20c和20d为对映异构体。
实施例21:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
(1S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
实施例21a-f都使用制备实施例1a-h的反应条件合成,其中试剂环丁酮替代为2,2-二甲基环丁-1-酮。各实施例为具有未确定立体化学构型的单一非对映异构体
实施例21a:4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.68–7.52(m,2H),7.36(tdd,J=7.5,1.2,0.6Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.62(d,J=5.0Hz,1H),5.42(d,J=9.2Hz,1H),3.94(ddd,J=8.9,4.8,2.1Hz,1H),2.06–1.92(m,1H),1.70(ddd,J=10.7,8.3,3.4Hz,1H),1.04(d,J=7.6Hz,6H)。;tR=1.61分钟(Whelk0-1 s,s(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例21b:4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.58(ddt,J=9.6,7.5,0.9Hz,2H),7.36(tdd,J=7.5,1.2,0.6Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.13(s,1H),5.36(d,J=7.6Hz,1H),5.14(d,J=6.9Hz,1H),4.03–3.81(m,1H),2.45–2.21(m,1H),1.46(dd,J=10.7,9.0Hz,1H),1.19–1.05(m,1H),1.01(s,3H),0.95(s,3H)。;tR=0.54min(ChiralpakAD(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例21c:4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.58(dd,J=7.6,1.2Hz,1H),7.36(t,J=7.9Hz,2H),7.23(td,J=7.5,1.1Hz,1H),7.09(s,1H),5.34(d,J=8.9Hz,1H),5.09(d,J=7.1Hz,1H),3.85(t,J=7.6Hz,1H),2.31–2.07(m,1H),1.65(td,J=9.7,9.3,1.0Hz,1H),1.52(t,J=10.3Hz,1H),1.05(s,3H),0.95(s,3H)。;tR=0.67分钟(Chiralpak AD(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例21d(实施例21b的对映异构体):4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;tR=0.74min(Cellulose-1(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例21e(实施例21a的对映异构体):4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;;tR=0.99分钟(Whelk0-1 s,s(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例21f(实施例21c的对映异构体):4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇:LCMS(ESI,m/z):255[M+H]+;tR=2.19分钟(Chiralpak AD(250x30mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例22:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
步骤1:
(E)-3,3-二甲基-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮
向2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(2.5g,6.03mmol)和3,3-二甲基环丁-1-酮(888mg,9.05mmol)在MeOH(40mL)中的溶液中滴加哌啶(0.595mL,6.03mmol)。将溶液回流过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离以得到(E)-3,3-二甲基-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮,其为淡黄色固体:LCMS(ESI,m/z):495.3[M+H]+.
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-酮
在90℃(E)-3,3-二甲基-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮在20%AcOH的MeOH溶液(20mL)中搅拌2h。冷却至室温后,在减压下去除溶剂且饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x10mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物。产物通过CombiFlash纯化以得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-酮,其为淡黄色固体:LCMS(ESI,m/z):253.3[M+H]+.
步骤3:
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-酮(1.04g,4.12mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(467mg,12.37mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用5%三氟乙醇在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到6种异构体,为白色固体。
异构体22a、22b、22c和22e的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例22a:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(d,J=0.7Hz,1H),7.70(dt,J=7.6,0.9Hz,1H),7.59(dt,J=7.6,0.9Hz,1H),7.40–7.33(m,1H),7.29–7.22(m,1H),7.14(s,1H),5.58(d,J=3.2Hz,1H),5.48(d,J=8.7Hz,1H),4.45(dq,J=6.5,3.1Hz,1H),2.28–2.17(m,1H),1.99–1.89(m,1H),1.71–1.64(m,1H),1.18(s,3H),1.04(s,3H)。
实施例22b:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.87(d,J=0.8Hz,1H),7.62–7.55(m,2H),7.40–7.33(m,1H),7.25(dd,J=7.6,1.1Hz,1H),7.14(s,1H),5.47–5.39(m,1H),5.11(d,J=7.5Hz,1H),4.45–4.32(m,1H),2.11(t,J=8.1Hz,1H),1.99(dd,J=10.4,7.8Hz,1H),1.53(dd,J=10.5,8.1Hz,1H),0.95(s,3H),0.84(s,3H)。
实施例22c:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.87(t,J=0.6Hz,1H),7.61–7.54(m,2H),7.40–7.32(m,1H),7.23(td,J=7.6,1.1Hz,1H),7.14(s,1H),5.42(d,J=8.0Hz,1H),5.11(d,J=7.4Hz,1H),4.39(p,J=7.9Hz,1H),2.11(t,J=8.1Hz,1H),2.03–1.94(m,1H),1.53(dd,J=10.4,8.1Hz,1H),0.94(s,3H),0.84(s,3H)。
实施例22d:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.59(d,J=7.4Hz,1H),7.46(d,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.09(s,1H),5.43(d,J=9.9Hz,1H),5.08(d,J=7.9Hz,1H),4.44(p,J=7.9Hz,1H),2.07(dd,J=10.5,7.7Hz,1H),1.91(dd,J=9.9,7.9Hz,1H),1.53(dd,J=10.5,8.2Hz,1H),1.19(s,3H),1.10(s,3H)。
实施例22e:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(t,J=0.6Hz,1H),7.73–7.66(m,1H),7.59(dt,J=7.5,0.9Hz,1H),7.40–7.31(m,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.59(d,J=3.2Hz,1H),5.48(d,J=8.7Hz,1H),4.44(tt,J=6.3,2.9Hz,1H),2.26–2.15(m,1H),1.94(ddd,J=11.6,5.9,1.0Hz,1H),1.67(ddd,J=11.9,2.7,0.8Hz,1H),1.18(s,3H),1.04(s,3H)。
实施例22f:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(d,J=0.7Hz,1H),7.61(dt,J=7.6,1.0Hz,1H),7.53–7.47(m,1H),7.42–7.36(m,1H),7.27(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.62(d,J=3.2Hz,1H),5.47(d,J=11.2Hz,1H),4.33(td,J=5.8,2.8Hz,1H),1.99–1.89(m,2H),1.68(dt,J=12.0,0.9Hz,1H),1.61(s,3H),1.08(s,3H)。
实施例22g:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(t,J=0.7Hz,1H),7.61(dt,J=7.6,0.9Hz,1H),7.52–7.46(m,1H),7.42–7.35(m,1H),7.28(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.62(d,J=3.0Hz,1H),5.47(d,J=11.2Hz,1H),4.36–4.30(m,1H),2.00–1.87(m,2H),1.74–1.64(m,1H),1.61(s,3H),1.08(s,3H)。
实施例22h:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.63–7.56(m,1H),7.45(dd,J=7.6,0.9Hz,1H),7.37(dd,J=7.9,7.1Hz,1H),7.27(dd,J=7.6,1.2Hz,1H),7.09(s,1H),5.43(d,J=10.0Hz,1H),5.08(d,J=7.9Hz,1H),4.44(p,J=7.9Hz,1H),2.11–2.02(m,1H),1.91(dd,J=9.9,8.0Hz,1H),1.53(dd,J=10.5,8.2Hz,1H),1.19(s,3H),1.09(s,3H)。
实施例23:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
步骤1:
(E)-2,2-二甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环戊烷-1-酮
将10%氢氧化钠水溶液(1.93mL,4.82mmol)添加至2,2-二甲基环戊烷-1-酮(281mg,2.51mmol)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(800mg,1.93mmol)在MeOH(15mL)中的搅拌混合物中。反应混合物在65℃加热6小时直到TLC显示SM消失。反应混合物用DCM(30mL)稀释且有机物用水洗涤,用Na2SO4干燥,过滤且浓缩。粗物质直接运至下一步:LCMS(ESI,m/z):509.4[M+H]+
步骤2:
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):267.4
步骤3:
(1R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
(1S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为8种非对映异构体的混合物,其通过手性SFC纯化。
所有异构体的绝对构型任意指定。
实施例23a:(1R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.91(s,1H),7.59(d,J=7.5Hz,1H),7.53(d,J=7.6Hz,1H),7.38(t,J=7.2Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.10(s,1H),5.43(d,J=4.4Hz,1H),4.89–4.83(m,1H),3.56(d,J=9.6Hz,1H),2.64(m,1H),1.39–1.20(m,3H),1.14–1.00(m,1H),0.90(s,3H),0.84(s,3H)。
实施例23b:(1R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.92(s,1H),7.60(d,J=7.5Hz,1H),7.48(d,J=8.5Hz,1H),7.40–7.32(m,1H),7.27–7.19(m,1H),7.11(s,1H),5.25(dd,J=15.3,7.6Hz,2H),3.61(dd,J=8.5,1.1Hz,1H),2.07(dd,J=13.3,4.4Hz,2H),2.00–1.87(m,1H),1.83–1.70(m,1H),1.45–1.34(m,1H),1.06(s,3H),0.79(s,3H)。
实施例23c:(1R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.88(s,1H),7.67(dd,J=7.6,0.8Hz,1H),7.58(d,J=7.5Hz,1H),7.37(t,J=7.7Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.37(d,J=7.6Hz,1H),5.28(d,J=5.2Hz,1H),3.72(t,J=5.1Hz,1H),2.41–2.28(m,1H),1.80–1.55(m,3H),1.35–1.26(m,1H),1.02(s,3H),0.82(s,3H)。
实施例23d:(1S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR实施例23a的对映异构体。
实施例23e:(1S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR实施例23c的对映异构体。
实施例23f:(1S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR实施例23b的对映异构体。
实施例24:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
步骤1:
(E)-2,2-二甲基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环己烷-1-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):533.2[M+H]+
步骤2:
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-酮
该标题化合物通过合成Int-3的通用步骤合成。
两种非对映异构体对未分离且用作混合物用于步骤3:LCMS(ESI,m/z):281.2
步骤3:
(1R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
(1S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为8种对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):283.2,对于所有异构体。
所有异构体的绝对构型任意指定。
实施例24a:(1R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR与实施例24h相同。
实施例24b:(1S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.93(t,J=0.6Hz,1H),7.64–7.55(m,2H),7.41–7.32(m,1H),7.23(td,J=7.6,1.2Hz,1H),7.10(d,J=0.5Hz,1H),5.15(d,J=7.3Hz,1H),4.83(d,J=5.8Hz,1H),3.42–3.38(m,1H),1.84–1.72(m,1H),1.66–1.46(m,4H),1.37(dtd,J=13.7,10.0,8.8,3.5Hz,1H),1.08–1.00(m,1H),0.91(s,3H),0.76(s,3H)。
实施例24c:(1R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.58(dt,J=7.5,1.0Hz,1H),7.47(dq,J=7.5,0.9Hz,1H),7.36(tdd,J=7.5,1.2,0.6Hz,1H),7.28(td,J=7.5,1.2Hz,1H),7.13(s,1H),5.68(d,J=2.4Hz,1H),5.18(d,J=6.5Hz,1H),2.23–2.11(m,1H),1.33(dd,J=13.0,2.6Hz,1H),1.26–1.12(m,2H),1.09–1.03(m,1H),1.02(s,3H),0.92(s,3H),0.68(d,J=13.2Hz,1H),0.21–0.05(m,1H)。
实施例24d:(1S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR与实施例24e相同。
实施例24e:(1R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.58(ddt,J=12.8,8.3,0.8Hz,2H),7.42–7.32(m,1H),7.27(td,J=7.5,1.2Hz,1H),7.10(s,1H),5.69(d,J=3.9Hz,1H),5.12(d,J=6.3Hz,1H),2.40–2.27(m,1H),1.31(dd,J=13.0,2.5Hz,1H),1.20–1.13(m,2H),0.98(s,3H),0.92(s,3H),0.52(d,J=13.1Hz,1H),0.23–0.04(m,1H)。
实施例24f:(1S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR与实施例24c相同。
实施例24g:(1R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR与实施例24b相同。
实施例24h:(1S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):281.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.97(t,J=0.7Hz,1H),7.56(dt,J=3.0,0.8Hz,1H),7.55–7.52(m,1H),7.41–7.31(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.08(s,1H),5.19(d,J=3.1Hz,1H),5.06(dd,J=6.0,0.7Hz,1H),3.63–3.55(m,1H),2.23–2.14(m,1H),1.48(td,J=13.2,4.3Hz,1H),1.40–1.19(m,2H),1.18–0.99(m,2H),0.94(s,3H),0.91(s,3H),0.77(dd,J=12.3,3.4Hz,1H)。
实施例25:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
该标题化合物通过与实施例5和6相同的方法合成
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,ChiralpakID,2.0cm I.Dx25cm;流动相:Hex:IPA=10:10;检测器,uv254nm;流速,20mL/min.
2.柱,ChiralpakIC,2x25cm,5um;流动相:Hex(0.1%DEA):IPA=30:30;检测器,uv254nm;流速,20mL/min.
所有异构体的绝对构型任意指定。
实施例25a:(1R,2S)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇:LCMS(ESI,m/z):273.2[M+H]+;1HNMR(300MHz,CD3OD)1HNMR(300MHz,CD3OD)δ7.90(s,1H),7.58-7.52(m,1H),7.43-7.38(m,1H),7.20(s,1H),7.09-7.02(m,1H),5.80(d,J=3.0Hz,1H),3.78-3.72(m,1H),2.26–2.03(m,2H),1.81–1.67(m,1H),1.39-1.31(m,2H),1.14-1.00(m,2H),0.75-0.60(m,1H),0.39-0.24(m,1H);tR=1.044分钟(Chiralpak IC-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=70:30;1.5ml/min)。25a和25b为对映异构体。
实施例25b:(1S,2R)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇:LCMS(ESI,m/z):273.2[M+H]+;tR=1.438分钟(Chiralpak IC-3,0.46x5cm,3um;Hex(0.1%DEA):IPA=70:30;1.5ml/min)。25a和25b为对映异构体。
实施例25c:(1S,2R)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇:LCMS(ESI,m/z):273.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.90(s,1H),7.50-7.34(m,2H),7.22(s,1H),7.07-7.04(m,1H),5.80(d,J=3.0Hz,1H),3.75-3.72(m,1H),2.22-1.96(m,2H),1.84-1.67(m,1H),1.45-1.39(m 2H),1.34-1.02(m,2H),0.96-0.83(m,1H),0.45-0.23(m,1H)。tR=3.432分钟(Chiralpak ID-3,0.46x10cm,3um;Hex(0.1%DEA):IPA=90:10;1mL/min)。25c和25d为对映异构体。
实施例25d:(1R,2S)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇:LCMS(ESI,m/z):273.2[M+H]+;tR=4.010分钟(Chiralpak ID-3,0.46x10cm,3um;Hex(0.1%DEA):IPA=90:10;1mL/min)。25c和25d为对映异构体。
实施例26:4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
_(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
将正丁基锂(2.5M在己烷中;1.13mL,2.83mmol)滴加至5H-咪唑并[5,1-a]异吲哚(442mg,2.83mmol)在6ml THF中的溶液中,该THF已被冷却至-78℃,且将混合物搅拌45分钟。缓慢添加3,4-环氧基四氢呋喃(292mg,3.40mmol)在THF(3mL)中的溶液,然后添加三氟化硼醚合物(0.42mL,3.40mmol)。将反应溶液温热至0℃且再搅拌5小时。随后将其用饱和氯化铵溶液水解且水相用DCM(30mL)萃取两次。干燥后,溶剂在减压下去除且粗产物通过Combi-快速色谱法纯化。产物获得为四种非对映异构体的混合物(501mg,73%)。在通过手性SFC纯化后得到纯的立体异构体。所有异构体的绝对构型任意指定。
实施例26a:(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.94(s,1H),7.59(d,J=7.6Hz,1H),7.54(dd,J=7.6,0.9Hz,1H),7.38(t,J=7.5Hz,1H),7.27(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.58(d,J=4.1Hz,1H),5.26(d,J=4.6Hz,1H),4.31(dt,J=8.5,4.2Hz,1H),3.73–3.67(m,1H),3.58(dd,J=9.2,5.7Hz,1H),3.43(dd,J=9.6,3.6Hz,1H),3.14(dd,J=9.1,6.5Hz,1H),2.86–2.79(m,1H)。
实施例26b:(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.2[M+H]+;1HNMR实施例26a的对映异构体。
实施例26c:(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.88(s,1H),7.60(d,J=7.5Hz,1H),7.52(dd,J=7.6,0.8Hz,1H),7.40(t,J=7.5Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.50(d,J=4.6Hz,1H),5.00(d,J=4.7Hz,1H),4.02(dd,J=9.2,7.8Hz,1H),3.85–3.78(m,2H),3.38(d,J=4.4Hz,2H),2.81–2.72(m,1H)。
实施例26d:(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.2[M+H]+;1HNMR实施例26c的对映异构体。
实施例14和27:2-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
实施例14:2-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
合成途径IIB
步骤1:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯和4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
在-60℃向5H-咪唑并[4,3-a]异吲哚(3.0g,19.21mmol)和四氢呋喃(40mL)的溶液滴加正丁基锂(10mL在己烷中,2.5mol/L,25mmol)。所得溶液在-40℃搅拌1小时。在-40℃滴加7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁酯(4.8g,24.09mmol)在四氢呋喃(10mL)中的溶液。反应缓慢升高至室温,然后再搅拌1.5h。反应然后通过饱和氯化铵(50mL)淬灭,用乙酸乙酯(3x100mL)萃取且真空浓缩。残余物通过硅胶柱色谱法纯化且用二氯甲烷/甲醇(10/1)洗脱以得到混合物(2.5g,37%)。
步骤2:3-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-4-醇和4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇
向3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯和4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(2.5g,9.80mmol)的混合物在二氯甲烷(30mL)中的溶液中添加TFA(10mL)。溶液在室温搅拌2h。溶液真空浓缩以得到3-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-4-醇和4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇的混合物,其为棕色油状物(2.8g,粗物质):LCMS(ESI,m/z):256.0[M+H]+;
步骤3:
2-((3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
向3-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-4-醇和4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(2.8g,粗物质)的混合物在二氯甲烷(50mL)中的溶液中添加三乙胺(50mL)和2-氯乙腈(1.4mL,22.06mmol)。所得溶液在室温搅拌6h。所得溶液用水(50mL)稀释,用二氯甲烷(3x100mL)萃取。合并的有机层用盐水(1x100mL)洗涤。将混合物用无水硫酸钠干燥且真空浓缩以得到粗产物(3.0g,粗物质),其为浅棕色固体。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.CHIRALCEL OD-H,20x250mm;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:10B至10B在24min内;
2.CHIRALPAK-AD-H-SL002,20x250mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:30B至30B在15min内;254/220nm;
所有异构体的绝对构型任意指定。
实施例27a:2-((3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(20.8mg,1%),其为灰白色固体:LCMS(ESI,m/z):295.1[M+H]+;1HNMR(300MHz,CD3OD)δ7.92(s,1H),7.65(d,J=7.5Hz,1H),7.56(d,J=7.5Hz,1H),7.47-7.42(m,1H),7.36-7.31(m,1H),7.18(s,1H),5.81(d,J=3.0Hz,1H),4.03-3.95(m,1H),3.64(s,2H),3.13-3.08(m,1H),2.65-2.61(m,1H),2.31-2.12(m,3H),0.82-0.70(m,2H)。tR=3.169分钟,(Chiralpak IC-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。27a和27b为对映异构体。
实施例27b:2-((3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(29.8mg,1%),其为灰白色固体:LCMS(ESI,m/z):295.1[M+H]+;tR=5.009分钟,(Chiralpak IC-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。27a和27b为对映异构体。
实施例27c:2-((3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(75.3mg,1%),其为白色固体:LCMS(ESI):348.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.90(s,1H),7.64(d,J=7.8Hz,1H),7.52(d,J=7.8Hz,1H),7.48-7.34(m,2H),7.20(s,1H),5.81(d,J=3.6Hz,1H),4.00-3.91(m,1H),3.65(s,2H),3.19-3.14(m,1H),2.63-2.60(m,1H),2.31-2.03(m,3H),0.94-0.89(m,1H),0.72-0.58(m,1H);tR=1.519分钟,(Chiralpak AD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。27c和27d为对映异构体。
实施例27d:2-((3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(94.8mg,1%),为白色固体:LCMS(ESI):348.2[M+H]+;tR=2.357分钟,(Chiralpak AD-3,0.46x5cm,3um;乙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。27c和27d为对映异构体。
所有异构体14a-d的绝对构型任意指定。
实施例14a:2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(249.8mg,1%):LCMS(ESI,m/z):295.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.93(s,1H),7.66(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.48-7.34(m,2H),7.22(s,1H),5.82(d,J=3.0Hz,1H),3.95-3.83(m,1H),3.52-3.33(m,2H),2.92-2.83(m,1H),2.47-2.05(m,4H),1.85-1.73(m,1H),1.48-1.41(m,1H);tR=1.156分钟,(Chiralpak AD-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。实施例14a和实施例14b为对映异构体。
实施例14b:2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(241.0mg,1%),其为灰白色固体。LCMS(ESI,m/z):295.2[M+H]+;tR=2.086分钟,(Chiralpak AD-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。实施例14a和实施例14b为对映异构体。
实施例14c:2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(61.9mg,1%),其为灰白色固体:LCMS(ESI,m/z):295.1[M+H]+.1HNMR(400MHz,CD3OD)δ7.89(s,1H),7.64(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.45-7.34(m,2H),7.20(s,1H),5.82(d,J=4.0Hz,1H),4.37-4.33(m,1H),3.86-3.71(m,2H),2.62-2.50(m,2H),2.27-2.20(m,1H),1.43(s,9H),0.87-0.83(m,1H),0.47-0.42(m,1H);tR=4.384分钟(Chiralpak AD-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。实施例14c和实施例14d为对映异构体。
实施例14d:2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(52.4mg,1%),其为灰白色固体:LCMS(ESI,m/z):295.1[M+H]+;tR=6.297分钟。(Chiralpak AD-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=30:70;1.0mL/min)。实施例14c和实施例14d为对映异构体。
实施例28:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-磺酰胺
步骤1:4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
向3-羟基-4-[5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-甲酸叔丁酯(2g,5.86mmol)在二氯甲烷(25mL)中的溶液中添加三氟乙酸(5mL,67.32mmol)。所得溶液在25℃搅拌1h,然后真空浓缩以得到4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇(3.4g,粗物质),其为黄色油状物:LCMS(ESI,m/z):242.2[M+H]+
步骤2:N-(3-羟基-4-[5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰基)氨基甲酸叔丁酯
向4-[5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-3-醇(1.8g,7.46mmol)在二氯甲烷(120mL)中的溶液中添加TEA(2.2g,21.74mmol)、2-甲基丙-2-醇(2.8g,37.776mmol)和[(氯磺酰基)亚氨基]甲酮(1.6g,11.31mmol)。所得溶液在25℃搅拌40分钟。所得混合物真空浓缩。残余物在硅胶柱上纯化,使用二氯甲烷/甲醇(15/1)以得到N-(3-羟基-4-[5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰基)氨基甲酸叔丁酯(1.45g,46%),其为黄色油状物:LCMS(ESI,m/z):421.1[M+H]+
步骤3:
(3R,4R)-3羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺
(3R,4R)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺
(3S,4S)-3-羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺
(3S,4S)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺
向N-(3-羟基-4-[5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰基)氨基甲酸叔丁酯(400mg,0.951mmol,)在1,4-二噁烷(6mL)中的溶液中添加氯化氢(2mL,65.82mmol)。所得溶液在25℃搅拌1.5h,然后真空浓缩。粗产物通过prep-HPLC纯化以得到两种产物。这些两种产物通过手性分离使用以下条件分离:
1.柱,Chiralpak IC,2x25cm,5um;流动相:乙醇:己烷=40:40;检测器,uv 254/220nm;流速,20mL/min
2.柱,Chiralpak IC,2x25cm,5um;流动相:己烷:乙醇:甲醇=50:25:25;检测器,uv 254/220nm;流速,20mL/min
所有异构体的绝对构型任意指定。
实施例28a:(3R,4R)-3-羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺(32.1mg,11%):LCMS(ESI,m/z):321[M+H]+;1HNMR(300MHz,DMSO)δ7.98(s,1H),7.62(d,J=3.7Hz,1H),7.57(d,J=3.7Hz,1H),7.41(t,J=3.6Hz,1H),7.33-7.28(m,1H),7.19(s,1H),6.72(s,2H),5.68(d,J=2.5Hz,1H),5.60(d,J=0.6Hz,1H),4.48-4.35(m,1H),3.32-3.27(m,1H),2.95-2.80(m,3H),2.18-2.08(m,1H);tR=3.129min,(ChiralpakIB-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。28a和28b为对映异构体
实施例28b:(3R,4R)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺(31.7mg,10%):LCMS(ESI,m/z):321[M+H]+;tR=4.425min,(Chiralpak IB-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。28a和28b为对映异构体。
实施例28c:(3S,4S)-3-羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺(15.4mg,5%):LCMS(ESI,m/z):321[M+H]+;1HNMR(300MHz,CD3OD)δ8.01(s,1H),7.64(d,J=3.7Hz,1H),7.57(d,J=3.9Hz,1H),7.45(t,J=3.6Hz,1H),7.37-7.32(m,1H),7.17(s,1H),5.57(d,J=2.1Hz,1H),4.05(d,J=2.7Hz,1H),3.52(dd,J=4.3Hz,1H),3.25-3.16(m,2H),3.06-2.95(m,2H);tR=2.173分钟,(Chiralpak IB-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH:MeOH(0.2%IPA)=50:30:20,1.0mL/min)。28c和28d为对映异构体。
实施例28d:(3S,4S)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺(22.9mg,8%):LCMS(ESI,m/z):321[M+H]+;tR=4.073min(Chiralpak IB-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH:MeOH(0.2%IPA)=50:30:20,1.0mL/min)。28c和28d为对映异构体。
实施例29:9-羟基-8-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-
4-酮
(8R,9R)-9-羟基-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8R,9R)-9-羟基-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8R,9S)-9-羟基-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8R,9S)-9-羟基-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8S,9R)-9-羟基-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8S,9R)-9-羟基-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8S,9S)-9-羟基-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
(8S,9S)-9-羟基-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
实施例29a-f从3,4-二氢-1H-喹嗪-1,6(2H)-二酮使用制备实施例1所述的反应条件合成。各实施例为单一非对映异构体。所有异构体的绝对构型任意指定。
实施例29a:1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.63(d,J=7.6Hz,1H),7.50–7.46(m,1H),7.45(dd,J=8.3,6.2Hz,1H),7.40(t,J=7.4Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.20(s,1H),6.57–6.50(m,2H),6.27(dt,J=9.0,1.0Hz,1H),5.74(d,J=2.2Hz,1H),4.90(d,J=10.9Hz,1H),4.04(dt,J=14.1,6.2Hz,1H),3.43–3.29(m,1H),2.62–2.48(m,1H),1.29–1.18(m,1H),0.88–0.76(m,1H);制备型SFC:Chiralpak AD(250x20mm,5μm),等度洗脱70:30–CO2:甲醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间0.999分钟。
实施例29b(实施例29a的对映异构体):1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.1[M+H]+;制备型SFC:Chiralpak AD(250x20mm,5μm),等度洗脱70:30–CO2:甲醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间1.177分钟。
实施例29c:1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.66–7.58(m,2H),7.43–7.35(m,2H),7.22(td,J=7.6,1.1Hz,1H),7.15(s,1H),6.35–6.27(m,2H),6.21(d,J=4.9Hz,1H),5.49(d,J=6.4Hz,1H),4.79(t,J=4.4Hz,1H),4.09(dt,J=14.5,5.2Hz,1H),3.61(ddd,J=15.2,9.0,6.8Hz,1H),2.39(dtd,J=10.3,6.7,3.8Hz,1H),2.03–1.89(m,2H);制备型SFC:Chiralpak AD(250x20mm,5μm),等度洗脱65:35–CO2:甲醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间1.235分钟。
实施例29d(实施例29c的对映异构体):1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.1[M+H]+;制备型SFC:Chiralcel OX(150x20mm,5μm),等度洗脱60:40–CO2:甲醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间1.458分钟。
实施例29e:1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.60(s,1H),7.58(s,1H),7.45(dd,J=9.1,6.8Hz,1H),7.39(dd,J=8.1,7.0Hz,1H),7.30(td,J=7.5,1.2Hz,1H),7.10(s,1H),6.51(s,1H),6.42(dd,J=7.5,1.3Hz,1H),6.31(dd,J=9.1,1.3Hz,1H),5.62(d,J=2.8Hz,1H),5.01(d,J=5.2Hz,1H),4.11(ddd,J=14.3,5.7,3.6Hz,1H),3.48–3.38(m,1H),2.85–2.74(m,1H),1.46–1.34(m,1H),1.23(dtd,J=13.6,10.7,5.7Hz,1H);制备型SFC:Chiralcel OX(150x20mm,5μm),等度洗脱60:40–CO2:乙醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间1.595分钟。
实施例29f(实施例29e的对映异构体):1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢-1H-喹嗪-6(2H)-酮:LCMS(ESI)m/z:320.1[M+H]+;制备型SFC:Chiralcel OX(150x20mm,5μm),等度洗脱60:40–CO2:乙醇w/0.1%NH4OH,40℃,70ml/min;分析型SFC:Chiralpak AD(50x4.6mm,3μm),等度洗脱25:75–CO2:乙醇w/0.1%NH4OH,40℃,4.0ml/min,保留时间1.771分钟。
实施例30:4-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
该标题化合物通过与实施例5和6相同的方法合成
混合物通过手性分离使用以下条件分离:柱,ChiralpakAD-H-SL002,20x250mm;流动相:Hex:IPA=20:20;检测器,uv 254nm;流速,20mL/min.
实施例30a:(3R,4S)-4-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇:LCMS(ESI,m/z):261.2[M+H]+;1HNMR(300MHz,CD3OD)δ8.01(s,1H),7.60-7.56(m,1H),7.43-7.39(m,1H),7.25(s,1H),7.07-7.05(m,1H),5.59(d,J=6Hz,1H),4.29-4.24(m,1H),3.94-3.90(m,1H),3.68-3.62(m,1H),3.57-3.50(m,1H),3.47-3.43(m,1H),3.00-2.89(m,1H)。tR=5.312分钟(Chiralpak AD-3,0.46x25cm,3um;Hex(0.1%DEA):IPA=80:20;1mL/min)。30a和30b为对映异构体。
实施例30b:(3S,4R)-4-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇:LCMS(ESI,m/z):261.2[M+H]+;tR=6.457分钟(Chiralpak AD-3,0.46x25cm,3um;Hex(0.1%DEA):IPA=80:20;1mL/min)。30a和30b为对映异构体。
实施例30c:(3S,4R)-4-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇:LCMS(ESI,m/z):261.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.97(s,1H),7.58-7.54(m,1H),7.47-7.41(m,1H),7.22(s,1H),7.10-7.03(m,1H),5.52(d,J=3.0Hz,1H),4.26-4.20(m,1H),4.09-4.05(m,1H),3.84-3.81(m,1H),3.53-3.51(m,2H),2.90-2.84(m,1H)。tR=10.558分钟(Chiralpak AD-3,0.46x25cm,3um;Hex(0.1%DEA):IPA=80:20;1mL/min)。30c和30d为对映异构体。
实施例30d:(3R,4S)-4-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇:LCMS(ESI,m/z):261.2[M+H]+;tR=15.264分钟(Chiralpak AD-3,0.46x25cm,3um;Hex(0.1%DEA):IPA=80:20;1mL/min)。30c和30d为对映异构体。
实施例31:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
步骤1:
(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹啉-5(6H)-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):544.2[M+H]+
步骤2:
(S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹啉-5(6H)-酮
该标题化合物通过合成Int-3的通用步骤合成。两种非对映异构体对未分离且用作混合物用于步骤3:LCMS(ESI,m/z):302.1
步骤3:
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为8种对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):303.1.
异构体31a、31b、31g和31h的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例31a:(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.56(dd,J=4.8,1.7Hz,1H),8.16(s,1H),7.84(dd,J=7.8,1.8Hz,1H),7.49(dt,J=7.6,1.0Hz,1H),7.41–7.32(m,2H),7.25(ddd,J=7.6,6.2,1.2Hz,2H),6.51(s,1H),5.50(s,1H),5.15–5.10(m,1H),4.94(s,1H),2.86(dd,J=17.7,5.1Hz,1H),2.68(ddd,J=18.2,12.6,6.2Hz,1H),2.41(dd,J=12.8,2.6Hz,1H),1.34(qd,J=12.9,5.6Hz,1H),1.11–1.03(m,1H)。
实施例31b:(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.42(ddd,J=4.8,1.8,0.7Hz,1H),7.91(ddd,J=7.8,1.7,1.0Hz,1H),7.67(s,1H),7.63–7.52(m,1H),7.50(dd,J=7.7,1.0Hz,1H),7.46–7.36(m,1H),7.31–7.21(m,1H),7.23(s,1H),7.18(dd,J=7.9,4.8Hz,1H),5.77(d,J=2.9Hz,1H),4.96(d,J=10.4Hz,1H),2.89(dd,J=8.9,4.0Hz,2H),2.59–2.49(m,1H),1.48–1.28(m,2H)。
实施例31c:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.48–8.43(m,1H),7.99(d,J=8.1Hz,1H),7.75(s,1H),7.58(d,J=7.6Hz,1H),7.45–7.38(m,1H),7.35(d,J=7.4Hz,1H),7.30(td,J=7.5,1.1Hz,1H),7.21(dd,J=7.9,4.7Hz,2H),5.84(s,1H),5.03(d,J=10.5Hz,1H),2.84(dd,J=10.1,6.2Hz,1H),2.40(dd,J=13.8,9.3Hz,1H),1.36–1.09(m,3H)。
实施例31d:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.49(dd,J=4.8,1.7Hz,1H),7.98(s,1H),7.64–7.54(m,3H),7.41(tt,J=7.6,0.8Hz,1H),7.27(td,J=7.6,1.2Hz,1H),7.18(s,1H),7.16(dd,J=7.7,4.7Hz,1H),5.37(d,J=7.6Hz,1H),4.89(s,1H),3.18(ddd,J=18.0,5.3,2.1Hz,1H),2.91(ddd,J=18.4,12.0,6.9Hz,1H),2.41–2.27(m,1H),2.13–2.04(m,1H)。
实施例31e:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇。LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.48(dd,J=4.8,1.7Hz,1H),7.98(s,1H),7.65–7.52(m,3H),7.45–7.34(m,1H),7.27(td,J=7.6,1.2Hz,1H),7.19–7.12(m,2H),5.37(d,J=7.6Hz,1H),4.89(d,J=3.0Hz,1H),3.18(ddd,J=17.9,5.4,2.1Hz,1H),2.91(ddd,J=18.3,12.0,6.8Hz,2H),2.42–2.28(m,1H),2.31(s,1H),2.08(ddt,J=9.1,7.7,3.7Hz,1H)。
实施例31f:5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.43(dd,J=4.9,1.6Hz,1H),8.03–7.97(m,1H),7.74(s,1H),7.57(d,J=7.5Hz,1H),7.41(td,J=7.4,1.1Hz,1H),7.34(d,J=7.5Hz,1H),7.30(dd,J=7.4,1.1Hz,1H),7.20(dd,J=7.9,4.7Hz,2H),5.85(s,1H),5.02(d,J=10.6Hz,1H),2.84(dt,J=9.7,4.4Hz,1H),2.41(t,J=11.5Hz,1H),1.34–1.24(m,2H),1.23–1.07(m,1H)。
实施例31g:(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇。LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.56(dd,J=4.8,1.7Hz,1H),8.16(s,1H),7.84(dd,J=7.8,1.8Hz,1H),7.49(dt,J=7.6,1.0Hz,1H),7.41–7.32(m,2H),7.25(ddd,J=7.6,6.2,1.2Hz,2H),6.51(s,1H),5.50(s,1H),5.15–5.10(m,1H),4.94(s,1H),2.86(dd,J=17.7,5.1Hz,1H),2.68(ddd,J=18.2,12.6,6.2Hz,1H),2.41(dd,J=12.8,2.6Hz,1H),1.34(qd,J=12.9,5.6Hz,1H),1.11–1.03(m,1H)。
实施例31h:(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):303.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.55(dd,J=4.8,1.8Hz,1H),8.17(s,1H),7.84(dd,J=7.8,1.8Hz,1H),7.49(dt,J=7.6,1.0Hz,1H),7.40–7.32(m,2H),7.30–7.18(m,2H),6.52(s,1H),5.50(d,J=1.7Hz,1H),5.12(dt,J=4.0,2.0Hz,1H),2.86(dd,J=17.7,5.3Hz,1H),2.68(ddd,J=18.2,12.6,6.2Hz,1H),2.42(dd,J=12.7,2.6Hz,1H),1.41–1.24(m,1H),1.06(dd,J=13.4,6.0Hz,1H)。
实施例32:4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-胺
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
Inter-4通过与实施例30相同的方法合成。
步骤1:4-[5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇
在氮气下向4-[5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-醇(2g,8.255mmol)在四氢呋喃/二氯甲烷(100/10mL)中的溶液中添加二异丙基偶氮二甲酸酯(1.94mL,9.786mmol)、三苯基膦(2.5g,9.532mmol)和2,3-二氢-1H-异吲哚-1,3-二酮(1.45g,9.855mmol),然后在室温搅拌5h。所得混合物真空浓缩且残余物通过硅胶柱使用二氯甲烷/乙酸乙酯(1:1)纯化以得到2-(4-[5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(1.2g,39%),其为黄色固体。LCMS(ES,m/z):372[M+H]+.
步骤2:(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢呋喃-3-胺
将2-(4-[5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(1.2g,3.231mmol)和水合肼(5mL,102.876mmol,31.839当量)在乙醇(50mL)中的溶液在80℃搅拌5h。所得混合物真空浓缩。残余物在硅胶柱上纯化,使用二氯甲烷/甲醇(20:1)。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱:Lux 5u Celluloes-3,AXIA Packed,250X21.2mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在22min内;254/220nm;
2.柱:Lux 5u Celluloes-3,AXIA Packed,250X21.2mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在17min内;254/220nm.
所有异构体的绝对构型任意指定。
实施例32a:(3S,4S)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺(86.7mg,11%):LCMS(ESI,m/z):242[M+H]+;1H NMR(300MHz,氯仿-d)δ7.70(s,1H),7.66(d,J=7.6Hz,1H),7.56(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.32-7.24(m,2H),7.19(s,1H),5.50(d,J=9.0Hz,1H),4.14(t,J=8.3Hz,1H),4.02(dd,J=9.6,8.2Hz,1H),3.93(dd,J=8.9,4.0Hz,1H),3.84-3.72(m,2H),2.49(qd,J=9.1,5.7Hz,1H);tR=3.249分钟(LuxCellulose-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。32a和32b为对映异构体。
实施例32b:(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺(78.8mg,10%):LCMS(ESI,m/z):242[M+H]+;tR=5.074分钟(Lux Cellulose-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。32a和32b为对映异构体。
实施例32c:(3R,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺(61.4mg,8%):LCMS(ESI,m/z):242[M+H]+;1H NMR(300MHz,氯仿-d)δ8.10(s,1H),7.57(d,J=7.6Hz,1H),7.39(t,J=7.4Hz,1H),7.28-7.14(m,3H),5.43(d,J=10.8Hz,1H),4.20(dd,J=9.5,4.7Hz,2H),3.93-3.76(m,2H),3.71(dd,J=5.4,3.2Hz,1H),2.47-2.28(m,1H);tR=3.584分钟(Lux Cellulose-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。32c和32d为对映异构体。
实施例32d:(3S,4S)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺(70.8mg,9%):LCMS(ESI,m/z):242[M+H]+;tR=4.409分钟(Lux Cellulose-3,0.46x5cm,3um,Hex(0.1%DEA):EtOH=70:30,1.0mL/min)。32c和32d为对映异构体。
实施例33和34:8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇和8-
氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
该标题化合物通过与实施例5和6相同的方法合成
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱:CHIRALPAK-AD-H-SL002,20x250mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在13.5min内;254/220nm;
2.柱:Lux 5u Celluloes-3,AXIA Packed,250X21.2mm;流动相A:EtOH(0.1%DEA)----HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:30B至30B在16min内;254/220nm;
3.柱:Chiralpak IC,2x25cm,5um;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:20B至20B在16min内;254/220nm.
所有异构体的绝对构型任意指定。
实施例33a:(3R,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)δ7.95(s,1H),7.49(dd,J=8.4Hz,4.8Hz,1H),7.41(dd,J=8.8Hz,2.4Hz,1H),7.25(s,1H),7.12-7.07(m,1H),5.80(s,1H),4.05(dd,J=10.8Hz,4.8Hz,1H),3.88-3.82(m,1H),3.70(dd,J=11.2Hz,4.8Hz,1H),3.28-3.16(m,2H),2.27(t,J=2.0Hz,1H),0.86(d,J=7.6Hz,1H),0.71-0.60(m,1H)。.tR=5.772分钟(CHIRALCEL AD-3,0.46x15cm,3um;Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。33a和33b为对映异构体。
实施例33b:(3S,4S)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):274.0[M+H]+;tR=6.618分钟(CHIRALCEL AD-3,0.46x15cm,3um;Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。33a和33b为对映异构体。
实施例33c:(3S,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)δ7.95(s,1H),7.56(dd,J=8.4Hz,4.8Hz,1H),7.42(dd,J=8.4Hz,2.4Hz,1H),7.22(s,1H),7.11-7.06(m,1H),5.79(s,1H),3.99(dd,J=10.4Hz,4.8Hz,1H),3.87-3.80(m,1H),3.72(d,J=6.8Hz,1H),3.29-3.22(m,1H),3.15(t,J=10.4Hz,1H),2.43-2.40(m,1H),0.77-0.73(m,2H)。tR=2.288min(CHIRALCEL Lux Cellulose-3,0.46x10cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。33c和33d为对映异构体。
实施例33d:(3S,4S)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)。tR=4.721分钟(CHIRALCELLux Cellulose-3,0.46x10cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。33c和33d为对映异构体。
实施例34a:(3R,4R)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)δ8.0(s,1H),7.59(dd,J=8.4Hz,4.8Hz,1H),7.42(dd,J=8.8Hz,2.4Hz,1H),7.23(s,1H),7.11-7.06(m,1H),5.76(s,1H),3.98-3.91(m,1H),3.88(dd,J=11.6Hz,4.8Hz,1H),3.34-3.26(m 1H),3.08(dd,J=11.6Hz,4.0Hz,1H),2.71(t,J=11.2Hz,1H),2.47-2.43(m,1H),1.97(dd,J=12.8Hz,2.4Hz,1H),.1.71-1.67(m,1H)。tR=2.133分钟(CHIRALCEL AD-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。34a和34b为对映异构体。
实施例34b:(3S,4S)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):274.0[M+H]+;tR=3.330分钟(CHIRALCEL AD-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。34a和34b为对映异构体。
实施例34c:(3R,4R)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)δ7.9(s,1H),7.53(dd,J=8.4Hz,4.8Hz,1H),7.41(dd,J=8.4Hz,2.4Hz,1H),7.25(s,1H),7.14-7.09(m,1H),5.80(s,1H),4.07-4.03(m,1H),3.90(dd,J=12.0Hz,4.8Hz,1H),3.33-3.29(m1H),3.16(dd,J=12.0Hz,4.4Hz,1H),2.51(t,J=11.2Hz,1H),2.34-2.31(m,1H),2.06(dd,J=10.4Hz,2.4Hz,1H),.1.75-1.71(m,1H)。tR=4.004min(CHIRALCELAD-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。34c和34d为对映异构体。
实施例34d:(3R,4R)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):274.0[M+H]+;1HNMR(300MHz,CD3OD)。tR=3.340分钟tR=4.489分钟(CHIRALCEL AD-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。34c和34d为对映异构体。
实施例35:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
步骤1:(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮
向2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(3.0g,7.24mmol)和环丁酮(1.01g,14.47mmol)在无水乙醇(30mL)中的溶液中添加哌啶(0.72mL,7.24mmol)且所得混合物在90℃搅拌6小时。混合物在冰浴上冷却且反应通过饱和NH4Cl(30mL)淬灭。水相用DCM萃取(3x20mL)且合并有机相,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离以得到(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮,其为黄色油状物:LCMS(ESI,m/z):466[M+H]+.
步骤2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮
向(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮添加MeOH(20mL)和AcOH(5mL)。所得混合物在90℃搅拌2小时。溶剂在减压下去除。反应通过30mL饱和NaHCO3溶液淬灭(30mL)且将混合物用二氯甲烷(3x20mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。粗产物通过CombiFlash分离以得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮,其为淡黄色油状物:LCMS(ESI,m/z):225.3[M+H]+.
步骤3:
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(0.41g,1.83mmol)在无水THF(10mL)中的溶液中滴加甲基溴化镁(0.73mL,2.19mmol)且溶液在0℃再搅拌1小时。反应通过30mL饱和NH4Cl溶液(10mL)淬灭且将混合物用二氯甲烷(3x10mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到6种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例35a:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇:LCMS(ESI,m/z):241.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.02(t,J=0.7Hz,1H),7.52(dt,J=7.6,1.1Hz,1H),7.48(dq,J=7.6,0.9Hz,1H),7.34(tdd,J=7.6,1.1,0.6Hz,1H),7.22(td,J=7.6,1.2Hz,1H),7.19(s,1H),5.46(d,J=5.9Hz,1H),2.65–2.56(m,1H),2.10–1.96(m,2H),1.82(dtd,J=11.9,8.8,6.2Hz,1H),1.70–1.63(m,1H),1.51(d,J=0.5Hz,3H)。
实施例35b:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇:LCMS(ESI,m/z):241.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.02(t,J=0.7Hz,1H),7.52(dt,J=7.6,1.1Hz,1H),7.48(dq,J=7.6,0.9Hz,1H),7.34(tdd,J=7.6,1.1,0.6Hz,1H),7.22(td,J=7.6,1.2Hz,1H),7.19(s,1H),5.46(d,J=5.9Hz,1H),2.65–2.56(m,1H),2.11–1.97(m,2H),1.82(dtd,J=11.9,8.8,6.2Hz,1H),1.66(ddt,J=11.9,10.4,6.7Hz,1H),1.51(d,J=0.5Hz,3H)。
实施例35c:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇:LCMS(ESI,m/z):241.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.00(s,1H),7.52(dt,J=7.4,1.0Hz,1H),7.37–7.32(m,2H),7.18(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.43(d,J=10.2Hz,1H),2.46–2.26(m,2H),2.19–2.03(m,3H),1.40(s,3H)。
实施例35d:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇:LCMS(ESI,m/z):241.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.00(s,1H),7.52(dt,J=7.5,1.1Hz,1H),7.39–7.31(m,2H),7.18(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.43(d,J=10.2Hz,1H),2.46–2.26(m,2H),2.21–2.02(m,3H),1.40(s,3H)。
实施例36:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
步骤1:(E)-6-(甲基硫基)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-3,4-二氢萘-1(2H)-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):589.3[M+H]
步骤2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基硫基)-3,4-二氢萘-1(2H)-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):347.19[M+H]+
步骤3:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基硫基)-1,2,3,4-四氢萘-1-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):349.1
步骤4:
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基硫基)-1,2,3,4-四氢萘-1-醇(1.5g,4.3mmol)在乙酸(10mL)中的溶液中添加过氧化氢(30%水溶液,4.88g,4.28mL,43.05mmol)且将反应在室温搅拌48小时。乙酸然后使用旋转蒸发器去除,剩余乙酸使用饱和碳酸钠溶液淬灭。将固体过滤出且滤液真空浓缩。粗产物通过prep-HPLC纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例36a:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.82(d,J=8.3Hz,1H),7.77(dd,J=8.2,1.9Hz,1H),7.66-7.58(m,3H),7.50(dd,J=7.7,1.0Hz,1H),7.45–7.37(m,1H),7.29-7.21(m,2H),5.78(d,J=2.9Hz,1H),4.96(d,J=10.5Hz,1H),3.02(s,3H),2.80(dd,J=11.5,5.5Hz,2H),2.55(s,1H),1.27–1.40(m,1H),1.26(s,1H)
实施例36b:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.92(d,J=8.2Hz,1H),7.68(s,1H),7.79(d,J=8.3Hz,1H),7.62-7.54(m,2H),7.40(t,J=7.5Hz,1H),7.31(dd,J=20.3,7.6Hz,2H),7.19(s,1H),5.86(s,1H),4.98(d,J=10.7Hz,1H),3.04(s,3H),2.80-2.69(m,2H),2.42(t,J=11.6Hz,1H),1.25(d,J=14.1Hz,1H),1.04(dd,J=12.4,6.9Hz,1H)
实施例36c:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.98(s,1H),7.78-7.72(m,2H),7.62-7.53(m,2H),7.57-7.47(m,1H),7.42(tt,J=7.6,7.6,0.8Hz,1H),7.30-7.21(m,1H),7.19(s,1H),5.39(d,J=7.4Hz,1H),4.91(d,J=3.0Hz,1H),3.15-3.02(m,1H),3.03(s,3H),2.85(ddd,J=17.8,11.6,6.8Hz,1H),2.69(s,1H),2.34-2.21(m,1H),2.25(s,1H),2.08(ddt,J=11.5,7.3,3.4Hz,1H)
实施例36d:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.92(d,J=8.2Hz,1H),7.68(s,1H),7.79(d,J=8.3Hz,1H),7.62-7.54(m,2H),7.40(t,J=7.5Hz,1H),7.31(dd,J=20.3,7.6Hz,2H),7.19(s,1H),5.86(s,1H),4.98(d,J=10.7Hz,1H),3.04(s,3H),2.80-2.69(m,2H),2.42(t,J=11.6Hz,1H),1.25(d,J=14.1Hz,1H),1.04(dd,J=12.4,6.9Hz,1H)
实施例36e:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.91(s,1H),7.81(dd,J=7.8,1.8Hz,1H),7.71-7.63(m,2H),7.55-7.49(m,1H),7.42-7.35(m,2H),7.36-7.21(m,1H),6.91(s,1H),5.47(d,J=1.9Hz,1H),5.15(d,J=3.4Hz,1H),3.06(s,3H),2.81(dd,J=17.1,5.2Hz,1H),2.64(ddd,J=17.8,12.4,6.0Hz,1H),2.45-2.38(m,1H),1.66-1.47(m,1H),1.16(dd,J=11.3,3.6Hz,1H)
实施例36f:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.91(s,1H),7.81(dd,J=7.8,1.8Hz,1H),7.71-7.63(m,2H),7.55-7.49(m,1H),7.42-7.35(m,2H),7.36-7.21(m,1H),6.91(s,1H),5.47(d,J=1.9Hz,1H),5.15(d,J=3.4Hz,1H),3.06(s,3H),2.81(dd,J=17.1,5.2Hz,1H),2.64(ddd,J=17.8,12.4,6.0Hz,1H),2.45-2.38(m,1H),1.66-1.47(m,1H),1.16(dd,J=11.3,3.6Hz,1H)
实施例36g:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.82(d,J=8.3Hz,1H),7.77(dd,J=8.2,1.9Hz,1H),7.66-7.58(m,3H),7.50(dd,J=7.7,1.0Hz,1H),7.45–7.37(m,1H),7.29-7.21(m,2H),5.78(d,J=2.9Hz,1H),4.96(d,J=10.5Hz,1H),3.02(s,3H),2.80(dd,J=11.5,5.5Hz,2H),2.55(s,1H),1.27–1.40(m,1H),1.26(s,1H)
实施例36h:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇。LCMS(ESI,m/z):381.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.98(s,1H),7.78-7.72(m,2H),7.62-7.53(m,2H),7.57-7.47(m,1H),7.42(tt,J=7.6,7.6,0.8Hz,1H),7.30-7.21(m,1H),7.19(s,1H),5.39(d,J=7.4Hz,1H),4.91(d,J=3.0Hz,1H),3.15-3.02(m,1H),3.03(s,3H),2.85(ddd,J=17.8,11.6,6.8Hz,1H),2.69(s,1H),2.34-2.21(m,1H),2.25(s,1H),2.08(ddt,J=11.5,7.3,3.4Hz,1H)
实施例37:3-(5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2S,3S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2S,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2S,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
步骤1:(E)-3-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)双环[2.2.2]辛-2-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):521.2[M+H]+
步骤2:(S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹啉-5(6H)-酮
该标题化合物通过合成Int-3的通用步骤合成。两种非对映异构体对未分离且用作混合物用于步骤3:LCMS(ESI,m/z):279.1.所有异构体的绝对构型任意指定。
步骤3:
(2S,3S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2S,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2S,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
(2R,3R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
该标题化合物通过合成Int-5的通用步骤合成。产物分离为6种对映异构体和1种非对映异构体的混合物,其通过手性SFC分离:LCMS(ESI,m/z):281.4。所有异构体的绝对构型任意指定。
实施例37a:(2S,3S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;由于样品量少无1H NMR数据
实施例37b:(2S,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;1H NMR(500MHz,氯仿-d)δ7.94(s,1H),7.59(dq,J=7.7,0.9Hz,1H),7.53(dt,J=7.5,0.9Hz,1H),7.34(tt,J=7.4,0.9Hz,1H),7.23(td,J=7.6,1.2Hz,1H),7.18(s,1H),5.64(d,J=6.6Hz,1H),4.35(dd,J=8.8,4.4Hz,1H),2.06(dd,J=8.7,6.8Hz,1H),1.98-1.92(m,1H),1.84-1.78(m,1H),1.71–1.60(m,1H),1.49–1.34(m,4H),1.33–1.24(m,2H)。
实施例37c:(2R,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;1H NMR(500MHz,氯仿-d)δ8.11(s,1H),7.54(dt,J=7.6,0.9Hz,1H),7.35(tt,J=7.6,0.8Hz,1H),7.29(dq,J=7.7,0.9Hz,1H),7.19(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.64(d,J=10.5Hz,1H),4.24(dd,J=8.3,4.5Hz,1H),2.11–1.92(m,2H),1.89(dd,J=5.9,3.3Hz,1H),1.70–1.56(m,5H),1.56–1.46(m,1H),1.45–1.24(m,2H)。
实施例37d:(2S,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;1H NMR(500MHz,氯仿-d)δ8.11(s,1H),7.54(dt,J=7.8,1.0Hz,1H),7.35(tt,J=7.6,0.8Hz,1H),7.29(dd,J=7.7,1.0Hz,1H),7.19(td,J=7.6,1.2Hz,1H),7.17(s,1H),5.64(d,J=10.5Hz,1H),4.25(dd,J=8.3,4.5Hz,1H),2.11–1.92(m,2H),1.92–1.87(m,1H),1.69–1.56(m,5H),1.56–1.47(m,1H),1.39–1.24(m,2H)。
实施例37e:(2R,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;1H NMR(500MHz,氯仿-d)δ7.95(s,1H),7.59(dq,J=7.6,0.9Hz,1H),7.53(dt,J=7.6,0.9Hz,1H),7.38–7.31(m,1H),7.23(td,J=7.6,1.2Hz,1H),7.18(s,1H),5.64(d,J=6.6Hz,1H),4.35(dd,J=8.8,4.4Hz,1H),2.07(t,J=7.7Hz,1H),1.98-1.92(m,1H),1.85-1.78(m,1H),1.71–1.60(m,1H),1.51(s,1H),1.49–1.33(m,3H),1.31–1.24(m,2H)。
实施例37f:(2R,3R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;由于样品量少无NMR数据.
实施例37g:3-(-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇:LCMS(ESI,m/z):281.4[M+H]+;由于样品量少无NMR数据。
实施例38:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
步骤1:
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
在-78℃向5H-咪唑并[5,1-a]异吲哚(600mg,3.84mmol)在无水THF(10mL)中的溶液中添加n-BuLi溶液(1.54mL,3.84mmol)且搅拌1小时。6-氧杂-3-硫杂双环[3.1.0]己烷3,3-二氧化物(618mg,4.61mmol)溶于无水THF(40mL)且将溶液滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应再保持16hr且用饱和NH4Cl溶液(10mL)淬灭。将混合物用DCM萃取(3x10mL)且将有机相合并,用Na2SO4干燥,且浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例38a:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物:LCMS(ESI,m/z):291.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.01(s,1H),7.58(d,J=7.6Hz,1H),7.43(dd,J=15.8,7.8Hz,2H),7.35(t,J=7.5Hz,1H),7.24(s,1H),5.78(d,J=2.8Hz,1H),4.76(q,J=8.9Hz,1H),3.62(dd,J=13.1,7.5Hz,1H),3.28–3.21(m,1H),2.74(dd,J=13.3,7.5Hz,1H),2.22(t,J=13.1Hz,1H)。
实施例38b:(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物:LCMS(ESI,m/z):291.3[M+H]+.1H NMR(500MHz,氯仿-d)δ8.17(s,1H),7.58(d,J=7.6Hz,1H),7.48–7.40(m,2H),7.36(t,J=7.8Hz,1H),7.25–7.24(m,1H),5.80(s,1H),4.78(q,J=8.9Hz,1H),3.63(dd,J=13.0,7.5Hz,1H),3.25(dd,J=12.9,9.0Hz,1H),2.74(dd,J=13.4,7.4Hz,1H),2.21(t,J=13.1Hz,2H)。
实施例38c:(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物:LCMS(ESI,m/z):291.3[M+H]+.1H NMR(500MHz,氯仿-d)δ7.76(s,1H),7.60(d,J=7.6Hz,1H),7.49–7.45(m,1H),7.43(d,J=7.7Hz,1H),7.35–7.29(m,1H),7.22(s,1H),5.64(d,J=3.7Hz,1H),4.62(q,J=7.7Hz,1H),3.46(dd,J=13.3,7.4Hz,1H),3.27(ddd,J=12.0,8.1,3.6Hz,1H),3.22–3.14(m,1H),2.96(dd,J=13.3,7.5Hz,1H),2.58–2.50(m,1H)。
实施例38d:(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物:LCMS(ESI,m/z):291.3[M+H]+.1H NMR(500MHz,氯仿-d)δ7.75(s,1H),7.60(d,J=7.7Hz,1H),7.49–7.45(m,1H),7.43(d,J=7.7Hz,1H),7.32(td,J=7.6,1.1Hz,1H),7.23(s,1H),5.63(d,J=3.7Hz,1H),4.62(q,J=7.7Hz,1H),3.45(dd,J=13.4,7.4Hz,1H),3.27(dp,J=11.9,4.1Hz,1H),3.18(ddd,J=13.3,7.4,1.5Hz,1H),2.97(dd,J=12.5,7.9Hz,1H),2.59–2.51(m,1H)。
实施例39:3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺
该标题化合物通过与实施例28相同的方法合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.CHIRALPAK ID,2.0cm I.Dx25cm L;流动相A:Hex--HPLC,流动相B:IPA--HPLC;流速:17mL/min;梯度:40B至40B在33min内;254/220nm;
2.Chiralpak IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:IPA--HPLC;流速:15mL/min;梯度:50B至50B在35min内;254/220nm.
所有异构体的绝对构型任意指定。
实施例39a:(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺:LCMS(ESI,m/z):298.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.94(s,1H),7.63(d,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.42-7.38(m,1H),7.31-7.28(m,1H),7.15(s,1H),6.78(s,2H),5.73-5.71(m,2H),3.78-3.65(m,2H),3.25-3.20(m,1H),2.32-2.20(m,3H),0.71-0.65(m,1H),0.58-0.40(m,1H);tR=2.772分钟,(CHIRALPAKID-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=40:60;1.0mL/min)。39a和39b为对映异构体。
实施例39b:(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺:LCMS(ESI,m/z):298.2[M+H]+;tR=3.522分钟,(CHIRALPAKID-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=40:60;1.0mL/min)。39a和39b为对映异构体。
实施例39c:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺:LCMS(ESI,m/z):298.2[M+H]+;1HNMR(300MHz,CD3OD)δ7.93(s,1H),7.64(d,J=7.5Hz,1H),7.49(d,J=7.5Hz,1H),7.46-7.34(m,2H),7.20(s,1H),5.82(d,J=1.5Hz,1H),4.01-3.92(m,2H),3.46-3.45(m,1H),2.58-2.41(m,2H),2.20-2.10(m,1H),0.99-0.93(m,1H),0.71-0.65(m,1H);tR=3.106分钟,(CHIRALPAKID-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=40:60;1.0mL/min)。39c和39d为对映异构体
实施例39d:(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺:LCMS(ESI,m/z):298.2[M+H]+;tR=7.043分钟,(CHIRALPAKID-3,0.46x5cm,3um;异丙醇:己烷(0.1%DEA)=40:60;1.0mL/min)。39c和39d为对映异构体
实施例40:1-(乙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3S,4S)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
步骤1:4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
在室温向3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-甲酸叔丁酯(500mg,1.46mmol)在无水DCM(10mL)中的溶液中滴加三氟乙酸(5mL)且搅拌30分钟。溶剂和额外TFA在减压下去除且粗产物置于真空泵过夜。产物直接使用而不用进一步纯化:LCMS(ESI,m/z):242.2[M+H]+.
步骤2:
(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
(3S,4S)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
向4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇(0.353g,1.46mmol)在无水DCM(10mL)中的溶液中添加三乙胺(0.41mL,2.93mmol)和乙基磺酰氯(0.153mL,1.61mmol)。将反应混合物在室温搅拌1小时。TLC指示起始材料未消耗且添加额外三乙胺(0.20mL,1.47mmol)。反应在室温再保持1hr且用饱和NaHCO3溶液(10mL)淬灭。所得溶液用DCM萃取(3x10mL)且将有机相合并,用无水Na2SO4干燥且浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例40a:(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇:LCMS(ESI,m/z):334.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.62(d,J=7.6Hz,1H),7.57(dd,J=7.6,1.0Hz,1H),7.40(d,J=7.5Hz,1H),7.31(dd,J=7.5,1.1Hz,1H),7.18(s,1H),5.71(d,J=4.9Hz,1H),5.60(d,J=3.3Hz,1H),4.37(dd,J=7.0,5.1Hz,1H),3.40(dd,J=9.7,6.6Hz,1H),3.08–3.00(m,2H),2.96(p,J=7.1Hz,3H),2.36(dd,J=9.3,8.1Hz,1H),1.08(t,J=7.3Hz,3H)。
实施例40b:(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇:LCMS(ESI,m/z):334.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.62(d,J=7.5Hz,1H),7.59–7.54(m,1H),7.41(t,J=7.7Hz,1H),7.33–7.26(m,1H),7.18(s,1H),5.71(d,J=4.9Hz,1H),5.60(d,J=3.3Hz,1H),4.42–4.33(m,1H),3.40(dd,J=9.7,6.6Hz,1H),3.08–3.00(m,2H),2.96(p,J=7.2Hz,3H),2.40–2.33(m,1H),1.08(t,J=7.4Hz,3H)。
实施例40c:(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇:LCMS(ESI,m/z):334.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.62(d,J=7.5Hz,1H),7.56(dd,J=7.8,1.0Hz,1H),7.42(t,J=7.5Hz,1H),7.32–7.27(m,1H),7.14(s,1H),5.55(d,J=4.5Hz,1H),5.38(d,J=4.6Hz,1H),4.00(t,J=5.3Hz,1H),3.45(dd,J=10.1,8.4Hz,1H),3.11(dd,J=10.2,6.4Hz,2H),3.08–2.99(m,3H),2.98–2.89(m,1H),1.15(t,J=7.4Hz,3H)。
实施例40d:(3S,4S)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇:LCMS(ESI,m/z):334.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.62(d,J=7.5Hz,1H),7.56(dd,J=7.6,1.0Hz,1H),7.45–7.38(m,1H),7.31(dd,J=7.6,1.1Hz,1H),7.14(s,1H),5.55(d,J=4.5Hz,1H),5.38(d,J=4.7Hz,1H),4.00(p,J=5.3Hz,1H),3.45(dd,J=10.1,8.4Hz,1H),3.11(dd,J=10.1,6.4Hz,2H),3.08–2.99(m,3H),2.94(td,J=7.5,3.6Hz,1H),1.15(t,J=7.3Hz,3H)。
实施例41:7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-
甲酸叔丁酯
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
实施例41a-h都使用制备实施例1a-h的反应条件合成,其中试剂环丁酮替代为5-氧代-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯。各实施例为具有未确定的绝对构型的单一立体异构体。
实施例41a:7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.89(t,J=0.6Hz,1H),7.65–7.51(m,1H),7.47–7.30(m,2H),7.24(td,J=7.7,1.1Hz,1H),7.10(s,1H),5.63(d,J=7.1Hz,1H),5.33(d,J=8.0Hz,1H),4.22–3.97(m,2H),3.73(s,2H),3.57(s,1H),2.05(dq,J=17.0,8.7Hz,1H),1.86(t,J=9.5Hz,1H),1.36(s,9H)。;tR=1.4分钟(ChiralcelOX(150x30mm,5uM)乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41b(实施例41a的对映异构体):7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;tR=2.00分钟。(Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41c:7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94–7.82(m,1H),7.64–7.51(m,2H),7.36(tdd,J=7.4,1.5,0.7Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.13(s,1H),6.12(d,J=4.7Hz,1H),5.38(d,J=7.6Hz,1H),4.39(t,J=5.8Hz,1H),4.13(d,J=8.9Hz,1H),3.89–3.56(m,2H),2.60(p,J=7.9Hz,1H),2.03(d,J=8.5Hz,2H),1.36(s,9H)。;tR=1.56分钟。(Chiralpak AD(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41d:7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.59(dd,J=7.6,1.1Hz,1H),7.51–7.30(m,2H),7.23(td,J=7.6,1.2Hz,1H),7.11(s,1H),6.11(d,J=5.2Hz,1H),5.31(d,J=10.1Hz,1H),4.33(q,J=5.0Hz,1H),4.14(d,J=9.0Hz,1H),3.81(d,J=11.4Hz,1H),3.63(s,1H),2.71–2.54(m,1H),2.23(dqd,J=11.5,8.3,4.6Hz,2H),1.38(s,9H)。;tR=1.18分钟。(Chiralpak AD(250x30mm,5um,乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41e(实施例41c的对映异构体):7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;tR=1.15min.(Chiralcel OX(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41f(实施例41d的对映异构体):7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;tR=0.89分钟(Chiralcel OX(250x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41g:7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.66–7.48(m,2H),7.46–7.32(m,1H),7.26(td,J=7.5,1.2Hz,1H),7.13(s,1H),5.69(d,J=6.8Hz,1H),5.36(d,J=7.4Hz,1H),4.16(t,J=7.3Hz,2H),3.75(d,J=9.0Hz,1H),3.66(s,1H),3.55(s,1H),2.14(p,J=8.6Hz,1H),1.89(dd,J=11.2,8.6Hz,1H),1.44(t,J=10.7Hz,1H),1.36(s,9H)。;tR=0.87分钟。Chiralpak IC(150x21.1mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例41h(实施例41g的对映异构体):7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯:LCMS(ESI,m/z):368[M+H]+;tR=1.13分钟。Chiralpak AD(150x30mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)
实施例42:1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇。
(42%)产率;根据通用步骤合成:LCMS(ESI,m/z):201.44[M+H]+.立体异构体通过手性SFC分离。
实施例42a:(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇:LCMS(ESI,m/z):201.1[M+H]+.1H NMR(DMSO-d6,500MHz):δ(ppm)7.79(s,1H),7.59(d,J=7.6Hz,1H),7.48–7.52(m,1H),7.8(t,J=7.1Hz,1H),7.26(td,J=7.5,1.1Hz,1H),7.14(s,1H),5.48(d,J=3.7Hz,1H),5.36(d,J=3.3Hz,1H),4.38(tdd,J=6.3,3.6,2.6Hz,1H),0.48(d,J=6.3Hz,3H)。
实施例42b:(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇:LCMS(ESI,m/z):201.1[M+H]+.1H NMR(DMSO-d6,500MHz):δ(ppm)0.93(d,J=6.3Hz,3H),4.00–4.16(m,1H),5.20(d,J=5.2Hz,1H),5.35(d,J=4.8Hz,1H),7.11(s,1H),7.26(td,J=7.6,1.1Hz,1H),7.35–7.43(m,1H),7.55–7.67(m,2H),7.87(s,1H)。
实施例42c:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇:LCMS(ESI,m/z):201.1[M+H]+.1H NMR(DMSO-d6,500MHz):与42a相同
实施例42d:(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇:LCMS(ESI,m/z):201.2[M+H]+.1H NMR(DMSO-d6,500MHz):与42b相同
实施例43:4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇。
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(S)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(57%)产率;根据通用步骤合成:LCMS(ESI,m/z):257.3[M+H]+.1H NMR(氯仿-d,400MHz):δ(ppm)7.98(s,1H),7.50(dd,J=12.4,7.6Hz,2H),7.38(t,J=7.5Hz,1H),7.25(t,J=7.6Hz,1H),7.11(s,1H),5.08(s,1H),3.76–3.95(m,2H),3.51–3.72(m,2H),3.31(d,J=36.2Hz,2H),2.15(ddd,J=13.0,10.3,7.0Hz,1H),1.68(d,J=12.7Hz,1H),1.05–1.28(m,1H),0.78(d,J=12.9Hz,1H)。
实施例44:2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇
(S)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇
在-40℃向5H-咪唑并[5,1-a]异吲哚(200mg,1.28mmol)在无水THF(3mL)中的溶液中添加n-BuLi溶液(2.2M的环己烷溶液,0.58mL,1.28mmol)且搅拌1小时。添加无水丙酮(0.18mL,2.56mmol)且反应缓慢温热至室温。2小时后,反应用饱和NH4Cl溶液(5mL)淬灭。将混合物用DCM萃取(3x10mL)且合并有机相,用Na2SO4干燥,且浓缩以得到粗2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇,其进一步通过CombiFlash纯化:LCMS(ESI,m/z):215[M+H]+.1HNMR(400MHz,氯仿-d)δ7.89(s,1H),7.54(d,J=7.6Hz,1H),7.49(d,J=7.7Hz,1H),7.38(t,J=7.5Hz,1H),7.23(dd,J=7.5,1.1Hz,1H),7.18(s,1H),5.09(s,1H),1.49(s,3H),0.83(s,3H)。
实施例45:3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇
(S)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇
步骤1:
3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(200mg,1.28mmol,1.000当量)在无水THF(3mL)中的溶液中添加n-BuLi溶液(0.57mL,1.41mmol,1.200当量)且搅拌1小时。将硫杂环丁烷-3-酮(94mg,0.70mmol,1.5当量)溶于无水THF(3mL)且将溶液滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温保持过夜且用饱和NH4Cl溶液(5mL)淬灭。将混合物用DCM萃取(3x10mL)且将有机相合并,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=96:4洗脱。所需产物分离为棕色固体。
实施例45:3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇:LCMS(ESI,m/z):245[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.71(d,J=7.7Hz,1H),7.61(d,J=7.6Hz,1H),7.41(t,J=7.5Hz,1H),7.20–7.29(m,1H),7.14(s,1H),6.61(s,1H),5.40(s,1H),3.45(d,J=10.4Hz,1H),3.27(d,J=10.5Hz,1H),3.14(s,2H)。
实施例46:1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇。
(45%)产率;根据通用步骤合成:LCMS(ESI,m/z):255.3[M+H]+.立体异构体通过手性SFC分离。
实施例46a:(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇。1H NMR(氯仿-d,400MHz):δ(ppm)8.00(s,1H),7.52(t,J=7.9Hz,2H),7.38(t,J=7.5Hz,1H),7.25(t,J=7.4Hz,1H),7.13(s,1H),5.05(s,1H),2.94(br s,1H),1.68(dt,J=39.3,11.9Hz,5H),1.34–1.53(m,2H),0.89–1.06(m,2H),0.81(dt,J=13.3,6.6Hz,1H)
实施例46b:(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇。1H NMR(DMSO-d6,400MHz):与46b相同
实施例47:1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇。
(39%)产率;根据通用步骤合成:LCMS(ESI,m/z):227.5[M+H]+.立体异构体通过手性SFC分离。
实施例47a:(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇。1H NMR(氯仿-d,400MHz):δ(ppm)7.95(s,1H),7.57(t,J=6.7Hz,2H),7.41(t,J=7.7Hz,1H),7.15(s,1H),7.22–7.36(m,1H),2.87(br s,H),5.22(s,1H),2.57(dd,J=8.5,4.4Hz,1H),2.28(p,J=8.7,8.2Hz,1H),1.78–2.04(m,3H),1.27–1.44(m,1H)
实施例47b:(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇。1H NMR(DMSO-d6,400MHz):与47a相同.
实施例48:3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇。
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇
(S)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇
(61%)产率;根据通用步骤合成:LCMS(ESI,m/z):229.1[M+H]+.1H NMR(DMSO-d6,400MHz):δ(ppm)7.92(s,1H),7.62(d,J=7.7Hz,2H),7.42(t,J=7.5Hz,1H),7.26(t,J=8.1Hz,1H),7.16(s,1H),6.51(s,1H),5.61(s,1H),4.71(d,J=7.1Hz,1H),4.60(d,J=7.0Hz,1H),4.52(d,J=7.1Hz,1H),4.47(d,J=7.1Hz,1H)。
实施例49:1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇。
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
步骤1:
将5H-咪唑并[5,1-a]异吲哚(1.0g,6.4mmol)在50mL THF中的溶液冷却至-78℃且填充2.5M正丁基锂的庚烷溶液(2.6mL,6.4mmol)。在-78℃搅拌30分钟后,向溶液填充50%乙醛酸乙酯在甲苯中的溶液(3.3g,16mmol)且温热至-45℃且在-45℃搅拌1小时。溶液然后用300mL EtOAc和100mL饱和氯化铵稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩以得到2-羟基-2-(5H-咪唑并[1,5-b]异吲哚-5-基)乙酸乙酯(1.5g,5.8mmol,90%产率),其为粗残余物。LCMS(ESI,m/z):259.1(M+H)。
步骤2:
将步骤1的粗残余物2-羟基-2-(5H-咪唑并[1,5-b]异吲哚-5-基)乙酸乙酯(500mg,1.9mmol)溶于8mL乙醇且冷却至0℃。向混合物然后填充预先溶于10mL乙醇的硼氢化锂(1.7g,3.9mmol)且使之温热至室温。在室温2小时后,向溶液填充4mL1M氯化铵。混合物然后通过反相HPLC纯化以得到1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇(100mg,23%产率),其为4种非对映异构体的混合物。混合物然后通过手性超临界流体色谱法使用所述条件分离以得到4种非对映异构体,实施例49a-d。各实施例为具有未知绝对构型的单一非对映异构体。
实施例49a:1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇。(3mg,3%产率)。LCMS(ESI,m/z):217.1[M+H]+;无NMR;tR=0.82分钟(Chiralpak IC(150x21.1mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例49b.1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇。(3mg,3%产率)。LCMS(ESI,m/z):217.1[M+H]+;无NMR;tR=1.03分钟(Chiralpak IC(150x21.1mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例49c:1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇。(7mg,7%产率)。LCMS(ESI,m/z):217.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.68(dt,J=7.6,1.0Hz,1H),7.59(dq,J=7.6,1.0Hz,1H),7.51–7.39(m,2H),7.35(td,J=7.5,1.2Hz,1H),5.56(d,J=4.0Hz,1H),5.46(d,J=4.9Hz,1H),4.84(t,J=5.2Hz,1H),4.20(p,J=5.2Hz,1H)。tR=1.03分钟(Chiralpak OX(150x21.1mm,5um),甲醇w/0.1%NH4OH,1.5ml/min)。
实施例49d:1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇。(5mg,5%产率)。LCMS(ESI,m/z):217.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.81(d,J=0.7Hz,1H),7.56(ddt,J=13.4,7.6,0.9Hz,2H),7.38(tdd,J=7.6,1.2,0.7Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.42(d,J=4.9Hz,1H),5.38(d,J=4.3Hz,1H),4.75(t,J=5.4Hz,1H),4.15–3.98(m,1H),3.22–3.06(m,2H)。tR=1.38分钟(Chiralpak IC(150x21.1mm,5um),乙醇w/0.1%NH4OH,1.5ml/min)。
实施例50:3,3-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
向在-78℃搅拌的5H-咪唑并[5,1-a]异吲哚(190mg,1.22mmol)在无水THF(10mL)中的溶液中,滴加n-BuLi溶液(2.5M在己烷中,0.535mL,1.34mmol)且搅拌1小时。将3,3-二氟环丁-1-酮(193.55mg,1.82mmol)在无水THF(1mL)中的溶液滴加至反应混合物且在-78℃搅拌90分钟。反应混合物温热至室温,搅拌2hrs且用饱和NH4Cl溶液(10mL)淬灭。有机层首先用EtOAc(10mL)萃取,然后用DCM(10mL)萃取且最后用5%CF3CH2OH在DCM中的溶液(10mL)萃取。汇聚有机层,通过无水Na2SO4干燥且通过CombiFlash纯化以得到3,3-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,其为棕色粉末:LCMS(ESI,m/z):263[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.57(ddt,J=12.0,7.6,0.9Hz,2H),7.41–7.37(m,1H),7.24(td,J=7.5,1.1Hz,1H),7.12(s,1H),5.85(s,1H),5.46(s,1H),3.17(m,2H),2.68–2.54(m,2H)。
实施例51:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇。
(25%)产率;根据通用步骤合成:LCMS(ESI,m/z):229.4[M+H]+.立体异构体通过手性SFC分离。
实施例51a:(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇。1HNMR(DMSO-d6,400MHz):δ(ppm)7.82(t,J=0.7Hz,1H),7.58(dt,J=7.5,1.0Hz,1H),7.49(dq,J=7.6,0.9Hz,1H),7.37(tdd,J=7.5,1.1,0.6Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.32(d,J=5.2Hz,1H),5.13(d,J=6.5Hz,1H),3.47(td,J=6.3,5.2Hz,1H),1.93(dt,J=13.3,6.6Hz,1H),0.99(d,J=6.6Hz,3H),0.93(d,J=6.8Hz,3H)。
实施例51b:(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇。1HNMR(DMSO-d6,400MHz):δ(ppm)7.81(t,J=0.7Hz,1H),7.59(dt,J=7.5,1.0Hz,1H),7.51(dq,J=7.6,0.9Hz,1H),7.37(tdd,J=7.5,1.1,0.6Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.11(s,1H),5.39(d,J=4.5Hz,1H),5.27(d,J=5.6Hz,1H),3.80(td,J=5.5,4.5Hz,1H),1.52–1.67(m,1H),0.81(d,J=6.8Hz,3H),0.66(d,J=6.7Hz,3H)。
实施例51c:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇。1HNMR(DMSO-d6,400MHz):与51b相同.
实施例51d:(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇。1HNMR(DMSO-d6,400MHz):与51a相同.
实施例52:环丙基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇。
(58%)产率;根据通用步骤合成:LCMS(ESI,m/z):227.4[M+H]+.立体异构体通过手性SFC分离。
实施例52a:(S)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇。1H NMR(DMSO-d6,400MHz):δ(ppm)-0.16–-0.06(m,1H)、-0.04–0.07(m,1H),0.16(dddd,J=9.2,7.9,5.6,1.7Hz,2H),0.26–0.39(m,1H),3.63(dt,J=7.4,4.1Hz,1H),5.39(d,J=3.8Hz,1H),5.43(d,J=4.3Hz,1H),7.12(s,1H),7.24(td,J=7.6,1.1Hz,1H),7.37(tt,J=7.6,0.9Hz,1H),7.56(ddt,J=15.1,7.6,0.9Hz,2H),7.82(t,J=0.6Hz,1H)
实施例52b:(S)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇。1H NMR(DMSO-d6,400MHz):与52a相同.
实施例52c:(R)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇。1H NMR(DMSO-d6,400MHz):δ(ppm)0.06–0.13(m,1H),0.26–0.41(m,3H),0.84(qt,J=7.8,5.0Hz,1H),3.32–3.38(m,1H),5.29(d,J=5.2Hz,1H),5.32(d,J=5.0Hz,1H),7.10(s,1H),7.24(td,J=7.5,1.2Hz,1H),7.37(tdd,J=7.5,1.1,0.6Hz,1H),7.58(dt,J=7.6,1.0Hz,1H),7.60–7.64(m,1H),7.87(t,J=0.6Hz,1H)。
实施例52d:(R)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇。1H NMR(DMSO-d6,400MHz):与52d相同.
实施例53:4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(S)-4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(400mg,2.56mmol,1.0当量)在无水THF(20mL)中的溶液中添加n-BuLi(1.54mL,3.84mmol,2.5M己烷溶液,1.5当量)。在-78℃搅拌1.5hr后,添加4,4-二氟环己烷-1-酮(550mg,4.1mmol,1.6当量)的混合物且将反应经2小时温热至室温。反应通过添加饱和NH4Cl水溶液(5mL)淬灭且用水(20mL)稀释,产物用CH2Cl2(3x20mL)萃取。合并的有机萃取物用Na2SO4干燥。产物通过CombiFlash纯化以得到4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,其为米色固体:LCMS(ESI,m/z):291[M+H]+
实施例54:3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(S)-3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(100mg,0.64mmol,1.0当量)在无水THF(5mL)中的溶液中添加n-BuLi(0.38mL,0.96mmol,2.5M己烷溶液,1.5当量)。在-78℃搅拌1.5hr后,添加3,3-二(氟甲基)环丁-1-酮(137mg,1.02mmol,1.6当量)的混合物且反应经2小时温热至室温。反应通过添加饱和NH4Cl水溶液(2mL)淬灭且用水(10mL)稀释,产物用CH2Cl2(3x10mL)萃取。合并的有机萃取物用Na2SO4干燥。产物通过CombiFlash纯化以得到3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,其为米色固体:LCMS(ESI,m/z):291[M+H]+
实施例55:1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
步骤1:
1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(300mg,1.92mmol,1.000当量)在无水THF(10mL)中的溶液中添加n-BuLi溶液(0.92mL,2.30mmol,1.200当量)且搅拌1小时。将环戊酮(0.26mL,2.9mmol,1.500当量)滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温再保持2hrs且用饱和NH4Cl溶液(20mL)淬灭。将混合物用DCM萃取(3x20mL)且将有机相合并,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱。所需产物分离为浅棕色固体。
实施例55:1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇:LCMS(ESI,m/z):241[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.86(d,J=0.7Hz,1H),7.59(d,J=1.0Hz,1H),7.57(d,J=1.1Hz,1H),7.37(ddd,J=8.0,6.9,0.8Hz,1H),7.23(td,J=7.5,1.2Hz,1H),7.10–7.13(m,1H),5.30–5.34(m,1H),4.97(s,1H),1.60–1.80(m,4H),1.35–1.51(m,4H)。
实施例56:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡
啶-4-醇
实施例56a-h都使用制备实施例1a-h的反应条件合成,其中试剂环丁酮替代为6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮。各实施例为具有未确定绝对构型的单一非对映异构体。56a、56c、56d和56e的绝对构型通过X-射线晶体学指定,而另一立体异构体任意指定。
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
实施例56a:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.01–1.16(m,2H),2.51–2.59(m,1H),3.73–3.84(m,1H),3.93–4.01(m,1H),5.03(dd,J=10.5,7.2Hz,1H),5.76(d,J=1.9Hz,1H),6.18(d,J=7.2Hz,1H),6.31(dd,J=1.9,0.8Hz,1H),7.19(s,1H),7.34(dd,J=7.5,1.1Hz,1H),7.38–7.46(m,2H),7.51(dd,J=7.6,1.0Hz,1H),7.64(dt,J=7.6,0.9Hz,1H),7.98(s,1H)。
实施例56b:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.88(d,J=12.3Hz,1H),2.28(qd,J=12.2,5.5Hz,1H),2.32–2.38(m,1H),3.80–3.91(m,1H),4.16(ddd,J=12.7,5.5,1.9Hz,1H),4.99(s,1H),5.48(d,J=5.7Hz,1H),5.83(d,J=5.4Hz,1H),6.22(d,J=1.8Hz,1H),7.14(s,1H),7.25(td,J=7.6,1.2Hz,1H),7.39(dd,J=6.3,1.4Hz,2H),7.62(dt,J=7.6,0.9Hz,1H),7.71(dd,J=7.8,0.9Hz,1H),7.97(s,1H)。
实施例56c:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.19(d,J=13.6Hz,1H),1.86(qd,J=12.6,5.8Hz,1H),2.55–2.66(m,1H),3.77(td,J=12.5,4.9Hz,1H),4.05(ddd,J=12.8,5.8,2.0Hz,1H),5.19(t,J=4.6Hz,1H),5.54(d,J=2.5Hz,1H),6.09(d,J=5.5Hz,1H),6.27(d,J=1.9Hz,1H),7.13(s,1H),7.30(td,J=7.6,1.2Hz,1H),7.36–7.44(m,2H),7.60(dt,J=7.6,0.9Hz,1H),7.64(dq,J=7.7,1.0Hz,1H),7.92(s,1H)。
实施例56d:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.01–1.16(m,2H),2.52(d,J=2.3Hz,1H),3.78(td,J=12.2,5.1Hz,1H),3.90–4.00(m,1H),5.03(dd,J=10.6,7.2Hz,1H),5.76(d,J=1.8Hz,1H),6.18(d,J=7.2Hz,1H),6.27–6.34(m,1H),7.19(s,1H),7.33(td,J=7.6,1.1Hz,1H),7.37–7.46(m,2H),7.51(dd,J=7.6,1.0Hz,1H),7.64(d,J=7.5Hz,1H),7.98(s,1H)。
实施例56e:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.19(d,J=13.5Hz,1H),1.77–1.95(m,1H),2.57–2.70(m,1H),3.76(td,J=12.2,4.7Hz,1H),3.99–4.12(m,1H),5.15–5.26(m,1H),5.54(d,J=2.6Hz,1H),6.09(d,J=5.6Hz,1H),6.27(d,J=2.2Hz,1H),7.13(s,1H),7.29(ddd,J=8.8,7.0,1.3Hz,1H),7.35–7.46(m,2H),7.62(dd,J=19.0,7.6Hz,2H),7.92(s,1H)。
实施例56f:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.03(s,1H),1.11–1.30(m,1H),2.71(s,1H),3.82(s,1H),3.97(s,1H),4.97(s,1H),5.77(s,1H),6.10–6.24(m,1H),6.28(s,1H),7.18(d,J=8.9Hz,1H),7.23–7.35(m,1H),7.40(d,J=16.2Hz,2H),7.63(m,2H),7.94(t,J=10.8Hz,1H)。
实施例56g:(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ1.88(d,J=10.6Hz,1H),2.28(tt,J=12.5,6.0Hz,1H),2.32–2.39(m,1H),3.86(td,J=12.3,4.8Hz,1H),4.16(ddd,J=12.7,5.5,1.8Hz,1H),4.99(dd,J=5.9,3.3Hz,1H),5.48(d,J=5.7Hz,1H),5.83(d,J=5.6Hz,1H),7.14(s,1H),7.25(dd,J=7.6,1.2Hz,1H),7.36–7.42(m,2H),7.62(dt,J=7.6,0.9Hz,1H),7.71(dd,J=7.7,0.9Hz,1H),7.97(s,1H)。
实施例57:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
步骤1:(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7-氧杂螺[3.5]壬-1-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):537.3[M+H]+
步骤2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):295.4[M+H]+
步骤3:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):297.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
实施例57a:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.85(s,1H),7.56–7.51(m,1H),7.37(d,J=3.2Hz,1H),7.35–7.32(m,1H),7.25–7.21(m,1H),7.13(s,1H),5.17(d,J=7.9Hz,1H),3.88(dt,J=11.5,4.2Hz,1H),3.84(d,J=8.0Hz,1H),3.77(dd,J=7.9,3.6Hz,1H),3.61–3.54(m,1H),3.51–3.41(m,1H),2.55(ddd,J=17.5,9.6,8.0Hz,1H),2.15–2.07(m,1H),1.93–1.84(m,1H),1.79(ddd,J=13.7,10.1,4.1Hz,1H),1.54–1.49(m,2H),1.42(d,J=13.3Hz,1H)。
实施例57b:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.78(s,1H),7.54(dd,J=11.9,7.6Hz,2H),7.36(d,J=7.8Hz,1H),7.23(dd,J=7.6,1.0Hz,1H),7.18(s,1H),5.46(d,J=8.8Hz,1H),4.30(dd,J=6.5,2.8Hz,1H),3.70(dq,J=9.3,5.1,4.1Hz,2H),3.59–3.51(m,2H),2.67–2.57(m,1H),2.07–2.02(m,2H),1.78–1.73(m,1H),1.67(s,1H),1.59(d,J=3.8Hz,1H),1.55(s,1H)。
实施例57c:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.95(s,1H),7.55(d,J=7.6Hz,1H),7.36(d,J=5.5Hz,1H),7.33–7.30(m,1H),7.22–7.19(m,1H),7.16(s,1H),5.44(d,J=11.0Hz,1H),4.25(dd,J=6.1,3.3Hz,1H),3.79–3.76(m,1H),3.74–3.67(m,1H),3.60(dddd,J=19.9,11.6,8.2,3.4Hz,2H),2.49–2.40(m,1H),2.30(t,J=10.4Hz,1H),2.15(ddd,J=11.3,8.5,3.4Hz,1H),1.89–1.82(m,1H),1.76–1.67(m,2H),1.53(s,1H)。
实施例57d:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.97(s,1H),7.55(d,J=7.6Hz,1H),7.37(d,J=7.4Hz,1H),7.31(d,J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),7.16(s,1H),5.44(d,J=11.0Hz,1H),4.25(dd,J=5.9,3.2Hz,1H),3.80–3.76(m,1H),3.70(dd,J=10.6,6.1Hz,1H),3.66–3.56(m,2H),2.49–2.39(m,1H),2.30(t,J=10.4Hz,1H),2.18–2.11(m,1H),1.84(td,J=8.7,8.2,4.1Hz,1H),1.72(s,1H),1.61–1.55(m,2H)。
实施例57e:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.78(s,1H),7.54(dd,J=11.1,7.6Hz,2H),7.36(t,J=7.4Hz,1H),7.24(td,J=7.6,1.1Hz,1H),7.19(s,1H),5.46(d,J=8.8Hz,1H),4.30(dd,J=6.5,2.8Hz,1H),3.75–3.68(m,2H),3.58–3.51(m,2H),2.62(qd,J=8.7,6.5Hz,1H),2.10–1.99(m,2H),1.76(ddd,J=12.8,8.7,3.8Hz,1H),1.63(ddd,J=18.6,10.4,4.4Hz,3H)。
实施例57f:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.86(s,1H),7.52(d,J=7.6Hz,1H),7.37(t,J=7.5Hz,1H),7.35–7.32(m,1H),7.23(td,J=7.6,1.1Hz,1H),7.11(s,1H),5.17(d,J=7.9Hz,1H),3.89(dt,J=11.4,4.3Hz,1H),3.76(dt,J=11.4,4.2Hz,1H),3.62–3.55(m,1H),3.50–3.42(m,1H),2.55(ddd,J=17.5,9.5,8.0Hz,1H),2.14–2.05(m,1H),1.90(ddd,J=13.6,10.3,3.9Hz,1H),1.79(ddd,J=13.9,10.2,4.2Hz,1H),1.54–1.49(m,2H),1.42(d,J=13.2Hz,1H)。
实施例57g:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1HNMR(500MHz,氯仿-d)δ7.69(s,1H),7.54(d,J=7.6Hz,1H),7.51–7.44(m,1H),7.38(t,J=7.4Hz,1H),7.28–7.26(m,1H),7.19(s,1H),5.25(d,J=6.8Hz,1H),4.07(d,J=8.1Hz,1H),3.87(dt,J=11.5,4.1Hz,1H),3.74(dt,J=11.8,4.1Hz,1H),3.54–3.47(m,1H),3.36(td,J=11.4,2.7Hz,1H),2.65–2.54(m,1H),1.90–1.76(m,3H),1.45(d,J=13.5Hz,1H),1.35(d,J=13.2Hz,1H),1.07(t,J=10.1Hz,1H)。
实施例57h:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):297.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.69(s,1H),7.54(d,J=7.6Hz,1H),7.50–7.45(m,1H),7.37(t,J=7.5Hz,1H),7.24(d,J=1.0Hz,1H),7.19(s,1H),5.25(d,J=6.8Hz,1H),4.08(d,J=8.1Hz,1H),3.87(dt,J=11.4,4.1Hz,1H),3.74(dt,J=11.5,4.0Hz,1H),3.51(td,J=10.9,10.5,2.3Hz,1H),3.36(td,J=11.4,2.7Hz,1H),2.69–2.54(m,1H),1.97–1.75(m,3H),1.46(d,J=13.4Hz,1H),1.36(d,J=13.2Hz,1H),1.07(t,J=10.5Hz,1H)。
实施例58:2-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
步骤1:
2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
向3-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-4-醇和4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(2.8g,5.48mmol)和TEA(1.4mL,16.46mmol)在DCM(50mL)中的溶液添加2-氯乙腈(0.42mL,6.58mmol)。所得溶液在室温搅拌6h。所得溶液用水稀释。所得溶液用DCM萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离使用以下条件进行分离:
1.柱:CHIRALPAK-AD-H-SL002,20x250mm;流动相A:Hex(0.1%DEA)--HPLC,流动相B:IPA--HPLC;流速:20mL/min;梯度:30B至30B在22min内;检测器,uv 254/220nm;
2.柱:CHIRALPAK IC,2x25cm,5um;流动相A:Hex(0.1%DEA)--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:35B至35B在20min内;检测器,uv 254/220nm.
所有异构体58a-d的绝对构型任意指定。
实施例58b:2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(249.8mg,25%),其为白色固体:LCMS(ESI,m/z):295.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.98(s,1H),7.66(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.48-7.34(m,2H),7.22(s,1H),5.82(d,J=3.0Hz,1H),3.95-3.83(m,1H),3.52-3.39(m,2H),2.87-2.83(m,1H),2.46-2.05(m,4H),1.83-1.65(m,1H),1.48-1.41(m,1H)。tR=1.156分钟(CHIRALPAKAD-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。58a和58b为对映异构体。
实施例58b:2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(241mg,24%),其为白色固体:LCMS(ESI,m/z):295.2[M+H]+.tR=2.086分钟(CHIRALPAK AD-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。58a和58b为对映异构体。
实施例58c:2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(61.9mg,6%),其为白色固体:LCMS(ESI,m/z):295.1[M+H]+.1H NMR(300MHz,CD3OD)δ7.94(s,1H),7.62(d,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),7.44-7.29(m,2H),7.16(s,1H),5.78(d,J=3.6Hz,1H),3.88-3.79(m,1H),3.49-3.32(m,2H),2.80-2.76(m,1H),2.53-2.46(m,1H),2.22-1.87(m,3H),1.76-1.67(m,1H),1.55-1.48(m,1H)。tR=4.384分钟(CHIRALPAK AD-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。58c和58d为对映异构体。
实施例58d:2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈(52.4mg,5%),其为白色固体:LCMS(ESI,m/z):295.1[M+H]+.tR=6.297分钟(CHIRALPAK AD-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。58c和58d为对映异构体。
实施例59:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯
并[c]吡啶-7-醇
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
步骤1:(E)-3-甲基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.0g,4.82mmol)和3-甲基-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮(780mg,5.31mmol)在MeOH(25mL)中的溶液中滴加哌啶(0.52mL,5.31mmol)。将混合物在80℃再搅拌3小时。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用EtOAc:Hex=70:30洗脱:LCMS(ESI,m/z):544.3[M+H]+.
步骤2:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮
(E)-3-甲基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮(1.46g,2.69mmol)在20%AcOH的MeOH溶液(20mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用5%三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化。产物用DCM:MeOH=96:4洗脱:LCMS(ESI,m/z):302.2[M+H]+.
步骤3:
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
在0℃向6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮(0.636g,2.11mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(160mg,4.22mmol)且溶液在0℃再搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用5%三氟乙醇在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=90:10洗脱。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例59a:(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.60(s,1H),8.19(s,1H),7.58(dt,J=7.5,0.9Hz,1H),7.48–7.44(m,1H),7.42–7.36(m,1H),7.25(d,J=1.1Hz,1H),7.20(s,1H),7.11(s,1H),5.61(d,J=10.5Hz,1H),5.42(d,J=5.4Hz,1H),3.43–3.33(m,1H),3.12(dd,J=16.0,7.7Hz,1H),2.56(s,3H),2.48–2.37(m,1H)。
实施例59b:(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.58–8.52(m,1H),8.30(s,1H),7.55(dd,J=7.5,1.0Hz,1H),7.47–7.41(m,1H),7.38(td,J=7.6,1.0Hz,1H),7.24(dd,J=7.6,1.1Hz,1H),7.15(s,1H),7.07(s,1H),5.63(d,J=10.4Hz,1H),5.41(d,J=5.6Hz,1H),3.42–3.32(m,1H),3.08(dd,J=16.0,7.7Hz,1H),2.51(s,3H),2.45–2.34(m,1H)。
实施例59c:(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.49(s,1H),7.79(s,1H),7.56(dd,J=7.7,1.0Hz,1H),7.52(dt,J=7.5,0.9Hz,1H),7.42–7.33(m,1H),7.28(dd,J=7.6,1.2Hz,1H),7.08(s,1H),6.85(s,1H),5.70(d,J=4.8Hz,1H),5.58(d,J=6.7Hz,1H),3.02–2.95(m,1H),2.69(dd,J=16.9,8.2Hz,1H),2.56–2.48(m,1H),2.44(s,3H)。
实施例59d:(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.54(s,1H),7.75(s,1H),7.61(dd,J=7.7,0.9Hz,1H),7.55(dt,J=7.5,0.9Hz,1H),7.42–7.37(m,1H),7.29(td,J=7.6,1.2Hz,1H),7.12(s,1H),6.93(s,1H),5.69(d,J=5.5Hz,1H),5.57(d,J=6.3Hz,1H),2.94–2.87(m,1H),2.79(dd,J=16.7,7.9Hz,1H),2.74–2.66(m,1H),2.50(s,3H)。
实施例60:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰
胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
步骤1:
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
向5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈(400mg,1.22mmol)在甲醇(15mL)中的溶液中添加氢氧化钠(488mg,12.22mmol)和过氧化氢(0.367mL,12.22mmol)且在室温搅拌2小时。去除溶剂且粗产物用5%2,2,2-三氟乙醇的DCM溶液萃取。合并的有机层用水、盐水洗涤,用硫酸钠干燥且蒸发以得到标题化合物,其进一步通过手性分离进行分离以得到6种异构体,为白色固体。异构体60c、60e和60f的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例60a:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.88(s,1H),7.75(d,J=7.7Hz,1H),7.68–7.59(m,4H),7.39(dt,J=7.4,3.5Hz,2H),7.28–7.22(m,2H),7.14(s,1H),5.61(d,J=6.1Hz,1H),5.45(d,J=6.0Hz,1H),4.85–4.78(m,1H),2.90-2,81(m,1H),2.73–2.62(m,1H),2.20–2.08(m,1H),2.08-1.91(m,1H),1.76-1.68(m,1H)。
实施例60b:(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(d,J=0.7Hz,1H),7.90(s,1H),7.71(dd,J=8.0,1.8Hz,1H),7.64–7.58(m,3H),7.46(d,J=8.0Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.29(td,J=8.0,1.4Hz,2H),7.11(s,1H),5.54(d,J=2.3Hz,1H),5.02(d,J=3.7Hz,1H),2.76-2.69(m,1H),2.59-2.54(s,1H),2.50-2.46(m,1H),1.54-1.43(m,1H),1.03-0.95(m,1H)。
实施例60c:(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.87(s,1H),7.74–7.68(m,2H),7.65–7.61(m,1H),7.53(d,J=1.6Hz,1H),7.49(dq,J=7.6,0.8Hz,1H),7.43–7.39(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.24(s,1H),7.18(s,1H),6.12(d,J=7.6Hz,1H),5.81(d,J=1.9Hz,1H),4.94(dd,J=10.7,7.6Hz,1H),2.66–2.57(m,2H),2.44–2.34(m,1H),0.99–0.86(m,1H),0.89–0.76(m,1H)。
实施例60d:(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.88(s,1H),7.75(d,J=7.7Hz,1H),7.68–7.59(m,4H),7.39(dt,J=7.4,3.5Hz,2H),7.28–7.22(m,2H),7.14(s,1H),5.61(d,J=6.1Hz,1H),5.45(d,J=6.0Hz,1H),4.85–4.78(m,1H),2.90-2,81(m,1H),2.73–2.62(m,1H),2.20–2.08(m,1H),2.08-1.91(m,1H),1.76-1.68(m,1H)。
实施例60e:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.87(s,1H),7.74–7.68(m,2H),7.65–7.61(m,1H),7.53(d,J=1.6Hz,1H),7.49(dq,J=7.6,0.8Hz,1H),7.43–7.39(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.24(s,1H),7.18(s,1H),6.12(d,J=7.6Hz,1H),5.81(d,J=1.9Hz,1H),4.94(dd,J=10.7,7.6Hz,1H),2.66–2.57(m,2H),2.44–2.34(m,1H),0.99–0.86(m,1H),0.89–0.76(m,1H)。
实施例60f:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.87(s,1H),7.74–7.68(m,2H),7.65–7.61(m,1H),7.53(d,J=1.6Hz,1H),7.49(dq,J=7.6,0.8Hz,1H),7.43–7.39(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.24(s,1H),7.18(s,1H),6.12(d,J=7.6Hz,1H),5.81(d,J=1.9Hz,1H),4.94(dd,J=10.7,7.6Hz,1H),2.66–2.57(m,2H),2.44–2.34(m,1H),0.99–0.86(m,1H),0.89–0.76(m,1H)。
实施例61:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
该标题化合物通过与实施例35相同的方法合成。
异构体的构型任意指定。
实施例61a:(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):271.2[M+H]+;1H NMR(500MHz,氯仿-d)δ8.15(s,1H),7.50(dt,J=7.6,1.0Hz,1H),7.36(tt,J=7.5,0.9Hz,1H),7.33(dq,J=7.7,1.0Hz,1H),7.28–7.24(m,1H),7.14(s,1H),5.49(s,1H),3.80–3.69(m,2H),3.25(t,J=11.4Hz,1H),3.02(dd,J=11.6,4.5Hz,1H),2.29(ddd,J=11.1,4.5,1.1Hz,1H),1.99(ddd,J=14.3,11.7,6.3Hz,2H),1.61(s,3H)。61a和61d为对映异构体。
实施例61b:(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):271.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.81(dt,J=7.8,1.0Hz,1H),7.71(s,1H),7.52(d,J=7.6Hz,1H),7.37–7.33(m,1H),7.22(td,J=7.6,1.2Hz,1H),7.17(s,1H),5.44(s,1H),3.78–3.73(m,2H),3.55(t,J=11.2Hz,1H),3.17(dd,J=11.5,4.4Hz,1H),2.29(ddd,J=10.8,4.4,1.7Hz,1H),1.93(ddd,J=14.2,10.5,6.6Hz,1H),1.58(m,1H),1.50(s,3H)。61b和61c为对映异构体。
实施例61c:(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):271.2[M+H]+;1H NMR(500MHz,氯仿-d)δ7.81(dq,J=7.7,0.9Hz,1H),7.71(s,1H),7.52(dt,J=7.8,1.0Hz,1H),7.35(tt,J=7.6,1.0Hz,1H),7.22(td,J=7.6,1.2Hz,1H),7.17(s,1H),5.44(d,J=1.6Hz,1H),3.81–3.72(m,2H),3.55(dd,J=11.6,10.8Hz,1H),3.17(dd,J=11.5,4.4Hz,1H),2.29(ddd,J=10.8,4.4,1.8Hz,1H),1.93(ddd,J=14.2,10.5,6.6Hz,1H),1.58(m,1H),1.50(s,3H)。61b和61c为对映异构体。
实施例61d:(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):271.2[M+H]+;1H NMR(500MHz,氯仿-d)δ8.15(s,1H),7.50(dt,J=7.6,0.9Hz,1H),7.36(tt,J=7.5,0.9Hz,1H),7.33(dq,J=7.7,1.0Hz,1H),7.26(td,J=7.5,1.1Hz,1H),7.14(s,1H),5.49(s,1H),3.79–3.70(m,2H),3.25(t,J=11.4Hz,1H),3.02(dd,J=11.6,4.5Hz,1H),2.29(ddd,J=11.1,4.5,1.1Hz,1H),1.99(ddd,J=14.3,11.8,6.3Hz,1H),1.61-1.58(m,4H)。61a和61d为对映异构体。
实施例62:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
步骤1:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5-氧代-5,6,7,8-四氢萘-2-甲腈
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2g,4.83mmol)和5-氧代-5,6,7,8-四氢萘-2-甲腈(1.24g,7.24mmol)在MeOH(20mL)中的溶液中添加乙醇钠(21%在乙醇中的溶液,2.7mL,7.24mmol)。将溶液回流。6h后,反应通过TLC指示完成。将乙酸(7mL)添加至反应混合物且回流2小时。甲醇和乙酸在旋转式蒸发器上蒸发且将粗物质溶于水,分批添加固体碳酸钠以中和剩余乙酸。粗物质然后使用DCM(2X 30mL)萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):326.2[M+H]+
步骤2:
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
将6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5-氧代-5,6,7,8-四氢萘-2-甲腈(1.6gmL,4.62mmol)在甲醇(15mL)中的溶液冷却至0℃。添加硼氢化钠(0.524g,13.85mmol)且反应混合物从冰浴去除。反应混合物在室温搅拌2小时。反应使用饱和NH4Cl溶液(15mL)淬灭。粗物质使用DCM中的5%2,2,2-三氟乙醇萃取,其在Combi-Flash上纯化且进一步通过手性分离进行分离以得到7种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例62a:(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR(500MHz,氯仿-d)δ7.99(s,1H),7.62–7.57(m,1H),7.55(dd,J=7.8,0.9Hz,1H),7.49(d,J=7.6Hz,1H),7.45(d,J=1.3Hz,1H),7.44–7.37(m,2H),7.24-7.28(s,1H),7.17(s,1H),5.38(d,J=7.3Hz,1H),4.88(d,J=3.1Hz,1H),3.02(dd,J=5.3,2.3Hz,1H),2.80(s,1H),2.22(dd,J=11.2,5.4Hz,2H),2.08(dd,J=7.6,3.7Hz,1H)。
实施例62b:(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR(500MHz,氯仿-d)δ7.71(d,J=8.2Hz,1H),7.68–7.65(m,1H),7.60(d,J=7.7Hz,1H),7.48(d,J=1.0Hz,2H),7.41(d,J=0.9Hz,1H),7.35(s,1H),7.21-7.25(m,2H),5.76(d,J=3.0Hz,1H),4.93(d,J=10.5Hz,1H),2.82–2.66(m,2H),2.52(d,J=11.1Hz,1H),1.41–1.33(m,1H),1.27(dd,J=12.6,5.5Hz,2H)。
实施例62c:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.09(s,1H),7.61(d,J=8.0Hz,1H),7.59–7.54(m,1H),7.53–7.49(m,1H),7.43(d,J=1.5Hz,1H),7.41–7.36(m,2H),7.24-7.29(s,1H),6.67(s,1H),5.48(s,1H),5.14–5.08(m,1H),2.73(dd,J=17.2,5.3Hz,1H),2.61(dd,J=12.3,5.8Hz,1H),2.42–2.35(m,1H),1.39(dd,J=12.9,5.5Hz,1H),1.09(dd,J=10.5,3.0Hz,1H)。
实施例62d:(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR(500MHz,氯仿-d)δ8.09(s,1H),7.61(d,J=8.0Hz,1H),7.59–7.54(m,1H),7.53–7.49(m,1H),7.43(d,J=1.5Hz,1H),7.41–7.36(m,2H),7.24-7.29(s,1H),6.67(s,1H),5.48(s,1H),5.14–5.08(m,1H),2.73(dd,J=17.2,5.3Hz,1H),2.61(dd,J=12.3,5.8Hz,1H),2.42–2.35(m,1H),1.39(dd,J=12.9,5.5Hz,1H),1.09(dd,J=10.5,3.0Hz,1H)。
实施例62e:(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR未报告。
实施例62f:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR未报告
实施例62g:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.1[M+H]+;1H NMR(500MHz,氯仿-d)δ7.71(d,J=8.2Hz,1H),7.68–7.65(m,1H),7.60(d,J=7.7Hz,1H),7.48(d,J=1.0Hz,2H),7.41(d,J=0.9Hz,1H),7.35(s,1H),7.21-7.25(m,2H),5.76(d,J=3.0Hz,1H),4.93(d,J=10.5Hz,1H),2.82–2.66(m,2H),2.52(d,J=11.1Hz,1H),1.41–1.33(m,1H),1.27(dd,J=12.6,5.5Hz,2H)。
实施例63:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
步骤1:(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢喹啉-8(5H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和6,7-二氢喹啉-8(5H)-酮(888mg,9.05mmol)在EtOH(20mL)中的溶液中滴加乙醇钠的乙醇溶液(2.25mL,6.03mmol)。将混合物在90℃再搅拌1小时。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过DCM:MeOH=97:3洗脱。
步骤2:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢喹啉-8(5H)-酮
(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢喹啉-8(5H)-酮(3.28g,6.03mmol)在20%AcOH的MeOH溶液(20mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x10mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过CombiFlash纯化:LCMS(ESI,m/z):302.2[M+H]+.
步骤3:
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
在0℃向(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢喹啉-8(5H)-酮(0.703g,2.33mmol)在MeOH(20mL)中的溶液中分批添加NaBH4(265mg,7.0mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用DCM萃取(3x10mL)。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例63a:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.47(ddt,J=4.7,1.6,0.8Hz,1H),7.74(d,J=0.7Hz,1H),7.54(dt,J=7.8,1.0Hz,1H),7.47(dq,J=7.7,1.0Hz,1H),7.43–7.35(m,2H),7.28(dd,J=7.5,1.1Hz,1H),7.18(dd,J=7.7,4.8Hz,1H),7.15(s,1H),5.63(d,J=2.8Hz,1H),5.17(d,J=5.0Hz,1H),2.72–2.63(m,1H),2.58(dd,J=10.4,4.9Hz,2H),1.64–1.56(m,2H),1.43–1.34(m,1H)。
实施例63b:(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.52–8.47(m,1H),7.80(t,J=0.7Hz,1H),7.58(dt,J=7.6,0.9Hz,1H),7.51(dd,J=7.6,1.0Hz,1H),7.46–7.39(m,2H),7.31(dd,J=7.5,1.1Hz,1H),7.21(dd,J=7.7,4.8Hz,1H),7.18(s,1H),5.67(d,J=2.8Hz,1H),5.21(d,J=5.0Hz,1H),2.73–2.68(m,1H),2.66–2.57(m,2H),1.77–1.56(m,2H),1.46–1.38(m,1H)。
实施例63c:(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.47–8.42(m,1H),7.96(s,1H),7.53(dt,J=7.7,0.9Hz,1H),7.47(dq,J=7.7,0.9Hz,1H),7.43–7.38(m,1H),7.33(tt,J=7.5,0.9Hz,1H),7.20(s,1H),7.16(dd,J=7.7,4.7Hz,1H),7.12(td,J=7.6,1.1Hz,1H),5.55(d,J=6.7Hz,1H),5.03(d,J=4.3Hz,1H),2.78–2.60(m,2H),2.44–2.30(m,1H),2.03–1.92(m,2H),1.61(s,1H)。
实施例63d:(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,氯仿-d)δ8.44(dd,J=4.8,1.6Hz,1H),7.96(s,1H),7.52(dt,J=7.8,1.0Hz,1H),7.48(dq,J=7.7,0.9Hz,1H),7.43–7.39(m,1H),7.33(tt,J=7.6,0.8Hz,1H),7.20(s,1H),7.16(dd,J=7.7,4.7Hz,1H),7.12(td,J=7.7,1.2Hz,1H),5.54(d,J=6.7Hz,1H),5.03(d,J=4.3Hz,1H),2.78–2.60(m,2H),2.36(dd,J=7.9,4.4Hz,1H),2.04–1.94(m,2H),1.65(s,1H)。
实施例64:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
步骤1:4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
向3-羟基-4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-1-甲酸叔丁酯(100mg,0.28mmol)在1,4-二噁烷(4mL)中的溶液中添加氯化氢(1mL)。所得溶液在室温搅拌4h。将混合物真空浓缩。这得到50mg(70%)4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇,其为黄色油状物:LCMS(ESI,m/z):256.0[M+H]+.
步骤2:
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
向4-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(50mg,0.20mmol)和TEA(1g,9.88mmol)在DCM(3mL)中的溶液中添加甲磺酰氯(100mg,0.873mmol)。所得溶液在室温搅拌3h。所得混合物真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离。所有异构体064a-d的绝对构型任意指定。
实施例64a:(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(9.9mg,3%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.1HNMR(300MHz,CD3OD)7.91(s,1H),7.65(d,J=3.6Hz,1H),7.50(d,J=3.6Hz,1H),7.44(t,J=7.2Hz,1H),7.36(t,J=7.2Hz,1H),7.21(s,1H),5.84(s,1H),4.02-3.91(m,2H),3.51(dd,J=9.6Hz,2.4Hz,1H),2.84(s,3H),2.68-2.57(m,2H),2.23(t,J=5.6Hz,1H),0.98(dd,J=13.6Hz,3.2Hz,1H)。0.68-0.64(m,1H)。tR=1.573分钟(CHIRALCEL PAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。64a和64b为对映异构体。
实施例64b:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(16.2mg,6%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.tR=2.048分钟(CHIRALCELPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。64a和64b为对映异构体。
实施例64c:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(4.4mg,2%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.1H NMR(300MHz,CD3OD)7.95(s,1H),7.66(d,J=3.6Hz,1H),7.54(d,J=3.6Hz,1H),7.47(t,J=7.2Hz,1H),7.40(t,J=7.2Hz,1H),7.22(s,1H),5.86(s,1H),4.02-3.91(m,2H),3.73(dd,J=9.6Hz,2.4Hz,1H),3.01(dd,J=4.8Hz,2.4Hz,1H),2.80-2.73(m,1H),2.63(s,3H),2.41-2.39(m,1H)。2.20(dd,J=10.4Hz,2.0Hz,1H),1.91(t,J=11.6Hz,1H),1.88-1.74(m,1H)。tR=2.268分钟(CHIRALCEL PAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。64c和64d为对映异构体。
实施例64d:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(6.7mg,2%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.tR=3.284分钟(CHIRALCELPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。64c和64d为对映异构体。
实施例66:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
步骤1:(E)-3,3-二甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)四氢-4H-吡喃-4-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):524.4[M+H]+
步骤2:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-4H-吡喃-4-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):283.2[M+H]+
步骤3:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):285.5[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
实施例66a:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.59(d,J=7.5Hz,1H),7.57(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.31(td,J=7.5,1.0Hz,1H),7.15(s,1H),5.65(d,J=2.3Hz,1H),5.43(d,J=6.3Hz,1H),3.60(dd,J=10.9,6.3Hz,1H),2.93(dd,J=11.2,3.9Hz,1H),2.89(d,J=11.4Hz,1H),2.44(ddt,J=15.1,7.0,4.1Hz,1H),2.29(t,J=11.3Hz,1H),0.99(s,3H),0.90(s,3H)。
实施例66b:(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.60(d,J=7.5Hz,1H),7.58–7.54(m,1H),7.40(t,J=7.4Hz,1H),7.31(td,J=7.5,1.1Hz,1H),7.16(s,1H),5.66(d,J=2.4Hz,1H),5.43(d,J=6.3Hz,1H),3.60(dd,J=10.9,6.3Hz,1H),2.94(dd,J=11.1,3.7Hz,1H),2.89(d,J=11.5Hz,1H),2.48–2.39(m,1H),2.29(t,J=11.3Hz,1H),0.99(s,3H),0.91(s,3H)。
实施例66c:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.61(d,J=8.5Hz,2H),7.40(t,J=7.5Hz,1H),7.30(td,J=7.5,1.0Hz,1H),7.13(s,1H),5.64(d,J=3.7Hz,1H),5.33(d,J=6.1Hz,1H),3.56(dd,J=11.0,6.1Hz,1H),2.90–2.74(m,2H),2.61(dq,J=11.2,3.7Hz,1H),2.41(t,J=11.4Hz,1H),0.98(s,3H),0.85(s,3H)。
实施例66d:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.06(dd,J=7.9,1.2Hz,1H),7.74(s,1H),7.30–7.27(m,1H),7.19(td,J=7.4,1.3Hz,1H),6.96(d,J=7.5Hz,1H),6.72(s,1H),5.25(d,J=4.8Hz,1H),4.36(d,J=12.5Hz,1H),4.02–3.85(m,2H),3.46(d,J=11.0Hz,1H),3.29–3.23(m,2H),0.95(s,3H),0.91(s,3H)。
实施例66e:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.66–7.61(m,1H),7.58(d,J=7.5Hz,1H),7.39(t,J=7.4Hz,1H),7.29(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.53–5.44(m,1H),5.23(d,J=4.9Hz,1H),3.80–3.61(m,1H),3.38(d,J=10.8Hz,1H),3.34(d,J=11.2Hz,1H),3.10(d,J=10.8Hz,1H),2.28(dq,J=8.2,3.7,2.4Hz,1H),0.94(s,3H),0.83(s,3H)。
实施例66f:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.61(d,J=8.6Hz,2H),7.40(t,J=7.5Hz,1H),7.30(td,J=7.5,1.1Hz,1H),7.13(s,1H),5.64(d,J=3.7Hz,1H),5.34(d,J=6.1Hz,1H),3.56(dd,J=11.0,6.0Hz,1H),2.88–2.78(m,2H),2.61(ddt,J=11.2,8.0,4.0Hz,1H),2.41(t,J=11.4Hz,1H),0.98(s,3H),0.85(s,3H)。
实施例66g:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):285.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.73–7.60(m,1H),7.58(d,J=7.5Hz,1H),7.39(t,J=7.4Hz,1H),7.28(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.48(d,J=4.9Hz,1H),5.23(d,J=4.9Hz,1H),3.70(d,J=3.2Hz,1H),3.38(d,J=10.8Hz,1H),3.34(d,J=11.2Hz,1H),3.10(d,J=10.8Hz,1H),2.30–2.23(m,1H),0.94(s,3H),0.82(s,3H)。
实施例67:1-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
步骤1:(E)-1-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)螺[3.3]庚-2-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和螺[3.3]庚-2-酮(863mg,7.84mmol)在MeOH(20mL)中的溶液中滴加哌啶(0.595mL,6.03mmol)。将溶液回流2hrs。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过EtOAc:己烷=25:75洗脱:LCMS(ESI,m/z):507.4[M+H]+.
步骤2:1-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-酮
(E)-1-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)螺[3.3]庚-2-酮(2.38g,4.70mmol)在20%AcOH的MeOH溶液(20mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x10mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化。产物用DCM:MeOH=98:2洗脱:LCMS(ESI,m/z):265.4[M+H]+.
步骤3:
(1R,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1S,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
(1R,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
在0℃向1-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-酮(1.05g,3.98mmol)在MeOH(15mL)中的溶液中分批添加NaBH4(301mg,7.97mmol)且溶液在0℃再搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用5%三氟乙醇在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例67a:(1R,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.63–7.61(m,1H),7.60–7.57(m,1H),7.42–7.36(m,1H),7.28(dd,J=7.6,1.2Hz,1H),7.18(s,1H),5.47(d,J=5.8Hz,1H),5.25(d,J=6.8Hz,1H),4.27–4.16(m,1H),2.32(s,2H),1.71(dd,J=10.4,8.2Hz,1H),1.64–1.55(m,3H),1.42(d,J=8.0Hz,1H),1.38–1.30(m,1H),1.23(d,J=7.4Hz,1H)。
实施例67b:(1R,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.13(s,1H),7.62–7.56(m,2H),7.38(t,J=0.9Hz,1H),7.30(dd,J=7.5,1.1Hz,1H),7.14(s,1H),5.68(d,J=3.9Hz,1H),5.40(d,J=3.9Hz,1H),4.52(dd,J=6.3,3.9Hz,1H),2.92–2.86(m,1H),2.32(ddd,J=11.7,7.3,2.4Hz,1H),1.97(ddd,J=11.8,6.2,1.1Hz,1H),1.80–1.71(m,2H),1.63–1.52(m,1H),1.38–1.28(m,2H),0.96–0.88(m,1H)。
实施例67c:(1S,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.88(s,1H),7.83(dd,J=7.7,1.0Hz,1H),7.61(dt,J=7.6,0.9Hz,1H),7.43–7.36(m,1H),7.32(dd,J=7.6,1.2Hz,1H),7.14(s,1H),5.55(d,J=3.8Hz,1H),5.47(d,J=8.4Hz,1H),4.38(tt,J=6.5,3.4Hz,1H),2.33(t,J=7.5Hz,1H),2.21–2.14(m,2H),2.07(dd,J=11.6,3.3Hz,1H),2.02(d,J=9.8Hz,1H),1.89(dt,J=11.2,8.8Hz,1H),1.75(tt,J=9.2,4.6Hz,2H),1.65(dd,J=7.7,3.8Hz,1H)。
实施例67d:(1S,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.65–7.56(m,2H),7.40(tt,J=7.5,0.8Hz,1H),7.31(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.46(d,J=7.9Hz,1H),5.14(d,J=7.3Hz,1H),4.13(p,J=7.8Hz,1H),2.44(dd,J=10.5,7.5Hz,1H),2.15(t,J=7.5Hz,2H),2.06–1.95(m,1H),1.87(dt,J=11.0,8.6Hz,1H),1.77–1.59(m,4H)。
实施例67e:(1S,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.13(s,1H),7.62–7.54(m,2H),7.38(tt,J=7.5,0.9Hz,1H),7.30(td,J=7.5,1.1Hz,1H),7.14(s,1H),5.68(d,J=3.8Hz,1H),5.40(d,J=4.0Hz,1H),4.52(tdd,J=7.5,6.2,3.8Hz,1H),2.91–2.85(m,1H),2.35–2.26(m,1H),1.97(ddd,J=11.8,6.2,1.1Hz,1H),1.81–1.71(m,2H),1.63–1.52(m,1H),1.37–1.27(m,2H),0.96–0.87(m,1H)。
实施例67f:(1S,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.65–7.55(m,2H),7.39(tt,J=7.5,0.9Hz,1H),7.28(td,J=7.6,1.1Hz,1H),7.18(s,1H),5.47(d,J=5.8Hz,1H),5.24(d,J=6.8Hz,1H),4.21(p,J=7.9Hz,1H),2.38–2.25(m,2H),1.71(dd,J=10.4,8.2Hz,1H),1.61(dt,J=4.4,2.3Hz,3H),1.49–1.38(m,1H),1.35(s,1H),1.23(d,J=7.5Hz,1H)。
实施例67g:(1R,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.88(s,1H),7.82(dq,J=7.7,0.9Hz,1H),7.60(dt,J=7.6,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.31(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.55(d,J=3.8Hz,1H),5.47(d,J=8.5Hz,1H),4.38(tt,J=6.5,3.4Hz,1H),2.33(t,J=7.5Hz,1H),2.19(ddt,J=9.5,5.1,2.8Hz,2H),2.07(dd,J=11.6,3.2Hz,1H),2.02(d,J=10.2Hz,1H),1.89(dt,J=11.4,8.8Hz,1H),1.75(ddd,J=9.8,6.0,3.4Hz,2H),1.65(dd,J=7.7,3.8Hz,1H)。
实施例67h:(1R,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇:LCMS(ESI,m/z):304.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.86(s,1H),7.64–7.54(m,2H),7.40(tt,J=7.5,0.8Hz,1H),7.31(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.46(d,J=7.9Hz,1H),5.14(d,J=7.4Hz,1H),4.13(p,J=7.8Hz,1H),2.44(dd,J=10.4,7.5Hz,1H),2.15(t,J=7.6Hz,2H),2.02(d,J=9.9Hz,1H),1.87(dd,J=9.0,2.3Hz,1H),1.76–1.60(m,4H)。
实施例68:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
步骤1:(E)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-8-氧杂螺[4.5]癸-1-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):551.6[M+H]+
步骤2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):309.4[M+H]+
步骤3:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):311.4[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
实施例68a:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.94(dd,J=7.8,1.4Hz,1H),7.71(s,1H),7.31(d,J=7.6Hz,1H),7.28(dd,J=1.9,1.2Hz,1H),7.22(td,J=7.5,1.4Hz,1H),7.17(td,J=7.4,1.4Hz,1H),6.66(d,J=2.0Hz,1H),5.22(d,J=5.4Hz,1H),4.04(d,J=5.3Hz,1H),3.70(ddt,J=19.2,11.1,3.9Hz,3H),3.42(dtd,J=16.8,11.3,2.5Hz,3H),2.48–2.43(m,1H),2.30(dt,J=17.4,9.4Hz,1H),1.94(ddd,J=13.1,9.5,3.8Hz,1H),1.82–1.73(m,1H),1.72–1.63(m,1H),1.43–1.34(m,1H),1.19(d,J=11.4Hz,1H),0.97(d,J=13.5Hz,1H)。
实施例68b:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.99–7.92(m,1H),7.72(s,1H),7.31(d,J=7.5Hz,1H),7.28(s,1H),7.23(t,J=6.9Hz,1H),7.17(t,J=6.8Hz,1H),6.69–6.64(m,1H),5.22(d,J=5.4Hz,1H),4.04(d,J=5.1Hz,1H),3.78–3.65(m,3H),3.49–3.37(m,3H),2.46(d,J=9.5Hz,1H),2.30(dt,J=17.3,8.3Hz,1H),1.95(ddd,J=12.9,9.5,3.7Hz,1H),1.82–1.73(m,1H),1.72–1.63(m,1H),1.44–1.34(m,1H),1.19(d,J=13.4Hz,1H),0.97(d,J=13.7Hz,1H)。
实施例68c:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(dd,J=7.8,1.4Hz,1H),7.72(s,1H),7.31(d,J=7.6Hz,1H),7.28(s,1H),7.23(td,J=7.5,1.4Hz,1H),7.17(td,J=7.4,1.4Hz,1H),6.67(d,J=2.0Hz,1H),5.22(d,J=5.4Hz,1H),4.04(d,J=5.3Hz,1H),3.70(dtd,J=15.2,7.7,3.8Hz,3H),3.43(dtd,J=16.8,11.4,2.5Hz,3H),2.48–2.44(m,1H),2.30(dt,J=17.3,8.4Hz,1H),1.95(ddd,J=13.0,9.5,3.8Hz,1H),1.82–1.73(m,1H),1.72–1.64(m,1H),1.44–1.35(m,1H),1.22(d,J=16.6Hz,1H),0.97(d,J=13.7Hz,1H)。
实施例68d:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.60(d,J=7.5Hz,1H),7.52(d,J=7.7Hz,1H),7.38(t,J=7.5Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.44(d,J=4.4Hz,1H),5.02(d,J=5.8Hz,1H),3.73(dt,J=11.3,4.3Hz,1H),3.70–3.63(m,1H),3.51(dd,J=9.6,5.7Hz,1H),3.38(td,J=11.7,2.4Hz,1H),3.27(td,J=11.9,2.6Hz,1H),2.63(qd,J=9.4,4.5Hz,1H),1.76–1.62(m,3H),1.36–1.20(m,1H),1.13–1.06(m,2H),0.98(dd,J=13.2,2.1Hz,1H),0.89–0.78(m,1H)。
实施例68e:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.59(d,J=7.5Hz,1H),7.56–7.50(m,1H),7.38(t,J=7.4Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.44(d,J=4.4Hz,1H),5.01(d,J=5.8Hz,1H),3.73(dt,J=11.3,4.2Hz,1H),3.69–3.62(m,1H),3.51(dd,J=9.6,5.8Hz,1H),3.38(td,J=11.7,2.4Hz,1H),3.26(td,J=11.7,2.4Hz,1H),2.63(qd,J=9.4,4.5Hz,1H),1.77–1.62(m,3H),1.27(tdd,J=13.9,10.0,5.5Hz,1H),1.09(dd,J=13.2,2.7Hz,2H),0.98(dd,J=13.2,2.1Hz,1H),0.84(dtd,J=13.2,9.6,5.9Hz,1H)。
实施例68f:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.70–7.65(m,1H),7.59(d,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.27(td,J=7.6,1.1Hz,1H),7.12(s,1H),5.40(d,J=7.8Hz,1H),5.29(d,J=5.3Hz,1H),3.90(t,J=5.1Hz,1H),3.71(dt,J=11.3,4.4Hz,1H),3.57(dt,J=11.5,4.3Hz,1H),3.47–3.37(m,2H),2.24(qd,J=8.9,4.6Hz,1H),1.73(dddt,J=23.1,13.7,9.9,4.5Hz,3H),1.64–1.55(m,2H),1.45(d,J=13.5Hz,1H),1.29(ddd,J=13.5,9.5,4.2Hz,1H),1.17(d,J=13.4Hz,1H)。
实施例68g:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.59(d,J=7.5Hz,1H),7.48(d,J=7.6Hz,1H),7.37(t,J=7.5Hz,1H),7.23(t,J=7.6Hz,1H),7.11(s,1H),5.29(d,J=9.7Hz,1H),5.22(d,J=5.8Hz,1H),3.84–3.78(m,1H),3.73(dt,J=11.3,4.2Hz,1H),3.54(dt,J=11.5,4.3Hz,1H),3.44–3.34(m,2H),2.16–2.05(m,1H),2.03–1.89(m,2H),1.70(ddd,J=13.8,9.9,3.8Hz,3H),1.49(d,J=13.5Hz,1H),1.25(ddd,J=13.6,9.7,4.2Hz,1H),1.12(d,J=13.4Hz,1H)。
实施例68h:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):311.4[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.68(d,J=7.6Hz,1H),7.59(d,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.27(td,J=7.6,1.1Hz,1H),7.12(s,1H),5.39(d,J=7.7Hz,1H),5.29(d,J=5.4Hz,1H),3.90(t,J=5.1Hz,1H),3.71(dt,J=11.4,4.4Hz,1H),3.57(dt,J=11.6,4.5Hz,1H),3.46–3.35(m,2H),2.29–2.20(m,1H),1.81–1.66(m,3H),1.65–1.54(m,2H),1.45(d,J=13.5Hz,1H),1.29(ddd,J=13.5,9.4,4.1Hz,1H),1.17(d,J=13.4Hz,1H)。
实施例69和69-1:4-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
和3-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
合成途径
步骤1:1-溴-2-(溴甲基)-3-氯苯
在90℃向1-溴-3-氯-2-甲基苯(5g,24.33mmol)在四氯甲烷(60mL)中的溶液中添加1-溴吡咯烷-2,5-二酮(2.33g),然后添加过氧化苯甲酰(147mg),将混合物加热至回流2小时。添加另一部分的1-溴吡咯烷-2,5-二酮(2.0g)和过氧化苯甲酰(148mg)且反应再持续3小时。冷却至室温后,该反应用二氯甲烷(60mL)稀释且有机层用冰冷的20%NaHCO3水溶液(20mL)和盐水(20mL)洗涤。有机相用Na2SO4干燥且在减压下浓缩以得到粗物质,其原样用于下一步(6.85g,99%)。1H NMR(氯仿-d,400MHz):δ(ppm)7.50(d,J=8.1Hz,1H),7.36(d,J=8.0Hz,1H),7.10(t,J=8.0Hz,1H),4.79(s,2H)。
步骤2:6-氯-5H-咪唑并[5,1-a]异吲哚
在室温向NaH(23.91mmol)在无水DSMO(50mL)中的悬浮液中添加咪唑(1.63g,23.91mmol)在DMSO(10mL)中的溶液。悬浮液在室温搅拌2hr。添加1-溴-2-(溴甲基)-3-氯苯(6.8g,23.91mmol)在DMSO(10mL)中的溶液且在室温持续搅拌过夜。将无水K2CO3(6.6g,47.82mmol)、Pd(OAc)2(429.5mg,1.91mmol)和PPh3(1.0g,3.83mmol)添加至混合物。溶液用氩气吹洗5分钟且混合物在130℃搅拌18小时。将溶液冷却至室温,用二氯甲烷(50mL)稀释且通过硅藻土过滤。在减压下去除溶剂以得到粗产物,其通过CombiFlash纯化(2.6g,57%):LCMS(ESI,m/z):191.19[M+H]+.1H NMR(氯仿-d,400MHz):δ(ppm)7.76(s,1H),7.43(d,J=7.3Hz,1H),7.33(t,J=7.8Hz,1H),7.25–7.17(m,2H),5.02(s,2H)。
步骤3:
(3R,4R)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
在-40℃向6-氯-5H-咪唑并[5,1-a]异吲哚(1.0g,5.25mmol)在无水THF(25mL)中的溶液中添加n-BuLi(2.3mL,5.77mmol,2.5M在己烷中的溶液)。在-40℃搅拌1.5hr后,添加3,7-二氧杂双环[4.1.0]庚烷(577mg,5.77mmol)且反应经2hr温热至室温且持续搅拌过夜(18hr)。反应通过添加饱和NH4Cl(5mL)淬灭且该反应用水(30mL)稀释,产物用CH2Cl2(3x40mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过CombiFlash纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。异构体的构型任意指定。
实施例69a:(3R,4R)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.60(dd,J=7.5,0.9Hz,1H),7.45(td,J=7.8,0.6Hz,1H),7.35(dd,J=8.0,0.9Hz,1H),7.23(s,1H),5.88(d,J=2.9Hz,1H),5.56(d,J=5.6Hz,1H),3.91(tt,J=10.4,5.1Hz,1H),3.75(dd,J=11.7,4.9Hz,1H),3.20–3.07(m,1H),2.92(dd,J=11.4,3.9Hz,1H),2.63(tt,J=10.9,3.5Hz,1H),2.22(t,J=11.3Hz,1H),1.92(ddt,J=12.7,4.2,1.9Hz,1H),1.58(tdd,J=12.7,10.5,4.8Hz,1H)。
实施例69b:(3R,4R)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.53(dd,J=7.5,0.9Hz,1H),7.36(ddd,J=8.1,7.5,0.6Hz,1H),7.26(dd,J=8.0,0.9Hz,1H),7.19(s,1H),5.54(s,1H),4.45(d,J=5.5Hz,1H),3.79(dd,J=11.3,4.4Hz,1H),3.61(dd,J=10.8,5.1Hz,1H),3.23(td,J=11.6,2.2Hz,1H),3.17(dq,J=10.3,5.1Hz,1H),2.83(t,J=10.3Hz,1H),2.60–2.52(m,1H),1.62(qd,J=12.8,4.7Hz,1H),1.52(d,J=12.7Hz,1H)。
实施例69c:(3S,4S)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.60(dd,J=7.6,0.9Hz,1H),7.45(td,J=7.8,0.6Hz,1H),7.35(dd,J=8.0,0.9Hz,1H),7.23(s,1H),5.88(d,J=2.9Hz,1H),5.56(d,J=5.6Hz,1H),3.91(tt,J=10.4,5.1Hz,1H),3.75(dd,J=11.7,4.7Hz,1H),3.18–3.09(m,1H),2.92(dd,J=11.4,3.8Hz,1H),2.68–2.58(m,1H),2.22(t,J=11.3Hz,1H),1.96–1.88(m,1H),1.64–1.51(m,1H)。
实施例69d:(3S,4S)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.53(dd,J=7.6,0.9Hz,1H),7.36(t,J=7.8Hz,1H),7.26(dd,J=8.0,0.9Hz,1H),7.19(s,1H),5.54(d,J=1.4Hz,1H),4.45(d,J=5.5Hz,1H),3.79(dd,J=11.3,4.3Hz,1H),3.61(dd,J=10.7,5.0Hz,1H),3.23(td,J=11.6,2.2Hz,1H),3.16(p,J=5.1Hz,1H),2.83(t,J=10.3Hz,1H),2.56(s,1H),1.62(qd,J=12.7,4.7Hz,1H),1.56–1.49(m,1H)。
实施例69-1a:(3S,4S)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.60(dd,J=7.6,0.9Hz,1H),7.44(td,J=7.8,0.6Hz,1H),7.33(dd,J=8.0,0.9Hz,1H),7.23(s,1H),5.87(d,J=2.6Hz,1H),5.58(d,J=5.7Hz,1H),3.90(dd,J=10.6,4.9Hz,1H),3.71(tt,J=10.3,5.3Hz,1H),3.58(dd,J=11.3,4.5Hz,1H),3.15–2.99(m,2H),2.68–2.56(m,1H),0.64(ddd,J=11.6,3.9,2.0Hz,1H),0.35(qd,J=12.6,4.9Hz,1H)。
实施例69-1b:(3S,4S)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.51(dd,J=7.5,0.9Hz,1H),7.39–7.32(m,1H),7.25(dd,J=8.0,1.0Hz,1H),7.18(s,1H),5.38(s,1H),4.25(d,J=5.3Hz,1H),3.92(dd,J=11.3,4.4Hz,1H),3.76(d,J=10.9Hz,1H),3.56(t,J=11.4Hz,1H),3.27(td,J=11.7,2.3Hz,1H),3.22–3.14(m,1H),2.69–2.56(m,1H),1.59–1.51(m,1H),1.40–1.28(m,1H)。
实施例69-1c:(3R,4R)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.51(dd,J=7.5,0.9Hz,1H),7.39–7.32(m,1H),7.25(dd,J=8.1,1.0Hz,1H),7.18(s,1H),5.38(s,1H),4.25(d,J=5.4Hz,1H),3.92(dd,J=11.5,4.5Hz,1H),3.76(d,J=10.5Hz,1H),3.56(t,J=11.4Hz,1H),3.29–3.22(m,1H),3.23–3.13(m,1H),2.64(s,1H),1.59–1.51(m,1H),1.40–1.28(m,1H)。
实施例69-1d:(3R,4R)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):291.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.60(dd,J=7.6,0.9Hz,1H),7.44(td,J=7.8,0.6Hz,1H),7.33(dd,J=8.0,0.9Hz,1H),7.23(s,1H),5.87(d,J=2.6Hz,1H),5.58(d,J=5.7Hz,1H),3.90(dd,J=10.6,4.9Hz,1H),3.71(tt,J=10.3,5.2Hz,1H),3.58(dd,J=11.3,4.6Hz,1H),3.14–3.01(m,2H),2.65–2.55(m,1H),0.68–0.60(m,1H),0.35(qd,J=12.7,4.9Hz,1H)。
实施例70:1-(环丙基磺酰基)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
步骤1:3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
该标题化合物通过与实施例064相同的方法合成。
步骤2:
(3S,4R)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
(3R,4S)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
(3S,4R)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
(3R,4S)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
向3-[5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-4-醇(100mg,0.39mmol)和TEA(2g,20.00mmol)在DCM(5mL)中的溶液中添加环丙烷磺酰氯(50mg,0.37mmol)。所得溶液在室温搅拌2h。所得混合物真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离。所有异构体070a-d的绝对构型任意指定。
实施例70a:(3S,4R)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇(10.8mg,1%),其为白色固体:LCMS(ESI,m/z):360.3[M+H]+.1H NMR(300MHz,CD3OD)7.98(s,1H),7.67(d,J=3.6Hz,1H),7.54(d,J=3.6Hz,1H),7.47(t,J=7.2Hz,1H),7.40(t,J=7.6Hz,1H),7.22(s,1H),5.87(s,1H),3.99-3.98(m,1H),3.77-3.73(m,1H),3.01(dd,J=5.6Hz,2.8Hz,1H),2.88(t,J=12.8Hz,1H),2.40-2.39(m,1H),2.26-2.17(m,1H)。1.99(t,J=12Hz,1H),1.77-1.76(m,1H),0.91-0.84(m,2H),0.77-0.74(m,1H)。tR=2.056分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。70a和70b为对映异构体。
实施例70b:(3R,4S)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇(11.8mg,2%),其为白色固体:LCMS(ESI,m/z):360.0[M+H]+.tR=3.268分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。70a和70b为对映异构体。
实施例70c:(3S,4R)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇(12.0mg,2%),其为白色固体:LCMS(ESI,m/z):360.2[M+H]+.1H NMR(300MHz,CD3OD)8.00(s,1H),7.67(d,J=3.6Hz,1H),7.62(d,J=3.6Hz,1H),7.46(t,J=7.2Hz,1H),7.36(t,J=7.6Hz,1H),7.22(s,1H),5.86(s,1H),3.98-3.97(m,1H),3.77-3.73(m,1H),2.88-2.79(m,2H),2.62-2.49(m,1H),2.27-2.23(m,1H),2.13-2.07(m,2H)。1.75-1.68(m,1H),1.77-1.76(m,1H),0.93-0.79(m,3H)。tR=1.740分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。70c和70d为对映异构体。
实施例70d:(3R,4S)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇(13.8mg,2%),其为白色固体:LCMS(ESI,m/z):360.1[M+H]+.tR=3.058分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。70c和70d为对映异构体。
实施例71:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡
啶-7-醇
步骤1:(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):530.6[M+H]+
步骤2:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6-二氢-7H-环戊二烯并[c]吡啶-7-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):288.3[M+H]+
步骤3:
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
向6-[5H-咪唑并[4,3-a]异吲哚-5-基]-5H,6H,7H-环戊二烯并[c]吡啶-7-酮(700mg,2.44mmol)在MeOH(20mL)中的溶液中添加NaBH4(278mg,7.35mmol)。所得溶液在室温搅拌0.5h。所得混合物真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离。所有异构体071a-f的绝对构型任意指定。
实施例71a:(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(3.0mg,1%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.1H NMR(300MHz,CD3OD)8.63(s,1H),8.32(d,J=5.1Hz,1H),7.73-7.59(m,3H),7.53-7.32(m,2H),7.17-7.03(m,2H),5.79(d,J=4.1Hz,1H),5.70(d,J=7.3Hz,1H),3.29(t,J=6.4Hz,1H),2.83(dd,J=17.3,8.4Hz,1H),2.43(dd,J=17.2,5.4Hz,1H),1.40-1.28(m,1H)。tR=3.265分钟(CHIRALCELPAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。71a和71b为对映异构体。
实施例71b:(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(4.2mg,1%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.tR=3.871分钟(CHIRALCELPAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。071a和071b为对映异构体。
实施例71c:(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(6.3mg,2%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.1H NMR(300MHz,CD3OD)8.66(d,J=1.3Hz,1H),8.42(d,J=5.1Hz,1H),8.20(s,1H),7.63(dd,J=18.3,7.7Hz,2H),7.48–7.18(m,4H),5.74-5.64(m,1H),5.44(d,J=6.1Hz,1H),4.83(s,2H),3.18(dd,J=16.6,7.9Hz,1H),2.62(s,1H),1.32(s,1H)。tR=3.877分钟(CHIRALCELPAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。71c和71d为对映异构体。
实施例71d:(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(3.1mg,1%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.tR=4.877分钟(CHIRALCELPAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。71c和71d为对映异构体。
实施例71e:(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(1.6mg,1%),其为白色固体:LCMS(ESI,m/z):290.1[M+H]+.1H NMR(300MHz,CD3OD)8.47(s,1H),8.37(d,J=4.9Hz,1H),8.01(s,1H),7.74-7.65(m,1H),7.61-7.40(m,2H),7.38-7.21(m,3H),5.80(d,J=4.0Hz,1H),5.25(d,J=5.5Hz,1H),3.44(s,4H),3.33(s,4H),3.17(dd,J=12.6,7.3Hz,2H),2.83-2.67(m,1H),1.40-1.29(m,1H)。tR=3.711min(CHIRALCEL PAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。71e和71f为对映异构体。
实施例71f:(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(1.2mg,1%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.tR=4.911min(CHIRALCELPAK AD-3,0.46x15cm;3um,100%MeOH(0.1%DEA),1.0ml/min)。71e和71f为对映异构体。
步骤4:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
在氮气下,在-65℃在干冰浴中向6-[5H-咪唑并[4,3-a]异吲哚-5-基]-5H,6H,7H-环戊二烯并[c]吡啶-7-酮(260mg,0.91mmol)在THF(30mL)中的溶液中添加L-selectride(6mL,6.00mmol,1mol/L的THF溶液)。所得溶液在-65℃搅拌1h。该反应然后通过MeOH(10mL)淬灭。所得溶液用水(20mL)稀释。将固体过滤出且通过DCM洗涤。所得溶液用DCM萃取(3x200mL)且合并有机层。溶液用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(13:1)洗脱。这得到60mg(23%)6-[5H-咪唑并[4,3-a]异吲哚-5-基]-5H,6H,7H-环戊二烯并[c]吡啶-7-醇,为淡黄色固体:LCMS(ESI,m/z):290.0[M+H]+.
步骤5:4-硝基苯甲酸6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-基酯
向6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(200mg,0.69mmol)、4-硝基苯甲酸(150mg,0.90mmol)和偶氮二甲酸二叔丁基酯(800mg,3.47mmol)在THF(30mL)中的溶液中添加正三丁基磷烷(0.9mL,3.60mmol)。所得溶液在室温搅拌16h。所得溶液用DCM(300mL)稀释。所得混合物用水洗涤(2x50mL)。将混合物用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(20:1)洗脱。这得到500mg(粗物质)4-硝基苯甲酸6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-基酯,其为棕色固体:LCMS(ESI,m/z):439.1[M+H]+.
步骤6:
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
向4-硝基苯甲酸6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-基酯(500mg,1.14mmol)在THF(5mL)和水(1mL)中的溶液中添加氢氧化锂(250mg,10.44mmol)。所得溶液在室温搅拌30分钟。将混合物用DCM(200mL)稀释且用水洗涤(1x20mL)。有机层用硫酸钠干燥且真空浓缩。该粗产物通过prep-HPLC和手性Prep-HPLC纯化,使用以下条件:
1.柱,XBridge Prep C18 OBD柱19×150mm 5um;流动相,水(0.05%NH4OH):乙腈=20%-35%;检测器,uv 254/220nm;流速,20.0mL/min以得到50mg.
2.柱:CHIRALPAK IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:20mL/min;梯度:50B至50B在18min内;220/254nm
实施例71aa:(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(1.6mg,1%),其为白色固体:LCMS(ESI,m/z):290.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.34(d,J=5.2Hz,1H),7.88(s,1H),7.63(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.43-7.41(m,1H),7.40-7.27(m,1H),7.27(s,1H),7.09(d,J=5.2Hz,1H),6.00(d,J=4.0Hz,1H),5.78(d,J=2.8Hz,1H),5.49(d,J=4.8Hz,1H),3.05-3.02(m,1H),2.49-2.47(m,1H),1.91-1.84(m,1H)。tR=2.243分钟(CHIRALPAK IC-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。71aa和71bb为对映异构体。
实施例71bb:(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇(13.0mg,1%),其为白色固体:LCMS(ESI,m/z):290.2[M+H]+.tR=3.152分钟(CHIRALPAK IC-3,0.46x15cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。71aa和71bb为对映异构体。
实施例72:4-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4R,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4R,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4S,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4S,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4R,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4R,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4S,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
(4S,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
该标题化合物通过与实施例67相同的方法合成。
异构体的构型任意指定。
实施例72a:(4R,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.77(dq,J=7.6,0.9Hz,1H),7.58(d,J=7.5Hz,1H),7.38–7.33(m,1H),7.26(td,J=7.5,1.2Hz,1H),7.10(s,1H),5.56(d,J=4.4Hz,1H),5.43(d,J=5.3Hz,1H),4.70–4.63(m,1H),3.00(t,J=6.4Hz,1H),2.14–2.02(m,2H),0.30(dddd,J=24.2,10.3,6.1,4.3Hz,2H),0.13(dt,J=9.9,5.6Hz,1H)。72a和72h为对映异构体。
实施例72b:(4R,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.59(d,J=7.5Hz,1H),7.39–7.33(m,2H),7.26(td,J=7.5,1.1Hz,1H),7.16(s,1H),5.21(d,J=3.8Hz,1H),5.01(d,J=6.7Hz,1H),3.67(p,J=6.3Hz,1H),2.98(s,1H),2.11–2.03(m,1H),1.97(dd,J=11.6,5.9Hz,1H),0.87–0.79(m,1H),0.60–0.47(m,3H)。72b和72g为对映异构体。
实施例72c:(4S,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.81(s,1H),7.71(d,J=1.1Hz,1H),7.60(s,1H),7.17(s,3H),6.26(s,1H),5.51(s,1H),5.06(s,1H),2.45(dd,J=11.2,7.6Hz,1H),2.22(dd,J=11.2,5.1Hz,1H),0.87–0.71(m,4H)。72c和72f为对映异构体。
实施例72d:(4S,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.56(dt,J=7.6,0.9Hz,1H),7.42–7.30(m,2H),7.24–7.19(m,1H),7.18(d,J=9.3Hz,1H),5.89(d,J=4.0Hz,1H),5.43–5.38(m,1H),4.87–4.78(m,1H),3.26–3.20(m,1H),2.15–2.02(m,2H),0.20(ddd,J=10.0,6.1,4.2Hz,1H)、-0.03–-0.10(m,1H)、-0.40(ddd,J=9.6,6.4,5.0Hz,1H)、-0.50(ddd,J=9.7,6.1,5.0Hz,1H)。72d和72e为对映异构体。
实施例72e:(4R,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),7.57(dt,J=7.6,0.9Hz,1H),7.39(dd,J=7.7,1.0Hz,1H),7.37–7.31(m,1H),7.26–7.15(m,2H),5.90(d,J=4.1Hz,1H),5.41(d,J=2.3Hz,1H),4.83(qd,J=7.8,4.0Hz,1H),3.25–3.20(m,1H),2.15–2.02(m,2H),0.20(ddd,J=10.0,6.1,4.2Hz,1H)、-0.07(dd,J=6.3,4.0Hz,1H)、-0.40(ddd,J=9.7,6.5,5.0Hz,1H)、-0.47–-0.54(m,1H)。72d和72e为对映异构体。
实施例72f:(4R,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.80(s,1H),7.71(d,J=1.1Hz,1H),7.58(s,1H),7.18(s,3H),6.23(s,1H),5.52(d,J=8.1Hz,1H),5.05(tdd,J=7.7,5.1,2.1Hz,1H),2.45(dd,J=11.2,7.7Hz,1H),2.22(dd,J=11.2,5.1Hz,1H),0.87–0.71(m,4H)。72c和72f为对映异构体。
实施例72g:(4S,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.59(dt,J=7.4,1.0Hz,1H),7.39–7.33(m,2H),7.26(td,J=7.6,1.2Hz,1H),7.16(s,1H),5.21(d,J=3.9Hz,1H),5.02(d,J=6.7Hz,1H),3.72–3.63(m,1H),3.00–2.95(m,1H),2.12–1.92(m,2H),0.86–0.78(m,1H),0.60–0.48(m,3H)。72b和72g为对映异构体。
实施例72h:(4S,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇:LCMS(ESI,m/z):253.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.77(dt,J=7.7,1.0Hz,1H),7.58(dt,J=7.5,0.9Hz,1H),7.36(tt,J=7.6,0.9Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.56(d,J=4.5Hz,1H),5.43(d,J=5.3Hz,1H),4.66(tdd,J=7.4,6.0,4.6Hz,1H),3.03–2.97(m,1H),2.12(ddd,J=11.4,7.3,1.8Hz,1H),2.06(dd,J=11.2,6.2Hz,1H),0.30(dddd,J=24.2,10.4,6.2,4.3Hz,2H),0.13(dt,J=9.7,5.6Hz,1H)。72a和72h为对映异构体。
实施例73:3-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
该标题化合物通过与实施例69相同的方法合成。
异构体的构型任意指定。
实施例73a:(3R,4R)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.99(t,J=0.6Hz,1H),7.51–7.36(m,2H),7.19(s,1H),7.14–7.05(m,1H),5.77(d,J=2.0Hz,1H),4.90(d,J=5.3Hz,1H),3.77(dd,J=11.7,4.4Hz,1H),3.66–3.55(m,1H),3.30–3.26(m,1H),3.22(td,J=12.0,2.3Hz,1H),2.96(t,J=11.3Hz,1H),2.34(s,1H),1.84–1.71(m,1H),1.44(qd,J=12.2,4.7Hz,1H)。73a和73c为对映异构体。
实施例73b:(3R,4R)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.53–7.43(m,2H),7.21(s,1H),7.17–7.10(m,1H),5.95(d,J=2.5Hz,1H),5.52(d,J=5.8Hz,1H),3.91(tt,J=10.4,5.2Hz,1H),3.77(dd,J=11.7,4.7Hz,1H),3.17(td,J=12.1,11.7,2.1Hz,1H),3.07–2.99(m,1H),2.35(t,J=10.9Hz,1H),2.32–2.23(m,1H),1.92(ddd,J=10.9,4.7,2.4Hz,1H),1.63–1.49(m,1H)。73b和73d为对映异构体。
实施例73c:(3S,4S)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.48–7.37(m,2H),7.19(s,1H),7.10(ddd,J=10.4,6.3,2.8Hz,1H),5.76(d,J=2.1Hz,1H),4.90(d,J=5.3Hz,1H),3.77(dd,J=11.8,4.4Hz,1H),3.60(tt,J=10.1,5.0Hz,1H),3.28(dd,J=11.6,4.1Hz,1H),3.22(td,J=12.0,2.3Hz,1H),2.96(t,J=11.3Hz,1H),2.34(s,1H),1.76(ddd,J=12.8,4.7,2.3Hz,1H),1.44(qd,J=12.2,4.8Hz,1H)。73a和73c为对映异构体。
实施例73d:(3S,4S)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.53–7.43(m,2H),7.21(s,1H),7.18–7.10(m,1H),5.95(d,J=2.4Hz,1H),5.52(d,J=5.8Hz,1H),3.91(tt,J=10.3,5.2Hz,1H),3.77(dd,J=11.7,4.7Hz,1H),3.22–3.12(m,1H),3.09–2.99(m,1H),2.35(t,J=10.9Hz,1H),2.32–2.25(m,1H),1.97–1.85(m,1H),1.56(tdd,J=12.6,10.5,4.8Hz,1H)。73b和73d为对映异构体。
实施例074:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌
啶-1-磺酰胺和(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-
磺酰胺
步骤1:
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
该标题化合物通过与实施例064相同的方法合成。
步骤2:
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺
在0℃向(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(81mg,0.32mmol)在DCM(5.0mL)中的溶液中添加TEA(0.26mL,1.871mmol)和N-甲基氨磺酰氯(80mg,0.617mmol)。所得溶液在室温搅拌12h。该反应然后通过添加水(10mL)淬灭。所得溶液用DCM(3x20mL)萃取且合并有机层。将混合物用无水硫酸钠干燥且真空浓缩。粗产物通过combi-flash纯化,使用(DCM/MeOH=10:1)。
实施例74a:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺(61.9mg,56%),其为白色固体:LCMS(ESI,m/z):349.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.63(d,J=7.6,1H),7.51(d,J=7.6,1H),7.43-7.39(m,1H),7.34-7.28(m,1H),7.15(s,1H),7.06(q,J=7.6,1H),5.72(d,J=3.3,2H),3.81-3.68(m,2H),3.30-3.27(m,1H),2.51-2.46(m,2H),2.43(s,3H),2.33-2.26(m,1H),0.70-0.64(m,1H),0.54-0.40(m,1H)。
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺
该标题化合物通过与实施例074b相同的方法合成。
实施例74b:(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺(31.7mg,32%),其为白色固体:LCMS(ESI,m/z):349.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.64(d,J=7.5,1H),7.49(d,J=7.5,1H),7.46-7.36(m,2H),7.20(s,1H),5.82(d,J=3.3,1H),3.97-3.91(m,2H),3.50-3.34(m,1H),2.72-2.58(m,2H),2.56(s,3H),2.27-2.12(m,1H),0.96-0.91(m,1H),0.67-0.63(m,1H)。
实施例75和75-1:3-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
和4-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇。
步骤1:8-氟-5H-咪唑并[5,1-a]异吲哚
该标题化合物通过与实施例065相同的方法合成。
步骤2:
(3R,4R)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
该标题化合物通过与实施例065相同的方法合成。
实施例75a:(3R,4R)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.63(dd,J=8.4,5.2Hz,1H),7.43–7.37(m,1H),7.24(ddd,J=9.0,8.1,2.4Hz,1H),7.10(s,1H),5.64(d,J=3.6Hz,1H),5.27(d,J=5.4Hz,1H),3.83–3.72(m,2H),3.20(td,J=12.1,2.3Hz,1H),2.97(dd,J=11.3,3.9Hz,1H),2.63(t,J=11.2Hz,1H),2.39(ddt,J=10.6,6.8,3.8Hz,1H),1.81(ddt,J=12.7,4.4,2.1Hz,1H),1.50(tdd,J=12.4,10.3,4.8Hz,1H)。
实施例75b:(3S,4S)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.4[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.97(d,J=0.6Hz,1H),7.62(dd,J=8.4,5.2Hz,1H),7.40(ddd,J=9.2,2.5,0.8Hz,1H),7.24(dddd,J=9.2,8.4,2.5,0.6Hz,1H),7.10(s,1H),5.64(d,J=3.6Hz,1H),5.27(d,J=5.4Hz,1H),3.77(ddd,J=14.0,10.1,4.7Hz,2H),3.20(td,J=12.1,2.3Hz,1H),3.00–2.94(m,1H),2.63(t,J=11.2Hz,1H),2.39(tt,J=10.2,3.6Hz,1H),1.81(ddd,J=10.6,4.7,2.4Hz,1H),1.55–1.44(m,1H)。
实施例75c:(3R,4R)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.2[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.49(ddd,J=9.0,2.5,1.0Hz,1H),7.24(dddd,J=9.3,8.5,2.5,0.7Hz,1H),7.12(s,1H),5.72(d,J=2.6Hz,1H),5.49(d,J=5.5Hz,1H),3.93(tt,J=10.3,5.0Hz,1H),3.77(dd,J=11.7,4.7Hz,1H),3.24–3.14(m,1H),3.02–2.95(m,1H),2.36(t,J=11.2Hz,1H),2.30–2.21(m,1H),1.96–1.88(m,1H),1.56(tdd,J=12.7,10.6,4.8Hz,1H)。
实施例75d:(3S,4S)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):275.2[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.49(ddd,J=9.1,2.4,1.0Hz,1H),7.24(dddd,J=9.3,8.4,2.4,0.6Hz,1H),7.12(s,1H),5.72(d,J=2.5Hz,1H),5.49(d,J=5.4Hz,1H),3.94(tt,J=10.3,5.0Hz,1H),3.77(dd,J=11.7,4.7Hz,1H),3.25–3.14(m,1H),3.02–2.95(m,1H),2.36(t,J=11.2Hz,1H),2.26(ddt,J=14.0,10.8,3.1Hz,1H),1.96–1.88(m,1H),1.62–1.50(m,1H)。
实施例75-1a:(3R,4R)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.2[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.91(t,J=0.6Hz,1H),7.65(dd,J=8.4,5.1Hz,1H),7.41–7.35(m,1H),7.26(ddt,J=10.4,8.1,1.4Hz,1H),7.10(s,1H),5.69(d,J=3.8Hz,1H),5.44(d,J=5.6Hz,1H),3.84(dd,J=10.5,4.8Hz,1H),3.71–3.57(m,2H),3.11(td,J=11.3,3.2Hz,1H),2.98(dd,J=10.6,9.8Hz,1H),2.43–2.34(m,1H),0.64–0.52(m,2H)。
实施例75-1b:(3S,4S)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.65(dd,J=8.4,5.2Hz,1H),7.41–7.35(m,
1H),7.31–7.22(m,1H),7.10(s,1H),5.69(d,J=3.8Hz,1H),5.44(d,J=5.6Hz,1H),3.84(dd,J=10.6,4.9Hz,1H),3.71–3.57(m,2H),3.11(td,J=11.3,3.2Hz,1H),2.98(t,J=10.2Hz,1H),2.38(ddd,J=15.2,11.0,4.3Hz,1H),0.65–0.51(m,2H)。
实施例75-1c:(3R,4R)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.2[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.41(ddd,J=9.1,2.4,1.0Hz,1H),7.27–7.18(m,1H),7.13(s,1H),5.74–5.69(m,1H),5.52(d,J=5.7Hz,1H),3.91(dd,J=10.6,4.8Hz,1H),3.73(tt,J=10.4,5.3Hz,1H),3.58(dd,J=11.1,4.7Hz,1H),3.17–3.08(m,1H),3.04(dd,J=10.6,9.9Hz,1H),2.29–2.19(m,1H),0.72–0.65(m,1H),0.45(qd,J=12.6,4.8Hz,1H)。
实施例75-1d:(3S,4S)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.5[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.41(ddd,J=9.0,2.6,1.0Hz,1H),7.26–7.20(m,1H),7.13(s,1H),5.73–5.70(m,1H),5.52(d,J=5.8Hz,1H),3.91(dd,J=10.6,4.9Hz,1H),3.73(tt,J=10.4,5.3Hz,1H),3.58(dd,J=11.2,4.7Hz,1H),3.13(td,J=11.7,2.3Hz,1H),3.04(dd,J=10.6,9.9Hz,1H),2.28–2.19(m,1H),0.72–0.64(m,1H),0.45(qd,J=12.6,4.9Hz,1H)。
实施例76:8-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]
癸-1-醇
(1S,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1S,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2S)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
步骤1:(E)-1-氧代-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):650.4[M+H]+
步骤2:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):408.4[M+H]+
步骤3:8-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯的非对映异构体混合物(600mg,1.47mmol)溶于无水MeOH(15mL)中的溶液中分四批添加硼氢化钠(170mg,4.42mmol)。将反应在室温搅拌2h。TLC显示无SM剩余。反应通过添加NH4Cl(5mL)淬灭且通过DCM(3X25mL)萃取,合并的有机相用盐水洗涤且用Na2SO4干燥。去除溶剂后残余物通过硅胶柱色谱纯化。在室温向醇的混合物(400mg,0.97mmol)添加8mL无水DCM,然后添加三氟乙酸(1.5mL,20mmol)且将反应混合物搅拌半小时。TLC指示无SM且反应混合物在减压下浓缩,残余物在高真空泵干燥过夜。该粗混合物运至下一步而不用纯化。在室温向化合物(0.25g,0.81mmol)在8mL无水DCM中的溶液添加三乙基胺(0.22mL,1.62mmol),然后添加乙基磺酰氯(0.08mL,0.89mmol)且搅拌半小时。半小时后,TLC指示起始材料。因此添加0.2mL三乙基胺且将反应混合物再搅拌半小时。TLC指示无SM且反应混合物用水(2mL)淬灭,且反应用DCM(3X5mL)处理。合并的残余物用Na2SO4干燥且在减压下浓缩且使用快速硅胶色谱法纯化:LCMS(ESI,m/z):402.3[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(1S,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1S,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2S)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
实施例76a:(1S,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):402.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(d,J=7.5Hz,1H),7.53(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.45(d,J=4.4Hz,1H),5.07(d,J=5.7Hz,1H),3.57(dd,J=9.6,5.7Hz,1H),3.47(d,J=12.2Hz,1H),3.41(d,J=12.4Hz,1H),2.99(q,J=7.3Hz,2H),2.87(td,J=12.0,2.7Hz,1H),2.75(td,J=12.0,2.7Hz,1H),2.70–2.60(m,1H),1.75–1.56(m,3H),1.30(td,J=9.7,4.5Hz,2H),1.19(t,J=7.4Hz,3H),1.10–1.00(m,1H),0.85(ddt,J=13.2,9.5,4.8Hz,1H)。
实施例76b:(1R,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):402.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.60(d,J=7.5Hz,1H),7.49(d,J=7.3Hz,1H),7.38(t,J=7.5Hz,1H),7.24(td,J=7.6,1.1Hz,1H),7.12(s,1H),5.32–5.27(m,2H),3.90–3.80(m,1H),3.46–3.36(m,1H),3.25–3.18(m,1H),3.05–2.99(m,2H),2.99–2.91(m,2H),2.12(dd,J=18.9,8.8Hz,1H),2.06–1.91(m,2H),1.77–1.69(m,1H),1.65(dt,J=13.2,6.1Hz,3H),1.32–1.24(m,2H),1.20(t,J=7.4Hz,3H)。
实施例76c:(1R,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):402.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.67(d,J=7.6Hz,1H),7.59(d,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.27(td,J=7.6,1.1Hz,1H),7.12(s,1H),5.39(dd,J=11.3,6.6Hz,2H),3.91(t,J=5.2Hz,1H),3.39(dt,J=10.0,4.5Hz,1H),3.28–3.20(m,1H),3.02(q,J=7.4Hz,2H),2.99–2.88(m,2H),2.34–2.25(m,1H),1.72(ddq,J=14.7,8.6,4.8Hz,3H),1.62–1.52(m,3H),1.35–1.30(m,2H),1.20(t,J=7.4Hz,3H)。
实施例76d:(1S,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):402.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.67(d,J=7.6Hz,1H),7.58(d,J=7.5Hz,1H),7.37(t,J=7.4Hz,1H),7.27(td,J=7.6,1.1Hz,1H),7.12(s,1H),5.38(dd,J=11.4,6.5Hz,2H),3.91(t,J=5.2Hz,1H),3.44–3.35(m,1H),3.27–3.19(m,1H),3.04–2.99(m,2H),2.98–2.89(m,2H),2.33–2.25(m,1H),1.71(dtt,J=13.1,9.2,5.4Hz,3H),1.62–1.51(m,3H),1.34–1.30(m,2H),1.20(t,J=7.4Hz,3H)。
实施例76e:(1R,2S)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇:LCMS(ESI,m/z):402.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(d,J=7.5Hz,1H),7.53(d,J=7.1Hz,1H),7.39(t,J=7.5Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.11(s,1H),5.45(d,J=4.4Hz,1H),5.08(d,J=5.7Hz,1H),3.57(dd,J=9.6,5.7Hz,1H),3.47(d,J=12.3Hz,1H),3.41(d,J=12.4Hz,1H),3.00(q,J=7.3Hz,2H),2.87(td,J=12.1,2.8Hz,1H),2.75(td,J=11.9,2.6Hz,1H),2.70–2.59(m,1H),1.73–1.56(m,3H),1.30(td,J=9.7,4.5Hz,2H),1.19(d,J=7.4Hz,3H),1.10–1.00(m,1H),0.85(ddt,J=19.1,9.6,5.4Hz,1H)。
实施例77:1-(环丙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
(3R,4R)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
(3S,4S)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
该标题化合物通过与实施例070a-d相同的方法合成。两种异构体的构型任意指定
实施例77a:(3R,4R)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇(34.6mg,18%),其为白色固体:LCMS(ESI,m/z):360.1[M+H]+.1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.65(d,J=7.5Hz,1H),7.50(d,J=7.9Hz,1H),7.44(t,J=7.4Hz,1H),7.41-7.35(m,1H),7.21(s,1H),5.92(s,1H),4.08-3.86(m,2H),3.55-3.48(m,1H),2.85-2.68(m,2H),2.47(tt,J=7.6,5.1Hz,1H),2.31-2.14(m,1H),1.32(d,J=6.5Hz,1H),1.09-0.88(m,5H),0.65(qd,J=12.7,4.6Hz,1H)。tR=1.478分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。077a和077b为对映异构体。
实施例77b:(3S,4SR)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇(23.4mg,12%),其为白色固体:LCMS(ESI,m/z):360.2[M+H]+.tR=2.199分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。077a和077b为对映异构体。
实施例78:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲
基哌啶-1-磺酰胺和(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲
基哌啶-1-磺酰胺
步骤1:
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基哌啶-1-磺酰胺
在0℃向(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(78mg,0.31mmol)在DCM(5.0mL)中的溶液中添加TEA(0.4mL,2.878mmol)。所得溶液在0℃搅拌20分钟。然后在0℃添加N,N-二甲基氨磺酰氯(58mg,0.41mmol)。所得溶液在室温在搅拌下再反应16h。该反应然后通过水(5mL)淬灭。所得溶液用DCM萃取(3x20mL)且合并有机层。真空浓缩后,粗产物通过prep-HPLC纯化,使用以下条件:柱,Xbridge C18;流动相,在40min内MeCN/H2O=1/30增加至MeCN/H2O=1/38;检测器,UV 254nm.
实施例78a:(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基哌啶-1-磺酰胺(27.7mg,25%),其为白色固体:LCMS(ESI,m/z):363.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.65(d,J=7.5,1H),7.56(d,J=7.5,1H),7.48-7.33(m,2H),7.18(s,1H),5.83(d,J=3.3,1H),3.95-3.82(m,2H),3.48-3.44(m,1H),2.76(s,6H),2.77-2.63(m,2H),2.41-2.25(m,1H),0.82-0.61(m,2H)。
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺
该标题化合物通过与实施例078a相同的方法合成。
实施例78b:(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺(46.2mg,38%),其为白色固体:LCMS(ESI,m/z):363.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.64(d,J=7.5,1H),7.49(d,J=7.5,1H),7.46-7.36(m,2H),7.20(s,1H),5.82(d,J=3.3,1H),3.95-3.90(m,2H),3.50-3.42(m,1H),2.79(s,6H),2.77-2.65(m,2H),2.21-2.12(m,1H),0.95-0.90(m,1H),0.67-0.63(m,1H)。
实施例79:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
该标题化合物通过与实施例064a-b相同的方法合成。两种异构体的构型任意指定。
实施例79a:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(34.6mg,18%),其为白色固体:LCMS(ESI,m/z):334.1[M+H]+.1H NMR(300MHz,DMSO-d6)δ7.92(s,1H),7.63(d,J=7.8Hz,1H),7.52(d,J=7.8Hz,1H),7.44-7.27(m,2H),7.15(s,1H),5.81(d,J=3.6Hz,1H),5.79(d,J=3.6Hz,1H),3.84-3.71(m,2H),3.34-3.29(m,1H),2.84(s,3H),2.55-2.51(m,1H),2.49-2.48(m,1H),2.34-2.21(m,1H),0.71-0.66(m,1H),0.55-0.54(m,1H)。tR=1.717分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。079a和079b为对映异构体。
实施例79b:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇(23.4mg,12%),其为白色固体:LCMS(ESI,m/z):334.1[M+H]+.tR=2.291分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。079a和079b为对映异构体。
实施例80:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
步骤1:
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
在0℃向(3S,4S)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇和(3R,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(99mg,0.39mmol)和TEA(0.45mL,3.24mmol)在DCM(5.0mL)中的溶液中添加丙烷-2-磺酰氯(100mg,0.70mmol)。所得溶液在室温搅拌20h。该反应然后通过添加水(10mL)淬灭。所得溶液用DCM萃取(3x20mL)。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离使用以下条件进行分离:
柱,CHIRALPAK IA,21.2x250mm,5微米;流动相:乙醇:己烷(0.1%DEA)=30:70;检测器,uv 254/220nm;流速,20mL/min.
所有异构体的绝对构型任意指定。
实施例80a:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇(4.8mg,1%),其为白色固体:LCMS(ESI,m/z):362.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.88(s,1H),7.62(d,J=7.8Hz,1H),7.47(d,J=7.8Hz,1H),7.44-7.32(m,2H),7.18(s,1H),5.81(d,J=3.6Hz,1H),4.03-3.95(m,1H),3.85-3.82(m,1H),3.55-3.50(m,1H),3.27-3.21(m,1H),2.84-2.70(m,2H),2.28-2.13(m,1H),1.26(d,J=2.1Hz,6H),0.94-0.88(m,1H),0.62-0.58(m,1H)。080a和080b为对映异构体。
实施例80b:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇(10.8mg,2%),其为白色固体:LCMS(ESI,m/z):362.3[M+H]+.080a和080b为对映异构体。
实施例81:1-(环丙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
步骤1:
(3R,4R)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
(3S,4S)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
在0℃向(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇和(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇(158mg,0.62mmol)和TEA(0.6mL,4.32mmol)在DCM(5.0mL)中的混合物添加环丙烷磺酰氯(260mg,1.849mmol)。所得溶液在室温搅拌1h。该反应然后通过添加水(10mL)淬灭。所得溶液用DCM萃取(3x20mL)。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离使用以下条件进行分离:
柱,Lux 5u Cellulose-4,AXIA Packed,250x21.2mm;流动相:乙醇:己烷(0.1%DEA)=50:50;检测器,uv 254/220nm;流速,20mL/min.
所有异构体081a-b的绝对构型任意指定。
实施例81a:(3R,4R)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇(13.3mg,1%),其为白色固体:LCMS(ESI,m/z):360.1[M+H]+.1H NMR(300MHz,CD3OD)δ7.91(s,1H),7.66(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.48-7.32(m,2H),7.19(s,1H),5.84(d,J=3.6Hz,1H),4.03-3.95(m,1H),3.85-3.82(m,1H),3.55-3.50(m,1H),2.78-2.70(m,2H),2.47-2.28(m,2H),1.04-0.96(m,4H),0.82-0.72(m,2H)。081a和081b为对映异构体。
实施例81b:(3S,4S)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇(18.8mg,1%),其为白色固体:LCMS(ESI,m/z):360.2[M+H]+.081a和81b为对映异构体。
实施例82:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙
基)哌啶-3-醇和(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)
哌啶-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇
在0℃向(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(70mg,0.27mmol)和TEA(0.27mL,1.94mmol)在DCM(3.0mL)中的溶液中添加2,2,2-三氟甲磺酸三氟乙酯(100mg,0.43mmol)。所得溶液在室温搅拌30h。该反应然后通过添加水(10mL)淬灭。所得溶液用DCM萃取(3x20mL)。合并有机层,用无水硫酸钠干燥,且真空浓缩。粗产物使用Combi-flash纯化。
实施例82a:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇(19.2mg,21%),其为白色固体:LCMS(ESI,m/z):338.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.91(s,1H),7.63(d,J=7.5,1H),7.55(d,J=7.5,1H),7.45-7.31(m,2H),7.16(s,1H),5.78(d,J=3.3,1H),3.93-3.81(m,1H),3.22-3.15(m,1H),3.09-2.98(m,2H),2.75-2.65(m,1H),2.16-2.05(m,3H),0.72-0.60(m,2H)。
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇
该标题化合物通过与实施例82a相同的方法合成。
实施例82b:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇(27.3mg,21%),其为白色固体:LCMS(ESI,m/z):338.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.63(d,J=7.5,1H),7.46(d,J=7.5,1H),7.42-7.33(m,2H),7.19(s,1H),5.78(d,J=3.3,1H),3.93-3.86(m,1H),3.30-3.26(m,1H),3.13-3.03(m,2H),2.75-2.70(m,1H),2.40-2.15(m,2H),2.04-2.02(m,1H),0.84-0.80(m,1H),0.65-0.59(m,1H)。
实施例83:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇
和(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇
向(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]哌啶-3-醇(107mg,0.42mmol)在水(4mL)中的溶液中添加乙酸(0.5mL,17.452mmol)和福尔马林(1mL,54.62mmol)。将混合物在室温搅拌4h。在0℃添加氰基硼氢化钠(200mg,3.18mmol)。所得溶液在室温搅拌2h。该反应然后通过添加饱和硫酸氢钠(20mL)淬灭。所得溶液用DCM萃取(3x30mL)且合并有机层。将混合物用无水硫酸钠干燥且真空浓缩。粗产物使用Combi-flash纯化。
实施例83a:(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-1-甲基哌啶-3-醇(1.7mg,1%),其为白色固体:LCMS(ESI,m/z):270.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.61(d,J=7.5,1H),7.51(d,J=7.5,1H),7.40-7.26(m,2H),7.13(s,1H),5.30(d,J=3.2,1H),5.37(d,J=3.2,1H),3.82-3.73(m,1H),2.95-2.92(m,1H),2.46-2.45(m,1H),2.08(s,3H),2.07-2.03(m,1H),1.76-1.58(m,2H),0.52-0.41(m,2H)。
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇
该标题化合物通过与实施例83a相同的方法合成。
实施例83b:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇(76.8mg,25%),其为白色固体:LCMS(ESI,m/z):270.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.63(d,J=7.5,1H),7.47(d,J=7.5,1H),7.42-7.33(m,2H),7.19(s,1H),5.80(d,J=3.3,1H),3.97-3.90(m,1H),3.18-3.13(m,1H),2.70-2.62(m,1H),2.63(s,3H),2.06-1.83(m,3H),0.91-0.86(m,1H),0.72-0.64(m,1H)。
实施例84:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
步骤1:(E)-2,2,5,5-四甲基-4-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)二氢呋喃-3(2H)-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):539.4[M+H]+
步骤2:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基二氢呋喃-3(2H)-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):297.4[M+H]+
步骤3:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):299.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
实施例84a:(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.16(d,J=7.9Hz,1H),7.71(s,1H),7.51(s,1H),7.33–7.25(m,1H),7.21–7.14(m,2H),6.60(d,J=2.2Hz,1H),5.74(d,J=5.0Hz,1H),4.37(dd,J=4.9,2.3Hz,1H),1.26(s,3H),1.24(s,3H),1.00(s,3H),0.83(s,3H)。
实施例84b:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.75(d,J=7.7Hz,1H),7.60(d,J=7.5Hz,1H),7.39(t,J=7.4Hz,1H),7.26(t,J=7.6Hz,1H),7.12(s,1H),5.78–5.59(m,2H),4.09(tt,J=5.2,3.1Hz,1H),3.17(d,J=5.3Hz,1H),1.20(s,3H),1.08(s,3H),1.06(s,3H),0.82(s,3H)。
实施例84c:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ0.81(s,3H),1.05(s,3H),1.07(s,3H),1.20(s,3H),3.17(d,J=5.3Hz,1H),4.08(td,J=5.1,2.7Hz,1H),5.61–5.74(m,2H),7.11(s,1H),7.26(td,J=7.6,1.3Hz,1H),7.39(t,J=7.5Hz,1H),7.60(d,J=7.6Hz,1H),7.74(d,J=7.7Hz,1H),8.00(s,1H)。
实施例84d:(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88–7.79(m,1H),7.74(s,1H),7.71(d,J=7.4Hz,1H),7.29(t,J=6.9Hz,1H),7.25–7.19(m,1H),7.16(s,1H),6.62(s,1H),5.23(d,J=5.0Hz,1H),4.08(d,J=4.7Hz,1H),1.39(d,J=12.3Hz,3H),1.35(d,J=7.2Hz,3H),1.18(s,3H),0.99(d,J=5.9Hz,3H)。
实施例84e:(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.82(dd,J=7.8,1.2Hz,1H),7.74(s,1H),7.72(d,J=7.4Hz,1H),7.30(td,J=7.5,1.2Hz,1H),7.23(td,J=7.5,1.3Hz,1H),7.17(s,1H),6.63(s,1H),5.24(d,J=5.0Hz,1H),4.10(dd,J=9.8,4.8Hz,1H),1.40(d,J=12.6Hz,3H),1.36(d,J=7.4Hz,3H),1.19(s,3H),1.00(d,J=6.0Hz,3H)。
实施例84f:(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇:LCMS(ESI,m/z):299.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.16(d,J=7.7Hz,1H),7.71(s,1H),7.51(dd,J=2.1,1.1Hz,1H),7.32–7.26(m,1H),7.21–7.13(m,2H),6.59(d,J=2.3Hz,1H),5.74(d,J=5.0Hz,1H),4.37(dd,J=5.0,2.4Hz,1H),1.26(s,3H),1.24(s,3H),1.00(s,3H),0.83(s,3H)。
实施例85:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
步骤1:(E)-2,2-二甲基-4-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)二氢呋喃-3(2H)-酮
将10%氢氧化钠水溶液(2.41mL,6.03mmol)添加至2,2-二甲基二氢呋喃-3(2H)-酮(330mg,2.89mmol)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.00g,2.41mmol)在MeOH(20mL)中的搅拌混合物中。反应混合物在65℃加热6小时直到LC-MS显示SM消失。反应混合物用DCM(60mL)稀释且有机物用水洗涤,用Na2SO4干燥,过滤且浓缩。粗物质直接运至下一步。
步骤2:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基二氢呋喃-3(2H)-酮
将粗物质(1.5g,2.94mmol)溶于MeOH(30mL)且添加AcOH(3.36mL,58.8mmol)和回流6h。将反应混合物浓缩。将粗物质溶于DCM(60mL)且用饱和NaHCO3水溶液(20mL)洗涤,用硫酸钠干燥,过滤且浓缩。粗产物通过combi-flash纯化,使用MeOH/DCM作为洗脱液:LCMS(ESI,m/z):269.2[M+H]+.
步骤3:
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
将4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基二氢呋喃-3(2H)-酮(900mgmg,3.35mmol)溶于MeOH(20mL)且冷却至0℃。添加NaBH4(381mg,10.1mmol)且将反应混合物在室温搅拌2h。将NH4Cl(10mL)添加至反应混合物且搅拌10分钟。将溶液倒入包含水(20mL)的分液漏斗。水层用DCM(2x30mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到所需产物,其为非对映异构体混合物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例85a:(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.27(t,J=7.6Hz,1H),7.12(s,1H),5.52(d,J=4.5Hz,1H),5.06(d,J=5.5Hz,1H),3.77(t,J=9.0Hz,1H),3.59(t,J=6.5Hz,1H),3.52(t,J=8.4Hz,1H),2.82(dq,J=12.6,7.6,6.3Hz,1H),1.01(d,J=7.7Hz,6H)。
实施例85b:(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.79(s,1H),7.70(d,J=8.2Hz,1H),7.60(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.28(t,J=7.6Hz,1H),7.12(s,1H),5.67(d,J=5.6Hz,1H),5.47(d,J=8.3Hz,1H),3.99(t,J=5.6Hz,1H),3.85(d,J=9.5Hz,2H),2.73–2.61(m,1H),1.22(s,3H),1.03(s,3H)。
实施例85c:(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.79(s,1H),7.70(d,J=8.2Hz,1H),7.60(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.28(t,J=7.6Hz,1H),7.12(s,1H),5.67(d,J=5.6Hz,1H),5.47(d,J=8.3Hz,1H),3.99(t,J=5.6Hz,1H),3.85(d,J=9.5Hz,2H),2.73–2.61(m,1H),1.22(s,3H),1.03(s,3H)。
实施例85d:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.27(t,J=7.6Hz,1H),7.12(s,1H),5.52(d,J=4.5Hz,1H),5.06(d,J=5.5Hz,1H),3.77(t,J=9.0Hz,1H),3.59(t,J=6.5Hz,1H),3.52(t,J=8.4Hz,1H),2.82(dq,J=12.6,7.6,6.3Hz,1H),1.01(d,J=7.7Hz,6H)。
实施例85e:(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.59(d,J=7.5Hz,1H),7.55(d,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.27(t,J=8.1Hz,1H),7.17(s,1H),5.55(d,J=3.5Hz,1H),5.45(d,J=5.3Hz,1H),3.92(dd,J=8.7,5.3Hz,1H),3.38(t,J=9.0Hz,1H),2.94(qd,J=8.6,3.7Hz,1H),2.81–2.70(m,1H),1.12(s,3H),1.04(s,3H)。
实施例85f:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.62(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.29(d,J=7.4Hz,1H),7.26–7.20(m,1H),7.15(s,1H),5.66(d,J=5.8Hz,1H),5.40(d,J=10.6Hz,1H),4.18(dd,J=10.1,8.0Hz,1H),3.96(t,J=8.2Hz,1H),3.94–3.90(m,1H),1.25(s,3H),1.01(s,3H)。
实施例85g:(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.59(d,J=7.5Hz,1H),7.55(d,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.27(t,J=8.1Hz,1H),7.17(s,1H),5.55(d,J=3.5Hz,1H),5.45(d,J=5.3Hz,1H),3.92(dd,J=8.7,5.3Hz,1H),3.38(t,J=9.0Hz,1H),2.94(qd,J=8.6,3.7Hz,1H),2.81–2.70(m,1H),1.12(s,3H),1.04(s,3H)。
实施例85h:(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇:LCMS(ESI,m/z):271.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.62(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.29(d,J=7.4Hz,1H),7.26–7.20(m,1H),7.15(s,1H),5.66(d,J=5.8Hz,1H),5.40(d,J=10.6Hz,1H),4.18(dd,J=10.1,8.0Hz,1H),3.96(t,J=8.2Hz,1H),3.94–3.90(m,1H),1.25(s,3H),1.01(s,3H)。
实施例86:3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
步骤1:氧杂环庚烷-4-酮
在-25℃向氧杂环己烷-4-酮(7mL,83.90mmol,1.000当量)和(重氮基甲基)三甲基硅烷(27.6mL,193.31mmol)在DCM(400mL)中的溶液中添加三氟化硼醚合物(14mL,128.23mmol)。所得溶液在-25℃搅拌2.5h。该反应然后用水(400mL)淬灭。所得溶液用DCM(2x200mL)萃取且合并有机层。所得混合物用水(1x200mL)洗涤。所得混合物真空浓缩。这得到250mg(3%)氧杂环庚烷-4-酮,其为黄色油状物。
步骤2:(E)-3-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)氧杂环庚烷-4-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):511.6[M+H]+.
步骤3:3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):269.0[M+H]+.
步骤4:
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
该标题化合物通过与实施例071相同的方法合成。
该标题化合物通过与实施例086a-g相同的方法合成。
实施例86a:(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(3.8mg,1%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.95(s,1H),7.74(d,J=7.7Hz,1H),7.69-7.57(m,1H),7.48-7.25(m,2H),7.14(s,1H),5.42(s,1H),4.88(d,J=2.1Hz,17H),4.04(s,1H),3.88-3.65(m,4H),3.42(s,1H),2.57(d,J=11.5Hz,1H),2.42-2.22(m,1H),1.86-1.66(m,2H),0.70-0.66(m,1H)。86a和86b为对映异构体。
实施例86b:(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(3.3mg,1%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.86a和86b为对映异构体。
实施例86c:(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(8.4mg,2%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.1H NMR(300MHz,CD3OD)δ8.22(s,2H),7.57-7.49(m,4H),7.47-7.27(m,4H),7.12(s,2H),5.46(s,2H),4.55(q,J=3.6,2.7Hz,2H),3.88-3.85(m,2H),3.77-3.57(m,4H),3.35-3.31(m,1H),2.65-2.61(m,2H),2.20-2.00(m,2H),1.99-1.67(m,4H),0.70-0.66(m,2H)。86c和86f为对映异构体。
实施例86d:(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(25.2mg,5.6%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.1H NMR(300MHz,CD3OD)δ8.23(d,J=2.1Hz,1H),7.58(dd,J=11.1,7.6Hz,2H),7.49-7.29(m,2H),7.17-7.09(m,1H),5.47(s,1H),4.57-4.47(m,1H),3.75-3.56(m,2H),3.36-3.23(m,1H),2.81(dt,J=12.6,2.6Hz,1H),2.66-2.53(m,1H),2.28-2.25(m,1H),2.03-2.01(m,2H),1.64-1.62(m,1H)。
实施例86e:(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(4.5mg,1%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.1H NMR(300MHz,CD3OD)δ8.01(s,1H),7.85(d,J=7.7Hz,1H),7.62(d,J=7.4Hz,1H),7.47-7.25(m,2H),7.17(s,1H),5.45(d,J=3.4Hz,1H),4.23(dd,J=5.5,2.9Hz,1H),3.85-3.68(m,3H),3.42(dt,J=14.6,4.8Hz,2H),2.54-2.52(m,1H),2.21-2.19(m,1H),2.03-1.72(m,2H),1.71-1.53(m,1H)。86e和86g为对映异构体。
实施例86f:(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(10.7mg,2%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.86c和86f为对映异构体。
实施例86g:(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇(5.5mg,1%),其为白色固体:LCMS(ESI,m/z):271.2[M+H]+.86e和86g为对映异构体。
实施例87:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
步骤1:(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-2-氧杂螺[3.3]庚-6-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和2-氧杂螺[3.3]庚-6-酮(879mg,7.84mmol)在MeOH(40mL)中的溶液中滴加哌啶(0.595mL,6.03mmol)。将溶液回流过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM(3x20mL)萃取且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过EtOAc:己烷=25:75洗脱:LCMS(ESI,m/z):509.2[M+H]+.
步骤2:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-酮
(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-2-氧杂螺[3.3]庚-6-酮(0.78g,1.53mmol)在20%AcOH的MeOH溶液(10mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x10mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化:LCMS(ESI,m/z):267.2[M+H]+.
步骤3:
(5R,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5R,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
(5S,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
在0℃向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-酮(0.3g,1.13mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(86mg,2.25mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用5%三氟乙醇在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例87a:(5R,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+.
实施例087b:(5S,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR 1H NMR(500MHz,DMSO-d6)δ8.18(s,1H),7.65–7.61(m,2H),7.43–7.38(m,1H),7.32–7.26(m,1H),7.19(s,1H),5.67(d,J=3.4Hz,1H),5.61(d,J=8.3Hz,1H),4.78(d,J=7.2Hz,1H),4.50(d,J=6.7Hz,1H),4.40(d,J=7.2Hz,1H),4.38–4.33(m,1H),4.32(d,J=6.8Hz,1H),2.65–2.58(m,1H),2.38(ddd,J=12.2,5.9,1.4Hz,1H),2.06(dd,J=12.4,2.5Hz,1H)。
实施例87c:(5S,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.89(dd,J=7.7,1.1Hz,1H),7.84(s,1H),7.67–7.61(m,1H),7.42(t,J=7.6Hz,1H),7.32(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.67(d,J=9.6Hz,1H),5.29(d,J=7.7Hz,1H),5.03(d,J=6.9Hz,1H),4.63(d,J=7.0Hz,1H),4.52(d,J=6.8Hz,1H),4.43(d,J=6.7Hz,1H),4.18(p,J=7.8Hz,1H),2.60(dd,J=11.3,7.5Hz,1H),2.17(dd,J=9.7,7.7Hz,1H),1.91(dd,J=11.3,8.3Hz,1H)。
实施例87d:(5R,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.89(dd,J=7.7,0.9Hz,1H),7.84(s,1H),7.64(dt,J=7.6,0.9Hz,1H),7.45–7.39(m,1H),7.32(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.67(d,J=9.7Hz,1H),5.29(d,J=7.7Hz,1H),5.03(d,J=7.0Hz,1H),4.64(d,J=7.0Hz,1H),4.52(d,J=6.8Hz,1H),4.43(d,J=6.8Hz,1H),4.23–4.13(m,1H),2.60(dd,J=11.2,7.5Hz,1H),2.17(dd,J=9.7,7.7Hz,1H),1.91(dd,J=11.3,8.3Hz,1H)。
实施例87e:(5R,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.18(d,J=2.0Hz,1H),7.67–7.60(m,2H),7.44–7.37(m,1H),7.33–7.27(m,1H),7.19(d,J=2.0Hz,1H),5.67(t,J=2.8Hz,1H),5.61(d,J=8.1Hz,1H),4.78(dd,J=7.3,2.0Hz,1H),4.51(dd,J=6.8,2.0Hz,1H),4.40(dd,J=7.1,2.0Hz,1H),4.35(dd,J=6.0,3.0Hz,1H),4.32(dd,J=6.9,2.0Hz,1H),2.62(t,J=7.6Hz,1H),2.38(dd,J=12.4,5.8Hz,1H),2.06(dt,J=12.3,2.4Hz,1H)。
实施例87f:(5S,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.99(s,1H),7.82(d,J=13.3Hz,1H),7.65(s,1H),7.51–7.26(m,3H),7.16(s,2H),5.67(s,2H),5.19(s,1H),5.02(s,1H),4.72(s,1H),4.53(s,1H),4.40(s,2H),4.27(s,1H),2.32(s,4H),2.07(s,2H),1.25(s,7H),0.86(s,3H)。
实施例87g:(5R,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.11(s,1H),7.66–7.61(m,2H),7.40(s,1H),7.26(d,J=1.2Hz,1H),7.20(s,1H),5.62(d,J=8.8Hz,1H),5.30(d,J=7.5Hz,1H),4.66(d,J=7.1Hz,1H),4.48(dd,J=12.2,6.9Hz,2H),4.21(dd,J=15.3,7.3Hz,2H),2.56(dd,J=11.3,7.7Hz,1H),2.30(t,J=8.3Hz,1H),1.91(dd,J=11.3,8.4Hz,1H)。
实施例87h:(5S,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇:LCMS(ESI,m/z):269.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.12(s,1H),7.67–7.60(m,2H),7.40(tt,J=7.7,0.8Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.20(s,1H),5.62(d,J=8.7Hz,1H),5.30(d,J=7.6Hz,1H),4.66(d,J=7.0Hz,1H),4.48(dd,J=12.4,6.9Hz,2H),4.26–4.17(m,2H),2.56(dd,J=11.3,7.6Hz,1H),2.30(t,J=8.4Hz,1H),1.91(dd,J=11.3,8.4Hz,1H)。
实施例88:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡
啶-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
步骤1:(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢咪唑并[1,2-a]吡啶-8(5H)-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):533.3[M+H]+
步骤2:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢咪唑并[1,2-a]吡啶-8(5H)-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):291.4[M+H]+
步骤3:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):293.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
实施例88a:(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.64(d,J=7.6Hz,1H),7.52(d,J=7.7Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.17(s,1H),6.96(d,J=1.0Hz,1H),6.90(d,J=1.0Hz,1H),6.11(d,J=6.1Hz,1H),5.75(d,J=3.3Hz,1H),4.90(dd,J=10.1,6.1Hz,1H),3.85–3.62(m,2H),2.83–2.68(m,1H),1.11–1.07(m,1H),1.04–0.99(m,1H)。
实施例88b:(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.67–7.63(m,1H),7.60(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.29(td,J=7.6,1.1Hz,1H),7.13(s,1H),7.01(d,J=1.1Hz,1H),6.93(d,J=1.1Hz,1H),6.22(d,J=4.9Hz,1H),5.51(d,J=2.2Hz,1H),5.18–4.84(m,1H),4.08–3.87(m,1H),3.64(td,J=12.5,4.8Hz,1H),2.62(dd,J=12.6,2.6Hz,1H),1.81(qd,J=12.8,5.9Hz,1H),1.16–1.00(m,1H)。
实施例88c:(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.64(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.42(t,J=7.4Hz,1H),7.33(td,J=7.5,1.0Hz,1H),7.18(s,1H),6.97(d,J=0.9Hz,1H),6.92(d,J=0.9Hz,1H),6.07(d,J=6.6Hz,1H),5.75(s,1H),4.97(dd,J=10.1,6.6Hz,1H),3.89–3.64(m,2H),2.59(dd,J=12.4,4.4Hz,1H),1.08–1.05(m,2H)。
实施例88d:(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.65(d,J=7.6Hz,1H),7.53(d,J=7.7Hz,1H),7.41(t,J=7.5Hz,1H),7.25(t,J=7.6Hz,1H),7.18(s,1H),6.96(s,1H),6.90(s,1H),6.13(d,J=6.1Hz,1H),5.75(d,J=3.2Hz,1H),4.90(dd,J=10.1,6.1Hz,1H),3.87–3.64(m,2H),2.85–2.71(m,1H),1.11–1.07(m,1H),1.05–0.99(m,1H)。
实施例88e:(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.64(d,J=7.5Hz,1H),7.51(d,J=7.5Hz,1H),7.43(t,J=7.5Hz,1H),7.33(t,J=7.5Hz,1H),7.18(s,1H),6.98(s,1H),6.92(s,1H),6.08(d,J=6.6Hz,1H),5.76(s,1H),4.97(dd,J=10.0,6.6Hz,1H),3.82–3.65(m,2H),2.63(s,1H),1.11–1.05(m,2H)。
实施例88f:(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.76(d,J=7.7Hz,1H),7.63(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.15(s,1H),7.03(d,J=1.0Hz,1H),6.92(d,J=1.1Hz,1H),6.01(d,J=5.1Hz,1H),5.47(d,J=6.0Hz,1H),4.95–4.85(m,1H),4.08(dd,J=12.8,4.6Hz,1H),3.74(td,J=12.4,4.8Hz,1H),2.34(dd,J=6.1,3.1Hz,1H),2.21(qd,J=12.8,5.9Hz,1H),1.81(d,J=12.6Hz,1H)。
实施例88g:(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.73–7.63(m,1H),7.60(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.29(td,J=7.6,1.1Hz,1H),7.13(s,1H),7.01(d,J=1.1Hz,1H),6.93(d,J=1.1Hz,1H),6.22(d,J=4.9Hz,1H),5.51(d,J=2.2Hz,1H),5.25–4.88(m,1H),4.05–3.87(m,1H),3.64(td,J=12.5,4.8Hz,1H),2.62(dd,J=12.6,2.6Hz,1H),1.81(qd,J=12.7,5.9Hz,1H),1.12(dd,J=16.3,2.1Hz,1H)。
实施例88h:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇:LCMS(ESI,m/z):293.2[M+H1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.75(d,J=7.8Hz,1H),7.62(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.14(s,1H),7.02(d,J=1.1Hz,1H),6.91(d,J=1.1Hz,1H),6.01(d,J=5.1Hz,1H),5.46(d,J=6.0Hz,1H),5.08–4.70(m,1H),4.07(dd,J=12.8,4.4Hz,1H),3.73(td,J=12.5,4.8Hz,1H),2.33(dd,J=6.1,3.1Hz,1H),2.20(qd,J=12.8,5.9Hz,1H),1.80(d,J=13.2Hz,1H)。
实施例89:4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
该标题化合物通过与实施例089a-b相同的方法合成。两种异构体的构型任意指定
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
实施例89a:(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇(36.0mg,15%),其为白色固体:LCMS(ESI,m/z):362.2[M+H]+.1H NMR(300MHz,CD3OD)δ7.91(s,1H),7.65(d,J=7.8Hz,1H),7.55(d,J=7.8Hz,1H),7.45-7.32(m,2H),7.17(s,1H),5.83(d,J=3.6Hz,1H),4.01-3.85(m,2H),3.58-3.52(m,1H),3.27-3.22(m,1H),2.82-2.70(m,2H),2.42-2.28(m,1H),1.27(d,J=2.1Hz,6H),0.82-0.58(m,2H)。89a和89b为对映异构体。
实施例89b:(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇(29.7mg,12%),其为白色固体:LCMS(ESI,m/z):362.2[M+H]+.89a和89b为对映异构体。
实施例90:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
步骤1:2-(羟基(2-(1-三苯甲基-1H-咪唑-4-基)苯基)甲基)-2,6,6-三甲基环己烷-1-酮
向二异丙基酰胺锂(2M,4.8mL,9.6mmol)在THF(50mL)在-78℃中的溶液中滴加2,2,6-三甲基环己烷-1-酮(1.35g,9.6mmol)。然后将反应混合物温热至室温且搅拌40分钟。添加ZnCl2溶液(0.5M,19.3mL)且将混合物再搅拌10分钟,然后冷却至-78℃。在-78℃添加2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(2g,4.8mmol)在THF(10mL)中的溶液。反应混合物搅拌0.5小时后,反应通过在-78℃添加10mL水然后添加30mL NH4Cl溶液淬灭。反应通过EtOAc(30mL x 3)萃取。合并的有机相用盐水洗涤且用Na2SO4干燥。产物通过combi-flash使用20%-30%of EtOAc/Hex纯化:LCMS(ESI,m/z):555.7[M+H]+.
步骤2:2-((2-(1H-咪唑-4-基)苯基)(羟基)甲基)-2,6,6-三甲基环己烷-1-酮
向2-(羟基(2-(1-三苯甲基-1H-咪唑-4-基)苯基)甲基)-2,6,6-三甲基环己烷-1-酮在MeOH(15mL)中的溶液中添加乙酸(6mL)且溶液在90℃加热3hr。在减压下去除溶剂。产物通过combiflash使用4%-5%MeOH/DCM纯化:LCMS(ESI,m/z):313.3[M+H]+.
步骤3:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-酮
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-酮(1.1g,3.52mmol)在THF(50mL)中的溶液中添加三苯基膦(1.85g,7.04mmol),然后添加(E)-二氮烯-1,2-二甲酸二异丙基酯(1.38mL,7.04mmol)且将溶液温热至25℃。在25℃搅拌2hr后,反应通过添加饱和NaHCO3溶液淬灭。产物用DCM(3x50mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩以得到粗产物且进一步通过硅胶柱色谱法纯化(MeOH/DCM=1%-2%):LCMS(ESI,m/z):296.3[M+H]+.
步骤4:
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-酮(1.06g,3.50mmol)在MeOH(25mL)中的溶液中分批添加NaBH4(280mg,7.40mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵(20mL)。水层用DCM(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到6种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例90a:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇:LCMS(ESI,m/z):297.5[M+H]+.1H NMR与实施例90b相同。
实施例90b:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇LCMS(ESI,m/z):297.5[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.63–7.52(m,2H),7.36(ddd,J=7.6,7.0,0.9Hz,1H),7.21(td,J=7.6,1.3Hz,1H),7.12(s,1H),5.30(s,1H),5.03(d,J=6.2Hz,1H),3.36(d,J=6.1Hz,1H),1.31(s,5H),1.08(dt,J=13.8,3.5Hz,1H),0.97(d,J=7.2Hz,6H),0.82(td,J=13.8,3.7Hz,1H),0.59(dd,J=13.2,2.7Hz,1H),0.24(td,J=13.3,4.0Hz,1H)。
实施例90c:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇:LCMS(ESI,m/z):297.5[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.66(d,J=7.8Hz,1H),7.57(d,J=7.4Hz,1H),7.38(t,J=7.6Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.31(s,1H),4.90(d,J=6.1Hz,1H),3.41(d,J=6.0Hz,1H),1.28(s,6H),1.14–1.07(m,1H),0.93(d,J=18.0Hz,6H),0.78(td,J=13.5,3.8Hz,1H),0.53(dd,J=13.0,2.7Hz,1H),0.39(td,J=13.3,4.0Hz,1H)。
实施例90d:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇LCMS(ESI,m/z):297.5[M+H]+.1H NMR与实施例90c相同
实施例90e:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇:LCMS(ESI,m/z):297.5[M+H]+.无1H NMR数据
实施例90f:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇:LCMS(ESI,m/z):297.5[M+H]+.无1H NMR数据
实施例91:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
步骤1:7-(甲基硫基)色满-4-酮
在氮气下,将7-溴-3,4-二氢-2H-1-苯并吡喃-4-醇(3g,13.10mmol)、DIPEA(5.1g,39.460mmol,3.013当量)、Pd2(dba)3CHCl3(1.35g,1.30mmol)、XantPhos(760mg,1.31mmol)和(甲基硫基)钠(1.39g,19.86mmol)在甲苯(100mL)中的混合物在油浴中在110℃搅拌3h。将固体过滤出。所得混合物真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(1:9)洗脱。这得到1.8g(70%)7-(甲基硫基)-3,4-二氢-2H-1-苯并吡喃-4-醇,其为黄色油状物。
步骤2:(E)-7-(甲基硫基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)色满-4-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):591.0[M+H]+.
步骤3:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)色满-4-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):349.3[M+H]+.
步骤4:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)色满-4-醇
该标题化合物通过合成Int-6的通用步骤合成:LCMS(ESI,m/z):351.3[M+H]+.
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3R,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
向3-[5H-咪唑并[4,3-a]异吲哚-5-基]-7-(甲基硫基)-3,4-二氢-2H-1-苯并吡喃-4-醇(1.2g,3.42mmol)在DCM(20mL)中的溶液中添加MCPBA(1.2g,6.95mmol)。所得溶液在室温搅拌3h。溶液的pH值用饱和碳酸氢钠调节至7。所得溶液用EtOAc萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。将粗产物纯化,用DCM/MeOH(90:10)洗脱,然后进一步通过Prep-HPLC和Chiral-Prep-HPLC使用以下条件分离:
1.柱,XBridge Shield RP18 OBD柱,5um,19x150mm;流动相,Waters(0.05%NH3H2O)和ACN(15.0%CAN至40.0%在12min内);检测器,UV 220nm.
2.柱,手性ART Cellulose-SB,250x20mm I.D.;流动相,己醇和乙醇-(保持35.0%乙醇-在21min内);检测器,UV 254/220nm.所有异构体091a-h的绝对构型任意指定。
实施例91a:(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(14.2mg,9%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.70(d,J=8.1Hz,1H),7.62(d,J=7.6Hz,1H),7.59-7.42(m,3H),7.36-7.27(m,2H)7.18(s,1H),5.60(d,J=4.2Hz,1H),5.03(d,J=8.0Hz,1H),4.01-3.89(m,2H),3.02(s,3H),2.83-2.75(m,1H)。tR=8.606分钟(手性Cellulose-SB,0.46x15cm,3um;Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。91a和91b为对映异构体。
实施例91b:(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(13.9mg,8%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.tR=10.172分钟(手性Cellulose-SB,0.46x15cm,3um;Hex(0.1%DEA):EtOH=70:30,1.0ml/min)。91a和91b为对映异构体。
实施例91c:(3R,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(5.2mg,3%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.1HNMR(400MHz,CDCl3)δ8.31(s,1H),7.82(d,J=8.1Hz,1H),7.61(d,J=7.4Hz,1H),7.59-7.43(m,3H),7.37-7.24(m,3H),5.87(d,J=3.0Hz,1H),5.19(d,J=9.9Hz,1H),3.82-3.77(m,1H),3.55(t,J=11.0Hz,1H),3.02(s,3H),2.85-2.76(m,1H)。tR=8.606分钟(CHIRALPAK IA-3,0.46x5cm;3um;Hex(0.1%DEA):EtOH=65:35,1.0ml/min)。91a和91b为对映异构体。
实施例91d:(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(2.9mg,2%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.tR=3.482分钟(CHIRALPAK IA-3,0.46x5cm;3um;Hex(0.1%DEA):EtOH=65:35,1.0ml/min)。91c和91d为对映异构体。
实施例91e:(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(26.9mg,16%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.68-7.57(m,3H),7.46-7.38(m,2H),7.28-7.21(m,2H),7.16(s,1H),6.13(d,J=5.5Hz,1H),5.53(d,J=6.4Hz,1H),4.84(dd,J=5.4,3.6Hz,1H),4.38-4.26(m,2H),3.19(s,3H),2.54(dd,J=7.0,3.5Hz,1H)。tR=5.875分钟(手性Cellulose-SB,0.46x15cm,3um;Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。91e和91f为对映异构体。
实施例91f:(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(24.3mg,15%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.tR=6.560分钟(手性Cellulose-SB,0.46x15cm,3um;Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。91e和91f为对映异构体。
实施例91g:(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(45.7mg,28%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.67(d,J=8.0Hz,1H),7.55-7.50(m,2H),7.44-7.37(m,3H),7.33-7.28(m,1H),6.91(s,1H),5.58(s,1H),5.17(d,J=3.0Hz,1H),3.76(t,J=11.2Hz,1H),3.60(dd,J=10.9,3.4Hz,1H),3.04(s,3H),2.73-2.68(m,1H)。tR=2.241分钟(CHIRALPAKIA-3,0.46x15cm,3um;Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。091g和091h为对映异构体。
实施例91h:(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇(51.8mg,32%),其为白色固体:LCMS(ESI,m/z):383.0[M+H]+.tR=2.971分钟(CHIRALPAK IA-3,0.46x15cm,3um;Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。91g和91h为对映异构体。
实施例92:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-
醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
合成途径
在-70℃在氮气下向2,3,6,7-四氢氮杂环庚三烯-1-甲酸叔丁酯(1,4.23g,21.4mmol,100质量%)在二氯甲烷(100mL,1560mmol,100质量%)中的溶液中添加3-氯过氧苯甲酸(9.7g,43mmol,77质量%),其为固体。将其在氮气下搅拌过夜,在过程中温热至室温。将反应过滤以去除固体且滤液在减压下浓缩以得到蜡状白色固体。然后将其溶于150mL二氯甲烷且用200mL1N碳酸钠溶液洗涤。有机层然后用硫酸钠干燥,过滤且浓缩以得到淡黄色油状物。然后将其浓缩,溶于35mL二氯甲烷且通过快速柱纯化以得到8-氧杂-4-氮杂双环[5.1.0]辛烷-4-甲酸叔丁酯,其为澄清油状物(3.87g)。1HNMR(400MHz,氯仿-d)δ3.78(dd,J=57.6,14.2Hz,2H),3.22–3.15(m,2H),2.81–2.65(m,2H),2.23–2.04(m,4H),1.45(s,9H)。
步骤2:4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-甲酸叔丁酯
在氮气氛下在-78℃向5H-咪唑并[5,1-a]异吲哚(3,1.9g,12mmol,100质量%)在四氢呋喃(40mL,491mmol,100质量%)中的溶液中经3-4mins滴加n-BuLi(2.5mol/L)在己烷(5.0mL,13mmol,2.5mol/L)中的溶液。然后将其在-78℃在氮气下搅拌60分钟。在-78℃在氮气下经3分钟向其滴加8-氧杂-4-氮杂双环[5.1.0]辛烷-4-甲酸叔丁酯(2,2.495g,11.70mmol,100质量%)在四氢呋喃(6mL,73.7mmol,100质量%)中的溶液。然后将其在-78℃在氮气下搅拌30分钟。该反应然后在氮气下温热至室温。2小时后该反应用饱和氯化铵溶液(10mL)淬灭且用乙酸乙酯(2x50mL)萃取。合并的有机层用硫酸镁干燥,过滤。然后将其在减压下浓缩且残余物通过快速柱纯化以得到4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-甲酸叔丁酯,其为灰白色泡沫固体(2.96g):LCMS(ESI,m/z):370[M+H]+.
步骤3:5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-4-醇
向4-羟基-5-(5H-咪唑并[1,5-b]异吲哚-5-基)氮杂环庚烷-1-甲酸叔丁酯(4,822mg,2.225mmol,100质量%)在二氯甲烷(20mL,312.0mmol,100质量%)中的溶液中添加三氟乙酸(5mL,66.13mmol,100质量%)且在室温搅拌45分钟。该反应然后在减压下浓缩且用作TFA盐用于下一步:LCMS(ESI,m/z):270[M+H]+.
步骤4:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
向5-(5H-咪唑并[1,5-b]异吲哚-5-基)氮杂环庚烷-4-醇;2,2,2-三氟过氧乙酸(5,2.22mmol,2.22mmol,100质量%)在乙腈(30mL,572mmol,100质量%)中的溶液中添加三乙胺(5mL,35.9mmol,100质量%)。然后将其搅拌5分钟。向其滴加搅拌甲磺酰氯(0.26mL,3.3mmol,100质量%)。然后将其在室温搅拌72h。反应在减压下浓缩且通过快速柱纯化以得到5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇。然后将其纯化且单独的异构体通过手性分离进行分离(SFC,柱,Whelko-01,150x21.2mm;流动相:CO2:甲醇=70:30;Isocratic,检测器,uv 270nm;流速70mL/min,40℃)以得到4种异构体。
实施例92a:LCMS(ESI,m/z):348.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(d,J=7.4Hz,1H),7.46(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.31(td,J=7.5,1.2Hz,1H),7.16(s,1H),5.77–5.74(m,1H),5.45(d,J=5.8Hz,1H),3.86(tdd,J=9.9,5.8,3.9Hz,1H),3.42–3.36(m,1H),3.12–3.02(m,2H),2.87(ddd,J=12.9,10.5,4.6Hz,1H),2.77(s,3H),2.34–2.28(m,1H),2.21–2.13(m,1H),1.85–1.75(m,1H),0.78–0.65(m,2H)。
实施例92b:LCMS(ESI,m/z):348.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(d,J=7.5Hz,1H),7.46(dd,J=7.6,1.1Hz,1H),7.40(t,J=7.4Hz,1H),7.33–7.29(m,1H),7.16(s,1H),5.76–5.74(m,1H),5.45(d,J=5.8Hz,1H),3.86(dt,J=9.9,5.9Hz,1H),3.41–3.36(m,1H),3.10–3.02(m,2H),2.91–2.84(m,1H),2.78(s,3H),2.36–2.29(m,1H),2.18(ddd,J=11.1,5.7,3.2Hz,1H),1.85–1.76(m,1H),0.77–0.67(m,2H)。
实施例92c:LCMS(ESI,m/z):348.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.62(d,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.76(d,J=3.6Hz,1H),5.40(d,J=5.2Hz,1H),3.83(dt,J=9.9,4.9Hz,1H),3.40–3.34(m,1H),3.11–3.02(m,2H),2.92–2.84(m,1H),2.77(s,3H),2.17–2.11(m,1H),1.82–1.73(m,1H),0.77–0.68(m,1H),0.62–0.56(m,1H)。
实施例92d:LCMS(ESI,m/z):348.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.62(d,J=7.5Hz,1H),7.56–7.53(m,1H),7.40(t,J=7.5Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.76(d,J=3.8Hz,1H),5.40(d,J=5.3Hz,1H),3.83(dt,J=9.9,5.1Hz,1H),3.39–3.34(m,1H),3.11–3.02(m,2H),2.92–2.85(m,1H),2.77(s,3H),2.14(ddt,J=12.1,6.3,3.3Hz,1H),1.82–1.74(m,1H),0.76–0.67(m,1H),0.62–0.55(m,1H)。
实施例93:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-
4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
该标题化合物通过与实施例88相同的方法合成。
异构体的构型任意指定。
实施例93a:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):307.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.63(d,J=7.5Hz,1H),7.45(d,J=7.6Hz,1H),7.43–7.29(m,3H),7.17(s,1H),5.76(s,1H),5.62(d,J=7.1Hz,1H),4.92(d,J=8.0Hz,1H),3.58(s,3H),2.44(dd,J=16.2,5.4Hz,1H),2.36–2.25(m,1H),2.20(td,J=11.9,2.5Hz,1H),0.96–0.79(m,2H)。93a和93e为对映异构体。
实施例93b:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):307.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.77(dt,J=7.8,1.0Hz,1H),7.60(dt,J=7.5,0.9Hz,1H),7.38(tt,J=7.6,0.9Hz,1H),7.32(s,1H),7.23(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.42(d,J=5.5Hz,1H),5.19(d,J=5.8Hz,1H),4.82(s,1H),3.62(s,3H),2.69(ddd,J=16.3,5.7,1.7Hz,1H),2.43–2.32(m,1H),2.08–2.02(m,1H),1.90(qd,J=12.5,5.6Hz,1H),1.65(dd,J=12.4,5.8Hz,1H)。93b和93d为对映异构体。
实施例93c:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):307.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.62–7.56(m,2H),7.38(d,J=4.9Hz,2H),7.28(td,J=7.5,1.2Hz,1H),7.11(s,1H),5.50–5.42(m,2H),4.99(dd,J=5.9,3.6Hz,1H),3.60(s,3H),2.58(dd,J=16.7,5.0Hz,1H),2.33(dd,J=12.6,3.1Hz,1H),2.26(ddd,J=16.8,12.0,6.0Hz,1H),1.49(qd,J=12.6,5.7Hz,1H),0.94(m 1H)。93c和93f为对映异构体。
实施例93d:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):306.9[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.77(dd,J=7.8,0.9Hz,1H),7.60(d,J=7.5Hz,1H),7.38(dd,J=7.9,7.0Hz,1H),7.32(s,1H),7.23(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.42(d,J=5.6Hz,1H),5.18(d,J=5.8Hz,1H),4.82(dd,J=5.9,3.3Hz,1H),3.62(s,3H),2.73–2.65(m,1H),2.43–2.32(m,1H),2.09–2.01(m,1H),1.90(qd,J=12.5,5.7Hz,1H),1.65(dd,J=12.6,5.8Hz,1H)。93b和93d为对映异构体。
实施例93e:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):306.9[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.63(dd,J=7.6,1.0Hz,1H),7.48–7.34(m,3H),7.32(td,J=7.5,1.1Hz,1H),7.17(s,1H),5.76(d,J=1.2Hz,1H),5.61(d,J=6.9Hz,1H),4.96–4.89(m,1H),3.58(s,3H),2.44(dd,J=16.2,5.3Hz,1H),2.31(ddd,J=16.5,11.4,5.8Hz,1H),2.24–2.16(m,1H),0.96–0.76(m,2H)。93a和93e为对映异构体。
实施例93f:(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):307.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(d,J=3.9Hz,1H),7.62–7.56(m,2H),7.42–7.34(m,2H),7.28(td,J=7.7,7.3,4.8Hz,1H),7.11(d,J=3.9Hz,1H),5.50–5.42(m,2H),4.98(dd,J=5.9,3.5Hz,1H),3.60(d,J=3.1Hz,3H),2.58(dd,J=16.2,5.3Hz,1H),2.36–2.20(m,2H),1.48(tt,J=12.0,6.0Hz,1H),0.94(d,J=13.7Hz,1H)。93c和93f为对映异构体。
实施例93g:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇:LCMS(ESI,m/z):307.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.64(dt,J=7.6,0.8Hz,1H),7.56(dd,J=7.7,1.0Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.36(s,1H),7.25(td,J=7.6,1.2Hz,1H),7.16(s,1H),5.76(d,J=3.1Hz,1H),5.64(d,J=6.5Hz,1H),4.91(dd,J=9.7,6.4Hz,1H),3.57(s,3H),2.48–2.28(m,3H),0.88(dq,J=9.1,4.9Hz,2H)。
实施例94:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
步骤1:
(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹唑啉-5(6H)-酮
将7,8-二氢喹唑啉-5(6H)-酮(715mg.,4.8mmol)添加至2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2g.,4.8mmol)和哌啶(205mg,0.12mmol)在乙醇溶液(30mL)中的搅拌混合物中。然后将反应混合物回流3小时。冷却至室温后,该反应用水(100mL)淬灭且通过DCM(50mLX 3)萃取。合并的有机相用Na2SO4干燥且通过CombiFlash纯化,使用2-4%MeOH/DCM:LCMS(ESI,m/z):545.6[M+H]+
步骤2:
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹唑啉-5(6H)-酮
(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹唑啉-5(6H)-酮在MeOH(15mL)和乙酸(5mL)中在80℃搅拌2小时。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(30mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM(2x20mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过combi-flash纯化,使用甲醇/DCM 2%-4%:LCMS(ESI,m/z):303.2[M+H]+
步骤3:
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
在0℃将6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹唑啉-5(6H)-酮(750mg,2.48mmol)溶于无水MeOH(15mL)。分四份添加NaBH4(375mg,9.92mmol)。将反应在室温搅拌0.5小时。反应通过水淬灭且通过DCM萃取(25mL x 3),合并的有机相用盐水洗涤且用Na2SO4干燥。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例94a:(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.67(s,1H),7.99(s,1H),7.75–7.70(m,1H),7.64–7.60(m,1H),7.43–7.37(m,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.79(d,J=5.9Hz,1H),5.47(d,J=6.0Hz,1H),4.93–4.87(m,1H),2.86(ddd,J=18.6,5.7,1.9Hz,1H),2.75(ddd,J=18.5,12.0,6.4Hz,1H),2.24(ddt,J=12.3,6.0,3.0Hz,1H),2.07(qd,J=12.7,5.8Hz,1H),1.86–1.78(m,1H)。
实施例94b:(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR与实施例94a相同。
实施例94c:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),8.91(d,J=0.8Hz,1H),7.97(s,1H),7.64(d,J=7.5Hz,1H),7.50(dq,J=7.6,0.9Hz,1H),7.42(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.6,1.1Hz,1H),7.19(s,1H),6.39(d,J=7.4Hz,1H),5.80(s,1H),5.08(dd,J=10.6,7.4Hz,1H),2.70–2.60(m,2H),2.48-2.40(m,1H),1.00–0.84(m,2H)。
实施例94d:(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.97(d,J=1.2Hz,1H),8.74(d,J=1.3Hz,1H),7.97(s,1H),7.61(dd,J=8.2,6.9Hz,2H),7.40(t,J=7.5Hz,1H),7.29(tt,J=7.4,1.3Hz,1H),7.13(s,1H),6.11(dd,J=5.8,1.2Hz,1H),5.57(s,1H),5.11(t,J=4.7Hz,1H),2.76(dd,J=18.6,5.4Hz,1H),2.63(ddd,J=18.7,12.3,6.3Hz,1H),2.5--2.50(m,1H,与DMSO融合),1.62(qd,J=12.6,5.7Hz,1H),1.07(d,J=9.9Hz,1H)。
实施例94e:(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.92(d,J=0.7Hz,1H),8.86(d,J=0.9Hz,1H),7.91(s,1H),7.64(ddd,J=9.1,7.7,1.0Hz,2H),7.41(tt,J=7.5,0.8Hz,1H),7.27(td,J=7.6,1.2Hz,1H),7.17(s,1H),6.36(d,J=7.2Hz,1H),5.80(d,J=3.3Hz,1H),5.01(dd,J=10.7,7.2Hz,1H),2.78–2.57(m,3H),1.01–0.89(m,2H)。
实施例94f:(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR与实施例94c相同。
实施例94g:(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR与实施例094e相同。
实施例94h:(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1H NMR与实施例94d相同。
实施例95:2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑
并[1,5-a]吡啶-4-醇
(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-2-(氟甲基)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
合成途径
步骤1:6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2’-[1,3]二氧戊环]-2-甲酸甲酯
将4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-甲酸甲酯(1.4g,7.21mmol)、三甲氧基甲烷(2.3g,22mmol)、乙烷-1,2-二醇(17.9g,288mmol)和pTSA(124mg,0.72mmol)溶于无水甲苯(30mL)。反应混合物加热至回流3小时。TLC显示无起始材料剩余。将混合物冷却至室温,真空浓缩,且用DCM(50mL X 3)和NaHCO3溶液萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过柱纯化(Hex/EtOAc 20-50%):LCMS(ESI,m/z):239.3[M+H]+;1H NMR(400MHz,氯仿-d)δ6.79(t,J=1.2Hz,1H),4.28–4.03(m,7H),3.97–3.85(m,3H),2.25(td,J=7.6,7.0,3.2Hz,2H),2.14–2.07(m,2H)。
步骤2:(6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2'-[1,3]二氧杂环戊烷]-2-基)甲醇
在0℃在Ar气下将6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2’-[1,3]二氧戊环]-2-甲酸甲酯(1.45g,6.1mmol)溶于无水甲苯(30mL)。在20分钟内将DIBAL-H(1.2M在甲苯中,15mL)缓慢添加至上述溶液。反应混合物在室温再搅拌2hr,此时TLC分析显示反应完成。反应通过缓慢添加1mL MeOH然后添加20mL水淬灭。水性混合物然后用DCM萃取(3×50mL)。合并的有机层用盐水洗涤(100mL),用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过柱纯化(EtOAc):LCMS(ESI,m/z):211.3[M+H]+;1H NMR(400MHz,氯仿-d)δ6.23(d,J=1.7Hz,1H),4.64(d,J=1.7Hz,2H),4.22–4.00(m,6H),2.21(pd,J=6.1,1.9Hz,2H),2.10–2.00(m,2H)。
步骤3:2-(氟甲基)-6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2'-[1,3]二氧戊环]
在0℃在氮气氛向(6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2'-[1,3]二氧杂环戊烷]-2-基)甲醇(900mg,4.28mmol)在无水DCM(20mL)中的溶液中添加(二乙基氨基)三氟化硫(1.5mL,8.56mmol)。反应静置以温热至室温保持1小时。添加碳酸氢钠(50mL饱和水溶液)后,反应混合物用DCM(3x50mL)洗涤,且将合并的有机萃取物过滤且真空浓缩。残余物通过快速色谱法纯化(洗脱液己烷:EtOAc[0-100%]梯度)以提供标题化合物,为白色固体。0.7g,69%产率:LCMS(ESI,m/z):213.3[M+H]+;1H NMR(400MHz,氯仿-d)δ6.34(d,J=1.9Hz,1H),5.34(dd,J=48.4,1.7Hz,2H),4.24–4.00(m,6H),2.23(pt,J=9.0,4.5Hz,2H),2.13–2.02(m,2H)。
步骤4:2-(氟甲基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
将2-(氟甲基)-6,7-二氢-5H-螺[吡唑并[1,5-a]吡啶-4,2'-[1,3]二氧戊环](700mg,3.30mmol)溶于30mL THF,将其用HCl溶液(13.2mL,5M)处理。在室温过夜后,反应用NaHCO3溶液碱化,反应混合物用DCM(3x50mL)洗涤,且将合并的有机萃取物过滤且真空浓缩。残余物通过快速色谱法纯化(洗脱液己烷:EtOAc[0-50%]梯度)以提供标题化合物,为白色固体。0.52g,95%产率:LCMS(ESI,m/z):169.3[M+H]+;1H NMR(400MHz,氯仿-d)δ6.97–6.92(m,1H),5.38(dd,J=48.3,0.4Hz,2H),4.43–4.37(m,2H),2.75–2.66(m,2H),2.44–2.34(m,2H)。
步骤4:(E)-2-(氟甲基)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
将2-(氟甲基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮(0.45g.,2.65mmol)添加至2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.1g.,2.65mmol)和乙醇钠(2.8mL,2.65mmol)在EtOH溶液(25mL)中的搅拌混合物中。然后将反应混合物回流5小时。TLC显示起始材料耗尽且形成新的点。冷却至室温后,该反应用水100mL淬灭且通过DCM萃取(50mL x 3)。合并的有机相用Na2SO4干燥且通过CombiFlash纯化,使用2-4%MeOH/DCM:LCMS(ESI,m/z):565.4[M+H]+;1H NMR(400MHz,氯仿-d)δ8.13(s,1H),7.77(s,1H),7.55(s,1H),7.33(d,J=6.7Hz,13H),7.19–7.04(m,9H),5.46(d,J=48.2Hz,2H),4.26(s,2H),3.09(t,J=6.3Hz,2H)。
步骤5:2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
将(E)-2-(氟甲基)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮在MeOH(25mL)和AcOH(8mL)中在80℃搅拌2小时。冷却至室温后,在减压下去除溶剂且饱和NaHCO3(30mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(2x20mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过combi-flash纯化,使用甲醇/dcm 4%-8%:LCMS(ESI,m/z):323.2[M+H]+;1H NMR(400MHz,氯仿-d)δ7.65–7.58(m,1H),7.54–7.32(m,3H),7.31–7.27(m,1H),7.26–7.21(m,1H),7.11(d,J=1.9Hz,1H),6.36–6.20(m,1H),5.41(dd,J=48.0,2.3Hz,2H),4.44–4.32(m,1H),4.31–4.17(m,1H),3.39(ddd,J=12.9,4.7,2.4Hz,1H),1.75–1.49(m,2H)。
步骤6:2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
在0℃将2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮(400mg,1.24mmol)溶于无水THF(30mL)。将LiAl(Ot-Bu)3(THF溶液,1.1M,3.4mL)缓慢添加至上述溶液,将反应搅拌温热至室温且将其保持1小时。反应通过水淬灭且通过CF3CH2OH/DCM(20%,50mL X 3)萃取,合并的有机相用盐水洗涤且用Na2SO4干燥。去除溶剂后且残余物通过硅胶柱色谱纯化(MeOH:DCM=4:96–10:90):LCMS(ESI,m/z):325.2[M+H]+;1H NMR(400MHz,氯仿-d)δ8.15(d,J=1.8Hz,1H),7.52–7.47(m,1H),7.40–7.32(m,2H),7.30–7.23(m,1H),6.82(d,J=1.8Hz,1H),6.46(d,J=2.1Hz,1H),5.49–5.35(m,2H),5.25(d,J=1.9Hz,1H),4.06(dd,J=13.0,5.5Hz,1H),3.92–3.57(m,2H),2.51(d,J=12.6Hz,1H),1.83(qd,J=13.1,5.7Hz,1H),1.13(d,J=13.5Hz,1H)。
步骤7:4-硝基苯甲酸(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-基酯
在氩气下,在0℃向2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(300mg,0.925mmol,1.000当量)、4-硝基苯甲酸(232mg,1.39mmol,1.5当量)在THF(15.0mL)中的溶液中添加n-Bu3P(10mL,4.62mmol,5.000当量,10%在己烷中)。然后在0℃向其添加偶氮二甲酸二叔丁基酯(6mL,4.62mol,5.000当量,20%在甲苯中)。所得溶液在室温搅拌16hr。所得溶液用DCM(20mL)稀释,然后通过添加水(20mL)淬灭。所得溶液用二氯甲烷(3x15mL)萃取且合并有机层且用无水硫酸钠干燥且真空浓缩。残余物施加至具有甲醇/二氯甲烷/(2-5%)的硅胶柱:LCMS(ESI,m/z):474.2[M+H]+;
步骤8:(4R,5R)-2-(氟甲基)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
向4-硝基苯甲酸(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-基酯(435mg,0.96mmol,1.000当量)在THF(20mL)和水(4mL)中的溶液中添加LiOH(402mg,9.6mmol,10当量)。所得溶液在室温搅拌16h。所得溶液用水(20mL)稀释。所得溶液用二氯甲烷萃取且合并有机层且用无水硫酸钠干燥。残余物施加至具有二氯甲烷/甲醇(10:1)的硅胶柱。这得到270mg(86%)产物,其为白色固体。产物进一步通过手性分离进行分离以得到8种异构体,其为白色固体。各异构体的立体化学任意指定。
实施例95a:(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇LCMS(ESI,m/z):325.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.01(s,1H),7.65(dt,J=7.6,0.9Hz,1H),7.51(dq,J=7.6,1.0Hz,1H),7.43(tdd,J=7.5,1.1,0.6Hz,1H),7.33(td,J=7.5,1.2Hz,1H),7.20(s,1H),6.46(dd,J=2.0,0.8Hz,1H),6.32(d,J=7.2Hz,1H),5.79–5.76(m,1H),5.28(d,J=48.7Hz,2H),5.05(dd,J=10.5,6.9Hz,1H),3.97(dd,J=12.8,5.5Hz,1H),3.86–3.75(m,1H),2.56(ddd,J=10.5,3.2,1.9Hz,1H),1.16–0.98(m,2H)。
实施例95b:(4R,5R)-2-(氟甲基)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇LCMS(ESI,m/z):325.2[M+H]+;1HNMR与实施例3a相同。
实施例96a:4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物
步骤1:硫代色满-4-酮1,1-二氧化物
向包含硫代色满-4-酮(1.6g,9.74mmol)的圆底烧瓶中添加12mL冰醋酸和4.6mL35%w/w H2O2溶液(1.66g,48.7mmol),将溶液在100℃加热2小时。反应混合物冷却在室温后,添加30mL水且产物用DCM从水层萃取两次。所得有机相用盐水洗涤一次且经Na2SO4干燥。去除溶剂后,形成固体,其通过用EtOH(20-30mL)重结晶而纯化。在减压下干燥固体后,得到1.53g(3.31mmol)产物,以80%产率。1H NMR(400MHz,氯仿-d)δ8.15(dd,J=7.7,1.4Hz,1H),8.04(dd,J=7.9,1.3Hz,1H),7.85(td,J=7.6,1.4Hz,1H),7.81–7.73(m,1H),3.77–3.69(m,2H),3.49–3.41(m,2H)。
步骤2:(Z)-3-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)硫代色满-4-酮1,1-二氧化物
将硫代色满-4-酮1,1-二氧化物(1.51g.,7.7mmol)添加至2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.9g.,7.0mmol)和哌啶(0.34mL,3.5mmol)在甲醇溶液(50mL)中的搅拌混合物中。然后将反应混合物回流1hr且冷却至室温。冷却至室温后,在减压下去除溶剂且将饱和NaCl溶液(50mL)添加至残余物,然后添加DCM(50mL)。收集有机层且水层用DCM(2x50mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过combi-flash纯化,使用DCM:LCMS(ESI,m/z):593.1[M+H]+
步骤3:3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满-4-酮1,1-二氧化物
将(Z)-3-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)硫代色满-4-酮1,1-二氧化物(3.2g.,5.4mmol)溶于无水甲醇(40mL)和乙酸(16mL,270mmol)。反应混合物回流1hr且冷却至室温。在减压下去除溶剂且将饱和NaHCO3(50mL)添加至残余物,然后添加DCM(50mL)。收集有机层且水层用DCM萃取(2x50mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过combi-flash纯化,使用MeOH/DCM 3%:LCMS(ESI,m/z):351.2[M+H]+
步骤3:4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物
在氩气下,向7-[5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-酮(30mg,0.086mmol,1.000当量)在THF(7mL)在-78℃中的溶液中添加L-Selectride(0.51mL,0.51mmol,6当量,1.0M在THF中)。所得溶液在室温搅拌3hr。该反应然后通过添加乙醇(1mL)淬灭。所得混合物真空浓缩。所得溶液用DCM(20mL)稀释。所得混合物用水和盐水洗涤。残余物施加至combiflash分离,使用二氯甲烷/甲醇(20:1)。这得到26mg(90%)产物,其为淡黄色固体:LCMS(ESI,m/z):353.3[M+H]+
步骤4:4-硝基苯甲酸3-(5H-咪唑并[5,1-a]异吲哚-5-基)-1,1-dioxido硫代色满-4-基酯
在氩气下,在0℃向4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物(50mg,0.141mmol,1.000当量)、4-硝基苯甲酸(36mg,0.212mmol,1.5当量)在THF(2.0mL)中的溶液中添加n-Bu3P(1.5mL,0.71mol,5.000当量,10%在己烷中)。然后在0℃向其添加偶氮二甲酸二叔丁基酯(DBAD,0.85mL,0.71mmol,5.000当量,20%在甲苯中)。所得溶液在室温搅拌16hr。所得溶液用DCM(20mL)稀释,然后通过添加水淬灭(20mL)。所得溶液用二氯甲烷(3x15mL)萃取且合并有机层且用无水硫酸钠干燥且真空浓缩。残余物施加至具有甲醇/二氯甲烷/(2%)的硅胶柱:LCMS(ESI,m/z):502.5[M+H]+
步骤5:4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物
向4-硝基苯甲酸3-(5H-咪唑并[5,1-a]异吲哚-5-基)-1,1-二氧化硫代色满-4-基酯(50mg,0.1mmol,1.000当量)在THF(2mL)和水(0.5mL)中的溶液中添加LiOH(42mg,1mmol,10当量)。所得溶液在室温搅拌40分钟。所得溶液用水(10mL)稀释。所得溶液用二氯甲烷萃取且合并有机层且用无水硫酸钠干燥。残余物施加至具有二氯甲烷/甲醇(10:1)的硅胶柱。这得到10mg(30%)产物,为对映异构体混合物:LCMS(ESI,m/z):353.2[M+H]+1HNMR(400MHz,DMSO-d6)δ7.99(s,1H),7.92(d,J=7.9Hz,1H),7.80–7.71(m,2H),7.69(d,J=7.6Hz,1H),7.58(t,J=7.6Hz,1H),7.53(d,J=7.7Hz,1H),7.47(t,J=7.6Hz,1H),7.40–7.33(m,1H),7.23(d,J=2.0Hz,1H),6.82–6.70(m,1H),5.97(s,1H),5.25(t,J=9.8Hz,1H),3.26(t,J=11.6Hz,1H),2.89(t,J=12.9Hz,1H),2.35(d,J=13.6Hz,1H)。
实施例97:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢
萘-2-甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
步骤1:N-甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺
向包含5-氧代-5,6,7,8-四氢萘-2-甲酸(2.00g,10.52mmol)在无水DCM(50mL)中的溶液的圆底烧瓶添加三乙胺(4.4mL,31.55mmol)和HATU(4.80g,12.62mmol)。将甲基胺在THF(6.31mL,12.62mmol)中的溶液添加至上述混合物。将反应混合物在室温搅拌18h且浓缩。残余物溶于二氯甲烷(30mL)且倒入水(30mL)中,水层用二氯甲烷(3x30mL)萃取。合并的有机层用水(3x10mL)、饱和NaHCO3(20mL)洗涤,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过EtOAc:Hex=75:25洗脱:LCMS(ESI,m/z):204.4[M+H]+.
步骤2:(E)-N-甲基-5-氧代-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-甲酰胺
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.6g,3.86mmol)和N-甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺(0.95g,4.63mmol)在乙醇(30mL)中的溶液中添加无水Ca(OH)2(143mg,1.93mmol)。将混合物在90℃搅拌过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过Hex:EtOAc=20:80洗脱:LCMS(ESI,m/z):600.4[M+H]+.
步骤3:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺
将(E)-N-甲基-5-氧代-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-甲酰胺(1.83g,3.05mmol)在20%AcOH的MeOH溶液(50mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用10%三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):358.2[M+H]+.
步骤4:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
在0℃向6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺(1.03g,2.88mmol)在MeOH(20mL)中的溶液中分批添加NaBH4(272mg,7.20mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(20mL)。水层用10%三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=90:10洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例97a:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.34(q,J=4.5Hz,1H),8.01(s,1H),7.75(dq,J=7.7,0.9Hz,1H),7.65–7.59(m,2H),7.56(d,J=1.7Hz,1H),7.42–7.36(m,2H),7.24(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.61(d,J=6.0Hz,1H),5.45(d,J=6.0Hz,1H),4.82(dd,J=6.0,3.4Hz,1H),2.85(dd,J=17.4,4.7Hz,1H),2.75(d,J=4.5Hz,3H),2.71–2.63(m,1H),2.15(ddd,J=12.4,6.1,3.0Hz,1H),1.95(qd,J=12.6,5.4Hz,1H),1.71(d,J=13.3Hz,1H)。
实施例97b:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.33(q,J=4.3Hz,1H),7.97(s,1H),7.76–7.66(m,2H),7.64(d,J=7.6Hz,1H),7.52–7.46(m,2H),7.41(t,J=7.4Hz,1H),7.35–7.27(m,1H),7.18(s,1H),6.09(d,J=7.7Hz,1H),5.81(s,1H),4.98–4.90(m,1H),2.75(d,J=4.5Hz,3H),2.68–2.55(m,2H),2.45–2.35(m,1H),0.92(d,J=3.4Hz,1H),0.84(dt,J=17.4,8.3Hz,1H)。
实施例97c:(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.35(q,J=4.5Hz,1H),7.94(s,1H),7.66(dd,J=8.0,1.8Hz,1H),7.63(dt,J=7.7,1.0Hz,1H),7.59(dt,J=7.5,0.9Hz,1H),7.54(d,J=1.8Hz,1H),7.46(d,J=8.0Hz,1H),7.39(tt,J=7.6,0.9Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.90(d,J=6.1Hz,1H),5.53(d,J=2.3Hz,1H),5.01(dd,J=6.1,3.8Hz,1H),2.76(d,J=4.5Hz,3H),2.74–2.69(m,1H),2.56(dt,J=10.4,5.2Hz,1H),2.47(dt,J=9.7,3.0Hz,1H),1.49(qd,J=12.7,5.4Hz,1H),0.99(dd,J=10.1,3.0Hz,1H)。
实施例97d:(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.32(q,J=4.3Hz,1H),7.91(s,1H),7.68–7.59(m,4H),7.48(d,J=1.6Hz,1H),7.42–7.38(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.17(s,1H),6.10(d,J=7.4Hz,1H),5.81(d,J=3.3Hz,1H),4.90(dd,J=10.7,7.5Hz,1H),2.75(d,J=4.5Hz,3H),2.70–2.53(m,3H),0.87(h,J=4.9Hz,2H)。
实施例97e:(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.33(q,J=4.5Hz,1H),7.97(s,1H),7.74–7.66(m,2H),7.64(d,J=7.5Hz,1H),7.51–7.46(m,2H),7.44–7.39(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.10(d,J=7.7Hz,1H),5.81(d,J=1.9Hz,1H),4.98–4.91(m,1H),2.75(d,J=4.5Hz,3H),2.65–2.55(m,2H),2.40(t,J=11.1Hz,1H),0.97–0.89(m,1H),0.83(dq,J=17.1,6.5Hz,1H)。
实施例97f:(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.35(q,J=4.5Hz,1H),7.94(s,1H),7.66(dd,J=8.0,1.8Hz,1H),7.63(dq,J=7.6,0.9Hz,1H),7.59(dt,J=7.6,0.9Hz,1H),7.54(d,J=1.7Hz,1H),7.46(d,J=8.0Hz,1H),7.39(tt,J=7.5,0.9Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.90(d,J=6.1Hz,1H),5.56–5.50(m,1H),5.04–4.98(m,1H),2.76(d,J=4.6Hz,3H),2.72(dd,J=16.7,4.2Hz,1H),2.56(dt,J=10.5,5.4Hz,1H),2.47(dd,J=12.5,3.1Hz,1H),1.49(qd,J=12.7,5.4Hz,1H),1.04–0.95(m,1H)。
实施例97g:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+.
实施例97h:(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):360.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.34(q,J=4.4Hz,1H),8.01(s,1H),7.75(dd,J=7.7,1.0Hz,1H),7.65–7.59(m,2H),7.56(d,J=1.7Hz,1H),7.42–7.35(m,2H),7.24(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.61(d,J=6.0Hz,1H),5.45(d,J=5.9Hz,1H),4.82(dd,J=6.1,3.4Hz,1H),2.85(dd,J=17.3,4.7Hz,1H),2.75(d,J=4.6Hz,3H),2.72–2.61(m,1H),2.15(dq,J=9.4,3.1Hz,1H),1.95(qd,J=12.6,5.4Hz,1H),1.71(d,J=11.3Hz,1H)。
实施例98:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四
氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
步骤1:
N,N-二甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺
向包含5-氧代-5,6,7,8-四氢萘-2-甲酸(2.00g,10.52mmol)在无水DCM(50mL)中的溶液的圆底烧瓶添加三乙胺(4.4mL,31.55mmol)和HATU(4.80g,12.62mmol)。将二甲基胺在THF中的溶液(6.31mL,12.62mmol)添加至上述混合物。将反应混合物在室温搅拌18h且浓缩。残余物溶于二氯甲烷(30mL)且倒入水(30mL)中,水层用二氯甲烷(3x30mL)萃取。合并的有机层用水(3x10mL)、饱和NaHCO3(20mL)洗涤,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过DCM:MeOH=97:3洗脱:LCMS(ESI,m/z):102.2[M+H]+.
步骤2:
(E)-N,N-二甲基-5-氧代-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-甲酰胺
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(3.0g,7.24mmol)和N,N-二甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺(2.04g,9.41mmol)在MeOH(30mL)中的溶液中滴加哌啶(0.36mL,3.62mmol)。将混合物在80℃搅拌过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过Hex:EtOAc=20:80洗脱:LCMS(ESI,m/z):614.4[M+H]+.
步骤3:
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺
将(E)-N,N-二甲基-5-氧代-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-甲酰胺(2.35g,3.83mmol)在20%AcOH的MeOH溶液(20mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且饱和NaHCO3(20mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x10mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):372.3[M+H]+.
步骤4:
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
在0℃向6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5-氧代-5,6,7,8-四氢萘-2-甲酰胺(0.703g,2.33mmol)在MeOH(20mL)中的溶液中分批添加NaBH4(265mg,7.0mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(10mL)。水层用DCM萃取(3x10mL)。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=92:8洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例98a:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.97(s,1H),7.70(d,J=8.0Hz,1H),7.63(d,J=7.6Hz,1H),7.48(dd,J=7.6,1.0Hz,1H),7.41(s,1H),7.31(d,J=1.2Hz,1H),7.28–7.24(m,1H),7.18(s,1H),7.03(d,J=1.7Hz,1H),6.08(d,J=7.7Hz,1H),5.81(s,1H),4.98–4.91(m,1H),2.95(s,3H),2.90(s,3H),2.60(dd,J=9.4,5.5Hz,2H),2.40(t,J=11.3Hz,1H),0.92(dd,J=12.9,3.8Hz,1H),0.88–0.76(m,1H)。
实施例98b:(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.91(s,1H),7.64(t,J=8.6Hz,3H),7.40(t,J=7.5Hz,1H),7.25(ddd,J=17.9,7.8,1.5Hz,2H),7.17(s,1H),7.02(d,J=1.7Hz,1H),6.09(d,J=7.4Hz,1H),5.80(d,J=3.3Hz,1H),4.89(dd,J=10.7,7.4Hz,1H),2.95(s,3H),2.89(s,3H),2.60(ddt,J=19.8,15.9,2.9Hz,3H),0.91–0.84(m,2H)。
实施例98c:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.95(s,1H),7.62(dt,J=7.7,1.0Hz,1H),7.59(dt,J=7.5,0.9Hz,1H),7.45(d,J=7.9Hz,1H),7.39(tt,J=7.5,0.9Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.24(dd,J=7.8,1.7Hz,1H),7.11(s,1H),7.08(d,J=1.6Hz,1H),5.90(d,J=6.0Hz,1H),5.56–5.50(m,1H),5.01(dd,J=6.1,3.7Hz,1H),2.96(s,3H),2.91(s,3H),2.71(dd,J=17.3,4.4Hz,1H),2.57–2.51(m,1H),2.47(dd,J=5.7,2.7Hz,1H),1.49(qd,J=12.7,5.4Hz,1H),0.97(dd,J=10.0,3.0Hz,1H)。
实施例98d:(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.95(s,1H),7.62(dt,J=7.7,0.9Hz,1H),7.61–7.57(m,1H),7.45(d,J=7.9Hz,1H),7.39(tt,J=7.5,0.8Hz,1H),7.28(td,J=7.5,1.2Hz,1H),7.24(dd,J=7.9,1.7Hz,1H),7.11(s,1H),7.08(d,J=1.6Hz,1H),5.90(d,J=6.0Hz,1H),5.56–5.50(m,1H),5.01(dd,J=6.0,3.7Hz,1H),2.96(s,3H),2.91(s,3H),2.71(dd,J=17.3,4.6Hz,1H),2.58–2.52(m,1H),2.47(dd,J=6.4,3.3Hz,1H),1.49(qd,J=12.7,5.4Hz,1H),0.97(dd,J=10.1,3.0Hz,1H)。
实施例98e:(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.01(s,1H),7.75(dq,J=7.7,0.9Hz,1H),7.61(d,J=7.5Hz,1H),7.38(dd,J=7.8,6.4Hz,2H),7.24(td,J=7.6,1.2Hz,1H),7.20(dd,J=7.9,1.7Hz,1H),7.13(s,1H),7.11(d,J=1.6Hz,1H),5.60(d,J=6.0Hz,1H),5.46(d,J=5.8Hz,1H),4.82(dd,J=6.0,3.4Hz,1H),2.95(s,3H),2.90(s,3H),2.83(dd,J=17.4,4.6Hz,1H),2.64(ddd,J=16.2,12.3,6.0Hz,1H),2.17(ddd,J=12.3,6.0,3.1Hz,1H),1.94(qd,J=12.6,5.4Hz,1H),1.72–1.64(m,1H)。
实施例98f:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.01(s,1H),7.75(dd,J=7.7,1.0Hz,1H),7.61(d,J=7.5Hz,1H),7.38(dd,J=7.9,6.5Hz,2H),7.24(td,J=7.6,1.2Hz,1H),7.20(dd,J=7.8,1.7Hz,1H),7.13(s,1H),7.11(d,J=1.7Hz,1H),5.60(d,J=5.9Hz,1H),5.46(d,J=5.8Hz,1H),4.82(dd,J=6.2,3.4Hz,1H),2.95(s,3H),2.90(s,3H),2.83(dd,J=17.4,4.5Hz,1H),2.69–2.59(m,1H),2.18(dq,J=9.3,3.0Hz,1H),1.94(qd,J=12.6,5.4Hz,1H),1.71–1.65(m,1H)。
实施例98g:(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.91(s,1H),7.64(t,J=8.6Hz,3H),7.40(t,J=7.5Hz,1H),7.29–7.21(m,2H),7.17(s,1H),7.02(d,J=1.7Hz,1H),6.08(d,J=7.4Hz,1H),5.80(d,J=3.2Hz,1H),4.92–4.85(m,1H),2.95(s,3H),2.89(s,3H),2.69–2.53(m,3H),0.92–0.84(m,2H)。
实施例98h:(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):374.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.97(s,1H),7.70(d,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.41(t,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H),7.25(dd,J=8.0,1.7Hz,1H),7.18(s,1H),7.03(d,J=1.7Hz,1H),6.08(d,J=7.6Hz,1H),5.81(s,1H),4.98–4.89(m,1H),2.95(s,3H),2.90(s,3H),2.60(q,J=6.3Hz,2H),2.46–2.37(m,1H),0.92(d,J=13.2Hz,1H),0.88–0.77(m,1H)。
实施例99:4-(9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
该标题化合物通过与实施例69相同的方法合成。
异构体的构型任意指定。
实施例99a:(3R,4R)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.42–7.32(m,2H),7.32–7.26(m,1H),7.11(s,1H),5.78(d,J=3.7Hz,1H),5.47(d,J=5.5Hz,1H),3.84(dd,J=10.5,4.8Hz,1H),3.73–3.57(m,2H),3.19–3.07(m,1H),2.99(t,J=10.2Hz,1H),2.40(tt,J=10.9,4.1Hz,1H),0.65–0.50(m,2H)。99a和99b为对映异构体。
实施例99b:(3S,4S)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.42–7.26(m,3H),7.11(s,1H),5.78(d,J=3.7Hz,1H),5.47(d,J=5.4Hz,1H),3.84(dd,J=10.6,4.9Hz,1H),3.68(tt,J=10.2,5.1Hz,1H),3.63–3.58(m,1H),3.19–3.07(m,1H),2.99(t,J=10.2Hz,1H),2.40(ddd,J=14.6,7.3,4.0Hz,1H),0.65–0.50(m,2H)。99a和99b为对映异构体。
实施例99c:(3S,4S)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.41–7.32(m,2H),7.27(dq,J=11.7,4.8Hz,1H),7.15(s,1H),5.82–5.77(m,1H),5.53(d,J=5.9Hz,1H),3.91(dd,J=10.6,4.8Hz,1H),3.74(tt,J=10.4,5.5Hz,1H),3.59(dd,J=11.3,4.5Hz,1H),3.19–3.08(m,1H),3.04(t,J=10.2Hz,1H),2.23(t,J=11.4Hz,1H),0.72–0.65(m,1H),0.47(qd,J=12.5,4.8Hz,1H)。99c和99d为对映异构体。
实施例99d:(3R,4R)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.36(td,J=3.9,2.1Hz,2H),7.29–7.24(m,1H),7.14(s,1H),5.80(d,J=2.3Hz,1H),5.53(d,J=5.9Hz,1H),3.91(dd,J=10.6,4.8Hz,1H),3.74(tt,J=10.5,5.4Hz,1H),3.58(dd,J=11.3,4.6Hz,1H),3.11(td,J=11.7,2.3Hz,1H),3.04(t,J=10.3Hz,1H),2.23(ddd,J=14.3,9.3,3.3Hz,1H),0.69(d,J=13.3Hz,1H),0.47(qd,J=12.6,4.8Hz,1H)。99c和99d为对映异构体。
实施例100:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺
酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
步骤1:
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5-氧代-5,6,7,8-四氢萘-2-磺酰胺
将甲醇锂(10%溶液,6.94mL,14.47mmol)滴加至2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.5g,3.62mmol)和5-氧代-5,6,7,8-四氢萘-2-磺酰胺(815.17mg,3.62mmol)在DMF/甲醇的7:3混合物(15mL)中的溶液中且在室温搅拌。反应在4小时后完成,如TLC所示。将水(30mL)添加至反应混合物且粗产物用DCM萃取(2X 20mL)。合并的有机层用水洗涤多次以去除过量DMF且蒸发。将甲醇(20mL)和乙酸(4mL)添加至粗产物且回流3小时。蒸发甲醇且添加固体碳酸钠以中和反应混合物。粗产物用DCM萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):380.2[M+H]+
步骤2:
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
在0℃将硼氢化钠(0.358g,9.49mmol)分批添加至6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5-氧代-5,6,7,8-四氢萘-2-磺酰胺(1.2g,3.16mmol)在甲醇(20mL)中的溶液中。反应烧瓶然后从冰浴移除且反应在室温搅拌2小时。将饱和氯化铵溶液(10mL)添加至反应混合物且在室温搅拌30分钟。甲醇在减压下蒸发且粗产物用10%2,2,2-三氟乙醇在DCM中的溶液(2X 20mL)萃取。合并的有机层蒸发以得到粗产物,其进一步通过Combi-Flash纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例100a:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.65(dd,J=8.1,1.9Hz,1H),7.62(dd,J=7.7,1.0Hz,1H),7.60(d,J=7.6Hz,1H),7.57(d,J=8.1Hz,1H),7.52(d,J=1.8Hz,1H),7.41–7.37(m,1H),7.30(dd,J=7.6,1.2Hz,1H),7.27(m,2H),7.12(s,1H),6.00(d,J=6.1Hz,1H),5.54(d,J=2.2Hz,1H),5.03(dd,J=6.1,3.8Hz,1H),2.76(dd,J=17.2,4.6Hz,1H),2.58(ddd,J=17.5,12.5,5.9Hz,1H),2.47(dd,J=6.5,3.3Hz,1H),1.50(qd,J=12.6,5.4Hz,1H),1.25-0.98(m,1H)。
实施例100b:(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J=8.2Hz,1H),7.68–7.60(m,3H),7.46(d,J=1.9Hz,1H),7.41(t,J=7.5Hz,1H),7.27(dd,J=7.6,1.2Hz,1H),7.25(s,2H),7.17(s,1H),6.21(d,J=7.5Hz,1H),5.81(d,J=3.3Hz,1H),4.90(dd,J=10.7,7.5Hz,1H),2.70–2.54(m,3H),0.89(d,J=4.7Hz,2H)。
实施例100c:(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.82(d,J=8.2Hz,1H),7.70–7.61(m,2H),7.51–7.45(m,2H),7.42(t,J=7.5Hz,1H),7.32(dd,J=7.6,1.1Hz,1H),7.25(s,2H),7.18(s,1H),6.21(d,J=7.6Hz,1H),5.81(s,1H),4.99–4.88(m,1H),2.69–2.57(m,2H),2.41(t,J=11.2Hz,1H),1.00–0.72(m,2H)。
实施例100d:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.10(s,1H),7.77(dd,J=8.3,3.0Hz,1H),7.71–7.61(m,3H),7.47(d,J=3.0Hz,1H),7.43(td,J=7.6,2.8Hz,1H),7.30(td,J=7.6,2.9Hz,2H),7.25(d,J=3.0Hz,2H),6.24(dd,J=7.5,3.0Hz,1H),5.85(d,J=3.7Hz,1H),4.90(t,J=9.0Hz,1H),2.74–2.54(m,3H),0.96–0.85(m,2H)。
实施例100e:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.74(d,J=7.8Hz,1H),7.64–7.59(m,2H),7.55(d,J=1.9Hz,1H),7.50(d,J=8.1Hz,1H),7.39(s,1H),7.26(d,J=11.2Hz,3H),7.14(s,1H),5.70(d,J=6.0Hz,1H),5.46(d,J=6.1Hz,1H),4.84(dd,J=6.1,3.3Hz,1H),2.94–2.85(m,1H),2.72(dd,J=12.1,5.9Hz,1H),2.19–2.12(m,1H),1.96(dd,J=12.5,5.4Hz,1H),1.74(d,J=12.6Hz,1H)。
实施例100f:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.74(d,J=7.8Hz,1H),7.64–7.59(m,2H),7.55(d,J=1.9Hz,1H),7.50(d,J=8.1Hz,1H),7.39(s,1H),7.26(d,J=11.2Hz,3H),7.14(s,1H),5.70(d,J=6.0Hz,1H),5.46(d,J=6.1Hz,1H),4.84(dd,J=6.1,3.3Hz,1H),2.94–2.85(m,1H),2.72(dd,J=12.1,5.9Hz,1H),2.19–2.12(m,1H),1.96(dd,J=12.5,5.4Hz,1H),1.74(d,J=12.6Hz,1H)。
实施例100g:((5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.82(d,J=8.2Hz,1H),7.70–7.61(m,2H),7.51–7.45(m,2H),7.42(t,J=7.5Hz,1H),7.32(dd,J=7.6,1.1Hz,1H),7.25(s,2H),7.18(s,1H),6.21(d,J=7.6Hz,1H),5.81(s,1H),4.99–4.88(m,1H),2.69–2.57(m,2H),2.41(t,J=11.2Hz,1H),1.00–0.72(m,2H)。
实施例100h:((5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.65(dd,J=8.1,1.9Hz,1H),7.62(dd,J=7.7,1.0Hz,1H),7.60(d,J=7.6Hz,1H),7.57(d,J=8.1Hz,1H),7.52(d,J=1.8Hz,1H),7.41–7.37(m,1H),7.30(dd,J=7.6,1.2Hz,1H),7.27(m,2H),7.12(s,1H),6.00(d,J=6.1Hz,1H),5.54(d,J=2.2Hz,1H),5.03(dd,J=6.1,3.8Hz,1H),2.76(dd,J=17.2,4.6Hz,1H),2.58(ddd,J=17.5,12.5,5.9Hz,1H),2.47(dd,J=6.5,3.3Hz,1H),1.50(qd,J=12.6,5.4Hz,1H),1.25-0.98(m,1H)。
实施例101:4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
合成途径
((4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-基)磺酰基)氨基甲酸叔丁酯.
向5-(5H-咪唑并[1,5-b]异吲哚-5-基)氮杂环庚烷-4-醇;2,2,2-三氟乙酸(5,2.01mmol,2.01mmol,100mass)在乙腈(20mL,381mmol,100质量%)中的溶液中添加三乙胺(4mL,28.7mmol,100质量%)。然后将其搅拌5分钟.
向氯磺酰异氰酸酯(1.5当量,3.01mmol,98质量%)在DCM中的溶液中添加叔丁基醇(2.4当量,4.82mmol,100质量%)。然后将其滴加至反应,然后在室温搅拌过夜。反应通过添加2-3mL水淬灭。该反应然后在减压下浓缩且残余物通过快速柱纯化以得到((4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-基)磺酰基)氨基甲酸叔丁酯,其为黄色油状物:LCMS(ESI,m/z):449[M+H]+.
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
向N-[4-羟基-5-(5H-咪唑并[1,5-b]异吲哚-5-基)氮杂环庚烷-1-基]磺酰基氨基甲酸叔丁酯(6,2.01mmol,2.01mmol,100质量%)在二氯甲烷(3mL,46.80mmol,100质量%)中的溶液中添加三氟乙酸(4.1mL,54mmol,100质量%)且在室温搅拌3小时。反应然后在减压下浓缩且然后纯化残余物,单独的异构体通过手性分离进行分离(SFC,柱,PPU,150x30mm;流动相:CO2:甲醇中的0.1%氢氧化铵=80:20;Isocratic,检测器,uv 270nm;流速150mL/min,40℃)以得到4种异构体。
实施例101a:LCMS(ESI,m/z):349.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(d,J=7.5Hz,1H),7.45(dd,J=7.5,1.1Hz,1H),7.39(t,J=7.4Hz,1H),7.31(td,J=7.5,1.2Hz,1H),7.15(s,1H),6.58(s,2H),5.74(d,J=2.2Hz,1H),5.40(d,J=5.7Hz,1H),3.88–3.81(m,1H),3.38–3.33(m,1H),3.01–2.93(m,2H),2.79(dt,J=12.9,7.5Hz,1H),2.34–2.29(m,1H),2.13(ddq,J=11.0,4.7,2.3,1.8Hz,1H),1.82(dtd,J=14.3,11.1,3.4Hz,1H),0.72(h,J=4.4Hz,2H)。
实施例101b:LCMS(ESI,m/z):349.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.62(d,J=7.6Hz,1H),7.54(dd,J=7.7,1.1Hz,1H),7.39(dd,J=8.0,6.9Hz,1H),7.30–7.26(m,1H),7.15(s,1H),6.58(s,2H),5.74(d,J=3.6Hz,1H),5.35(d,J=5.2Hz,1H),3.82(dt,J=9.9,4.9Hz,1H),3.06–3.00(m,1H),2.97–2.90(m,1H),2.84–2.77(m,1H),2.47(dd,J=4.0,2.4Hz,1H),2.12–2.07(m,1H),1.84–1.75(m,1H),0.77–0.69(m,1H),0.60–0.54(m,1H)。
实施例101c:LCMS(ESI,m/z):349.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.62(d,J=7.5Hz,1H),7.54(d,J=7.6Hz,1H),7.39(t,J=7.3Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.15(s,1H),6.58(s,2H),5.74(d,J=3.6Hz,1H),5.35(d,J=5.2Hz,1H),3.82(dt,J=10.0,5.1Hz,1H),3.03(dt,J=12.9,4.3Hz,1H),2.97–2.90(m,1H),2.84–2.77(m,1H),2.47–2.43(m,1H),2.13–2.07(m,1H),1.84–1.75(m,1H),0.78–0.68(m,1H),0.61–0.54(m,1H)。
实施例101d:LCMS(ESI,m/z):349.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(d,J=7.5Hz,1H),7.45(dd,J=7.6,1.1Hz,1H),7.41–7.37(m,1H),7.33–7.29(m,1H),7.15(s,1H),6.58(s,2H),5.74(d,J=2.3Hz,1H),5.40(d,J=5.7Hz,1H),3.88–3.82(m,1H),3.38–3.34(m,1H),3.00–2.94(m,2H),2.83–2.76(m,1H),2.33–2.29(m,1H),2.17–2.11(m,1H),1.86–1.78(m,1H),0.72(dt,J=8.7,4.6Hz,2H)。
实施例102:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
步骤1:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢萘-1(2H)-酮
将3,4-二氢萘-1(2H)-酮(1.27g,8.68mmol)添加至2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(3g,7.24mmol)和乙醇钠(9mL,8.68mmol)在乙醇溶液(50mL)中的搅拌混合物中。然后将反应混合物回流2hr且冷却至室温。然后将乙酸(9mL,145mmol)添加至反应混合物。反应在80℃加热2小时。在减压下去除溶剂且将饱和NaHCO3(30mL)添加至残余物,然后添加DCM(30mL)。收集有机层且水层用DCM萃取(2x30mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过combi-flash纯化,使用甲醇/DCM 2%-4%:LCMS(ESI,m/z):301.3[M+H]+
步骤2:
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
在0℃将2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,4-二氢萘-1(2H)-酮(2.1g,6.99mmol)溶于无水MeOH(40mL)。NaBH4(1.06mg,28mmol)分四份添加。将反应在室温搅拌0.5小时。反应通过水淬灭且通过CF3CH2OH/DCM(15%,40mL x 3)萃取,合并的有机相用盐水洗涤且用Na2SO4干燥。去除溶剂后残余物通过硅胶柱色谱纯化(甲醇/DCM 4%-8%.)。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。LCMS(ESI,m/z):303.3.异构体102e和102f的绝对构型通过X-射线晶体学指定。剩余异构体的绝对构型任意指定。
实施例102a:(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.62(d,J=7.6Hz,1H),7.59(d,J=7.4Hz,1H),7.42–7.35(m,2H),7.28(td,J=7.5,1.2Hz,1H),7.22–7.18(m,2H),7.11(s,1H),7.06(dd,J=6.8,2.1Hz,1H),5.78(d,J=6.1Hz,1H),5.52(d,J=2.1Hz,1H),4.98(dd,J=6.1,3.8Hz,1H),2.74–2.65(m,1H),2.47–2.44(m,1H),2.43(q,J=2.9Hz,1H),1.50(qd,J=12.8,5.6Hz,1H)。
实施例102b:(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR与实施例102a相同。
实施例102c:(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.76(d,J=7.7Hz,1H),7.61(d,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.35–7.30(m,1H),7.24(td,J=7.6,1.2Hz,1H),7.20–7.16(m,2H),7.13(s,1H),7.10–7.06(m,1H),5.49(d,J=5.9Hz,1H),5.44(d,J=6.0Hz,1H),4.79(dd,J=6.2,3.3Hz,1H),2.81(ddd,J=17.3,5.6,2.1Hz,1H),2.63(ddd,J=17.4,12.3,5.9Hz,1H),2.12(ddt,J=12.3,6.1,3.0Hz,1H),1.95(qd,J=12.5,5.4Hz,1H),1.74–1.63(m,1H)。
实施例102d:(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR与实施例102c相同。
实施例102e:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.66(d,J=7.7Hz,1H),7.63(d,J=7.4Hz,1H),7.50–7.46(m,1H),7.41(t,J=7.4Hz,1H),7.31(td,J=7.5,1.2Hz,1H),7.23(td,J=7.5,1.4Hz,1H),7.18(s,1H),7.14(td,J=7.4,1.4Hz,1H),7.00(dd,J=7.5,1.3Hz,1H),5.97(d,J=7.7Hz,1H),5.84–5.78(m,1H),4.93(dd,J=10.6,7.8Hz,1H),2.56(s,3H),2.38(tt,J=11.2,2.9Hz,1H),0.95–0.73(m,2H)。
实施例102f:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR与实施例102e相同。
实施例102g:(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.63(t,J=6.8Hz,2H),7.60(d,J=4.5Hz,1H),7.40(t,J=7.4Hz,1H),7.26(td,J=7.5,1.2Hz,1H),7.21(td,J=7.6,1.4Hz,1H),7.17(s,1H),7.13(td,J=7.4,1.5Hz,1H),6.99(d,J=7.6Hz,1H),5.98(d,J=7.4Hz,1H),5.80(d,J=3.3Hz,1H),4.89(dd,J=10.6,7.5Hz,1H),2.68–2.53(m,3H),0.85(h,J=5.3,4.8Hz,2H)。
实施例102h:(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):303.3[M+H]+;1H NMR与实施例102g相同。
实施例103:(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(氧杂环丁烷-
3-基)哌啶-3-醇
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(氧杂环丁烷-3-基)哌啶-3-醇
将(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶鎓2,2,2-三氟乙酸盐(310mg,0.84mmol)和氧杂环丁烷-3-酮(180mg,2.50mmol)在DCE(5mL)中的溶液在室温搅拌16h。添加NaBH3CN(210mg,3.34mmol)后,所得溶液在搅拌下在室温再反应2h。该反应然后通过添加饱和碳酸氢钠(10mL)淬灭。所得溶液用DCM萃取(3x20mL)且合并有机层。将混合物用无水硫酸钠干燥且真空浓缩。残余物使用Combi-flash纯化。
实施例103:(3S,4S)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-1-(氧杂环丁烷-3-基)哌啶-3-醇(66.0mg,25%),其为白色固体:LCMS(ESI,m/z):312.3[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.63(d,J=7.5,1H),7.48-7.33(m,3H),7.20(s,1H),5.79(d,J=3.3,1H),4.71-4.47(m,4H),3.97-3.96(m,1H),3.54-3.50(m,1H),3.09-3.04(m,1H),2.61-2.49(m,1H),2.12-2.02(m,1H),1.89-1.65(m,2H),0.92-0.87(m,1H),0.71-0.55(m,1H)。
实施例104:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-
甲酰胺
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
步骤1:5-氧代-5,6,7,8-四氢喹啉-2-甲腈
在氮气下将2-氯-7,8-二氢喹啉-5(6H)-酮(200mg,1.10mmol)、氰化锌(211mg,2.31mmol)和四(三苯基膦)钯(64mg,0.05mmol)悬浮于2mL无水N,N-二甲基乙酰胺(水含量<0.01%,预先用氮气脱气),加热至100℃。且在该温度搅拌2小时。完全转化后(通过TLC监测,流动相石油醚/乙酸乙酯2:1),反应混合物(灰色悬浮液)冷却至室温。反应混合物用EtOAc(10mL)稀释且用水洗涤(3X2mL)。合并的有机层然后用盐水洗涤(2mL)且用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用combi快速柱色谱法纯化。LCMS(ESI,m/z):173.2[M+H]+
步骤2:5-氧代-5,6,7,8-四氢喹啉-2-甲酰胺
在0℃向5-氧代-5,6,7,8-四氢喹啉-2-甲腈(200mg,1.16mmol)在甲醇(2mL)中的溶液中添加NaOH溶液(0.58mL,6M,3.48mmol),然后添加过氧化氢(~0.28mL),且将混合物在室温搅拌1小时。1小时后,TLC指示无起始材料。反应混合物用水稀释,然后使用EtOAc(3X5mL)萃取且合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到5-氧代-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):191.2[M+H]+
步骤3:(E)-5-氧代-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢喹啉-2-甲酰胺
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):587.3[M+H]+
步骤4:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5-氧代-5,6,7,8-四氢喹啉-2-甲酰胺
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):345.2[M+H]
步骤5:5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):347.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。sdfgfd
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
实施例104a:(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.11(d,J=8.0Hz,1H),7.97(s,1H),7.90(d,J=8.0Hz,1H),7.88(s,1H),7.65(t,J=8.4Hz,2H),7.52(s,1H),7.41(t,J=7.4Hz,1H),7.28(td,J=7.6,1.1Hz,1H),7.20(s,1H),6.34(d,J=7.3Hz,1H),5.82(d,J=3.1Hz,1H),4.96(dd,J=10.7,7.4Hz,1H),2.76(dd,J=8.1,4.7Hz,2H),2.68–2.60(m,1H),1.05–0.90(m,2H)。
实施例104b:(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.16(d,J=8.0Hz,1H),7.99(s,1H),7.91(d,J=8.0Hz,1H),7.87(s,1H),7.64(d,J=7.6Hz,1H),7.53(s,1H),7.50(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),7.32(td,J=7.5,1.0Hz,1H),7.19(s,1H),6.33(d,J=7.5Hz,1H),5.81(s,1H),5.02(dd,J=10.6,7.7Hz,1H),2.82–2.64(m,2H),2.48–2.43(m,1H),1.08–0.84(m,2H)。
实施例104c:(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97–7.93(m,2H),7.90(t,J=6.9Hz,2H),7.62(dd,J=14.9,7.6Hz,2H),7.56(s,1H),7.40(t,J=7.5Hz,1H),7.30(t,J=7.5Hz,1H),7.12(s,1H),6.09(d,J=6.1Hz,1H),5.57(s,1H),5.15–5.06(m,1H),2.85(dd,J=17.8,3.9Hz,1H),2.68(td,J=12.2,6.3Hz,1H),2.56(d,J=2.7Hz,1H),1.62(qd,J=12.8,5.5Hz,1H),1.04(d,J=6.1Hz,1H)。
实施例104d:(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.92(s,1H),7.87(q,J=7.9Hz,2H),7.74(d,J=7.7Hz,1H),7.62(d,J=7.5Hz,1H),7.56(s,1H),7.39(t,J=7.4Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.15(s,1H),5.79(d,J=6.1Hz,1H),5.49(d,J=6.0Hz,1H),4.91(dd,J=5.8,3.2Hz,1H),2.96(dd,J=17.9,3.7Hz,1H),2.79(ddd,J=18.1,12.3,6.4Hz,1H),2.27(dq,J=9.2,3.1Hz,1H),2.07(qd,J=12.7,5.5Hz,1H),1.81(d,J=10.0Hz,1H)。
实施例104e:(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.93(s,1H),7.87(q,J=7.9Hz,2H),7.74(d,J=7.7Hz,1H),7.63(d,J=7.5Hz,1H),7.56(s,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.15(s,1H),5.79(d,J=6.1Hz,1H),5.49(d,J=5.9Hz,1H),4.92(dd,J=5.7,3.2Hz,1H),3.04–2.91(m,1H),2.79(ddd,J=18.0,12.4,6.3Hz,1H),2.27(dq,J=9.3,3.0Hz,1H),2.07(qd,J=12.7,5.5Hz,1H),1.81(d,J=7.1Hz,1H)。
实施例104f:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.16(d,J=8.0Hz,1H),7.98(s,1H),7.91(d,J=8.0Hz,1H),7.87(s,1H),7.64(d,J=7.6Hz,1H),7.53(s,1H),7.50(d,J=7.2Hz,1H),7.42(t,J=7.5Hz,1H),7.32(td,J=7.5,1.0Hz,1H),7.19(s,1H),6.33(d,J=7.5Hz,1H),5.81(s,1H),5.02(dd,J=10.6,7.7Hz,1H),2.82–2.63(m,2H),2.45(d,J=11.0Hz,1H),1.07–0.87(m,2H)。
实施例104g:(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97–7.93(m,2H),7.91(s,1H),7.89(d,J=7.9Hz,1H),7.63(d,J=7.6Hz,1H),7.60(d,J=7.5Hz,1H),7.56(s,1H),7.40(t,J=7.5Hz,1H),7.30(t,J=7.5Hz,1H),7.12(s,1H),6.09(d,J=3.8Hz,1H),5.57(s,1H),5.10(s,1H),2.85(dd,J=17.7,3.9Hz,1H),2.67(td,J=12.3,6.3Hz,1H),2.55(dd,J=12.6,2.9Hz,1H),1.62(qd,J=12.9,5.7Hz,1H),1.09(d,J=10.0Hz,1H)。
实施例104h:(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺:LCMS(ESI,m/z):347.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.11(d,J=8.0Hz,1H),7.92(s,1H),7.90(d,J=8.1Hz,1H),7.88(s,1H),7.65(t,J=7.5Hz,2H),7.52(s,1H),7.41(t,J=7.6Hz,1H),7.27(t,J=7.7Hz,1H),7.18(s,1H),6.33(d,J=7.3Hz,1H),5.81(d,J=2.7Hz,1H),4.96(dd,J=10.5,7.6Hz,1H),2.76(dd,J=8.1,4.6Hz,2H),2.64(t,J=11.2Hz,1H),0.97(dd,J=20.0,6.5Hz,2H)。
实施例105:8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺
酰胺
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
步骤1:
(E)-8-氧代-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-磺酰胺
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和8-氧代-5,6,7,8-四氢萘-2-磺酰胺(1.63g,7.24mmol)在乙醇(30mL)中的溶液中添加无水Ca(OH)2(223mg,3.02mmol)。将混合物在90℃搅拌过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且通过EtOAc洗脱:LCMS(ESI,m/z):622.3[M+H]+.
步骤2:
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢萘-2-磺酰胺
(E)-8-氧代-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢萘-2-磺酰胺(3.5g,5.63mmol)在20%AcOH的MeOH溶液(100mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(50mL)添加至残余物,然后添加DCM(30mL)。收集有机层且水层用10%三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):380.2[M+H]+.
步骤3:
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
在0℃向7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢萘-2-磺酰胺(2.0g,5.27mmol)在MeOH(50mL)中的悬浮液中分批添加NaBH4(398mg,10.54mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(50mL)。水层用DCM萃取(3x30mL)。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=90:10洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例105a:(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.88(d,J=2.0Hz,1H),7.63(dd,J=8.0,2.0Hz,2H),7.60(d,J=7.5Hz,1H),7.42–7.36(m,1H),7.33–7.27(m,3H),7.25(d,J=8.1Hz,1H),7.12(s,1H),6.10(d,J=6.5Hz,1H),5.54(d,J=2.4Hz,1H),5.03(dd,J=6.5,3.7Hz,1H),2.80–2.71(m,1H),2.55(ddd,J=18.5,12.6,6.3Hz,1H),2.48–2.43(m,1H),1.49(qd,J=12.6,5.4Hz,1H),1.06–0.96(m,1H)。
实施例105b:(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.11(dd,J=2.1,0.9Hz,1H),7.91(s,1H),7.64(ddd,J=7.3,5.7,1.0Hz,2H),7.58(dd,J=7.9,2.0Hz,1H),7.41(ddd,J=8.1,7.2,1.1Hz,1H),7.32–7.23(m,3H),7.21–7.13(m,2H),6.29(d,J=7.6Hz,1H),5.81(d,J=3.3Hz,1H),4.95–4.87(m,1H),2.70–2.53(m,3H),0.86(t,J=7.1Hz,2H)。
实施例105c:(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.93(s,1H),7.88(d,J=2.0Hz,1H),7.63(dd,J=8.0,2.2Hz,2H),7.60(d,J=7.5Hz,1H),7.39(t,J=7.5Hz,1H),7.33–7.27(m,3H),7.25(d,J=8.1Hz,1H),7.12(s,1H),6.10(d,J=6.5Hz,1H),5.57–5.50(m,1H),5.03(dd,J=6.5,3.7Hz,1H),2.80–2.72(m,1H),2.56(ddd,J=18.3,12.5,6.2Hz,1H),2.46(dd,J=12.3,3.2Hz,1H),1.49(qd,J=12.7,5.3Hz,1H),1.05–0.98(m,1H)。
实施例105d:(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.16(d,J=2.1Hz,1H),7.98(s,1H),7.64(d,J=7.6Hz,1H),7.60(dd,J=8.0,2.0Hz,1H),7.48(dd,J=7.6,1.0Hz,1H),7.42(t,J=7.6Hz,1H),7.35–7.27(m,3H),7.19(d,J=7.9Hz,2H),6.26(d,J=7.8Hz,1H),5.82(s,1H),4.99–4.91(m,1H),2.66–2.59(m,2H),2.41(t,J=11.3Hz,1H),0.96–0.88(m,1H),0.88–0.77(m,1H)。
实施例105e:(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.11(d,J=2.0Hz,1H),7.90(s,1H),7.64(dd,J=7.6,5.9Hz,2H),7.58(dd,J=8.0,2.0Hz,1H),7.41(t,J=7.6Hz,1H),7.32–7.23(m,3H),7.21–7.13(m,2H),6.29(d,J=7.6Hz,1H),5.81(d,J=3.3Hz,1H),4.95–4.87(m,1H),2.67–2.54(m,3H),0.85(t,J=7.3Hz,2H)。
实施例105f:(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.02(s,1H),7.83(d,J=2.0Hz,1H),7.73(dq,J=7.7,0.9Hz,1H),7.65–7.59(m,2H),7.42–7.35(m,1H),7.31–7.20(m,4H),7.14(s,1H),5.82(d,J=6.5Hz,1H),5.46(d,J=6.2Hz,1H),4.85(dd,J=6.5,3.4Hz,1H),2.88(dd,J=17.5,5.1Hz,1H),2.72–2.62(m,1H),2.14(ddt,J=12.5,6.3,3.1Hz,1H),1.94(qd,J=12.7,5.5Hz,1H),1.73(d,J=12.9Hz,1H)。
实施例105g:(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.16(dd,J=2.1,0.9Hz,1H),7.98(s,1H),7.64(d,J=7.6Hz,1H),7.60(dd,J=8.0,2.0Hz,1H),7.51–7.45(m,1H),7.44–7.39(m,1H),7.32(td,J=7.5,3.2Hz,3H),7.19(d,J=7.7Hz,2H),6.26(d,J=7.8Hz,1H),5.82(d,J=1.9Hz,1H),4.99–4.91(m,1H),2.66–2.59(m,2H),2.41(t,J=11.1Hz,1H),0.92(dq,J=12.6,4.3Hz,1H),0.89–0.77(m,1H)。
实施例105h:(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.02(s,1H),7.83(d,J=1.9Hz,1H),7.73(d,J=7.7Hz,1H),7.65–7.59(m,2H),7.39(t,J=7.5Hz,1H),7.30–7.21(m,4H),7.14(s,1H),5.82(d,J=6.4Hz,1H),5.46(d,J=6.1Hz,1H),4.85(dd,J=6.6,3.3Hz,1H),2.89(dt,J=17.8,3.3Hz,1H),2.67(ddd,J=17.7,12.0,6.1Hz,1H),2.14(ddd,J=12.6,6.3,3.2Hz,1H),1.95(qd,J=12.6,5.4Hz,1H),1.73(d,J=10.3Hz,1H)。
实施例106:2,2-二氟-6-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,6R)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,6S)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,6S)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,6R)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
步骤1:
(1R,6R)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,6S)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1S,6S)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
(1R,6R)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(800mg,5.12mmol)在无水THF(3mL)中的溶液中添加n-BuLi溶液(2.05mL,5.12mmol)且搅拌1小时。将2,2-二氟-7-氧杂双环[4.1.0]庚烷(755mg,5.63mmol)溶于无水THF(10mL)且将溶液滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应保持过夜且用饱和NH4Cl溶液(30mL)淬灭。将混合物用20%三氟乙醇在DCM中的溶液(3x30mL)萃取且将有机相合并,用Na2SO4干燥,且浓缩。产物通过制备型HPLC纯化。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例106a:(1R,6R)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.60(dt,J=7.6,0.9Hz,1H),7.51–7.47(m,1H),7.42–7.36(m,1H),7.29(td,J=7.5,1.1Hz,1H),7.17(s,1H),6.04(d,J=7.0Hz,1H),5.65(d,J=2.3Hz,1H),3.99–3.86(m,1H),2.30(t,J=12.0Hz,1H),1.98(s,1H),1.71(dt,J=32.1,13.8Hz,1H),1.46(d,J=13.8Hz,1H),1.27–1.12(m,1H),0.71(d,J=13.5Hz,1H),0.36(qd,J=13.1,3.9Hz,1H)。
实施例106b:(1S,6S)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.60(dt,J=7.6,0.9Hz,1H),7.49(dt,J=7.6,0.9Hz,1H),7.41–7.36(m,1H),7.29(td,J=7.6,1.2Hz,1H),7.16(s,1H),6.04(d,J=7.0Hz,1H),5.65(d,J=2.4Hz,1H),3.99–3.86(m,1H),2.30(t,J=12.0Hz,1H),1.98(s,1H),1.81–1.63(m,1H),1.46(d,J=13.8Hz,1H),1.20(q,J=14.3,13.1Hz,1H),0.71(d,J=13.5Hz,1H),0.36(qd,J=13.1,4.0Hz,1H)。
实施例106c:(1S,6S)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.93(s,1H),7.62(d,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.41(t,J=7.5Hz,1H),7.29(td,J=7.6,1.1Hz,1H),7.13(s,1H),6.07(d,J=6.2Hz,1H),5.65(d,J=3.8Hz,1H),3.93–3.80(m,1H),1.97(s,1H),1.64(dt,J=32.3,14.0Hz,1H),1.46(d,J=13.8Hz,1H),1.21(q,J=13.7Hz,1H),0.57(d,J=13.5Hz,1H),0.38(td,J=13.1,3.8Hz,1H)。
实施例106d:(1R,6R)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇:LCMS(ESI,m/z):291.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.93(s,1H),7.62(dt,J=7.6,0.8Hz,1H),7.52(dd,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.8Hz,1H),7.30(dd,J=7.6,1.2Hz,1H),7.13(s,1H),6.07(d,J=6.5Hz,1H),5.65(d,J=3.8Hz,1H),3.86(dddd,J=21.6,10.9,6.5,3.9Hz,1H),1.97(s,1H),1.74–1.55(m,1H),1.46(d,J=13.7Hz,1H),1.28–1.14(m,1H),0.57(d,J=13.3Hz,1H),0.38(td,J=13.1,3.8Hz,1H)。
实施例107:8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-
甲腈
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
步骤1:(E)-8-氧代-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢喹啉-3-甲腈
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.0g,4.82mmol)和8-氧代-5,6,7,8-四氢喹啉-3-甲腈(914mg,5.31mmol)在乙醇(50mL)中的溶液中添加无水Ca(OH)2(178mg,2.41mmol)。将混合物在90℃搅拌过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(30mL)以淬灭反应。水相用DCM萃取(3x20mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用EtOAc洗脱:LCMS(ESI,m/z):569.1[M+H]+;
步骤2:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢喹啉-3-甲腈
(E)-8-氧代-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢喹啉-3-甲腈(1.55g,2.73mmol)在20%AcOH的MeOH溶液(200mL)在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(60mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用20%三氟乙醇在DCM中的溶液(3x50mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=97:3洗脱:LCMS(ESI,m/z):327.2[M+H]+.
步骤3:
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
在0℃向7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢喹啉-3-甲腈(0.70g,2.14mmol)在MeOH(20mL)中的溶液中分批添加NaBH4(243mg,6.43mmol)且溶液在0℃搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(30mL)。水层用20%三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=90:10洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例107a:(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.91(d,J=2.0Hz,1H),8.51(s,1H),8.05–8.02(m,1H),7.76(d,J=7.6Hz,1H),7.65(d,J=7.7Hz,1H),7.49(s,1H),7.47(d,J=7.6Hz,1H),7.37(td,J=7.5,1.1Hz,1H),6.19(d,J=4.6Hz,1H),5.94(d,J=3.5Hz,1H),4.89(dd,J=10.7,3.6Hz,1H),2.85–2.76(m,1H),2.73–2.62(m,2H),0.99(dd,J=8.6,4.6Hz,2H)。
实施例107b:(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.90(d,J=2.0Hz,1H),8.09(d,J=2.0Hz,1H),8.05(s,1H),7.65(dq,J=7.6,0.9Hz,1H),7.63–7.60(m,1H),7.41(tt,J=7.6,0.8Hz,1H),7.31(td,J=7.5,1.2Hz,1H),7.18(s,1H),6.34(d,J=5.5Hz,1H),5.58(s,1H),5.04(dd,J=5.3,3.8Hz,1H),2.78(dd,J=17.5,5.3Hz,1H),2.58(dd,J=12.2,5.7Hz,2H),1.50(qd,J=12.8,5.5Hz,1H),1.07–0.99(m,1H)。
实施例107c:(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.86(d,J=2.0Hz,1H),8.11(d,J=2.0Hz,1H),8.01(s,1H),7.75(dd,J=7.7,1.0Hz,1H),7.62(d,J=7.5Hz,1H),7.39(t,J=7.5Hz,1H),7.26(dd,J=7.7,1.2Hz,1H),7.14(s,1H),6.09(d,J=5.3Hz,1H),5.48(d,J=6.0Hz,1H),4.86–4.79(m,1H),2.89(dd,J=17.5,5.3Hz,1H),2.69(ddd,J=17.8,12.2,6.1Hz,1H),2.28(dq,J=9.4,3.0Hz,1H),1.93(qd,J=12.7,5.5Hz,1H),1.76–1.69(m,1H)。
实施例107d:(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.86(d,J=2.0Hz,1H),8.11(d,J=2.0Hz,1H),8.01(s,1H),7.78–7.73(m,1H),7.62(d,J=7.5Hz,1H),7.39(td,J=7.5,0.9Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),6.09(dd,J=5.5,0.7Hz,1H),5.48(d,J=6.0Hz,1H),4.82(dd,J=5.2,3.4Hz,1H),2.89(dd,J=17.5,4.9Hz,1H),2.69(ddd,J=17.8,12.3,6.1Hz,1H),2.33–2.25(m,1H),1.93(qd,J=12.8,5.5Hz,1H),1.75–1.68(m,1H)。
实施例107e:(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.92(d,J=2.0Hz,1H),8.02(dd,J=2.0,1.0Hz,1H),7.93(s,1H),7.64(d,J=7.5Hz,1H),7.51(dd,J=7.5,1.0Hz,1H),7.42(t,J=7.5Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.10(d,J=5.2Hz,1H),5.80(d,J=2.2Hz,1H),4.95(dd,J=10.7,5.2Hz,1H),2.66(ddd,J=13.3,10.0,3.7Hz,2H),2.57(t,J=11.3Hz,1H),1.01–0.95(m,1H),0.89(ddt,J=18.2,12.3,6.2Hz,1H)。
实施例107f:(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.92(d,J=2.0Hz,1H),8.02(dd,J=2.0,1.0Hz,1H),7.93(s,1H),7.64(dt,J=7.5,0.9Hz,1H),7.51(dq,J=7.6,0.9Hz,1H),7.42(tt,J=7.6,0.8Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.10(d,J=5.1Hz,1H),5.80(d,J=2.2Hz,1H),4.95(dd,J=10.8,5.2Hz,1H),2.71–2.61(m,2H),2.60–2.53(m,1H),1.01–0.94(m,1H),0.94–0.84(m,1H)。
实施例107g:(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.90(d,J=2.0Hz,1H),8.02(dd,J=2.1,1.0Hz,1H),7.93(s,1H),7.65(d,J=7.6Hz,1H),7.62–7.57(m,1H),7.41(t,J=7.5Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.17(s,1H),6.13(d,J=4.7Hz,1H),5.78(d,J=3.6Hz,1H),4.87(dd,J=10.7,4.7Hz,1H),2.77–2.64(m,3H),0.92(h,J=4.8Hz,2H)。
实施例107h:(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈:LCMS(ESI,m/z):329.3[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.90(d,J=2.0Hz,1H),8.09(d,J=2.0Hz,1H),7.97(s,1H),7.64(dq,J=7.6,0.9Hz,1H),7.60(dt,J=7.6,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.29(td,J=7.6,1.2Hz,1H),7.12(s,1H),6.32(dd,J=5.6,0.7Hz,1H),5.55(d,J=2.5Hz,1H),5.04(dd,J=5.5,3.8Hz,1H),2.82–2.75(m,1H),2.60–2.53(m,2H),1.51(qd,J=12.8,5.5Hz,1H),1.03(d,J=13.1Hz,1H)。
实施例108:3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环
丁烷-3-醇
步骤1:l-氧杂-5-氮杂螺[2.3]己烷-5-甲酸1,1-二甲基乙基酯
向3-亚甲基氮杂环丁烷-l-甲酸1,1-二甲基乙基酯(5g,29.72mmol)在DCM(100mL)中的溶液中添加MCPBA(18g,104.31mmol)。所得溶液在室温搅拌48h。将固体过滤出。该反应然后通过添加饱和碳酸氢钠(100mL)淬灭。所得溶液用DCM萃取(3x50mL)且合并有机层。将混合物用无水硫酸钠干燥且真空浓缩。残余物通过经Combi-flash洗脱纯化,用DCM/石油醚(1/1)洗脱。这得到750mg(14%)l-氧杂-5-氮杂螺[2.3]己烷-5-甲酸1,1-二甲基乙基酯,为黄色油状物:LCMS(ESI,m/z):186.0[M+H]+.
步骤2:
3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯
在氮气下,在-78℃向5H-咪唑并[4,3-a]异吲哚(590mg,3.78mmol)在THF(20mL)中的溶液中添加n-BuLi(2.27mL,5.67mmol,2.5mol/L在THF中)。所得溶液在-70℃搅拌4h。添加1-氧杂-5-氮杂螺[2.3]己烷-5-甲酸叔丁酯(700mg,3.78mmol)后,所得溶液在搅拌下在室温再反应16h。该反应然后通过添加5mL水淬灭。所得混合物真空浓缩。残余物通过combi-flash纯化,用DCM/MeOH(5/95)洗脱。这得到1g(78%)3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯,其为黄色固体:LCMS(ESI,m/z):342.1[M+H]+.
步骤3:3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)氮杂环丁烷-3-醇
将3-羟基-3-[5H-咪唑并[4,3-a]异吲哚-5-基甲基]氮杂环丁烷-1-甲酸叔丁酯(1g,2.9mmol)和三氟乙酸(2mL)在DCM(20mL)中的溶液在室温搅拌2h。所得混合物真空浓缩。这得到550mg(78%)3-[5H-咪唑并[4,3-a]异吲哚-5-基甲基]氮杂环丁烷-3-醇,其为黄色油状物:LCMS(ESI,m/z):242.1[M+H]+.
步骤4:
(S)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇
(R)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇
在氮气下,向3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)氮杂环丁烷-3-醇(300mg,1.24mmol)和碳酸钾(515mg,3.73mmol)在1,4-二噁烷(20mL)中的混合物添加乙烷磺酰氯(240mg,1.87mmol)。所得溶液在室温搅拌4h。将固体过滤出。所得混合物真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离。两种异构体的构型任意指定。
实施例108a:(S)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇(5.9mg,1%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.1H NMR(400MHz,CD3OD)δ8.01(s,1H),7.66-7.50(m,2H),7.48-7.28(m,2H),7.15(s,1H),5.44(dd,J=8.5,3.6Hz,1H),4.12-3.94(m,3H),3.78-3.68(m,1H),3.09(q,J=7.4Hz,2H),2.67(dd,J=14.9,3.7Hz,1H),2.27(ddd,J=14.9,8.6,1.1Hz,1H),1.33(t,J=7.4Hz,3H)。tR=4.390分钟(CHIRALPAK IC-3,0.46x5cm,Hex(0.1%DEA):EtOH=70:30,1ml/min)。108a和108b为对映异构体。
实施例108b:(R)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇(6.4mg,4%),其为白色固体:LCMS(ESI,m/z):334.0[M+H]+.tR=5.525分钟(CHIRALPAK IC-3,0.46x5cm,Hex(0.1%DEA):EtOH=70:30,1ml/min)。108a和108b为对映异构体。
实施例109:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
步骤1:(E)-2-(4-氟-2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7-氧杂螺[3.5]壬-1-酮
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):555.5[M+H]+
步骤2:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-酮
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):313.4[M+H]+
步骤3:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):315.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(1S,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1R,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
(1S,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
实施例109a:(1S,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.48(dd,J=9.0,2.5Hz,1H),7.40(dd,J=8.4,5.0Hz,1H),7.16(s,1H),7.04(td,J=9.5,2.5Hz,1H),5.72(d,J=5.9Hz,1H),5.38(d,J=10.9Hz,1H),4.06(td,J=5.9,3.2Hz,1H),3.61(ddd,J=10.6,6.7,3.5Hz,1H),3.54(dt,J=10.3,5.0Hz,1H),3.50–3.43(m,2H),2.31(dd,J=16.4,9.2Hz,1H),2.20(t,J=10.4Hz,1H),1.91(ddd,J=11.2,8.4,3.2Hz,1H),1.73(ddd,J=11.2,7.5,3.4Hz,1H),1.50(q,J=5.9,4.9Hz,3H)。
实施例109b:(1S,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.46(dd,J=9.0,2.5Hz,1H),7.40(dd,J=8.4,5.0Hz,1H),7.14(s,1H),7.05(ddd,J=9.5,8.5,2.5Hz,1H),5.36(d,J=8.5Hz,1H),5.16(d,J=7.0Hz,1H),3.84(t,J=7.4Hz,1H),3.71(dt,J=11.2,4.1Hz,1H),3.63(dt,J=11.2,4.1Hz,1H),3.47–3.39(m,1H),3.36–3.31(m,1H),2.38–2.25(m,1H),1.88(t,J=10.2Hz,1H),1.71–1.56(m,2H),1.50(t,J=10.3Hz,1H),1.36(d,J=13.7Hz,2H),1.06–0.99(m,1H)。
实施例109c:(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.58(dd,J=8.4,5.1Hz,1H),7.46(dd,J=9.0,2.5Hz,1H),7.17(s,1H),7.07(ddd,J=9.6,8.5,2.5Hz,1H),5.39(d,J=7.5Hz,1H),5.24(d,J=6.7Hz,1H),3.99(t,J=7.3Hz,1H),3.71(dt,J=11.1,4.1Hz,1H),3.62(dt,J=11.2,4.2Hz,1H),3.40(td,J=11.1,2.7Hz,1H),3.27(td,J=11.1,2.7Hz,1H),2.40(ddd,J=17.2,9.4,7.9Hz,1H),1.77–1.58(m,3H),1.32(dd,J=36.9,13.3Hz,2H),1.06(t,J=10.3Hz,1H)。
实施例109d:(1R,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.46(dd,J=9.0,2.5Hz,1H),7.17(s,1H),7.08(ddd,J=9.5,8.5,2.5Hz,1H),5.70(d,J=5.5Hz,1H),5.43(d,J=9.0Hz,1H),4.08(td,J=6.4,3.1Hz,1H),3.59(ddd,J=10.5,6.7,3.6Hz,1H),3.53(dt,J=10.2,4.8Hz,1H),3.44(ddt,J=16.1,8.0,4.4Hz,2H),1.95–1.88(m,1H),1.82(ddd,J=11.2,8.4,3.0Hz,1H),1.70(ddd,J=11.3,7.7,3.5Hz,1H),1.48(d,J=4.3Hz,2H),1.43(ddd,J=13.1,6.6,3.3Hz,1H)。
实施例109e:(1R,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.48(dd,J=9.0,2.5Hz,1H),7.40(dd,J=8.4,5.0Hz,1H),7.15(s,1H),7.03(ddd,J=9.5,8.5,2.5Hz,1H),5.72(d,J=4.4Hz,1H),5.38(d,J=10.9Hz,1H),4.06(s,2H),3.60(ddd,J=10.5,6.6,3.5Hz,1H),3.54(dt,J=10.2,4.9Hz,1H),3.46(dq,J=11.1,4.2,3.0Hz,2H),2.37–2.27(m,1H),2.23–2.14(m,1H),1.90(ddd,J=11.2,8.4,3.2Hz,1H),1.73(ddd,J=11.2,7.6,3.5Hz,1H),1.50(q,J=5.9,4.9Hz,3H)。
实施例109f:(1R,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.47(dd,J=9.0,2.5Hz,1H),7.40(dd,J=8.4,5.0Hz,1H),7.14(s,1H),7.05(ddd,J=9.5,8.5,2.5Hz,1H),5.36(d,J=8.5Hz,1H),5.17(d,J=7.0Hz,1H),3.84(t,J=7.3Hz,1H),3.71(dt,J=11.2,4.1Hz,1H),3.64(dt,J=11.2,4.1Hz,1H),3.43(td,J=11.2,2.7Hz,1H),3.36–3.31(m,1H),2.36–2.26(m,1H),1.88(t,J=10.2Hz,1H),1.72–1.58(m,2H),1.50(t,J=10.3Hz,1H),1.37(d,J=13.6Hz,2H)。
实施例109g:(1S,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.63(dd,J=8.4,5.1Hz,1H),7.46(dd,J=9.0,2.5Hz,1H),7.17(s,1H),7.08(ddd,J=9.6,8.5,2.5Hz,1H),5.70(d,J=5.5Hz,1H),5.43(d,J=9.0Hz,1H),4.08(td,J=6.4,3.1Hz,1H),3.58(ddd,J=10.5,6.7,3.5Hz,1H),3.53(dt,J=10.2,4.8Hz,1H),3.43(ddt,J=16.1,7.9,4.4Hz,2H),1.96–1.88(m,1H),1.81(ddd,J=11.2,8.4,3.0Hz,1H),1.70(ddd,J=11.4,7.7,3.5Hz,1H),1.48(d,J=4.4Hz,2H),1.43(ddd,J=13.2,6.7,3.4Hz,1H)。
实施例109h:(1S,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):315.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.06(s,1H),7.60(dd,J=8.4,5.0Hz,1H),7.49(dd,J=9.0,2.5Hz,1H),7.27(s,1H),7.11(ddd,J=9.5,8.5,2.5Hz,1H),5.44(d,J=7.6Hz,1H),5.24(d,J=6.7Hz,1H),3.98(t,J=7.2Hz,1H),3.70(dt,J=11.2,4.2Hz,1H),3.62(dt,J=11.2,4.1Hz,1H),3.39(td,J=11.2,2.7Hz,1H),3.29–3.24(m,2H),2.44–2.36(m,1H),1.76–1.70(m,1H),1.69–1.58(m,2H),1.36(d,J=13.6Hz,1H),1.29(d,J=13.2Hz,1H),1.13–0.98(m,2H)。
实施例110:4-(7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
该标题化合物通过与实施例69相同的方法合成。
异构体的构型任意指定。
实施例110a:(3S,4R)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.48(d,J=7.7Hz,1H),7.36(dd,J=1.7,0.8Hz,1H),7.20(ddt,J=7.7,1.5,0.7Hz,1H),7.11(s,1H),5.54(d,J=4.0Hz,1H),5.26(d,J=4.6Hz,1H),4.33(dq,J=5.7,4.2Hz,1H),3.69(dd,J=9.2,8.1Hz,1H),3.61(dd,J=9.2,5.7Hz,1H),3.46–3.36(m,1H),3.10(dd,J=9.2,6.5Hz,1H),2.80(ddt,J=8.0,6.4,4.0Hz,1H),2.35(s,3H)。110a和110b为对映异构体。
实施例110b:(3R,4S)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.48(d,J=7.7Hz,1H),7.38–7.33(m,1H),7.20(ddt,J=7.8,1.6,0.7Hz,1H),7.10(s,1H),5.54(d,J=4.0Hz,1H),5.26(d,J=4.5Hz,1H),4.33(dq,J=5.7,4.2Hz,1H),3.69(dd,J=9.2,8.1Hz,1H),3.61(dd,J=9.2,5.7Hz,1H),3.43(dd,J=9.2,4.1Hz,1H),3.10(dd,J=9.2,6.5Hz,1H),2.80(ddt,J=8.1,6.5,4.0Hz,1H),2.35(s,3H)。110a和110b为对映异构体。
实施例110c:(3S,4R)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.51(d,J=7.7Hz,1H),7.35(dd,J=1.6,0.8Hz,1H),7.22(ddt,J=7.7,1.4,0.7Hz,1H),7.12(s,1H),5.48(d,J=4.6Hz,1H),5.01(d,J=4.7Hz,1H),4.03(dd,J=9.2,7.7Hz,1H),3.87–3.79(m,2H),3.42–3.34(m,2H),2.76(dtt,J=7.8,5.3,2.9Hz,1H),2.37(s,3H)。110c和110d为对映异构体。
实施例110d:(3R,4S)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.48(d,J=7.7Hz,1H),7.33(dq,J=1.5,0.8Hz,1H),7.21(ddt,J=7.7,1.5,0.7Hz,1H),7.05(s,1H),5.44(d,J=4.5Hz,1H),5.00(d,J=4.7Hz,1H),4.03(dd,J=9.2,7.8Hz,1H),3.82(ddd,J=8.1,5.1,3.4Hz,2H),3.42–3.32(m,2H),2.79–2.71(m,1H),2.36(s,3H)。110c和110d为对映异构体。
实施例111:2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-
5-醇
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
步骤1:(E)-2-氨基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹唑啉-5(6H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(3.0g,7.24mmol)和2-氨基-7,8-二氢喹唑啉-5(6H)-酮(984mg,6.03mmol)在乙醇(60mL)中的溶液中添加无水Ca(OH)2(1.12g,15.08mmol)。将混合物在90℃搅拌40小时。在热的情况下,将沉淀过滤且重悬浮于热的MeOH(50mL)中。将固体再次过滤且风干。产物直接使用而不用进一步纯化:LCMS(ESI,m/z):560.3[M+H]+.
步骤2:2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹唑啉-5(6H)-酮
(E)-2-氨基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹唑啉-5(6H)-酮(3.38g,6.04mmol)在20%AcOH的MeOH溶液(200mL)中的溶液中在90℃搅拌3h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(60mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用20%三氟乙醇在DCM中的溶液(3x50mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=90:10洗脱:LCMS(ESI,m/z):318.2[M+H]+.
步骤3:
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
在0℃向2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹唑啉-5(6H)-酮(0.705g,2.22mmol)在MeOH(50mL)中的悬浮液中分批添加NaBH4(336mg,8.89mmol)且溶液在室温搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(30mL)。水层用20%三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=80:20洗脱。最终产物进一步通过手性分离进行分离以得到7种异构体且各异构体的立体化学任意指定。
实施例111a:(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.21(s,1H),8.19(s,1H),7.65(d,J=1.6Hz,1H),7.63(s,1H),7.42(t,J=7.5Hz,1H),7.33(td,J=7.6,1.1Hz,1H),7.27(s,1H),6.47(s,2H),5.69(d,J=5.6Hz,1H),5.58(d,J=2.3Hz,1H),4.92(dd,J=5.5,3.4Hz,1H),2.49–2.44(m,1H),2.43–2.34(m,2H),1.55(qd,J=12.7,5.7Hz,1H),0.96(d,J=12.4Hz,1H)。
实施例11b:(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.73(s,1H),8.35(s,1H),7.77(d,J=7.5Hz,1H),7.61(s,1H),7.57(d,J=7.6Hz,1H),7.51(t,J=7.5Hz,1H),7.48–7.40(m,1H),6.41(s,2H),5.94(s,1H),5.81(d,J=7.5Hz,1H),4.84–4.74(m,1H),2.49–2.34(m,3H),1.07–0.95(m,2H)。
实施例111c:(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.34(s,1H),7.99(s,1H),7.65(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.41(t,J=7.5Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.21(s,1H),6.37(s,2H),5.94(d,J=7.1Hz,1H),5.77(d,J=3.2Hz,1H),4.85(dd,J=10.3,7.1Hz,1H),2.49–2.41(m,2H),2.40–2.31(m,1H),0.91–0.79(m,2H)。
实施例111d:(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.19(s,1H),7.99(s,1H),7.61(dt,J=7.7,0.9Hz,1H),7.60–7.57(m,1H),7.42–7.36(m,1H),7.28(td,J=7.5,1.2Hz,1H),7.11(s,1H),6.46(s,2H),5.63(d,J=5.7Hz,1H),5.51–5.46(m,1H),4.90(dd,J=5.5,3.2Hz,1H),2.48–2.44(m,1H),2.43–2.31(m,2H),1.58(tt,J=12.7,6.3Hz,1H),0.98(d,J=9.2Hz,1H)。
实施例111e:(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.13(s,1H),7.97(s,1H),7.73(dd,J=7.7,1.0Hz,1H),7.61(d,J=7.5Hz,1H),7.41–7.36(m,1H),7.25(td,J=7.6,1.2Hz,1H),7.13(s,1H),6.44(s,2H),5.39(d,J=5.2Hz,1H),5.37(d,J=5.7Hz,1H),4.71(d,J=5.9Hz,1H),2.65–2.56(m,1H),2.06–1.98(m,2H),1.77–1.70(m,1H)。
实施例111f:(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.38(s,1H),7.94(s,1H),7.64–7.60(m,1H),7.48(dd,J=7.6,1.0Hz,1H),7.41(t,J=7.5Hz,1H),7.31(td,J=7.5,1.1Hz,1H),7.17(s,1H),6.38(s,2H),5.94(d,J=7.3Hz,1H),5.76(d,J=1.8Hz,1H),4.89(dd,J=10.3,7.4Hz,1H),2.42(dd,J=11.8,6.1Hz,1H),2.39–2.26(m,2H),0.86(ddt,J=12.2,9.2,4.4Hz,1H),0.79(dt,J=12.7,6.1Hz,1H)。
实施例111g:(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):320.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.34(s,1H),7.90(s,1H),7.63(d,J=7.6Hz,1H),7.60(d,J=7.7Hz,1H),7.40(t,J=7.5Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.16(s,1H),6.37(s,2H),5.93(d,J=7.1Hz,1H),5.75(d,J=3.2Hz,1H),4.84(dd,J=10.3,7.1Hz,1H),2.45(q,J=9.6,9.2Hz,2H),2.36(dt,J=17.9,4.0Hz,1H),0.83(dd,J=9.5,4.4Hz,2H)。
实施例112:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
步骤1:1,2,4,5-四嗪
在氮气下,在0℃向甲脒(50g,480.27mmol)和水合肼(50mL,1.03mol)在MeOH(80mL)和AcOH(150mL)中的溶液中添加NaNO2(66g,956.59mmol)。所得溶液在0℃搅拌2.5h.溶液的pH值用饱和碳酸氢钠调节至7。所得溶液用DCM萃取(4x300mL)且合并有机层。所得混合物用盐水洗涤(2x800mL)。将混合物用无水硫酸钠干燥且真空浓缩。这得到2g(5%)1,2,4,5-四嗪,其为红色固体。
步骤2:6,7,8,8a-四氢酞嗪-5(4aH)-酮
将1,2,4,5-四嗪(2g,24.37mmol)和环己-2-烯-1-酮(3.5g,36.41mmol)在二甲苯(30mL)中的溶液在120℃搅拌4h。所得混合物真空浓缩。将残余物使用硅胶柱纯化,用DCM/MeOH(1/99)洗脱。这得到2g 6,7,8,8a-四氢酞嗪-5(4aH)-酮,其为黄色油状物:LCMS(ESI,m/z):151.1[M+H]+.
步骤3:(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢酞嗪-5(6H)-酮
将6,7,8,8a-四氢酞嗪-5(4aH)-酮(2g,13.32mmol)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(5.5g,13.27mmol)和Ca(OH)2(1g,13.50mmol)在乙醇(100mL)中的混合物在80℃搅拌48h。将固体滤出。所得混合物真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(96/4)洗脱。这得到3g(41%)(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢酞嗪-5(6H)-酮,其为黄色固体:LCMS(ESI,m/z):545.1[M+H]+.
步骤4:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢酞嗪-5(6H)-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):303.0[M+H]+.
步骤5:
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
该标题化合物通过合成Int-6的通用步骤合成。所有异构体112a-h的绝对构型任意指定。
实施例112a:(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(8.9mg,0.8%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.1H NMR(400MHz,CD3OD)δ9.30(s,1H),8.88(d,J=1.0Hz,1H),8.30(s,1H),7.78-7.69(m,1H),7.60-7.34(m,4H),5.97(d,J=1.5Hz,1H),5.04(d,J=10.8Hz,1H),2.75(dd,J=8.7,3.9Hz,2H),2.66-2.50(m,1H),1.36-1.08(m,2H)。tR=1.693分钟(CHIRALPAK AD-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112a和112b为对映异构体。
实施例112b:(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(8.3mg,0.8%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.tR=2.124分钟(CHIRALPAK AD-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112a和112b为对映异构体。
实施例112c:(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(2.1mg,0.2%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.1H NMR(400MHz,CD3OD)δ9.29(s,1H),8.86(d,J=1.1Hz,1H),7.93(s,1H),7.66(dd,J=13.1,7.7Hz,2H),7.51-7.39(m,1H),7.33(td,J=7.6,1.2Hz,1H),7.21(s,1H),5.91(d,J=3.2Hz,1H),5.09(d,J=11.0Hz,1H),2.79-2.57(m,3H),1.19-1.04(m,2H)。tR=4.577分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112c和112d为对映异构体。
实施例112d:(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(2.1mg,0.2%),其为白色固体:LCMS(ESI,m/z):305.4[M+H]+.tR=3.942分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112c和112d为对映异构体。
实施例112e:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(10.2mg,1%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.1H NMR(400MHz,CD3OD)δ9.06-8.92(m,2H),8.04(s,1H),7.76-7.60(m,2H),7.43(t,J=7.6Hz,1H),7.29(td,J=7.6,1.2Hz,1H),7.17(s,1H),5.57(d,J=5.8Hz,1H),4.88(d,J=3.6Hz,1H),2.94(ddd,J=18.4,4.9,2.6Hz,1H),2.78-2.74(m,1H),2.44-2.29(m,1H),2.19-1.96(m,2H)。tR=1.957分钟(CHIRALPAK IA-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112e和112f为对映异构体。
实施例112f:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(13.0mg,1%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.tR=3.540分钟(CHIRALPAK IA-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112e和112f为对映异构体。
实施例112g:(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(95.5mg,9%),其为白色固体:LCMS(ESI,m/z):305.3[M+H]+.1H NMR(400MHz,CD3OD)δ9.14(d,J=1.1Hz,1H),8.94(d,J=1.1Hz,1H),8.08(s,1H),7.67-7.53(m,2H),7.49-7.28(m,2H),7.15(s,1H),5.65(s,1H),5.17(d,J=3.7Hz,1H),2.80(dd,J=18.2,4.8Hz,1H),2.57-2.55(m,2H),1.56-1.54(m,1H),1.23-1.10(m,1H)。tR=2.863分钟(LuxCellulose-4,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112g和112h为对映异构体。
实施例112h:(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇(83.9mg,8%),其为白色固体:LCMS(ESI,m/z):305.2[M+H]+.tR=6.421分钟(LuxCellulose-4,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。112g和112h为对映异构体。
实施例113:8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲
腈
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
步骤1:
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢萘-2-甲腈
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2g,4.83mmol)和8-氧代-5,6,7,8-四氢萘-2-甲腈(1.03g,6.03mmol)在MeOH(100mL)中的溶液中添加乙醇钠(21%在乙醇中的溶液,2.7mL,7.24mmol)。将溶液回流。5h后,反应通过TLC指示完成。将乙酸(7mL)添加至反应混合物且回流4小时。甲醇和乙酸在旋转式蒸发器上蒸发且粗物质悬浮于水,分批添加固体碳酸钠以中和剩余乙酸。粗物质然后使用DCM(2X30mL)萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):326.3[M+H]+
步骤2:
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
将7-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧代-5,6,7,8-四氢萘-2-甲腈(1.5gmL,4.61mmol)在甲醇(100mL)中的溶液冷却至0℃。分批添加硼氢化钠(0.523g,13.83mmol)且反应混合物从冰浴去除。反应混合物在室温搅拌2小时。反应使用饱和NH4Cl溶液(15mL)淬灭。粗物质使用2,2,2-三氟乙醇在DCM中的5%溶液萃取,其进一步通过Combi-Flash纯化且进一步通过手性分离进行分离以得到7种异构体,为白色固体。异构体113d、113e的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例113a:(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H),1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例113b:(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H,1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例113c:(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H),1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例113d:(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺:LCMS(ESI,m/z):382.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.10(s,1H),7.77(dd,J=8.3,3.0Hz,1H),7.71–7.61(m,3H),7.47(d,J=3.0Hz,1H),7.43(td,J=7.6,7.6,2.8Hz,1H),7.30(td,J=7.8,7.7,2.9Hz,2H),7.25(d,J=3.0Hz,2H),6.24(dd,J=7.5,3.0Hz,1H),5.85(d,J=3.7Hz,1H),4.90(t,J=9.0Hz,1H),2.74–2.54(m,3H),0.96–0.85(m,2H)。
实施例113e:(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H),1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例113f:(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H),1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例113g:(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈:LCMS(ESI,m/z):328.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.84(d,J=1.8Hz,1H),7.68–7.56(m,3H),7.44–7.35(m,1H),7.32–7.23(m,2H),7.11(s,1H),6.03(d,J=5.6Hz,1H),5.54(d,J=2.3Hz,1H),5.08–5.00(m,1H),2.78(dd,J=17.9,5.1Hz,1H),2.68–2.52(m,1H),1.47(qd,J=12.6,5.4Hz,1H),0.99(d,J=12.8Hz,1H)。
实施例114:7-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺
[3.5]壬-1-醇
(1S,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
步骤1:
(E)-1-氧代-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):636.3[M+H]+
步骤2:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):394.4[M+H]+
步骤3:
1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):396.2[M+H]+
步骤4:
7-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
在0℃向1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(400mg,1.0mmol)溶于无水MeOH(15mL)中的非对映异构体混合物分四份添加硼氢化钠(120mg,3.0mmol)。将反应在室温搅拌2h。TLC显示无SM剩余。反应通过添加饱和NH4Cl溶液(5mL)淬灭且通过DCM(3X25mL)萃取,合并的有机相用盐水洗涤且用Na2SO4干燥。去除溶剂后且残余物通过硅胶柱色谱纯化。向该混合物添加8mL无水二氯甲烷,然后在室温添加三氟乙酸(1.5mL,20mmol)且将反应混合物搅拌半小时。TLC指示无SM且反应混合物在减压下浓缩,且残余物在高真空泵干燥几小时。该粗混合物运至下一步而不用纯化。在室温向该在8mL无水二氯甲烷中的粗反应混合物添加三乙基胺(0.22mL,1.62mmol),然后添加乙基磺酰氯(0.08mL,0.89mmol)且搅拌半小时。半小时后,TLC指示起始材料。因此添加0.2mL三乙胺且将反应混合物再搅拌半小时。TLC指示无起始材料且反应混合物用水(2mL)淬灭且反应使用DCM处理。合并的残余物用Na2SO4干燥且在减压下浓缩且通过快速柱色谱法纯化。分离该标题化合物且进行手性分离:LCMS(ESI,m/z):388.2[M+H]+.纯的对映异构体通过手性分离方法分离且异构体的构型任意指定。
(1S,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
(1R,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
实施例114a:(1S,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.57(d,J=7.7Hz,2H),7.36(t,J=7.6Hz,1H),7.26(td,J=7.6,1.0Hz,1H),7.14(s,1H),5.42(d,J=7.1Hz,1H),5.31(d,J=6.4Hz,1H),4.11–4.02(m,1H),3.45–3.35(m,1H),2.98(q,J=7.4Hz,3H),2.87–2.77(m,1H),2.47(d,J=7.6Hz,1H),1.65(dtd,J=27.0,11.9,10.1,5.1Hz,3H),1.53(d,J=14.2Hz,1H),1.46–1.34(m,1H),1.17(t,J=7.4Hz,3H),0.97(t,J=10.4Hz,1H)。
实施例114b:(1S,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.59(d,J=7.5Hz,1H),7.45–7.33(m,2H),7.24(td,J=7.6,1.1Hz,1H),7.10(s,1H),5.38(d,J=8.6Hz,1H),5.24(d,J=6.7Hz,1H),3.95(t,J=7.2Hz,1H),3.43–3.37(m,1H),3.37–3.33(m,1H),3.00(q,J=7.4Hz,3H),2.93–2.86(m,1H),2.32(p,J=9.4Hz,1H),1.86(t,J=10.2Hz,1H),1.71–1.59(m,2H),1.58–1.44(m,3H),1.19(t,J=7.4Hz,3H)。
实施例114c:(1R,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.60(d,J=7.5Hz,1H),7.48–7.31(m,2H),7.22(t,J=7.2Hz,1H),7.11(s,1H),5.77(d,J=6.0Hz,1H),5.40(d,J=10.9Hz,1H),4.32–3.96(m,1H),3.24(td,J=7.6,7.0,3.4Hz,1H),3.20–3.13(m,1H),3.09(dt,J=10.5,4.7Hz,2H),3.03(q,J=7.4Hz,2H),2.34(dt,J=17.2,9.2Hz,1H),2.21(t,J=10.4Hz,1H),1.91(td,J=9.9,8.4,3.1Hz,1H),1.78(ddd,J=11.9,8.0,3.4Hz,1H),1.68–1.60(m,1H),1.58(s,2H),1.21(t,J=7.4Hz,3H)。
实施例114d:(1R,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.62(d,J=7.6Hz,1H),7.58(d,J=7.5Hz,1H),7.37(dd,J=9.3,5.8Hz,1H),7.26(td,J=7.6,1.1Hz,1H),7.13(s,1H),5.81–5.69(m,1H),5.45(d,J=8.8Hz,1H),4.11(td,J=6.5,3.1Hz,1H),3.23(ddd,J=11.4,7.3,3.4Hz,1H),3.20–3.13(m,1H),3.07(dt,J=13.2,6.0Hz,1H),3.04–2.98(m,3H),2.60–2.53(m,1H),1.89(q,J=10.9Hz,1H),1.81–1.68(m,2H),1.58–1.51(m,3H),1.19(td,J=7.4,3.1Hz,3H)。
实施例114e:(1S,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.60(d,J=7.5Hz,1H),7.46–7.32(m,2H),7.22(td,J=7.6,1.0Hz,1H),7.12(s,1H),5.77(d,J=5.9Hz,1H),5.40(d,J=10.9Hz,1H),4.08(td,J=6.1,3.2Hz,1H),3.25(ddd,J=11.0,6.9,3.2Hz,1H),3.17(dt,J=11.0,4.8Hz,1H),3.09(dt,J=10.1,4.8Hz,2H),3.03(q,J=7.3Hz,2H),2.34(dt,J=17.4,9.6Hz,1H),2.21(t,J=10.4Hz,1H),1.91(ddd,J=11.3,8.4,3.1Hz,1H),1.78(ddd,J=11.7,8.0,3.5Hz,1H),1.66–1.60(m,1H),1.58(s,2H),1.21(t,J=7.4Hz,3H)。
实施例114f:(1R,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.58(d,J=7.5Hz,1H),7.45–7.33(m,2H),7.23(td,J=7.6,1.0Hz,1H),7.10(s,1H),5.38(d,J=8.6Hz,1H),5.24(d,J=6.7Hz,1H),3.95(t,J=7.2Hz,1H),3.45–3.36(m,1H),3.37–3.31(m,1H),3.00(q,J=7.4Hz,3H),2.94–2.84(m,1H),2.36–2.28(m,1H),1.85(t,J=10.2Hz,1H),1.69–1.59(m,2H),1.57–1.45(m,3H),1.19(t,J=7.4Hz,3H)。
实施例114g:(1S,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.62(d,J=7.6Hz,1H),7.58(d,J=7.5Hz,1H),7.36(t,J=7.5Hz,1H),7.25(td,J=7.6,1.0Hz,1H),7.12(s,1H),5.81–5.68(m,1H),5.45(d,J=8.8Hz,1H),4.11(td,J=6.4,3.1Hz,1H),3.22(ddd,J=11.2,7.2,3.8Hz,1H),3.19–3.12(m,1H),3.07(q,J=6.6,6.1Hz,1H),3.04–2.96(m,3H),2.60–2.52(m,1H),1.93–1.85(m,1H),1.82–1.71(m,2H),1.55(dt,J=11.4,5.7Hz,3H),1.19(t,J=7.4Hz,3H)。
实施例114h:(1R,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.57(d,J=7.9Hz,2H),7.36(t,J=7.6Hz,1H),7.25(t,J=7.9Hz,1H),7.13(s,1H),5.41(d,J=7.0Hz,1H),5.31(d,J=6.4Hz,1H),4.14–3.96(m,1H),3.42–3.35(m,1H),3.31(s,1H),2.97(q,J=7.4Hz,3H),2.88–2.74(m,1H),2.48–2.42(m,1H),1.64(dtd,J=27.0,12.0,10.1,5.2Hz,3H),1.52(d,J=13.8Hz,1H),1.40(d,J=13.4Hz,1H),1.17(t,J=7.4Hz,3H),0.96(t,J=10.4Hz,1H)。
实施例115:2-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
合成途径:
在氮气氛下在-78℃向5H-咪唑并[5,1-a]异吲哚(3,500mg,3.2014mmol,100质量%)在四氢呋喃(10mL,123mmol,100质量%)中的溶液中经2mins滴加n-BuLi(2.5mol/L)在己烷(1.0当量,3.2014mmol,2.5mol/L)中的溶液。然后将其在-78℃在氮气下搅拌45分钟。在-78℃在氮气下向其经3分钟滴加8-氧杂双环[5.1.0]辛烷(1,384.9mg,3.260mmol,95质量%)在四氢呋喃(2mL,24.6mmol,100质量%)中的溶液。然后将其在-78℃在氮气下搅拌,在该过程温热至室温。反应用饱和氯化铵(20mL)淬灭且搅拌5分钟。然后将其用乙酸乙酯(3X50mL)萃取。合并的乙酸乙酯层用硫酸镁干燥,过滤。滤液在减压下浓缩且残余物然后纯化,单独的异构体通过手性分离进行分离(SFC,柱,Chiralpak OX,250x21.2mm;流动相:CO2:甲醇中的0.1%氢氧化铵=70:30;Isocratic,检测器,uv 270nm;流速70mL/min,40℃)以得到4种异构体。
实施例115a:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.59(dt,J=7.7,0.9Hz,1H),7.45(dt,J=7.5,0.9Hz,1H),7.39–7.35(m,1H),7.29(td,J=7.5,1.2Hz,1H),7.13(s,1H),5.66–5.64(m,1H),5.15(d,J=5.4Hz,1H),3.92–3.86(m,1H),2.13(ddd,J=9.6,7.1,2.4Hz,1H),1.98–1.92(m,1H),1.74–1.66(m,1H),1.64–1.56(m,1H),1.46–1.26(m,4H),1.10–1.03(m,1H),0.59–0.45(m,2H)。
实施例115b:LCMS(ESI,m/z):269.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.60(dd,J=7.5,1.0Hz,1H),7.53(dd,J=7.8,1.0Hz,1H),7.39–7.35(m,1H),7.27–7.23(m,1H),7.12(s,1H),5.65(d,J=3.3Hz,1H),5.10(d,J=4.7Hz,1H),3.90–3.85(m,1H),2.29(ddt,J=9.4,6.2,2.8Hz,1H),1.89(ddq,J=10.2,6.4,1.9Hz,1H),1.68–1.57(m,2H),1.50–1.44(m,1H),1.35(tdd,J=8.3,4.4,2.6Hz,2H),1.29–1.23(m,1H),1.13–1.06(m,1H),0.51(q,J=4.1,3.0Hz,2H)。
实施例115c:LCMS(ESI,m/z):269.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.59(d,J=7.5Hz,1H),7.45(d,J=7.4Hz,1H),7.37(t,J=7.5Hz,1H),7.31–7.27(m,1H),7.13(s,1H),5.66–5.65(m,1H),5.15(d,J=5.4Hz,1H),3.92–3.87(m,1H),2.13(ddd,J=9.6,7.1,2.4Hz,1H),1.98–1.92(m,1H),1.74–1.67(m,1H),1.61(ddq,J=10.9,5.6,2.3Hz,1H),1.46–1.28(m,4H),1.06(dq,J=13.9,4.3,3.7Hz,1H),0.56(tt,J=6.5,3.2Hz,1H),0.52–0.44(m,1H)。
实施例115d:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.60(dd,J=7.5,1.0Hz,1H),7.53(dd,J=7.6,1.1Hz,1H),7.39–7.35(m,1H),7.12(s,1H),5.65(d,J=3.2Hz,1H),5.09(d,J=4.9Hz,1H),3.87(dt,J=6.7,1.8Hz,1H),2.29(td,J=5.9,5.0,2.7Hz,1H),1.89(dtd,J=8.3,4.5,2.3Hz,1H),1.67–1.57(m,2H),1.48(dt,J=7.7,3.0Hz,1H),1.36(dtd,J=8.1,4.4,2.5Hz,2H),1.26(ddd,J=9.1,5.1,2.5Hz,1H),1.13–1.07(m,1H),0.52–0.49(m,2H)。
实施例116:3-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
步骤1:
3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-甲酸叔丁酯
在-78℃向5H-咪唑并[5,1-a]异吲哚(3.0g,19.2mmol)在无水THF(30mL)中的溶液中添加n-BuLi溶液(9.2mL,23.05mmol)且搅拌1小时。将3-氧代吡咯烷-1-甲酸叔丁酯(5.34g,28.81mmol)溶于无水THF(10mL)且将溶液滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温保持过夜且用饱和NH4Cl溶液(20mL)淬灭。将混合物用DCM萃取(3x20ml)且将有机相合并,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):342.2[M+H]+.
步骤2:
3-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
在室温向3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-甲酸叔丁酯(1.0g,2.93mmol)在无水DCM(30mL)中的溶液中添加三氟乙酸(2.24mL,29.29mmol)且搅拌2小时。在减压下去除溶剂且残余物置于真空泵过夜以去除三氟乙酸。产物直接使用而不用进一步纯化:LCMS(ESI,m/z):242.3[M+H]+.
步骤3:
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
在冰浴上向3-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇(707mg,2.93mmol)和三甲基胺(1.22mL,8.79mmol)在无水DCM(30mL)中的溶液中添加甲磺酰氯(0.25mL,3.22mmol)且搅拌2小时。反应通过饱和氯化铵溶液(30mL)淬灭。将混合物用20%2,2,2-三氟乙醇在DCM中的溶液(3x20ml)萃取且将有机相合并,用Na2SO4干燥,且浓缩。产物通过Combi-Flash分离且用DCM:MeOH=92:8洗脱。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例116a:(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇:LCMS(ESI,m/z):320.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.85(s,1H),7.59(ddd,J=9.6,7.6,0.9Hz,2H),7.44–7.37(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.48(s,1H),5.47(s,1H),3.50(d,J=11.1Hz,1H),3.34(d,J=4.6Hz,4H),2.84(s,3H),2.07(dt,J=12.7,9.8Hz,1H),1.92–1.81(m,1H)。
实施例116b:(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇:LCMS(ESI,m/z):320.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.61(dt,J=7.7,1.0Hz,1H),7.51(dq,J=7.7,0.9Hz,1H),7.44–7.38(m,1H),7.28(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.48(s,1H),5.39(s,1H),3.47(d,J=10.9Hz,1H),3.41–3.34(m,2H),3.19(dd,J=11.0,1.5Hz,1H),2.83(s,3H),2.20(ddd,J=12.7,10.8,8.8Hz,1H),2.13–2.03(m,1H)。
实施例116c:(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇:LCMS(ESI,m/z):320.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.90(d,J=0.7Hz,1H),7.61(dt,J=7.5,0.9Hz,1H),7.51(dq,J=7.7,0.9Hz,1H),7.41(tdd,J=7.6,1.1,0.6Hz,1H),7.28(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.48(s,1H),5.39(s,1H),3.47(d,J=10.9Hz,1H),3.42–3.33(m,2H),3.22–3.16(m,1H),2.83(s,3H),2.20(ddd,J=12.7,10.7,8.7Hz,1H),2.13–2.04(m,1H)。
实施例116d:(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇:LCMS(ESI,m/z):320.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.85(s,1H),7.60(ddt,J=9.5,7.7,0.8Hz,2H),7.41(tt,J=7.5,0.8Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.15(s,1H),5.49(s,1H),5.48(s,1H),3.50(d,J=11.0Hz,1H),3.34(t,J=4.8Hz,3H),2.85(s,3H),2.12–2.01(m,1H),1.92–1.82(m,1H)。
实施例117:7-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-
醇
步骤1:
(E)-7-(4-氟-2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢异喹啉-8(5H)-酮
该标题化合物通过合成Int-2的通用步骤合成:LCMS(ESI,m/z):562.1[M+H]+.
步骤2:
7-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢异喹啉-8(5H)-酮
该标题化合物通过合成Int-3的通用步骤合成:LCMS(ESI,m/z):320.1[M+H]+.
步骤3:
7-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
在氮气下,在-78℃向7-[8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-酮(1.6g,5.01mmol)在THF(100mL)中的溶液中添加L-selectride(15mL,15.0mmol,1mol/L在THF中)。所得溶液在-78℃搅拌3h。所得混合物真空浓缩。所得溶液用水(20mL)稀释。将固体过滤出且通过DCM洗涤。所得溶液用DCM萃取(3x100mL)且合并有机层。溶液用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(12:1)洗脱。这得到1.5g(93%)7-[8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]-5,6,7,8-四氢异喹啉-8-醇,为黄色固体:LCMS(ESI,m/z):322.1[M+H]+.
步骤4:
4-硝基苯甲酸7-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-基酯
该标题化合物通过合成071aa和071bb的通用步骤合成:LCMS(ESI,m/z):471.1[M+H]+.
步骤5:
(7S,8S)-7-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(7R,8R)-7-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
该标题化合物通过合成071aa和071bb的通用步骤合成。所有异构体117a-b的绝对构型任意指定。
实施例117a:(7S,8S)-7-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(56.2mg,14%),其为白色固体:LCMS(ESI,m/z):322.3[M+H]+.1H NMR(400MHz,CD3OD)δ8.79(s,1H),8.28(dd,J=5.2,0.8Hz,1H),8.05(s,1H),7.55-7.39(m,2H),7.28(s,1H),7.17-7.03(m,2H),5.90(d,J=1.8Hz,1H),5.09(d,J=10.7Hz,1H),2.78-2.67(m,2H),2.55-2.39(m,1H),1.23-0.91(m,2H)。tR=2.134分钟(Lux Cellulose-4,0.46x5cm,Hex(0.1%DEA):EtOH=65:35,1ml/min)。117a和117b为对映异构体。
实施例117b:(7R,8R)-7-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇(61.9mg,15%),其为白色固体:LCMS(ESI,m/z):322.2[M+H]+.tR=2.737分钟(Lux Cellulose-4,0.46x5cm,Hex(0.1%DEA):EtOH=65:35,1ml/min)。117a和117b为对映异构体。
实施例118:3-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-
醇
(3S,4R)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇
(3R,4S)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇
(3S,4R)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇
(3R,4S)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇
该标题化合物通过与实施例92相同的方法合成。
异构体的构型任意指定。
实施例118a:(3S,4R)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.59–7.47(m,2H),7.19(s,1H),7.11(ddd,J=9.5,8.5,2.6Hz,1H),5.69(d,J=3.5Hz,1H),5.43(d,J=5.3Hz,1H),3.72(tt,J=10.2,4.7Hz,1H),3.52–3.44(m,1H),2.77–2.63(m,5H),2.45(ddt,J=10.9,7.6,3.8Hz,1H),2.03–1.94(m,2H),1.62–1.47(m,1H)。118a和118d为对映异构体。
实施例118b:(3R,4S)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.62–7.56(m,1H),7.51(dd,J=9.0,2.5Hz,1H),7.21(s,1H),7.14(ddd,J=9.6,8.4,2.5Hz,1H),5.76–5.70(m,1H),5.56(dd,J=5.7,1.2Hz,1H),3.91–3.78(m,1H),3.53–3.47(m,1H),2.83–2.64(m,5H),2.31(ddt,J=11.1,6.5,3.4Hz,1H),2.10–2.00(m,1H),1.83(t,J=11.6Hz,1H),1.66–1.51(m,1H)。118b和118c为对映异构体。
实施例118c:(3S,4R)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.59(ddd,J=8.5,5.1,0.9Hz,1H),7.51(dd,J=9.0,2.5Hz,1H),7.21(s,1H),7.14(ddd,J=9.5,8.4,2.5Hz,1H),5.73(t,J=1.7Hz,1H),5.56(d,J=5.7Hz,1H),3.85(dp,J=10.3,5.0Hz,1H),3.50(ddq,J=12.1,4.7,2.5Hz,1H),2.80(ddd,J=11.6,3.7,2.0Hz,1H),2.72(td,J=12.6,2.8Hz,1H),2.66(s,3H),2.36–2.25(m,1H),2.11–2.00(m,1H),1.83(t,J=11.6Hz,1H),1.66–1.51(m,1H)。118b和118c为对映异构体。
实施例118d:(3R,4S)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.59–7.47(m,2H),7.19(s,1H),7.11(ddd,J=9.5,8.4,2.6Hz,1H),5.69(d,J=3.7Hz,1H),5.43(d,J=5.3Hz,1H),3.72(tt,J=10.1,4.7Hz,1H),3.52–3.44(m,1H),2.79–2.62(m,5H),2.48–2.41(m,1H),2.03–1.94(m,2H),1.62–1.47(m,1H)。118a和118d为对映异构体。
实施例119:4-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-
醇
(3S,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3R,4R)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
(3R,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
该标题化合物通过与实施例92相同的方法合成。
异构体的构型任意指定。
实施例119a:(3S,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.54–7.49(m,2H),7.19(s,1H),7.11(ddd,J=9.4,8.4,2.5Hz,1H),5.76(d,J=4.8Hz,1H),5.71(d,J=3.7Hz,1H),3.73(ddt,J=12.1,6.6,4.7Hz,2H),3.35(ddt,J=4.5,3.0,0.7Hz,1H),2.84(s,3H),2.56–2.53(m,1H),2.28(h,J=6.5,5.4Hz,1H),0.70(dd,J=13.3,3.4Hz,1H),0.52(qd,J=12.7,4.6Hz,1H)。119a和119b为对映异构体。
实施例119b:(3R,4R)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.56–7.47(m,2H),7.19(s,1H),7.14–7.08(m,1H),5.76(d,J=4.8Hz,1H),5.71(d,J=3.6Hz,1H),3.78–3.67(m,2H),3.35(dt,J=4.2,2.3Hz,1H),2.84(s,3H),2.56–2.51(m,1H),2.28(tt,J=10.2,3.7Hz,1H),0.70(dd,J=13.4,3.3Hz,1H),0.52(qd,J=12.7,4.5Hz,1H)。119a和119b为对映异构体。
实施例119c:(3R,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇:LCMS(ESI,m/z):352.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.50(ddd,J=8.4,4.6,1.4Hz,2H),7.21(s,1H),7.12(ddd,J=9.5,8.4,2.5Hz,1H),5.79(d,J=5.1Hz,1H),5.72(d,J=2.0Hz,1H),3.86–3.73(m,2H),3.35(ddd,J=4.1,2.4,1.3Hz,1H),2.84(s,3H),2.59–2.52(m,2H),2.19–2.08(m,1H),0.87–0.79(m,1H),0.44(qd,J=12.7,4.6Hz,1H)。
实施例120:4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3S,4S)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(3R,4R)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
该标题化合物通过与实施例69相同的方法合成。
异构体120a和120b的绝对构型通过X-射线晶体学测定。剩余异构体的构型任意指定。
实施例120a:(3S,4S)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.52–7.41(m,2H),7.22(s,1H),7.17–7.05(m,1H),5.95(d,J=2.4Hz,1H),5.57(d,J=5.9Hz,1H),3.90(dd,J=10.6,4.9Hz,1H),3.71(tt,J=10.4,5.3Hz,1H),3.60(dd,J=11.4,4.6Hz,1H),3.19–3.09(m,1H),3.05(dd,J=10.7,9.8Hz,1H),2.28(s,1H),0.82–0.68(m,1H),0.45(qd,J=12.7,4.8Hz,1H)。120a和120b为对映异构体。
实施例120b:(3R,4R)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.54–7.41(m,2H),7.22(s,1H),7.17–7.07(m,1H),5.95(d,J=2.3Hz,1H),5.57(d,J=5.9Hz,1H),3.90(dd,J=10.7,4.9Hz,1H),3.71(tt,J=10.4,5.4Hz,1H),3.60(dd,J=11.4,4.6Hz,1H),3.20–3.09(m,1H),3.05(dd,J=10.7,9.8Hz,1H),2.28(s,1H),0.82–0.65(m,1H),0.45(qd,J=12.7,4.9Hz,1H)。120a和120b为对映异构体。
实施例120c:(3S,4S)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.56–7.39(m,2H),7.19(s,1H),7.16–7.06(m,1H),5.87(d,J=2.4Hz,1H),5.13(d,J=5.4Hz,1H),3.80(dd,J=10.6,5.0Hz,1H),3.65(dd,J=11.2,4.2Hz,1H),3.56(tt,J=10.1,5.0Hz,1H),3.22–3.08(m,1H),2.93(td,J=10.3,1.8Hz,1H),2.37–2.26(m,1H),1.01–0.79(m,2H)。120c和120d为对映异构体。
实施例120d:(3R,4R)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):275.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.54–7.39(m,2H),7.19(d,J=1.2Hz,1H),7.16–7.05(m,1H),5.87(d,J=2.3Hz,1H),5.13(d,J=5.3Hz,1H),3.80(dd,J=10.6,5.0Hz,1H),3.65(dd,J=11.0,4.0Hz,1H),3.56(tt,J=10.3,5.2Hz,1H),3.13(td,J=11.5,2.7Hz,1H),3.01–2.88(m,1H),1.00–0.76(m,2H)。120c和120d为对映异构体。
实施例121:2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-
醇
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
步骤1:
(E)-2-氨基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹啉-5(6H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和2-氨基-7,8-二氢喹啉-5(6H)-酮(1.17g,7.24mmol)在乙醇(50mL)中的溶液中添加无水Ca(OH)2(1.12g,15.08mmol)。将混合物在90℃搅拌过夜。在热的情况下,将沉淀过滤且重悬浮于热的MeOH(20mL)。将固体再次过滤且风干。产物直接使用而不用进一步纯化:LCMS(ESI,m/z):559.2[M+H]+.
步骤2:
2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹啉-5(6H)-酮
(E)-2-氨基-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹啉-5(6H)-酮(3.37g,6.03mmol)在20%AcOH的MeOH溶液(200mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(60mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用20%三氟乙醇在DCM中的溶液(3x50mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=90:10洗脱:LCMS(ESI,m/z):317.3[M+H]+.
步骤3:
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
在0℃向2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹啉-5(6H)-酮(0.724g,2.29mmol)在MeOH(50mL)中的悬浮液中分批添加NaBH4(346mg,9.15mmol)且溶液在室温搅拌2小时。将溶剂蒸馏掉且添加饱和氯化铵溶液(30mL)。水层用20%三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=80:20洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例121a:(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121b:(5R,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121c:(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121d:(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121e:(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121f:(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121g:(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例121h:(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):319.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.69–7.59(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.41(tt,J=7.6,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.37(d,J=8.5Hz,1H),5.84(s,2H),5.78–5.74(m,2H),4.89–4.78(m,1H),2.47–2.23(m,3H),1.28–1.22(m,2H)。
实施例122:8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲
酰胺
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
步骤1:
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
向8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈(1.45g,4.43mmol)在甲醇(100mL)中的溶液中添加氢氧化钠(1.77g,44.29mmol)和过氧化氢(30%水溶液,1.33mL,13.29mmol)且在室温搅拌2小时。去除溶剂且粗产物用5%2,2,2-三氟乙醇在DCM中的溶液萃取。合并的有机层用水、盐水洗涤,用硫酸钠干燥且蒸发以得到粗产物。将粗产物通过Combi-Flash纯化且进一步通过手性分离进行分离以得到6种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例122a:(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.22(dd,J=1.9,0.9Hz,1H),7.95(t,J=0.6Hz,1H),7.90(s,1H),7.69–7.61(m,2H),7.48(dq,J=7.6,0.9Hz,1H),7.46–7.37(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.24(s,1H),7.18(s,1H),7.06(d,J=7.9Hz,1H),6.06(d,J=7.8Hz,1H),5.83(d,J=1.9Hz,1H),5.04–4.85(m,1H),3.51–3.39(m,1H),2.65–2.56(m,2H),2.45–2.32(m,1H),1.30–1.19(m,1H)。
实施例122b:(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.27–8.19(m,1H),7.95(s,1H),7.90(s,1H),7.69–7.60(m,2H),7.48(dq,J=7.5,0.9Hz,1H),7.41(tt,J=7.7,0.9Hz,1H),7.31(td,J=7.5,1.2Hz,1H),7.26(d,J=10.9Hz,1H),7.06(d,J=8.0Hz,1H),6.06(d,J=7.8Hz,1H),5.83(d,J=2.0Hz,1H),4.97–4.90(m,1H),4.33(t,J=5.1Hz,1H),3.44(qd,J=7.0,5.1Hz,1H),2.61(dd,J=8.9,4.6Hz,2H),2.06–1.90(m,2H)。
实施例122c:(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.98–7.94(m,2H),7.91(s,1H),7.70(dd,J=8.0,1.9Hz,1H),7.64(dq,J=7.6,0.9Hz,1H),7.59(dt,J=7.6,0.9Hz,1H),7.42–7.36(m,1H),7.29(td,J=7.5,1.2Hz,2H),7.16–7.08(m,2H),5.85(d,J=6.1Hz,1H),5.56–5.50(m,1H),5.01(dd,J=6.1,3.6Hz,1H),2.75(dd,J=17.5,5.1Hz,1H),2.61–2.53(m,1H),2.43(dq,J=12.6,3.1Hz,1H),1.60–1.46(m,1H),1.05–0.98(m,1H)。
实施例122d:(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.20–8.13(m,1H),7.91(t,J=0.6Hz,1H),7.88(s,1H),7.67–7.59(m,3H),7.40(tt,J=7.6,0.8Hz,1H),7.26(td,J=7.6,1.2Hz,2H),7.17(d,J=0.5Hz,1H),7.06(d,J=8.0Hz,1H),6.08(d,J=7.6Hz,1H),5.82(d,J=3.3Hz,1H),4.95–4.85(m,1H),2.66–2.54(m,3H),0.91–0.80(m,2H)。
实施例122e:(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.99–7.93(m,2H),7.91(d,J=2.5Hz,1H),7.70(dd,J=8.0,1.9Hz,1H),7.61(ddt,J=16.2,7.6,0.9Hz,2H),7.47–7.35(m,1H),7.29(td,J=7.6,1.2Hz,2H),7.15–7.09(m,2H),5.85(d,J=6.1Hz,1H),5.54(d,J=2.5Hz,1H),5.01(dd,J=6.2,3.6Hz,1H),3.44(qd,J=7.0,5.1Hz,1H),2.75(dd,J=17.3,5.2Hz,1H),2.56(dt,J=11.3,5.8Hz,1H),2.44(dt,J=12.7,3.1Hz,1H),1.53(tt,J=12.7,6.3Hz,1H)。
实施例122f:((7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺:LCMS(ESI,m/z):346.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.01(t,J=0.7Hz,1H),7.89(d,J=1.9Hz,1H),7.87(s,1H),7.75(dq,J=7.8,0.9Hz,1H),7.69(dd,J=7.9,1.9Hz,1H),7.62(dt,J=7.7,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,2H),7.18–7.10(m,2H),5.58(d,J=5.9Hz,1H),5.44(d,J=6.1Hz,1H),4.82(dd,J=6.0,3.2Hz,1H),2.88(dd,J=17.4,5.1Hz,1H),2.73–2.60(m,1H),2.11(ddt,J=12.2,6.0,2.9Hz,1H),1.99(qd,J=12.4,5.4Hz,1H),1.80–1.71(m,1H)。
实施例123:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
步骤1:
(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹喔啉-5(6H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.4g,5.79mmol)和7,8-二氢喹喔啉-5(6H)-酮(944mg,6.37mmol)在乙醇(50mL)中的溶液中添加氢氧化钙(643mg,8.68mmol)。将混合物在100℃搅拌16hrs。将混合物冷却至室温且添加水(50mL)以淬灭反应。水相用DCM萃取(3x30mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。所需产物通过CombiFlash分离且用EtOAc:Hex=90:10洗脱:LCMS(ESI,m/z):545.3[M+H]+.
步骤2:
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹喔啉-5(6H)-酮
将(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-7,8-二氢喹喔啉-5(6H)-酮(1.8g,3.30mmol)在甲醇(16mL)和乙酸(4mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(50mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x50mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=92:8洗脱:LCMS(ESI,m/z):303.1[M+H]+.
步骤3:
(5R)-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
在-78℃向6-(5H-咪唑并[5,1-a]异吲哚-5-基)-7,8-二氢喹喔啉-5(6H)-酮(200mg,0.66mmol)在无水THF(10mL)中的悬浮液滴加L-selectride的THF溶液(1.32mL,1.32mmol)且将反应温热至-10℃,在0℃再保持5分钟。TLC指示起始材料完全消耗。该反应用甲醇(5mL)淬灭且将混合物倒入饱和氯化铵溶液(20mL)。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。产物通过CombiFlash分离且用DCM:MeOH=96:4洗脱:LCMS(ESI,m/z):305.3[M+H]+.
步骤4:
4-硝基苯甲酸(5S)-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-基酯
在氮气下,在0℃向(5R)-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇(270mg,0.89mmol)、4-硝基苯甲酸(222mg,1.33mmol)在THF(10mL)中的溶液中添加n-Bu3P(12mL,4.44mmol,10%在己烷中)。然后在0℃向其添加DBAD(5.8mL,4.44mmol,20%在甲苯中)。所得溶液在室温搅拌2h。所得溶液用DCM(20mL)稀释,然后通过添加水淬灭(20mL)。所得溶液用在二氯甲烷中的20%2,2,2,-三氟乙醇(3x20mL)萃取,且合并有机层且用无水硫酸钠干燥且真空浓缩。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):454.2[M+H]+.
步骤5:
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
向4-硝基苯甲酸(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-基酯(135mg,0.3mmol)在THF(3mL)和水(1mL)中的溶液中添加LiOH.H2O(187mg,4.47mmol)。所得溶液在室温搅拌2h。LC-MS指示起始材料消耗。所得溶液用水(20mL)稀释。所得溶液用20%2,2,2,-三氟乙醇的二氯甲烷溶液(3x20mL)萃取且合并有机层且用无水硫酸钠干燥。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到2种异构体且各异构体的立体化学任意指定。
实施例123a:(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.55(dd,J=2.5,0.9Hz,1H),8.45(dd,J=2.5,0.8Hz,1H),7.94(t,J=0.6Hz,1H),7.65(dt,J=7.5,1.0Hz,1H),7.55–7.49(m,1H),7.46–7.39(m,1H),7.32(td,J=7.5,1.1Hz,1H),7.19(s,1H),6.10(d,J=5.5Hz,1H),5.82–5.78(m,1H),5.01(dd,J=10.7,5.4Hz,1H),2.85–2.65(m,2H),2.59(tdd,J=10.7,4.1,2.2Hz,1H),0.98(ddd,J=13.5,8.5,3.3Hz,2H)。
实施例123b:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇:LCMS(ESI,m/z):305.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.55(dd,J=2.5,0.9Hz,1H),8.45(dd,J=2.5,0.8Hz,1H),7.94(d,J=0.6Hz,1H),7.64(dt,J=7.6,0.9Hz,1H),7.55–7.48(m,1H),7.46–7.39(m,1H),7.32(td,J=7.5,1.2Hz,1H),7.19(s,1H),6.10(d,J=5.5Hz,1H),5.82–5.77(m,1H),5.00(dd,J=10.8,5.3Hz,1H),2.85–2.65(m,2H),2.64–2.54(m,1H),1.04–0.94(m,2H)。
实施例124:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-
5-醇
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇
该标题化合物通过与实施例096和169相同的方法合成。产物通过手性分离进行分离以得到2种异构体,为白色固体。各异构体的立体化学任意指定。
实施例124a:(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):319.4[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.35(ddd,J=4.7,1.8,0.7Hz,1H),8.01(s,1H),8.00–7.97(m,1H),7.53(ddd,J=9.6,6.4,3.7Hz,2H),7.27(dd,J=7.8,4.7Hz,1H),7.23(s,1H),7.14(ddd,J=9.6,8.4,2.5Hz,1H),6.21(d,J=7.5Hz,1H),5.80(s,1H),4.97(dd,J=10.6,7.6Hz,1H),2.68(dd,J=8.8,4.0Hz,2H),2.47–2.38(m,1H),1.02–0.82(m,2H)。
实施例124b:(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇:LCMS(ESI,m/z):319.4[M+H]+;1H NMR与实施例124a相同。
实施例125:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-
醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
步骤1:
(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢苯并[d]噻唑-4(5H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.25g,5.43mmol)和6,7-二氢苯并[d]噻唑-4(5H)-酮(915mg,5.97mmol)在甲醇(30mL)中的溶液中添加吡咯烷(0.49mL,5.97mmol)。将混合物在90℃搅拌24hrs。将混合物冷却至室温且添加水(30mL)以淬灭反应。水相用DCM萃取(3x30mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。所需产物通过CombiFlash分离且用EtOAc:Hex=60:40洗脱:LCMS(ESI,m/z):550.4[M+H]+.
步骤2:
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢苯并[d]噻唑-4(5H)-酮
(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢苯并[d]噻唑-4(5H)-酮(2.41g,4.38mmol)在甲醇(40mL)和乙酸(10mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(50mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x50mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=96:4洗脱:LCMS(ESI,m/z):308.2[M+H]+.
步骤3:
(4R)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
在-78℃向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢苯并[d]噻唑-4(5H)-酮(1.08g,3.51mmol)在无水THF(15mL)中的溶液中滴加L-Selectride(5.3mL,5.27mmol)在THF中的溶液且溶液在-78℃搅拌1小时。该反应用甲醇(5mL)淬灭且将混合物倒入饱和氯化铵溶液(20mL)。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=94:6洗脱:LCMS(ESI,m/z):310.2[M+H]+.
步骤4:
4-硝基苯甲酸(4S)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-基酯
在氮气下,在0℃向(4R)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇(270mg,0.89mmol)、4-硝基苯甲酸(222mg,1.33mmol)在THF(10mL)中的溶液中添加n-Bu3P(12mL,4.44mmol,10%在己烷中)。然后在0℃向其添加DBAD(5.8mL,4.44mmol,20%在甲苯中)。所得溶液在室温搅拌2h。反应通过添加水(20mL)淬灭。所得溶液用20%2,2,2,-三氟乙醇的二氯甲烷溶液(3x20mL)萃取且合并有机层且用无水硫酸钠干燥且真空浓缩。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):459.4[M+H]+.
步骤5:
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
向4-硝基苯甲酸(4S)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-基酯(1.17g,2.55mmol)在THF(15mL)和水(5mL)中的溶液中添加LiOH.H2O(1.07g,25.52mmol)。所得溶液在室温搅拌2h。LC-MS指示起始材料消耗。所得溶液用水(20mL)稀释。所得溶液用20%2,2,2,-三氟乙醇的二氯甲烷溶液(3x20mL)萃取且合并有机层且用无水硫酸钠干燥。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到2种异构体且各异构体的立体化学任意指定。
实施例125a:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇:LCMS(ESI,m/z):310.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.94(d,J=0.6Hz,1H),7.94(s,1H),7.63(dt,J=7.7,1.0Hz,1H),7.49(dq,J=7.6,1.0Hz,1H),7.46–7.39(m,1H),7.32(td,J=7.5,1.2Hz,1H),7.17(s,1H),5.91(d,J=6.6Hz,1H),5.77(t,J=1.4Hz,1H),5.06(t,J=8.2Hz,1H),2.69–2.55(m,2H),2.48–2.42(m,1H),1.03–0.86(m,2H)。
实施例125b:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇:LCMS(ESI,m/z):310.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.94(d,J=0.6Hz,1H),7.94(s,1H),7.63(dt,J=7.7,1.0Hz,1H),7.49(dq,J=7.6,1.0Hz,1H),7.46–7.39(m,1H),7.32(td,J=7.5,1.2Hz,1H),7.17(s,1H),5.91(d,J=6.6Hz,1H),5.77(t,J=1.4Hz,1H),5.06(t,J=8.2Hz,1H),2.69–2.55(m,2H),2.48–2.42(m,1H),1.03–0.86(m,2H)。
实施例126:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
步骤1:
(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢喹啉-8(5H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.5g,6.03mmol)和6,7-二氢喹啉-8(5H)-酮(1.07g,7.24mmol)在乙醇(20mL)中的溶液中添加乙醇钠的乙醇溶液(2.7mL,7.24mmol)。将混合物在90℃搅拌1小时。将混合物冷却至室温且添加水(50mL)以淬灭反应。水相用DCM萃取(3x30mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。所需产物通过CombiFlash分离且用EtOAc:Hex=80:20洗脱:LCMS(ESI,m/z):544.3[M+H]+.
步骤2:
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢喹啉-8(5H)-酮
将(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢喹啉-8(5H)-酮(2.05g,3.77mmol)在甲醇(40mL)和乙酸(10mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(50mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用DCM萃取(3x50mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):302.2[M+H]+.
步骤3:
(8R)-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
在-78℃向7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢喹啉-8(5H)-酮(810mg,2.69mmol)在无水THF(10mL)中的悬浮液滴加L-selectride的THF溶液(1.32mL,1.32mmol)且将反应温热至-10℃且在0℃再保持5分钟。TLC指示起始材料完全消耗。该反应用甲醇(5mL)淬灭且将混合物倒入饱和氯化铵溶液(20mL)。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。产物通过CombiFlash分离且用DCM:MeOH=96:4洗脱:LCMS(ESI,m/z):304.1[M+H]+.
步骤4:
4-硝基苯甲酸(8S)-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-基酯
在氮气下,在0℃向(8R)-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇(200mg,0.66mmol)、4-硝基苯甲酸(165mg,0.99mmol)在THF(10mL)中的溶液中添加n-Bu3P(5.34mL,1.98mmol,10%在己烷中)。然后在0℃向其添加DBAD(2.59mL,1.98mmol,20%在甲苯中)。所得溶液在室温搅拌2h。所得溶液用DCM(20mL)稀释,然后通过添加水(20mL)淬灭。所得溶液用二氯甲烷(3x20mL)萃取且合并有机层且用无水硫酸钠干燥且真空浓缩。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):453.2[M+H]+.
步骤5:
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
向4-硝基苯甲酸(8S)-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-基酯(298mg,0.66mmol,基于步骤4计算)在THF(3mL)和水(1mL)中的溶液中添加LiOH。H2O(276mg,6.59mmol)。所得溶液在室温搅拌2h。LC-MS指示起始材料消耗。所得溶液用水(20mL)稀释。所得溶液用二氯甲烷(3x20mL)萃取且合并有机层且用无水硫酸钠干燥。所需产物通过CombiFlash分离且用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到2种异构体且各异构体的立体化学任意指定。
实施例126a:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.48(dd,J=4.7,1.6Hz,1H),7.93(s,1H),7.64(dt,J=7.5,0.9Hz,1H),7.52(dq,J=7.6,1.0Hz,1H),7.47(ddd,J=7.7,1.7,0.9Hz,1H),7.45–7.39(m,1H),7.32(td,J=7.5,1.1Hz,1H),7.23(ddd,J=7.7,4.7,0.7Hz,1H),7.18(s,1H),5.80(d,J=2.1Hz,1H),5.72(d,J=4.1Hz,1H),4.91(dd,J=10.6,4.0Hz,1H),2.70–2.58(m,2H),2.58–2.52(m,1H),0.95(dtd,J=9.7,6.8,6.3,3.5Hz,1H),0.91–0.80(m,1H)。
实施例126b:(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇:LCMS(ESI,m/z):304.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.48(dd,J=4.7,1.7Hz,1H),7.93(t,J=0.6Hz,1H),7.64(dt,J=7.5,1.0Hz,1H),7.52(dq,J=7.6,1.0Hz,1H),7.47(ddd,J=7.7,1.8,0.9Hz,1H),7.45–7.38(m,1H),7.32(td,J=7.5,1.2Hz,1H),7.23(ddd,J=7.7,4.7,0.7Hz,1H),7.18(s,1H),5.85–5.77(m,1H),5.71(d,J=4.1Hz,1H),4.91(dd,J=10.5,4.0Hz,1H),2.71–2.59(m,2H),2.59–2.54(m,1H),1.01–0.79(m,2H)。
实施例127:3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
在-78℃向5H-咪唑并[5,1-a]异吲哚(1.00g,6.40mmol)在无水THF(50mL)中的溶液中添加n-BuLi(3.20mL,7.04mmol,2.2M溶液环己烷)。在-78℃搅拌0.5后,添加3-氧代哌啶-1-甲酸叔丁酯(2.55g,12.8mmol)在THF(8mL)中的溶液且反应经2h温热至室温且持续搅拌过夜(18h)。反应通过添加饱和NH4Cl(50mL)淬灭且该反应用水(20mL)稀释,产物用CH2Cl2(3x40mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩。粗物质通过combi-flash纯化,使用MeOH/DCM(5:95)作为洗脱液。最终产物进一步通过手性分离进行分离以得到3种异构体且各异构体的立体化学任意指定。
实施例127a:(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯:LCMS(ESI,m/z):356.4[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.87(s,1H),7.60(d,J=7.6Hz,2H),7.43–7.36(m,1H),7.29–7.22(m,1H),7.13(s,1H),5.25(s,1H),5.22(s,1H),3.87–3.68(m,2H),3.04–2.85(m,1H),1.72–1.59(m,1H),1.39(s,9H),1.35–1.25(m,1H),1.21–1.08(m,2H)。
实施例127b:(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯:LCMS(ESI,m/z):356.4[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.89(s,1H),7.61(dd,J=12.4,7.7Hz,2H),7.40(t,J=7.6Hz,1H),7.26(t,J=7.6Hz,1H),7.14(s,1H),5.22(s,2H),3.85–3.72(m,1H),1.86–1.46(m,3H),1.45–1.38(m,1H),1.34(s,9H)。
实施例127c:(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯:LCMS(ESI,m/z):356.4[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.87(s,1H),7.60(d,J=7.6Hz,2H),7.43–7.36(m,1H),7.29–7.22(m,1H),7.13(s,1H),5.25(s,1H),5.22(s,1H),3.87–3.68(m,2H),3.04–2.85(m,1H),1.72–1.59(m,1H),1.39(s,9H),1.35–1.25(m,1H),1.21–1.08(m,2H)。
实施例128:1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
在-40℃向5H-咪唑并[5,1-a]异吲哚(500mg,3.20mmol)在无水THF(20mL)中的溶液中添加n-BuLi(1.28mL,3.20mmol,2.5M在己烷中的溶液)。在-40℃搅拌1.0hr后,添加环庚酮(395mg,3.52mmol)且反应经2hr温热至室温且持续搅拌过夜(18hr)。反应通过添加饱和NH4Cl(5mL)和水(15mL)淬灭,产物用CH2Cl2(3x30mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩,粗物质通过CombiFlash纯化以得到1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,其为米色固体(187mg,22%产率):LCMS(ESI,m/z):269.21[M+H]+.1H NMR(氯仿-d,400MHz):δ(ppm)7.96(s,1H),7.53(t,J=6.8Hz,2H),7.37(t,J=7.6Hz,1H),7.22(td,J=7.6,1.0Hz,1H),7.15(s,1H),5.30(s,1H),5.10(s,1H),2.11-1.78(m,3H),1.69-1.40(m,5H),1.38-1.14(m,3H),1.14-1.01(m,1H)。
实施例129:3-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
步骤1:
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(500mg,3.2mmol)在无水THF(10mL)中的溶液中添加n-BuLi溶液(1.54mL,3.84mmol)且搅拌1小时。将二氢呋喃-3(2H)-酮(0.37mL,4.8mmol)滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温再保持2hrs且用饱和NH4Cl溶液(20mL)淬灭。将混合物用DCM萃取(3x20ml)且将有机相合并,用Na2SO4干燥,且浓缩。产物通过制备型HPLC分离。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例129a:(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.84(t,J=0.6Hz,1H),7.61–7.54(m,2H),7.42–7.36(m,1H),7.24(d,J=1.2Hz,1H),7.12(s,1H),5.46(s,1H),5.45(s,1H),3.96(d,J=9.3Hz,1H),3.79(ddd,J=9.1,8.1,6.7Hz,1H),3.71–3.62(m,2H),1.91(dt,J=12.7,8.9Hz,1H),1.82–1.72(m,1H)。
实施例129b:(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.87(d,J=0.7Hz,1H),7.58(s,1H),7.50(d,J=0.9Hz,1H),7.39(s,1H),7.24(d,J=1.2Hz,1H),7.12(s,1H),5.46(s,1H),5.40(s,1H),3.85–3.76(m,2H),3.73(td,J=8.4,3.2Hz,1H),3.56(dd,J=9.3,0.7Hz,1H),2.09(ddd,J=12.7,9.4,8.6Hz,1H),1.98–1.89(m,1H)。
实施例129c:(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.87(t,J=0.7Hz,1H),7.59(dt,J=7.6,1.0Hz,1H),7.51(dq,J=7.7,0.9Hz,1H),7.39(tdd,J=7.5,1.1,0.6Hz,1H),7.24(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.47(s,1H),5.40(s,1H),3.86–3.76(m,2H),3.73(td,J=8.4,3.2Hz,1H),3.56(dd,J=9.2,0.7Hz,1H),2.09(ddd,J=12.7,9.4,8.6Hz,1H),1.94(dddd,J=12.8,6.5,3.3,0.8Hz,1H)。
实施例129d:(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):243.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.84(t,J=0.6Hz,1H),7.62–7.54(m,2H),7.42–7.36(m,1H),7.24(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.46(s,1H),5.45(s,1H),3.96(d,J=9.3Hz,1H),3.79(ddd,J=9.2,8.1,6.7Hz,1H),3.71–3.62(m,2H),1.91(dt,J=12.7,8.9Hz,1H),1.80–1.72(m,1H)。
实施例130:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲
唑-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
该标题化合物通过与实施例88相同的方法合成。
异构体的构型任意指定。
实施例130a:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.65–7.61(m,1H),7.59–7.53(m,2H),7.41–7.36(m,1H),7.25(td,J=7.6,1.2Hz,1H),7.16(s,1H),5.74(d,J=2.9Hz,1H),5.63(d,J=6.6Hz,1H),4.90(dd,J=10.1,6.6Hz,1H),3.74(s,3H),2.42–2.18(m,3H),0.83(m,2H)。130a和130h为对映异构体。
实施例130b:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.59(dt,J=10.7,2.8Hz,3H),7.38(t,J=7.6Hz,1H),7.28(t,J=7.7Hz,1H),7.11(d,J=2.3Hz,1H),5.46(s,1H),5.41(dd,J=5.9,2.3Hz,1H),5.02(d,J=4.4Hz,1H),3.76(d,J=2.5Hz,3H),2.34(d,J=12.2Hz,1H),2.21(t,J=12.9Hz,1H),1.48(dd,J=12.8,5.0Hz,1H),0.89(d,J=13.5Hz,1H)。130b和130g为对映异构体。
实施例130c:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.77(d,J=7.7Hz,1H),7.61(d,J=7.5Hz,1H),7.54(s,1H),7.37(dd,J=7.8,6.8Hz,1H),7.24(td,J=7.7,1.0Hz,2H),5.37(s,1H),5.12(d,J=5.4Hz,1H),4.83(s,1H),3.74(s,3H),2.63(dd,J=16.0,4.6Hz,1H),2.39–2.24(m,1H),2.05(d,J=16.2Hz,1H),1.91(dq,J=13.6,8.5Hz,1H),1.65(s,1H)。130c和130f为对映异构体。
实施例130d:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.62(dd,J=7.6,0.9Hz,1H),7.58(s,1H),7.46(dd,J=7.5,1.0Hz,1H),7.43–7.38(m,1H),7.31(td,J=7.5,1.1Hz,1H),7.17(s,1H),5.74(d,J=1.6Hz,1H),5.62(d,J=7.0Hz,1H),4.93(dd,J=10.1,7.1Hz,1H),3.75(s,3H),2.42–2.32(m,1H),2.32–2.15(m,2H),0.92–0.83(m,1H),0.76(qd,J=12.5,5.6Hz,1H)。130d和130e为对映异构体。
实施例130e:(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.65–7.57(m,2H),7.46(d,J=7.6Hz,1H),7.41(t,J=7.4Hz,1H),7.31(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.74(s,1H),5.62(d,J=7.0Hz,1H),4.93(dd,J=10.1,7.0Hz,1H),3.75(s,3H),3.29–3.23(m,1H),2.37(dd,J=16.1,5.0Hz,1H),2.32–2.15(m,2H),0.92–0.68(m,2H)。130d和130e为对映异构体。
实施例130f:(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.77(d,J=7.7Hz,1H),7.60(d,J=7.6Hz,1H),7.54(s,1H),7.37(td,J=7.5,1.0Hz,1H),7.24(td,J=7.6,1.0Hz,2H),5.37(s,1H),5.12(d,J=5.5Hz,1H),4.83(s,1H),3.74(s,3H),2.63(dd,J=16.1,4.5Hz,1H),2.41–2.26(m,1H),2.03(s,1H),1.92(tt,J=12.7,6.3Hz,1H),1.64(d,J=10.9Hz,1H)。130c和130f为对映异构体。
实施例130g:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.98(d,J=0.7Hz,1H),7.62–7.56(m,3H),7.40–7.35(m,1H),7.27(td,J=7.5,1.2Hz,1H),7.10(s,1H),5.46(d,J=1.9Hz,1H),5.41(dd,J=5.8,0.5Hz,1H),5.02(dd,J=5.7,3.6Hz,1H),3.76(s,3H),2.37–2.30(m,1H),2.27–2.16(m,1H),1.48(qd,J=12.8,5.5Hz,1H),0.94–0.83(m,1H)。130b和130g为对映异构体。
实施例130h:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.64(d,J=7.5Hz,1H),7.56(d,J=9.2Hz,2H),7.42–7.36(m,1H),7.25(td,J=7.5,1.0Hz,2H),5.72(s,1H),5.63(d,J=6.6Hz,1H),4.90(dd,J=9.9,6.6Hz,1H),3.74(s,3H),2.39-2.24(m,3H),0.82(m,2H)。130a和130h为对映异构体。
实施例131:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-
醇
在-40℃向5H-咪唑并[5,1-a]异吲哚(1.71g,10.92mmol)在无水THF(25mL)中的溶液中添加n-BuLi(2.18mL,5.46mmol,2.5M在己烷中的溶液)。在-40℃搅拌1.0h后,添加1-(四氢-2H-吡喃-4-基)乙-1-酮(700mg,5.46mmol)且将反应温热至-20℃且搅拌1小时。反应通过添加饱和NH4Cl(10mL)和水(20mL)淬灭,产物用CH2Cl2(3x35mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩以得到粗混合物。将粗混合物通过CombiFlash纯化以得到一对非对映异构体(455mg,29%产率),其立体化学任意指定:LCMS(ESI,m/z):285.21[M+H]+.
实施例131a:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇和(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇的混合物:LCMS(ESI,m/z):285.21[M+H]+.1H NMR(氯仿-d,400MHz):δ(ppm)7.85(s,1H),7.65-7.54(m,2H),7.41(t,J=7.6Hz,1H),7.26(td,J=7.8,1.2Hz,1H),7.20(s,1H),5.31(s,1H),4.02(d,J=10.3Hz,1H),3.91(dd,J=11.5,4.4Hz,1H),3.40–3.30(m,1H),3.25(td,J=11.9,2.2Hz,1H),1.79–1.56(m,3H),2.90(s,1H),1.55–1.41(m,1H),1.21(d,J=13.2Hz,1H),1.13(s,3H)。
实施例131b:(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇和(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇的混合物:LCMS(ESI,m/z):285.21[M+H]+.1H NMR(氯仿-d,400MHz):δ(ppm)8.01(s,1H),7.58(d,J=7.5Hz,1H),7.42(t,J=7.7Hz,1H),7.35(d,J=7.4Hz,1H),7.32–7.24(m,1H),7.20(s,1H),5.42(s,1H),4.25–4.17(m,1H),4.17-4.08(m,1H),3.65-3.44(m,3H),2.17-2.05(m,2H),1.97(d,J=11.0Hz,1H),1.87(dq,J=19.2,7.6,6.1Hz,1H),1.58(d,J=13.0Hz,1H),0.58(s,3H)。
实施例132:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(300mg,1.92mmol)在无水THF(15mL)中的溶液中添加n-BuLi(0.85mL,2.11mmol,2.5M在己烷中的溶液)。在-78℃搅拌1hr后,上述悬浮液混合物用4,4’-二甲基环己酮(363mg,2.88mmol)在3mL THF中的溶液处理。在-78℃ 1hr后,该反应用水(1mL)和NH4Cl溶液(20mL)淬灭。分离的水层随后用DCM萃取(20mL x 3)。合并的有机相用Na2SO4干燥,过滤且通过Combi-Flash使用MeOH/DCM(4%-8%)纯化:LCMS(ESI,m/z):283.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.60(ddt,J=9.1,7.4,0.9Hz,2H),7.39(ddd,J=8.0,7.4,0.9Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.11(s,1H),5.04(s,1H),1.69–1.51(m,2H),1.44(ddd,J=13.3,8.8,2.7Hz,2H),1.14–0.91(m,3H),0.84(s,3H),0.79(d,J=2.9Hz,1H),0.63(s,3H)。
实施例133:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-
a]氮杂环庚三烯-4-醇
步骤1:5-(1H-吡唑-1-基)戊酸乙酯
在0℃向氢化钠(3.5g,87.5mmol,60%油分散体)在乙二醇二甲醚(300mL)中的混合物分批添加1H-吡唑(5.0g,73.45mmol)。所得溶液在0℃搅拌20分钟。添加5-溴戊酸乙酯(20g,95.66mmol)。所得溶液在60℃在搅拌下再反应16h。该反应然后通过添加水淬灭(100mL)。所得溶液用醚(3x100mL)萃取。合并的有机层用无水硫酸钠干燥且真空浓缩。残余物施加至具有EtOAc/石油醚(1:3)的硅胶柱。这得到12g(83%)5-(1H-吡唑-1-基)戊酸乙酯,为淡黄色油状物:LCMS(ESI,m/z):197.2[M+H]+.
步骤2:5-(1H-吡唑-1-基)戊酸
向5-(1H-吡唑-1-基)戊酸乙酯(12g,61.15mmol)在THF(100mL)中的溶液中添加氢氧化钠溶液(200mL,4.0mol,2.0M在水中)。所得溶液在室温搅拌16h。溶液的pH值用6M氯化氢调节至5。所得溶液用EtOAc(3x500mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。这得到10g(97%)5-(1H-吡唑-1-基)戊酸,为淡黄色油状物:LCMS(ESI,m/z):169.1[M+H]+.
步骤3:5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮
在氮气下在-70℃向5-(1H-吡唑-1-基)戊酸(5.0g,29.73mmol)在THF(200mL)中的溶液中添加正丁基锂(30mL,75.00mmol,2.5M在THF中)。所得溶液在-45℃搅拌1h。所得溶液在室温在搅拌下再反应1h。该反应然后通过添加饱和氯化铵(30mL)淬灭。将混合物真空浓缩。所得溶液用醚(3x200mL)萃取。合并的有机层用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(1:3)洗脱。这得到600mg(13%)5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮,其为淡黄色油状物:LCMS(ESI,m/z):151.1[M+H]+.
步骤4:(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮
向5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮(600mg,3.995mmol)和2-[1-(三苯基甲基)-1H-咪唑-4-基]苯甲醛(1.5g,3.619mmol)在MeOH(30mL)中的混合物中添加乙醇钠(3.1mL,9.57mmol,21%在MeOH中)。所得溶液在油浴中在80℃搅拌16h。所得溶液用DCM(50mL)稀释。反应然后通过添加水淬灭(20mL)。所得溶液用DCM萃取(3x100mL)。合并的有机层用硫酸钠干燥且真空浓缩。残余物施加至具有DCM/MeOH(13:1)的硅胶柱。这得到1.9g(87%)(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮,其为淡黄色固体:LCMS(ESI,m/z):547.3[M+H]+
步骤5:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮
向(E)-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮(1.9g,3.48mmol)在MeOH(20mL)中的混合物添加乙酸(4mL)。所得溶液在油浴中在80℃搅拌16h。所得混合物真空浓缩。所得溶液用EtOAc(500mL)稀释。所得混合物用饱和氯化铵(1x50mL)和盐水(1x50mL)洗涤。固体用硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(13:1)洗脱。这得到800mg(76%)5-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮,其为黄色固体:LCMS(ESI,m/z):305.1[M+H]+
步骤6:
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吡唑并[1,5-a]氮杂环庚三烯-4-酮(1.2g,3.943mmol)在MeOH(100mL)中的溶液中添加硼氢化钠(1.5g,39.65mmol)。所得溶液在室温搅拌30分钟。所得混合物真空浓缩。残余物用DCM(300mL)稀释。将固体过滤出。所得混合物真空浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离。所有异构体133a-h的绝对构型任意指定。
实施例133a:(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(9.1mg,1%),其为白色固体:LCMS[M+H]+307.3;1HNMR(300MHz,CD3OD)δ7.92(s,1H),7.68-7.59(m,2H),7.46-7.37(m,1H),7.34-7.26(m,1H),7.20(d,J=2.4Hz,1H),7.12(s,1H),5.98(d,J=2.1Hz,1H),5.44(d,J=1.8Hz,1H),4.75(d,J=1.2Hz,1H),4.39-4.00(m,2H),2.50-2.39(m,2H),2.18-2.06(m,1H),1.81-1.60(m,2H):LCMS(ESI,m/z):307.1[M+H]+.tR=1.111分钟(CHIRALPAK IB-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133a和133b为对映异构体。
实施例133b:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(8.0mg,1%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.tR=2.647分钟(CHIRALPAK IB-3,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133a和133b为对映异构体。
实施例133c:(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(7.5mg,1%),其为白色固体:LCMS(ESI,m/z):307.1[M+H]+.1H NMR(300MHz,CD3OD)δ7.90(s,1H),7.69-7.65(m,2H),7.45-7.35(m,3H),7.20(s,1H),6.45(d,J=1.5Hz,1H),6.04(d,J=3.6Hz,1H),5.04(d,J=10.3Hz,1H),4.38-4.26(m,1H),3.93-3.81(m,1H),2.59-2.42(m,1H),1.87-1.71(m,1H),1.49-1.27(m,1H),1.08-0.82(m,2H)。tR=2.067分钟(CHIRALPAK IA-3,0.46x5cm,Hex(0.1%DEA):EtOH=80:20,1ml/min)。133c和133d为对映异构体。
实施例133d:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(8.8mg,1%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=6.144分钟(CHIRALPAK IA-3,0.46x5cm,Hex(0.1%DEA):EtOH=80:20,1ml/min)。133c和133d为对映异构体。
实施例133e:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(38.3mg,31%),其为白色固体:LCMS(ESI,m/z):307.4[M+H]+.1H NMR(300MHz,CD3OD)δ8.18(s,1H),7.61-7.59(m,1H),7.48-7.33(m,3H),7.31(d,J=1.5Hz,1H),7.17(s,1H),6.34(d,J=1.5Hz,1H),5.58(d,J=1.5Hz,1H),5.40(d,J=10.2Hz,1H),4.32-4.28(m,2H),2.49-2.41(m,1H),1.92-1.68(m,2H),1.57-1.36(m,1H),1.05-0.92(m,1H)。tR=2.991分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133e和133h为对映异构体。
实施例133f:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(41.5mg,31%),其为白色固体:LCMS(ESI,m/z):307.4[M+H]+.1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.64-7.62(m,1H),7.43-7.33(m,4H),7.22(s,1H),6.47(d,J=1.5Hz,1H),6.00(d,J=1.5Hz,1H),5.05(d,J=10.2Hz,1H),4.30-4.28(m,1H),3.98-3.89(m,1H),2.41-2.32(m,1H),1.70-1.66(m,1H),1.42-1.16(m,2H),0.99-0.81(m,1H)。tR=4.079分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133f和133g为对映异构体。
实施例133g:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇(33.3mg,3%),其为白色固体:LCMS(ESI,m/z):307.1[M+H]+.tR=3.049分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133f和133g为对映异构体。
实施例133h:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇40.2mg,3%),其为白色固体:LCMS(ESI,m/z):307.1[M+H]+.tR=5.696分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=50:50,1ml/min)。133e和133h为对映异构体。
实施例134a:(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌
啶-3-醇
在室温,向(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯(实施例127c,72.2mg,0.20mmol)在无水MeOH中的溶液中添加4N HCl(0.51mL,20mmol)且再搅拌4小时。反应通过LC-MS监测。起始材料消耗后,蒸发溶剂且粗产物真空干燥。在0℃将粗产物溶于无水DCM且添加三乙胺(72uL,0.51mmol)。然后将甲磺酰氯(24uL,0.31mmol)添加至混合物。将反应温热至室温且再搅拌2小时。反应通过添加饱和NaHCO3水溶液(10mL)淬灭。粗产物用DCM萃取(3 x mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=94:6洗脱:LCMS(ESI,m/z):334.1[M+H]+;1H NMR(400MHz,DMSO-d6)7.88(s,1H),7.66(dd,J=7.6,1.0Hz,1H),7.63-7.59(m,1H),7.44 7.38(m,1H),7.30-7.24(m,1H),7.15(s,1H),5.50 5.48(m,1H),5.34-5.31(m,1H),3.53-3.47(m,1H),2.93(s,3H),2.71-2.60(m,1H),1.86-1.75(m,1H),1.53-1.41(m,1H),1.18-1.10(m,2H)。
实施例135:1-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇
该标题化合物通过与实施例128相同的方法合成,产物以30%产率得到。立体异构体通过手性SFC分离,立体化学任意指定:LCMS(ESI,m/z):247.34[M+H]+.
实施例135a:(S)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇:LCMS(ESI,m/z):247.34[M+H]+.1H NMR(DMSO-d6,400MHz):δ(ppm)7.85(d,J=0.7Hz,1H),7.56–7.43(m,2H),7.16(s,1H),7.06(ddd,J=9.6,8.4,2.5Hz,1H),5.38(d,J=4.6Hz,1H),5.26(d,J=5.8Hz,1H),3.80–3.71(m,1H),1.63(dq,J=13.4,6.7Hz,1H),0.84(d,J=6.8Hz,3H),0.69(d,J=6.6Hz,3H)。
实施例135b:(R)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇:LCMS(ESI,m/z):247.34[M+H]+.1H NMR(DMSO-d6,400MHz):δ(ppm)7.84(s,1H),7.54–7.42(m,2H),7.16(s,1H),7.06(ddd,J=9.6,8.4,2.5Hz,1H),5.33(d,J=4.8Hz,1H),5.11(d,J=6.4Hz,1H),3.48(td,J=6.5,4.9Hz,1H),1.89(h,J=6.6Hz,1H),0.98(d,J=6.6Hz,3H),0.94(d,J=6.8Hz,3H)。
实施例135c:(R)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇:LCMS(ESI,m/z):247.34[M+H]+.1H NMR(DMSO-d6,400MHz):与135a相同
实施例135d:(S)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇:LCMS(ESI,m/z):247.34[M+H]+.1H NMR(DMSO-d6,400MHz):与135b相同.
实施例136:7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
步骤1:
(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吲嗪-8(5H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(3.0g,7.24mmol)和6,7-二氢吲嗪-8(5H)-酮(1.17g,8.68mmol)在乙醇(50mL)中的溶液中添加无水Ca(OH)2(268mg,3.62mmol)。将混合物在90℃搅拌过夜。将混合物冷却至室温且添加饱和NH4Cl溶液(50mL)以淬灭反应。水相用DCM萃取(3x50mL)且将有机相合并,用无水Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用EtOAc:Hex=50:50洗脱:LCMS(ESI,m/z):532.3[M+H]+.
步骤2:
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吲嗪-8(5H)-酮
(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吲嗪-8(5H)-酮(3.2g,6.02mmol)在20%AcOH的MeOH溶液(50mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且将饱和NaHCO3(60mL)添加至残余物,然后添加DCM(20mL)。收集有机层且水层用20%三氟乙醇在DCM中的溶液(3x50mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且通过DCM:MeOH=97:3洗脱:LCMS(ESI,m/z):290.4[M+H]+.
步骤3:
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
在0℃向7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吲嗪-8(5H)-酮(1.0g,3.46mmol)在MeOH(50mL)中的溶液中分批添加硼氢化钠(261mg,6.91mmol)。反应在0℃保持2小时。反应通过饱和氯化铵溶液(30mL)淬灭。水层用DCM萃取(3x30mL)。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。产物通过CombiFlash分离且用MeOH:DCM=2:98洗脱。最终产物进一步通过手性分离进行分离以得到7种异构体且各异构体的立体化学任意指定。
实施例136a:(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.93(d,J=0.6Hz,1H),7.63(dt,J=7.5,1.0Hz,1H),7.49(dd,J=7.5,0.9Hz,1H),7.44–7.39(m,1H),7.33(dd,J=7.5,1.2Hz,1H),7.18(s,1H),6.54–6.50(m,1H),6.09(ddd,J=3.5,1.8,1.0Hz,1H),6.02(dd,J=3.5,2.6Hz,1H),5.79(d,J=7.5Hz,1H),5.76(s,1H),4.96(dd,J=10.3,7.4Hz,1H),3.81–3.74(m,1H),3.65–3.55(m,1H),2.47–2.38(m,1H),0.99(dq,J=9.0,4.9Hz,2H)。
实施例136b:(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.94(d,J=0.7Hz,1H),7.64(dt,J=7.6,1.0Hz,1H),7.59(dt,J=7.6,1.0Hz,1H),7.43–7.36(m,1H),7.29(td,J=7.5,1.2Hz,1H),7.12(s,1H),6.58(dd,J=2.6,1.7Hz,1H),6.04(dd,J=3.6,1.7Hz,1H),6.02(dd,J=3.5,2.6Hz,1H),5.63(dd,J=5.2,0.7Hz,1H),5.49(d,J=2.6Hz,1H),5.10(t,J=4.4Hz,1H),3.91(ddd,J=12.4,5.6,2.1Hz,1H),3.59(td,J=12.3,4.6Hz,1H),1.82(qd,J=12.5,5.7Hz,1H),1.17–1.07(m,1H)。
实施例136c:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.98(d,J=0.7Hz,1H),7.74(dq,J=7.8,0.9Hz,1H),7.62(dt,J=7.6,1.0Hz,1H),7.41–7.36(m,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),6.59(dd,J=2.5,1.9Hz,1H),6.01–5.96(m,2H),5.42(d,J=6.1Hz,1H),5.39(dd,J=5.1,0.7Hz,1H),4.91(ddd,J=4.8,3.3,0.9Hz,1H),4.05(ddd,J=12.4,5.4,1.8Hz,1H),3.68(td,J=12.1,4.6Hz,1H),2.30–2.12(m,2H),1.79(d,J=3.4Hz,1H)。
实施例136d:(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.94(s,1H),7.67–7.62(m,1H),7.58(dd,J=7.6,1.0Hz,1H),7.44–7.38(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.19(s,1H),6.51(dd,J=2.6,1.8Hz,1H),6.06(ddd,J=3.5,1.8,1.0Hz,1H),6.00(dd,J=3.5,2.6Hz,1H),5.80(d,J=7.0Hz,1H),5.76(d,J=3.2Hz,1H),4.91(dd,J=10.4,7.0Hz,1H),3.79(ddt,J=11.3,5.8,2.9Hz,1H),3.63(td,J=12.2,4.7Hz,1H),2.63–2.54(m,1H),1.05(ddt,J=17.6,12.2,6.1Hz,1H),0.99–0.89(m,1H)。
实施例136e:(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.98(s,1H),7.76–7.70(m,1H),7.61(dt,J=7.6,1.0Hz,1H),7.42–7.35(m,1H),7.24(td,J=7.6,1.2Hz,1H),7.13(s,1H),6.59(dd,J=2.5,1.9Hz,1H),6.01–5.96(m,2H),5.42(d,J=6.1Hz,1H),5.39(dd,J=5.1,0.7Hz,1H),4.94–4.87(m,1H),4.08–4.00(m,1H),3.68(td,J=12.1,4.6Hz,1H),2.30–2.11(m,2H),1.81(d,J=12.5Hz,1H)。
实施例136f:(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.94(d,J=0.7Hz,1H),7.64(dd,J=7.6,0.9Hz,1H),7.61–7.57(m,1H),7.42–7.36(m,1H),7.29(td,J=7.6,1.2Hz,1H),7.12(s,1H),6.58(dd,J=2.6,1.7Hz,1H),6.03(d,J=1.7Hz,1H),6.02(dd,J=3.5,2.6Hz,1H),5.63(dd,J=5.1,0.7Hz,1H),5.49(d,J=2.6Hz,1H),5.10(t,J=4.2Hz,1H),3.91(ddd,J=12.4,5.6,2.1Hz,1H),3.59(td,J=12.3,4.7Hz,1H),1.83(qd,J=12.5,5.7Hz,1H),1.15–1.07(m,1H)。
实施例136g:(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇:LCMS(ESI,m/z):292.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.93(d,J=0.6Hz,1H),7.63(dt,J=7.7,1.0Hz,1H),7.49(dd,J=7.5,1.0Hz,1H),7.45–7.39(m,1H),7.33(dd,J=7.5,1.2Hz,1H),7.18(s,1H),6.52(dd,J=2.6,1.8Hz,1H),6.09(dq,J=2.8,0.9Hz,1H),6.02(dd,J=3.5,2.6Hz,1H),5.79(d,J=7.4Hz,1H),5.76(d,J=1.8Hz,1H),5.00–4.91(m,1H),3.78(dt,J=12.3,3.9Hz,1H),3.66–3.55(m,1H),2.46–2.38(m,1H),0.99(dq,J=9.2,5.0Hz,2H)。
实施例137:1-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇
实施例137a:(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇:LCMS(ESI,m/z):215.21[M+H]+.1H NMR(DMSO-d6,400MHz):δ(ppm)7.85(s,1H),7.61–7.50(m,2H),7.37(tdd,J=7.5,1.2,0.6Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.11(s,1H),5.27(s,1H),5.24(s,1H),3.90–3.79(m,1H),1.27(qd,J=7.8,6.0Hz,2H),0.88(t,J=7.4Hz,3H)。
实施例137b:(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇:LCMS(ESI,m/z):215.21[M+H]+.1H NMR(DMSO-d6,400MHz):与137a相同
实施例137c:(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇:LCMS(ESI,m/z):215.21[M+H]+.1H NMR(DMSO-d6,400MHz):δ(ppm)7.79(s,1H),7.59(dt,J=7.7,1.1Hz,1H),7.50(dq,J=7.6,0.9Hz,1H),7.38(tdd,J=7.5,1.1,0.6Hz,1H),7.26(td,J=7.5,1.1Hz,1H),7.13(s,1H),5.46(d,J=4.7Hz,1H),5.37(d,J=3.7Hz,1H),4.06(ddt,J=9.5,4.6,3.4Hz,1H),0.90–0.67(m,5H)
实施例137d:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇:LCMS(ESI,m/z):215.21[M+H]+.1H NMR(DMSO-d6,400MHz):与137c相同
实施例138:(5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
步骤1:
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
该标题化合物通过与实施例148相同的方法合成。
实施例138a:(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇:LCMS(ESI,m/z):271.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.59(dd,J=7.6,1.0Hz,1H),7.51(dd,J=7.5,1.0Hz,1H),7.38(ddd,J=8.2,7.5,1.1Hz,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.42(d,J=4.0Hz,1H),5.33(d,J=5.7Hz,1H),3.87(td,J=5.8,4.1Hz,1H),3.74(dd,J=10.9,3.8Hz,2H),3.20–3.05(m,2H),1.56(tt,J=10.2,5.3Hz,1H),1.45–1.31(m,1H),1.31–1.19(m,3H)。tR=0.956分钟(Chiralpak AD,15%CH3OH具有0.1%NH4OH共溶剂)。
实施例138b:(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇:LCMS(ESI,m/z):271.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.59(dd,J=7.6,1.0Hz,1H),7.51(dd,J=7.5,1.0Hz,1H),7.38(ddd,J=8.2,7.5,1.1Hz,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.42(d,J=4.0Hz,1H),5.33(d,J=5.7Hz,1H),3.87(td,J=5.8,4.1Hz,1H),3.74(dd,J=10.9,3.8Hz,2H),3.20–3.05(m,2H),1.56(tt,J=10.2,5.3Hz,1H),1.45–1.31(m,1H),1.31–1.19(m,3H)。tR=1.024分钟(Chiralpak AD,15%CH3OH具有0.1%NH4OH共溶剂)。
实施例138c:(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇:LCMS(ESI,m/z):271.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.61–7.54(m,1H),7.51(dd,J=7.5,1.0Hz,1H),7.37(tt,J=7.7,0.8Hz,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.36(d,J=4.2Hz,1H),5.10(d,J=6.5Hz,1H),3.92–3.78(m,2H),3.64(td,J=6.8,4.2Hz,1H),1.93–1.79(m,1H),1.78–1.69(m,1H),1.51–1.30(m,3H)。tR=1.545分钟(Chiralpak AD,15%CH3OH具有0.1%NH4OH共溶剂)。
实施例138d:(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇:LCMS(ESI,m/z):271.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.61–7.54(m,1H),7.51(dd,J=7.5,1.0Hz,1H),7.37(tt,J=7.7,0.8Hz,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.36(d,J=4.2Hz,1H),5.10(d,J=6.5Hz,1H),3.92–3.78(m,2H),3.64(td,J=6.8,4.2Hz,1H),1.93–1.79(m,1H),1.78–1.69(m,1H),1.51–1.30(m,3H)。tR=1.521分钟(Chiralpak AD,15%CH3OH具有0.1%NH4OH共溶剂)。
实施例139和139-1:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]
三唑并[1,5-a]吡啶-4-醇和6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-
2H-吲唑-7-醇
步骤1:3-(苄基氧基)2-吡啶甲醛
向(3-(苄基氧基)吡啶-2-基)甲醇(6.9g,32.06mmol)在1,4-二噁烷(150mL)中的溶液中添加二氧化锰(15.4g,177.14mmol)。所得溶液在油浴中在80℃搅拌20h。将固体过滤出。所得混合物真空浓缩。这得到5.6g(82%)3-(苄基氧基)2-吡啶甲醛,为棕色油状物:LCMS(ESI,m/z):214.2[M+H]+.
步骤2:4-(苄基氧基)-[1,2,3]三唑并[1,5-a]吡啶
向3-(苄基氧基)2-吡啶甲醛(5.6g,26.26mmol)在DCM(30mL)和MeOH(30mL)中的溶液中添加4-甲基苯-1-磺酰肼(5.6g,30.070mmol)。所得溶液在室温搅拌1.5h。所得混合物真空浓缩。残余物用吗啉(15mL)稀释。所得溶液在油浴中在95℃搅拌2h。所得混合物真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(1:3)洗脱。这得到4.6g(78%)4-(苄基氧基)-[1,2,3]三唑并[1,5-a]吡啶,其为淡黄色固体:LCMS(ESI,m/z):226.1[M+H]+.
步骤3:6,7-二氢-[1,2,3]三唑并[1,5-a]吡啶-4(5H)-酮
在氢气中,向4-(苄基氧基)-[1,2,3]三唑并[1,5-a]吡啶(2.0g,8.88mmol)在MeOH(80mL)中的混合物添加钯碳(1.45g,13.625mmol)。所得溶液在室温搅拌20h。将固体过滤出。所得混合物真空浓缩。残余物用EtOAc(600mL)稀释。溶液用饱和碳酸钾洗涤。所得混合物用硫酸钠干燥且真空浓缩。这得到500mg(41%)4H,5H,6H,7H-[1,2,3]三唑并[1,5-a]吡啶-4-酮,其为淡黄色固体:LCMS(ESI,m/z):138.2[M+H]+.
步骤4:(5E)-5-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)-4H,5H,6H,7H-[1,2,3]三唑并[1,5-a]吡啶-4-酮
该标题化合物通过合成Int-2的通用步骤合成。
步骤5:5-[5H-咪唑并[4,3-a]异吲哚-5-基]-4H,5H,6H,7H-[1,2,3]三唑并[1,5-a]吡啶-4-酮
该标题化合物通过合成Int-3的通用步骤合成。
步骤6:
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
在氮气下,在-65℃向5-[5H-咪唑并[4,3-a]异吲哚-5-基]-4H,5H,6H,7H-[1,2,3]三唑并[1,5-a]吡啶-4-酮(580mg,1.99mmol)在THF(20mL)中的溶液中添加L-Selectride(10mL,10mmol,1mol/L在THF中)。所得溶液在-65℃搅拌1h。该反应然后通过添加乙醇(10mL)淬灭。所得溶液用水(50mL)稀释。所得溶液用DCM萃取(3x200mL)。合并的有机层用无水硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(13:1)洗脱。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.XBridge Prep C18 OBD柱19×150mm 5um;流动相A:水(0.05%NH3H2O),流动相B:ACN;流速:20mL/min;梯度:10%B至27%B在11min内;254/220nm.
2.柱:Chiralpak IC,2x25cm,5um;流动相A:Hex--HPLC,流动相B:EtOH--HPLC;流速:16mL/min;梯度:50B至50B在24min内;220/254nm.
所有异构体139a-b的绝对构型任意指定。
实施例139a:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇(21.4mg,2%),其为白色固体:LCMS(ESI,m/z):294.3[M+H]+.1H NMR(300MHz,DMSO-d6)δ7.93(s,1H),7.76(s,1H),7.63(d,J=7.8Hz,1H),7.61(d,J=7.8Hz,1H),7.43-7.39(m,1H),7.33-7.28(m,1H),7.15(s,1H),6.33(d,J=5.4Hz,1H),5.58(d,J=4.8Hz,1H),5.31-5.29(m,1H),4.44-4.38(m,1H),4.05-3.95(m,1H),2.71-2.66(m,1H),1.92-1.76(m,1H),1.30-1.17(m,1H)。tR=4.092分钟(CHIRALPAK IC-3,0.46x5cm,Hex(0.1%DEA):EtOH=40:60,1ml/min)。139a和139b为对映异构体。
实施例139b:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇(17.4mg,2%),其为白色固体:LCMS(ESI,m/z):294.2[M+H]+.tR=5.055分钟(CHIRALPAK IC-3,0.46x5cm,Hex(0.1%DEA):EtOH=40:60,1ml/min)。139a和139b为对映异构体。
步骤1:
2-甲基-2H-吲唑-7-胺
向2-甲基-7-硝基-2H-吲唑(10g,56.45mmol5)和钯碳(2g,18.80mmol,5%)在MeOH(100mL)中的混合物中添加肼(20mL)。所得溶液在70℃搅拌4h。将固体过滤出。所得混合物真空浓缩。这得到7g(84%)2-甲基-2H-吲唑-7-胺:LCMS(ESI,m/z):148.2[M+H]+.
步骤2:
2-甲基-2H-吲唑-7-醇
向2-甲基-2H-吲唑-7-胺(3g,20.38mmol)在水(40mL)和硫酸(30mL,562.82mmol)中的溶液中添加NaNO2(1.4g,20.29mmol)在水(20mL)中的溶液。所得溶液在0℃搅拌1.5h。使所得溶液在100℃反应3h。该反应然后通过饱和碳酸氢钠(200mL)淬灭。溶液的pH值用碳酸氢钠调节至8。所得溶液用EtOAc(3x200mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(3/7)洗脱。这得到0.8g(27%)2-甲基-2H-吲唑-7-醇,为黄色固体:LCMS(ESI,m/z):149.2[M+H]+.
步骤3:
2-甲基-4,5,6,7-四氢-2H-吲唑-7-酮
向2-甲基-2H-吲唑-7-醇(1.8g,12.15mmol)在MeOH(50mL)中的溶液中添加钯碳(300mg,2.82mmol,10%)。混合物在20巴氢气下在25℃氢化24h。将固体过滤出。所得混合物真空浓缩。这得到1.5g(82%)2-甲基-4,5,6,7-四氢-2H-吲唑-7-酮,其为黑色油状物。
步骤4:(6E)-2-甲基-6-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)-4,5,6,7-四氢-2H-吲唑-7-酮
该标题化合物通过合成Int-2的通用步骤合成。
步骤5:
6-[5H-咪唑并[4,3-a]异吲哚-5-基]-2-甲基-4,5,6,7-四氢-2H-吲唑-7-酮
该标题化合物通过合成Int-3的通用步骤合成。
步骤6:
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
向6-[5H-咪唑并[4,3-a]异吲哚-5-基]-2-甲基-4,5,6,7-四氢-2H-吲唑-7-酮(900mg,2.96mmol)在THF(30mL)中的溶液中添加L-Selectride(8.42mL,8.42mmol,1mol/L在THF中)。所得溶液在-78℃搅拌3h。该反应然后通过水(4mL)淬灭。所得混合物真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(96/4)洗脱。粗产物通过prep-HPLC纯化且进一步通过手性分离进行分离。
所有异构体139-1a-d的绝对构型任意指定。
实施例139-1a:(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(3.7mg,0.4%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1HNMR(300MHz,CD3OD)δ7.92(s,1H),7.64(dd,J=23.2,7.6Hz,2H),7.44(dd,J=8.1,7.2Hz,1H),7.32(td,J=7.6,1.1Hz,1H),7.22(d,J=15.5Hz,2H),5.86(d,J=3.0Hz,1H),5.08(d,J=10.2Hz,1H),3.86(s,3H),2.56(ddd,J=14.1,10.4,3.5Hz,1H),2.46-2.28(m,2H),1.04-0.88(m,2H)。tR=2.164分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=40:60,1ml/min)。139-1a和139-1b为对映异构体。
实施例139-1b:(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(3.7mg,0.4%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=4.219分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=40:60,1ml/min)。139-1a和139-1b为对映异构体。
实施例139-1c:(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(16.1mg,0.4%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1HNMR(300MHz,CD3OD)δ8.16(s,1H),7.66-7.54(m,2H),7.47-7.25(m,3H),7.16(s,1H),5.60(s,1H),5.16(d,J=3.5Hz,1H),3.88(s,3H),2.56(ddd,J=16.1,5.5,2.3Hz,2H),2.31-2.18(m,1H),1.51(qd,J=12.7,5.5Hz,1H),1.01-0.91(m,1H)。tR=3.828分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=60:40,1ml/min)。139-1c和139-1d是对映异构体。
实施例139-1d:(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(14.7mg,2%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=4.616分钟(手性Cellulose-SB,0.46x5cm,Hex(0.1%DEA):EtOH=60:40,1ml/min)。139-1c和139-1d为对映异构体。
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
该标题化合物通过合成117a-b的通用步骤合成。所有异构体139-1e-f的绝对构型任意指定。
实施例139-1e:(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(30.4mg,6%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1HNMR(300MHz,CD3OD)δ7.97(s,1H),7.66(d,J=7.5Hz,1H),7.50(d,J=7.6Hz,1H),7.46(t,J=7.4Hz,1H),7.37(td,J=7.5,0.9Hz,2H),7.25(s,1H),7.21(s,1H),5.86(s,1H),5.06(d,J=10.2Hz,1H),2.48-2.24(m,3H),1.11-1.00(m,1H),0.95-0.84(m,1H)。tR=5.758分钟(CHIRALPAK AD-3,0.46x5cm,Hex(0.1%DEA):EtOH=80:20,1ml/min)。139-1e和139-1f为对映异构体。
实施例139-1f:(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇(29.9mg,6%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=7.006分钟(CHIRALPAK AD-3,0.46x5cm,Hex(0.1%DEA):EtOH=80:20,1ml/min)。139-1e和139-1f为对映异构体。
实施例140:4-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
向4-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈(实施例145,540mg,2.1mmol)在甲醇(15mL)中的溶液中,添加氢氧化钠(840mg,21mmol)和30%过氧化氢(2.11mL,21mmol)且在室温搅拌过夜。去除溶剂且粗产物用5%2,2,2-三氟乙醇的DCM溶液萃取。合并的有机层用水、盐水洗涤,用硫酸钠干燥且通过Combi-Flash使用MeOH/DCM(6%-10%)纯化。产物进一步通过手性分离进行分离以得到4种异构体,其为白色固体。各异构体的立体化学任意指定。
实施例140a:(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺:LCMS(ESI,m/z):298.1[M+H]+;1H NMR(DMSO-d6)δ:7.79(s,1H),7.56(dt,J=7.6,0.9Hz,1H),7.51(dd,J=7.8,1.0Hz,1H),7.42–7.32(m,1H),7.22(td,J=7.6,1.2Hz,1H),7.10(s,1H),7.08–7.00(m,1H),6.60(s,1H),5.10(s,1H),4.99(s,1H),2.36–2.26(m,1H),1.89–1.55(m,5H),1.42(d,J=7.0Hz,1H),1.23(td,J=12.9,4.3Hz,1H),0.82(d,J=13.3Hz,1H)
实施例140b:(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺:LCMS(ESI,m/z):298.1[M+H]+;1H NMR与实施例140a相同。
实施例140c:(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺,LCMS(ESI,m/z):298.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.61–7.56(m,2H),7.39(ddt,J=8.0,7.5,0.6Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.12(d,J=0.5Hz,1H),7.04(s,1H),6.59(s,1H),5.14(s,1H),5.11(s,1H),1.88–1.54(m,4H),1.43(ddd,J=29.0,26.2,13.7Hz,3H),1.04–0.95(m,1H),0.86(td,J=13.3,4.2Hz,1H)。
实施例140d:(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺:LCMS(ESI,m/z):298.1[M+H]+;1H NMR与实施例140c相同。
实施例141:8-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(R)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(S)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(R)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
(S)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
在-70℃向5H-咪唑并[5,1-a]异吲哚(573mg,3.67mmol)在无水THF(15mL)中的溶液中添加n-BuLi(1.47mL,3.67mmol,2.5M在己烷中的溶液)。在-70℃搅拌1hr后,添加6,7-二氢异喹啉-8(5H)-酮(180mg,1.22mmol)在5mL THF中的混合物。在-78℃1hr后,该反应用水(1mL)和NH4Cl溶液(20mL)淬灭。分离的水层随后用DCM萃取(20mLX 3)。合并的有机相用Na2SO4干燥,过滤且通过Combi-Flash使用MeOH/DCM(4%-10%)纯化。产物进一步通过手性分离进行分离以得到4种异构体,其为白色固体。各异构体的立体化学任意指定。
实施例141a:(R)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1H NMR与实施例141d相同。
实施例141b:(S)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.48(d,J=5.0Hz,1H),7.94(s,1H),7.59(dt,J=7.7,1.0Hz,1H),7.30(tt,J=7.6,1.0Hz,1H),7.23–7.16(m,2H),6.92(td,J=7.6,1.1Hz,1H),6.31(s,1H),6.04(s,1H),5.74(dq,J=7.8,0.9Hz,1H),2.60(dt,J=17.4,4.7Hz,1H),2.23–2.10(m,1H),1.59–1.43(m,1H),1.28–1.10(m,2H),0.85(ddd,J=13.6,11.2,2.9Hz,1H)。
实施例141c:(R)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1H NMR与实施例141b相同。
实施例141d:(S)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇:LCMS(ESI,m/z):304.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.46(d,J=5.0Hz,1H),7.81(dq,J=7.7,1.0Hz,1H),7.61(dt,J=7.5,1.0Hz,1H),7.42(tdd,J=7.5,1.2,0.6Hz,1H),7.31(td,J=7.6,1.2Hz,1H),7.18(dd,J=5.0,0.8Hz,1H),7.08(s,1H),6.31(s,1H),5.99(s,1H),5.90(s,1H),2.68–2.56(m,1H),2.24(ddd,J=16.6,10.2,5.2Hz,1H),1.64–1.49(m,1H),1.35(dd,J=12.8,6.1Hz,1H),1.16(t,J=7.0Hz,1H),0.92(ddd,J=14.3,11.4,3.1Hz,1H)。
实施例142:2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢
萘-1-醇
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
步骤1:
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)-3,4-二氢萘-1(2H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(1.5g,3.62mmol)和7-(甲基硫基)-3,4-二氢萘-1(2H)-酮(869mg,4.52mmol)在甲醇(120mL)中的溶液中添加乙醇钠(2.03mL,5.43mmol,21%的乙醇溶液)且反应回流5小时。将乙酸(7mL)添加至反应混合物且回流2小时。甲醇和乙酸在旋转式蒸发器上蒸发且将粗物质溶于水,分批添加固体碳酸钠以中和剩余乙酸。粗物质然后使用DCM(2X30mL)萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):347.2[M+H]+
步骤2:
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)-1,2,3,4-四氢萘-1-醇
在氩气下,在-78℃将2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)-3,4-二氢萘-1(2H)-酮(800mg,2.31mmol,1.000当量)在THF(50mL)中的溶液添加至L-Selectride(3.46mL,3.46mmol,1.0M在THF中)。所得溶液在-78℃搅拌15分钟。反应然后通过添加乙醇(25mL)淬灭。所得混合物真空浓缩,用水和盐水洗涤。残余物施加至Combi-Flash以进一步纯化:LCMS(ESI,m/z):349.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.65–7.57(m,2H),7.39(tt,J=7.6,0.9Hz,1H),7.32–7.22(m,3H),7.15–7.09(m,3H),7.03(t,J=7.8Hz,1H),5.86(d,J=5.7Hz,1H),5.51(d,J=2.2Hz,1H),4.99–4.93(m,1H),2.48(s,3H),2.45(s,1H),1.47(qd,J=12.6,5.4Hz,1H),0.95(d,J=12.9Hz,1H)。
步骤3:
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基硫基)-1,2,3,4-四氢萘-1-醇(0.4g,1.15mmol)在乙酸(3mL)中的溶液中添加过氧化氢(30%水溶液,0.39g,1.14mL,11.48mmol)且将反应在室温搅拌28小时。乙酸然后使用旋转蒸发器去除,残余乙酸使用饱和碳酸钠溶液淬灭。粗产物使用2,2,2-三氟乙醇在DCM中的溶液(2X 30mL)萃取。合并的有机层用盐水洗涤,用硫酸钠干燥,在旋转蒸发器上蒸发以得到粗产物。残余物施加至Combi-Flash以进一步纯化:LCMS(ESI,m/z):381.2[M+H]+
步骤4:
4-硝基苯甲酸(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-基酯
在氩气下,在0℃向2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇(420mg,1.1mmol)、4-硝基苯甲酸(276mg,1.66mmol,1.5当量)在THF(20mL)中的溶液中添加n-Bu3P(16.92mL,5.52mmol,10%在己烷中)。然后在0℃向其添加DBAD(7.39mL,5.52mmol,20%在甲苯中)。所得溶液在室温搅拌16h。所得溶液用DCM(30mL)稀释,然后通过添加水(10mL)淬灭。所得溶液用二氯甲烷(3x15mL)萃取且合并有机层且用无水硫酸钠干燥且真空浓缩。粗产物进一步在Combi-Flash上纯化:LCMS(ESI,m/z):530.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.41–8.35(m,2H),8.25(d,J=8.8Hz,2H),8.07(s,1H),7.81(dd,J=8.0,2.0Hz,1H),7.68(s,1H),7.63–7.55(m,2H),7.43(dd,J=21.3,7.8Hz,2H),7.30(d,J=1.2Hz,1H),6.65(d,J=10.1Hz,1H),5.63(s,1H),3.15(s,3H),1.96–1.81(m,2H),1.80–1.57(m,3H)。
步骤5:
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
向4-硝基苯甲酸2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-基酯(360mg,0.68mmol)在THF(10mL)和水(2mL)中的溶液中添加LiOH(167mg,6.8mmol)。所得溶液在室温搅拌40分钟。所得溶液用水(10mL)稀释。所得溶液用二氯甲烷萃取且合并有机层且用无水硫酸钠干燥以得到粗产物,其在Combi-Flash上纯化且进一步通过手性分离进行分离以得到2种异构体,为白色固体。所有异构体的绝对构型任意指定。
实施例142a:(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇:LCMS(ESI,m/z):381.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.22–8.18(m,1H),7.98(s,1H),7.71(dd,J=8.0,2.1Hz,1H),7.64(d,J=7.5Hz,1H),7.52–7.47(m,1H),7.42(t,J=7.4Hz,1H),7.34–7.28(m,2H),7.19(s,1H),6.36(d,J=7.6Hz,1H),5.82(s,1H),5.06–4.94(m,1H),3.20(s,3H),2.68(dd,J=8.5,4.5Hz,2H),2.43(s,1H),0.97–0.78(m,2H)。
实施例142b:(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
实施例143:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
步骤1:
1-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)乙-1-酮
向1-(1H-咪唑-2-基)乙酮(500mg,4.54mmol)在DCM(20mL)中的溶液中添加DIPEA(1.58ml,9.09mmol)和SEM氯化物(0.80ml溶于5mL DCM中,4.54mmol)。所得混合物在室温搅拌1小时。然后添加饱和碳酸氢钠水溶液(10mL)且水相用DCM萃取(3X 10mL萃取)。合并的有机萃取物干燥(Na2SO4),过滤且真空浓缩以得到标题化合物,其为黄色油状物。LCMS(ESI,m/z):183.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.66(d,J=1.1Hz,1H),7.16(d,J=1.0Hz,1H),5.68(s,2H),3.55–3.44(m,2H),2.55(s,3H),0.87–0.74(m,2H)、-0.07(s,9H)。
步骤2:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)乙-1-醇
在-40℃向5H-咪唑并[5,1-a]异吲哚(870mg,5.57mmol)在无水THF(20mL)中的溶液中添加n-BuLi(2.5M己烷中的溶液,0.357g,2.23mL,5.57mmol)且搅拌1小时。滴加1-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)乙-1-酮(0.67g,2.79mmol)在无水THF(3mL)中的溶液且将反应经3小时缓慢温热至0℃。反应再次冷却至40℃且用饱和NH4Cl溶液淬灭。粗产物使用DCM萃取且进一步在Combi-Flash上纯化。LCMS(ESI,m/z):397.3[M+H]+.
步骤3:
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
将4M HCl在二噁烷(3mL)中的溶液添加至1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)乙-1-醇(480mg)且混合物在50℃搅拌3小时。反应通过饱和Na2CO3溶液淬灭,且粗产物使用DCM中的10%TFE萃取。粗产物进一步在Combi-Flash上纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例143a:(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇:LCMS(ESI,m/z):267.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.24(s,1H),7.64(s,1H),7.57(d,J=7.6Hz,1H),7.32(dd,J=8.0,7.1Hz,1H),7.24–7.22(m,1H),7.15(s,1H),7.05–6.99(m,2H),6.20(s,1H),6.03–5.98(m,1H),5.79(s,1H),0.92(s,3H)。
实施例143b:(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇:LCMS(ESI,m/z):267.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.13(s,1H),7.59–7.55(m,1H),7.38(ddd,J=7.6,6.8,1.0Hz,1H),7.29(d,J=7.6Hz,1H),7.21(td,J=7.6,1.1Hz,1H),7.18(dd,J=2.1,1.2Hz,1H),7.06(s,1H),6.98(t,J=1.3,1.3Hz,1H),6.54(s,1H),6.17(s,1H),5.74(s,1H),1.10(s,3H)。
实施例143c:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇:LCMS(ESI,m/z):267.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.24(s,1H),7.64(s,1H),7.57(dd,J=7.6,0.9Hz,1H),7.32(t,J=0.9,0.9Hz,1H),7.23(dd,J=2.1,1.2Hz,1H),7.15(s,1H),7.06–6.98(m,2H),6.20(s,1H),6.01(dd,J=7.7,1.0Hz,1H),5.79(s,1H),0.92(s,3H)。
实施例143d:(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇:LCMS(ESI,m/z):267.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.13(s,1H),7.57(dt,J=7.5,0.9Hz,1H),7.38(tt,J=7.5,0.8Hz,1H),7.29(d,J=7.6Hz,1H),7.25–7.13(m,2H),7.07(s,1H),6.98(s,1H),6.54(s,1H),6.17(s,1H),5.74(s,1H),1.11(s,3H):LCMS(ESI,m/z):381.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.22–8.18(m,1H),7.98(s,1H),7.71(dd,J=8.0,2.1Hz,1H),7.64(d,J=7.5Hz,1H),7.52–7.47(m,1H),7.42(t,J=7.4Hz,1H),7.34–7.28(m,2H),7.19(s,1H),6.36(d,J=7.6Hz,1H),5.82(s,1H),5.06–4.94(m,1H),3.20(s,3H),2.68(dd,J=8.5,4.5Hz,2H),2.43(s,1H),0.97–0.78(m,2H)。
实施例144:3-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
步骤1:
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(500mg,3.20mmol)在无水THF(5mL)中的溶液中添加n-BuLi(1.28mL,3.20mmol,2.5M己烷溶液)。在-78℃搅拌0.5后,添加二氢-2H-吡喃-3(4H)-酮(160mg,1.60mmol)在THF(2mL)中的溶液且将反应经3h温热至室温且通过添加饱和NH4Cl(5mL)淬灭,该反应用水(30mL)稀释,产物用CH2Cl2(3x40mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩。粗物质通过combi-flash纯化,使用MeOH/DCM(1:9)作为洗脱液。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例144a:(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):257.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.61(dq,J=7.6,0.9Hz,1H),7.58(dt,J=7.6,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.36(s,1H),5.19(s,1H),3.69(d,J=11.2Hz,1H),3.28–3.21(m,2H),3.16(td,J=11.2,2.6Hz,1H),1.86(ddt,J=21.4,10.6,5.1Hz,1H),1.58–1.47(m,2H)。
实施例144b:(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):257.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.84(s,1H),7.59(dt,J=7.6,0.9Hz,1H),7.55(dq,J=7.9,1.0Hz,1H),7.39(tt,J=7.5,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.37(s,1H),5.20(s,1H),3.70(dd,J=11.5,2.2Hz,2H),3.58(d,J=11.5Hz,1H),3.14(td,J=11.3,2.6Hz,1H),1.16–1.02(m,2H)。
实施例144c:(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):257.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.84(s,1H),7.59(dt,J=7.6,0.9Hz,1H),7.55(dq,J=7.9,1.0Hz,1H),7.39(tt,J=7.5,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.37(s,1H),5.20(s,1H),3.70(dd,J=11.5,2.2Hz,2H),3.58(d,J=11.5Hz,1H),3.14(td,J=11.3,2.6Hz,1H),1.16–1.02(m,2H)。
实施例144d:(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇:LCMS(ESI,m/z):257.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.87(s,1H),7.61(dq,J=7.6,0.9Hz,1H),7.58(dt,J=7.6,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.36(s,1H),5.19(s,1H),3.69(d,J=11.2Hz,1H),3.28–3.21(m,2H),3.16(td,J=11.2,2.6Hz,1H),1.86(ddt,J=21.4,10.6,5.1Hz,1H),1.58–1.47(m,2H)。
实施例145:4-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
在-78℃向5H-咪唑并[5,1-a]异吲哚(600mg,3.84mmol)在无水THF(15mL)中的溶液中添加n-BuLi(1.54mL,3.84mmol,2.5M己烷溶液)。在-78℃搅拌1hr后,将溶液温热至0℃。将包含4-氧代环己烷-1-甲腈(473mg,3.84mmol)在10mL THF中的混合物的第二烧瓶冷却至-78℃,将其在10分钟内用上述原位产生的锂试剂逐滴处理。在-78℃ 1hr后,该反应用水(1mL)和NH4Cl溶液(20mL)淬灭。分离的水层随后用DCM萃取(20mL X 3)。合并的有机相用Na2SO4干燥,过滤且通过Combi-Flash使用MeOH/DCM(4%-8%)纯化。产物进一步通过手性分离进行分离以得到4种异构体,其为白色固体。各异构体的立体化学任意指定。
实施例145a:(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈:LCMS(ESI,m/z):280.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.59(dt,J=7.6,0.9Hz,1H),7.56(dt,J=7.8,1.0Hz,1H),7.39(tt,J=7.5,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.35(s,1H),5.14(s,1H),1.90–1.78(m,2H),1.78–1.66(m,2H),1.62(dd,J=13.4,3.0Hz,1H),1.47(td,J=13.1,6.1Hz,1H),1.00(dd,J=13.1,3.1Hz,1H),0.93(td,J=12.8,4.8Hz,1H)。
实施例145b:(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈:LCMS(ESI,m/z):280.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.85(d,J=0.6Hz,1H),7.62(dt,J=1.7,0.9Hz,1H),7.60(dq,J=2.0,0.9Hz,1H),7.40(tt,J=7.6,0.8Hz,1H),7.27(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.33(s,1H),5.16(s,1H),3.07(s,1H),1.92(ddt,J=12.8,8.7,4.0Hz,1H),1.85–1.60(m,4H),1.53(d,J=13.6Hz,1H),1.09(td,J=13.6,4.0Hz,1H),0.96(d,J=14.2Hz,1H)。
实施例145c:(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈:LCMS(ESI,m/z):280.2[M+H]+;1H NMR与实施例145b相同。
实施例145d:(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈:LCMS(ESI,m/z):280.2[M+H]+;1H NMR与实施例145a相同。
实施例146和146-1:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]
三唑并[1,5-a]吡啶-4-醇和7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]
三唑并[4,3-a]吡啶-8-醇
步骤1:
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成117a-b的通用步骤合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge Prep C18 OBD柱19×150mm 5um;流动相,水(0.05%NH4OH):乙腈=10%-27%;检测器,uv 254/220nm;流速,20.0mL/min.
2.柱,EnantioPak A1-5,2.12x25cm,5um;流动相:IPA:己烷=30:70;检测器,uv254/220nm;流速,20mL/min以得到2种化合物:
所有异构体146a-b的绝对构型任意指定。
实施例146a:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇(11.0mg,1%),其为白色固体:LCMS(ESI,m/z):294.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.04(s,1H),7.76(s,1H),7.66(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.46-7.42(m,1H),7.36-7.31(m,1H),7.21(s,1H),6.46(d,J=7.2Hz,1H),5.78(d,J=2.4Hz,1H),5.18-5.12(m,1H),4.32-4.26(m,1H),4.08-4.00(m,1H),2.64-2.51(m,1H),1.26-1.07(m,2H)。tR=3.570分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=70:30,1ml/min)。146a和146b为对映异构体。
实施例146b:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇(12.5mg,1%),其为白色固体:LCMS(ESI,m/z):294.2[M+H]+.tR=4.661分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=70:30,1ml/min)。146a和146b为对映异构体。
步骤1:3-(苄基氧基)-2-氯吡啶
向2-氯吡啶-3-醇(20g,154.39mmol)和碳酸钾(23g,166.42mmol)在丙酮(150mL)中的混合物添加BnBr(28.9g,168.97mmol)。所得溶液在室温搅拌16h。将固体过滤出。所得溶液真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(3.5/96.5)洗脱。这得到27g(80%)3-(苄基氧基)-2-氯吡啶,为灰白色油状物:LCMS(ESI,m/z):220.2[M+H]+.
步骤2:
3-(苄基氧基)-2-肼基吡啶
向3-(苄基氧基)-2-氯吡啶(7g,31.87mmol)、肼(50mL)在2-甲基丙-2-醇(90mL)中的溶液添加碳酸钾(13g,94.06mmol)。所得溶液在100℃搅拌5天。将固体滤器出。所得溶液真空浓缩。这得到3.5g(50%)3-(苄基氧基)-2-肼基吡啶,其为黄色固体:LCMS(ESI,m/z):216.2[M+H]+.
步骤3:8-(苄基氧基)-[1,2,4]三唑并[4,3-a]吡啶
将3-(苄基氧基)-2-肼基吡啶(22g,102.21mmol)在(二乙氧基甲氧基)乙烷(100mL)中的溶液在160℃搅拌3h。固体通过过滤收集。这得到15g(65%)8-(苄基氧基)-[1,2,4]三唑并[4,3-a]吡啶,其为黄色固体:LCMS(ESI,m/z):226.2[M+H]+.
步骤4:5H,6H,7H,8H-[1,2,4]三唑并[4,3-a]吡啶-8-醇
在氢气中,向8-(苄基氧基)-[1,2,4]三唑并[4,3-a]吡啶(6.5g,28.86mmol)在MeOH(200mL)中的溶液中添加钯碳(2g,18.793mmol)。所得混合物在室温搅拌24h。将固体过滤出。所得溶液真空浓缩。这得到3.8g(95%)5H,6H,7H,8H-[1,2,4]三唑并[4,3-a]吡啶-8-醇,为黄色固体:LCMS(ESI,m/z):140.2[M+H]+.
步骤5:6,7-二氢-[1,2,4]三唑并[4,3-a]吡啶-8(5H)-酮
向5H,6H,7H,8H-[1,2,4]三唑并[4,3-a]吡啶-8-醇(2g,14.37mmol,1.000当量)在DCM(100mL)中的溶液中添加DMP(12g,28.29mmol)。所得溶液在25℃搅拌3h。溶液的pH值用Ca(OH)2调节至7-8。将固体过滤出。残余物通过硅胶柱纯化,用DCM/MeOH(95/5)洗脱。这得到1.6g(81%)5H,6H,7H,8H-[1,2,4]三唑并[4,3-a]吡啶-8-酮,其为白色固体。
步骤6:(E)-7-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢-[1,2,4]三唑并[4,3-a]吡啶-8(5H)-酮
该标题化合物通过合成Int-2的通用步骤合成。
步骤7:
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-[1,2,4]三唑并[4,3-a]吡啶-8(5H)-酮
该标题化合物通过合成Int-3的通用步骤合成。
步骤8:
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇
该标题化合物通过合成139-1a-d的通用步骤合成。所有异构体146c-d的绝对构型任意指定。
实施例146-1a:(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇(14.8mg,1%),其为白色固体:LCMS(ESI,m/z):294.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.41(s,1H),8.13(s,1H),7.69-7.56(m,2H),7.50-7.29(m,2H),7.17(s,1H),5.68(s,1H),5.47(d,J=3.5Hz,1H),4.25-4.12(m,1H),3.79-3.61(m,1H),2.88-2.75(m,1H),1.95-1.89(m,1H),1.24(d,J=13.9Hz,1H)。tR=2.759分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=50:50,1ml/min)。146c和146d为对映异构体。
实施例146-1b:(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇(11.0mg,1%),其为白色固体:LCMS(ESI,m/z):294.2[M+H]+.tR=3.867分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=50:50,1ml/min)。146c和146d为对映异构体。
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇
该标题化合物通过合成117a-b的通用步骤合成。
所有异构体146e-f的绝对构型任意指定。
实施例146-1c:(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇(8mg,6%),其为白色固体:LCMS(ESI,m/z):294.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.38(s,1H),8.03(s,1H),7.68(d,J=7.6Hz,1H),7.59-7.33(m,3H),7.27-7.20(m,1H),5.90(s,1H),5.21(d,J=10.7Hz,1H),4.12-4.00(m,1H),3.92-3.75(m,1H),2.73(s,1H),1.35-1.28(m,3H)。tR=3.994分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=50:50,1ml/min)。146e和146f为对映异构体。
实施例146-1d:(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇(8.1mg,6%),其为白色固体:LCMS(ESI,m/z):294.2[M+H]+.tR=4.805分钟(修复的手性ADH,0.46x5cm,Hex(0.2%IPAmine):IPA=50:50,1ml/min)。146e和146f为对映异构体。
实施例147:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
最终产物(外消旋化合物)为以下异构体的混合物:
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
步骤1:
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(400mg,2.56mmol)在无水四氢呋喃(10mL)中的溶液中添加n-BuLi溶液(1.23mL,3.07mmol)且搅拌1小时。将3,3-二甲基环丁-1-酮(0.377g,3.84mmol)滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温再保持2hrs且用饱和NH4Cl溶液(20mL)淬灭。将混合物用20%2,2,2-三氟乙醇的二氯甲烷溶液(3x20ml)萃取且将有机相合并,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=97:3洗脱。产物以对映异构体混合物获得。
实施例147a:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇:LCMS(ESI,m/z):255.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.84(s,1H),7.57(d,J=7.5Hz,1H),7.52(d,J=7.6Hz,1H),7.36(t,J=7.5Hz,1H),7.23(d,J=7.7Hz,1H),7.10(s,1H),5.27(s,1H),5.23(s,1H),2.19(dd,J=20.2,12.4Hz,2H),1.88–1.69(m,2H),1.21(s,3H),0.93(s,3H)。
实施例148:环己基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
步骤1:
(R)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
在氮气气氛在丙酮-干冰浴将5H-咪唑并[5,1-a]异吲哚(1.00g,6.40mmol,1.0当量)的无水THF(32mL)溶液冷却至-78℃保持15分钟。经5分钟滴加环己烷中的仲丁基锂(1.4mol/L,5.0mL,7.04mmol,1.10当量)。溶液然后在-78℃搅拌60分钟。在-78℃沿着烧瓶侧壁添加环己烷甲醛(790mg,7.04mmol,1.10当量)的无水THF(6.4mL)溶液。30分钟后,将烧瓶从冷却浴移出且使之温热至室温保持60分钟。反应通过缓慢添加饱和氯化铵水溶液(100mL)淬灭。将两相混合物转移至分液漏斗且用二氯甲烷(3x50mL)萃取。合并的有机萃取物干燥(Na2SO4)且浓缩。粗产物通过combi-flash纯化且进一步通过手性分离进行分离以得到4种异构体,其为无色固体。异构体的相对构型通过1H NMR指定。绝对构型任意指定。
实施例148a:(R)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.62–7.55(m,1H),7.48(dd,J=7.5,1.0Hz,1H),7.37(td,J=7.5,1.3Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.11(s,1H),5.40(d,J=4.3Hz,1H),5.17(d,J=5.8Hz,1H),3.79(td,J=5.9,4.4Hz,1H),1.63–1.44(m,4H),1.36(s,1H),1.20–0.94(m,3H)。tR=0.945分钟(Chiralcel-3,10%EtOH具有0.1%NH4OH共溶剂)。
实施例148b:(S)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.62–7.55(m,1H),7.48(dd,J=7.5,1.0Hz,1H),7.37(td,J=7.5,1.3Hz,1H),7.25(td,J=7.5,1.2Hz,1H),7.11(s,1H),5.40(d,J=4.3Hz,1H),5.17(d,J=5.8Hz,1H),3.79(td,J=5.9,4.4Hz,1H),1.63–1.44(m,4H),1.36(s,1H),1.20–0.94(m,3H)。tR=0.807分钟(Chiralcel-3,10%EtOH具有0.1%NH4OH共溶剂)。
实施例148c:(R)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.58(dt,J=7.6,0.9Hz,1H),7.45(dt,J=7.5,1.0Hz,1H),7.46–7.32(m,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.35(d,J=5.1Hz,1H),5.04(d,J=6.5Hz,1H),3.50(td,J=6.4,4.9Hz,1H),1.93(d,J=12.7Hz,1H),1.84–1.51(m,2H),1.36–1.06(m,4H)。tR=0.820分钟(Chiralcel-3,10%EtOH具有0.1%NH4OH共溶剂)。
实施例148d:(S)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):269.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.58(dt,J=7.6,0.9Hz,1H),7.45(dt,J=7.5,1.0Hz,1H),7.46–7.32(m,1H),7.26(td,J=7.5,1.2Hz,1H),7.12(s,1H),5.35(d,J=5.1Hz,1H),5.04(d,J=6.5Hz,1H),3.50(td,J=6.4,4.9Hz,1H),1.93(d,J=12.7Hz,1H),1.84–1.51(m,2H),1.36–1.06(m,4H)。tR=0.691分钟(Chiralcel-3,10%EtOH具有0.1%NH4OH共溶剂)。
实施例149:4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]
噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
步骤1:3-溴环己烷-1,2-二酮
在0℃向1,2-环己烷二酮(5.1g,45.5mmol)在乙醚(46mL)中的溶液中经10分钟滴加Br2(2.34mL,45.5mmol)。当添加完成后,将反应恢复至室温且搅拌15分钟,此时反应混合物在减压下浓缩。所得深色油状物倒入2.5%MeOH/CHCl3且运行通过硅胶垫,用相同溶剂混合物洗脱。溶剂然后在减压下去除且所得黄色固体用冷乙醚(15mL)研磨。将产物过滤且干燥。1HNMR(400MHz,氯仿-d)δ6.45(s,1H),2.90(td,J=6.0,5.6,0.6Hz,2H),2.54–2.61(m,2H),2.05–2.13(m,2H)。
步骤2:4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酸乙酯
将3-溴环己烷-1,2-二酮3(10.76g,56.32mmol)和2-氨基-2-硫代乙酸乙酯(5.0g,37.55mmol)在乙醇(150mL)中的混合物加热至回流且搅拌15h。将混合物冷却至室温。在减压下去除溶剂且产物通过CombiFlash分离。产物用EtOAc:己烷=50:50洗脱:LCMS(ESI,m/z):226.2[M+H]+.
步骤3:4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
在室温向4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酸乙酯(1.6g,7.1mmol)在乙醇(10mL)中的溶液中添加氢氧化铵水溶液(26.88mL,426mmol)。所得混合物在95℃搅拌30分钟。TLC指示起始材料完全消耗且将混合物冷却至室温。将沉淀过滤且用冷甲醇(10mL)洗涤。将产物干燥且直接使用而不用进一步纯化:LCMS(ESI,m/z):197.2[M+H]+.
步骤4:(E)-4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.0g,4.82mmol)和6,7-二氢苯并[d]噻唑-4(5H)-酮(1.14g,5.79mmol)在甲醇(30mL)中的溶液中添加吡咯烷(0.48mL,5.79mmol)。将混合物在90℃搅拌6hrs。将固体过滤且用冷甲醇(10mL)洗涤。收集所需产物为淡黄色固体且直接使用而不用进一步纯化:LCMS(ESI,m/z):593.2[M+H]+.
步骤5:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(E)-4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺(1.37g,2.30mmol)在甲醇(55mL)和乙酸(12.5mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且添加饱和NaHCO3(20mL)以淬灭乙酸。水层用10%2,2,2-三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且用DCM:MeOH=94:6洗脱:LCMS(ESI,m/z):351.2[M+H]+.
步骤6:
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
在0℃向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺(755mg,2.15mmol)在甲醇(15mL)中的悬浮液中分批添加硼氢化钠(163mg,4.31mmol)。混合物温热至室温且再搅拌1小时。该反应用饱和氯化铵溶液(20mL)淬灭。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=90:10洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例149a:(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.90(s,1H),7.84(s,1H),7.81(s,1H),7.64(d,J=7.6Hz,1H),7.56(d,J=7.7Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.91(d,J=7.0Hz,1H),5.77(d,J=3.3Hz,1H),5.04–4.97(m,1H),2.70–2.61(m,3H),1.03–0.94(m,2H)。
实施例149b:(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.87(s,1H),7.81(s,1H),7.64(d,J=7.6Hz,1H),7.49(dd,J=7.6,1.0Hz,1H),7.42(dd,J=8.0,7.1Hz,1H),7.33(td,J=7.5,1.1Hz,1H),7.18(s,1H),5.88(d,J=7.5Hz,1H),5.78(s,1H),5.05(t,J=8.7Hz,1H),2.72–2.56(m,3H),1.03–0.91(m,2H)。
实施例149c:(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.04(s,1H),7.99(s,1H),7.78(s,1H),7.65(dd,J=7.6,1.0Hz,1H),7.60(d,J=7.5Hz,1H),7.39(dd,J=7.9,7.0Hz,1H),7.29(td,J=7.5,1.1Hz,1H),7.13(s,1H),5.97(d,J=6.9Hz,1H),5.52(s,1H),5.11(dd,J=7.0,3.5Hz,1H),2.88(dd,J=17.6,5.2Hz,1H),2.61–2.52(m,2H),1.56(qd,J=12.8,5.6Hz,1H),1.05(d,J=13.2Hz,1H)。
实施例149d:(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.99(s,1H),7.97(s,1H),7.78(s,1H),7.77(s,1H),7.62(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.28–7.23(m,1H),7.14(s,1H),5.75(d,J=7.0Hz,1H),5.45(d,J=5.9Hz,1H),4.91(dd,J=7.1,3.3Hz,1H),2.98(dd,J=17.4,5.3Hz,1H),2.68(dt,J=11.4,5.8Hz,1H),2.23(d,J=11.1Hz,1H),1.97(tt,J=12.9,6.5Hz,1H),1.74(d,J=12.7Hz,1H)。
实施例149e:(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.87(s,1H),7.81(s,1H),7.64(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),7.33(td,J=7.6,1.2Hz,1H),7.18(s,1H),5.88(d,J=7.4Hz,1H),5.78(s,1H),5.05(t,J=8.6Hz,1H),2.72–2.56(m,2H),1.04–0.89(m,2H)。
实施例149f:(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.04(s,1H),7.99(s,1H),7.82–7.74(m,1H),7.65(dq,J=7.7,1.0Hz,1H),7.62–7.57(m,1H),7.43–7.36(m,1H),7.29(td,J=7.6,1.1Hz,1H),7.13(s,1H),5.97(d,J=6.9Hz,1H),5.54–5.49(m,1H),5.11(dd,J=7.0,3.5Hz,1H),2.88(dd,J=17.3,5.3Hz,1H),2.57(dd,J=11.9,5.7Hz,1H),1.56(qd,J=12.7,5.5Hz,1H),1.05(d,J=11.7Hz,1H)。
实施例149g:(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+.
实施例149h:(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):353.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.90(s,1H),7.84(s,1H),7.81(s,1H),7.64(d,J=7.6Hz,1H),7.56(d,J=7.7Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.91(d,J=7.0Hz,1H),5.77(d,J=3.3Hz,1H),5.01(s,1H),2.66(s,3H),1.05–0.90(m,2H)。
实施例150:3,3-二(氟甲基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2R)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
步骤1:
(E)-3,3-二(氟甲基)-2-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁-1-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.4g,5.79mmol)和3,3-二(氟甲基)环丁-1-酮(932mg,6.95mmol)在无水乙醇(30mL)中的溶液中添加氢氧化钙(515mg,6.95mmol)且所得混合物在90℃搅拌16小时。反应通过50mL水淬灭且将混合物用二氯甲烷(3x30mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥:LCMS(ESI,m/z):531.4[M+H]+.
步骤2:
3,3-二(氟甲基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮
向(E)-2-(2-(1H-咪唑-4-基)亚苄基)-3,3-二(氟甲基)环丁-1-酮(510mg,1.77mmol)在DCM(10mL)中的溶液中添加三氟乙酸(2.73mL,35.38mmol)且溶液在室温搅拌过夜。在减压下蒸发溶剂且反应通过30mL饱和NaHCO3溶液淬灭且混合物通过20%2,2,2-三氟乙醇在DCM中的溶液(3x30mL)萃取。合并有机层,用盐水和水洗涤,且通过无水Na2SO4干燥。产物通过CombiFlash分离且用DCM:MeOH=94:6洗脱:LCMS(ESI,m/z):289.2[M+H]+.
步骤3:
(1R,2R)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1R,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
(1S,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
在0℃向3,3-二(氟甲基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-酮(346mg,1.2mmol)在MeOH(10mL)中的溶液中分批添加NaBH4(91mg,2.4mmol)且溶液在0℃搅拌30分钟。反应通过饱和氯化铵(10mL)淬灭。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x10mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=94:6洗脱。最终产物进一步通过手性分离进行分离以得到6种异构体且各异构体的立体化学任意指定。
实施例105a:(1R,2R)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.73(dt,J=7.8,0.9Hz,1H),7.60(dd,J=7.7,1.0Hz,1H),7.41–7.34(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.15(s,1H),6.01(d,J=3.2Hz,1H),5.55(d,J=8.8Hz,1H),4.89(dd,J=47.7,9.7Hz,1H),4.65–4.45(m,3H),4.42–4.36(m,1H),4.30(d,J=9.5Hz,1H),2.55(t,J=7.8Hz,1H),2.12(dt,J=12.5,4.7Hz,1H),1.64(d,J=12.5Hz,1H)。
实施例150b:(1R,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.86(s,1H),7.62–7.56(m,1H),7.50(dd,J=7.7,0.9Hz,1H),7.38(dd,J=7.9,7.1Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.09(s,1H),5.52(d,J=10.0Hz,1H),5.33(d,J=7.8Hz,1H),4.91(dd,J=46.8,10.1Hz,1H),4.75–4.59(m,2H),4.52(dd,J=47.5,9.5Hz,1H),4.38(dd,J=47.5,9.5Hz,1H),2.25–2.19(m,1H),2.10(dd,J=11.4,7.9Hz,1H),1.75(ddd,J=12.0,8.1,4.8Hz,1H)。
实施例150c:(1S,2S)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.73(dd,J=7.7,1.0Hz,1H),7.60(d,J=7.5Hz,1H),7.41–7.35(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.15(s,1H),6.01(d,J=3.3Hz,1H),5.55(d,J=8.8Hz,1H),4.89(dd,J=47.8,9.7Hz,1H),4.56(dd,J=47.4,9.6Hz,1H),4.48(d,J=9.4Hz,2H),4.41–4.37(m,1H),4.30(d,J=9.5Hz,1H),2.56(s,1H),2.16–2.08(m,1H),1.64(d,J=12.7Hz,1H)。
实施例150d:(1S,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.83(s,1H),7.59(ddt,J=8.3,7.3,0.9Hz,2H),7.37(tt,J=7.5,0.8Hz,1H),7.24(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.50(d,J=8.7Hz,1H),5.33(d,J=7.6Hz,1H),4.74–4.51(m,3H),4.46–4.41(m,1H),4.32(dd,J=20.2,9.5Hz,1H),4.21(d,J=9.5Hz,1H),2.36(t,J=8.4Hz,1H),2.10(dd,J=11.5,8.0Hz,1H),1.74(ddd,J=11.8,8.1,4.2Hz,1H)。
实施例150e:(1R,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.83(s,1H),7.58(tt,J=7.5,0.9Hz,2H),7.37(tt,J=7.6,0.8Hz,1H),7.24(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.50(d,J=8.7Hz,1H),5.33(d,J=7.6Hz,1H),4.74–4.56(m,2H),4.55–4.40(m,2H),4.32(dd,J=20.2,9.5Hz,1H),4.21(d,J=9.5Hz,1H),2.36(t,J=8.4Hz,1H),2.10(dd,J=11.4,8.0Hz,1H),1.74(ddd,J=11.8,8.1,4.3Hz,1H)。
实施例150f:(1S,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇:LCMS(ESI,m/z):291.1[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.86(s,1H),7.59(dt,J=7.6,0.9Hz,1H),7.54–7.48(m,1H),7.38(tt,J=7.6,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.09(s,1H),5.52(d,J=10.0Hz,1H),5.33(d,J=7.7Hz,1H),4.91(ddd,J=46.9,10.2,1.8Hz,1H),4.75–4.59(m,2H),4.52(dd,J=47.5,9.4Hz,1H),4.38(dd,J=47.5,9.4Hz,1H),2.22(dd,J=9.9,7.9Hz,1H),2.10(dd,J=11.4,7.9Hz,1H),1.75(ddd,J=11.4,8.1,4.8Hz,1H)。
实施例151:3-氟-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,
5-a]吡啶-4-醇
步骤1:
O-(均三甲苯基磺酰基)羟胺
在0℃向(Z)-(N-[[(2,4,6-三甲基苯)磺酰基]氧基]-乙烯甲亚胺酸乙酯)(43.5g,152.44mmol)在1,4-二噁烷(100mL)中的溶液中滴加高氯酸(50mL,70%溶液)。所得溶液在0℃搅拌1h。该反应然后通过添加冰水淬灭。固体通过过滤收集。这得到30g(粗物质)氨基O-(均三甲苯基磺酰基)羟胺,其为白色固体。粗产物直接用于下一步反应而不用表征。
步骤2:
1-氨基-3-甲氧基吡啶-1-鎓2,4,6-三甲基苯-1-醇盐
在0℃向氨基3-甲氧基吡啶(15g,137.46mmol)在DCM(100mL)中的溶液中添加2,4,6-三甲基苯-1-磺酸盐(30g,139.36mmol)在DCM(50mL)中的溶液。所得溶液在室温搅拌1过夜。所得混合物真空浓缩。这得到33g1-氨基-3-甲氧基吡啶-1-鎓2,4,6-三甲基苯-1-醇盐,为无色油状物:LCMS(ESI,m/z):226.2[M+H]+.
步骤3:
4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯
向1-氨基-3-甲氧基吡啶-1-鎓2,4,6-三甲基苯-1-醇盐(33g,126.76mmol)和丙-2-炔酸乙酯(18.2g,185.56mmol)在DMF(100mL,1.29mol)中的溶液中添加碳酸钾(25.6g,185.23mmol)。所得溶液在室温搅拌24h。将固体过滤出。溶液用水(500mL)稀释。所得溶液用EtOAc(2x300mL)萃取且合并有机层。所得混合物用盐水洗涤(1x200mL)。有机层真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(13:87)洗脱。这得到11.3g(40%)4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯,为棕色油状物:LCMS(ESI,m/z):221.3[M+H]+.
步骤4:吡唑并[1,5-a]吡啶-4-醇
将4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯(5g,22.70mmol)在HBr(100mL,48%w/v)中的溶液在油浴中在100℃搅拌2天。所得混合物真空浓缩。溶液的pH值用2M氢氧化钠溶液调节至弱酸。所得溶液用EtOAc(2x200mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(30:70)洗脱。这得到1.6g(53%)吡唑并[1,5-a]吡啶-4-醇,为白色固体:LCMS(ESI,m/z):135.3[M+H]+.
步骤5:4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇
在氢气中,向吡唑并[1,5-a]吡啶-4-醇(1.6g,11.93mmol)在MeOH(100mL)中的溶液中添加钯碳(1.6g,10%)。所得溶液在室温搅拌3天。将固体过滤出。所得混合物真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(98:2)洗脱。这得到900mg(55%)4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇,为白色固体:LCMS(ESI,m/z):139.2[M+H]+.
步骤6:3-氟-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇
向4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇(900mg,6.52mmol)在乙腈(30mL)中的溶液中添加selectfluor(4.6g,12.99mmol)。所得溶液在室温搅拌4h,然后用水(100mL)淬灭。所得溶液用EtOAc(3x100mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(30:70)洗脱。这得到400mg(39%)3-氟-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇,其为黄色油状物:LCMS(ESI,m/z):157.2[M+H]+.
步骤7:3-氟-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮
向3-氟-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-醇(750mg,4.80mmol)在DCM(30mL)中的溶液中添加DMP(4.05g,9.55mmol)。所得溶液在室温搅拌2h。该反应然后通过添加Ca(OH)2(4g)淬灭。将固体过滤出。残余物通过硅胶柱纯化,用EtOAc/石油醚(30:70)洗脱。这得到400mg(54%)3-氟-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮,其为黄色油状物。
步骤8:(E)-3-氟-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤9:3-氟-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤10:(4S,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(4R,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成146c-d的通用步骤合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge C18 OBD Prep柱,100,10μm,19mm X 250mm;流动相,水(10MMOL/LNH4HCO3)和ACN(15.0%ACN至37.0%在10min内);检测器,UV 254/220nm.
2.柱,Chiralpak IC,2x25cm,5um;流动相,Hex—HPLC和乙醇-HPLC(保持50%乙醇--HPLC在25min内);检测器,UV 220/254nm。所有异构体151a-b的绝对构型任意指定。
实施例151a:(4S,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(25.8mg,13%),其为白色固体:LCMS(ESI,m/z):311.3[M+H]+.1HNMR(300MHz,CD3OD)δ8.15(s,1H),7.63(td,J=7.7,1.0Hz,2H),7.47-7.34(m,3H),7.18(s,1H),5.65(d,J=1.7Hz,1H),5.42-5.41(m,1H),4.16-4.10(m,1H),3.85-3.76(m,1H),2.75-2.68(m,1H),2.00-1.91(m,1H),1.27-1.22(m,1H)。tR=1.397分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。151a和151b为对映异构体。
实施例151b:(4R,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(30.4mg,15%),其为白色固体:LCMS(ESI,m/z):311.2[M+H]+.tR=1.997分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。151a和151b为对映异构体。
(4R,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成146e-f的通用步骤合成。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge C18 OBD Prep柱,100,10μm,19mm X 250mm;流动相,水(10MMOL/LNH4HCO3)和ACN(15.0%ACN至37.0%在10min内);检测器,UV 254/220nm.
2.柱,Chiralpak IC,2x25cm,5um;流动相,Hex--HPLC和乙醇-HPLC(保持50%乙醇--HPLC在25min内);检测器,UV 220/254nm。所有异构体151c-d的绝对构型任意指定。
实施例151c:(4R,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(32.7mg,10%),其为白色固体:LCMS(ESI,m/z):311.3[M+H]+.1HNMR(300MHz,CD3OD)δ7.99(s,1H),7.68(d,J=7.5Hz,1H),7.59-7.38(m,4H),7.23(s,1H),5.87(d,J=1.9Hz,1H),5.25(d,J=10.3Hz,1H),3.98-3.77(m,2H),2.61-2.59(m,1H),1.32-1.28(m,2H)。tR=1.296分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。151c和151d为对映异构体。
实施例151d:(4S,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(30.8mg,9%),其为白色固体:LCMS(ESI,m/z):311.2[M+H]+.tR=1.898分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。151c和151d为对映异构体。
实施例152a:(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇:LCMS(ESI,m/z):264.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.27–8.22(m,2H),7.83(t,J=0.7Hz,1H),7.43(dt,J=7.6,1.0Hz,1H),7.40(dt,J=7.6,1.0Hz,1H),7.30(tdd,J=7.5,1.2,0.6Hz,1H),7.21(td,J=7.5,1.2Hz,1H),6.96(s,1H),6.91–6.86(m,2H),6.35(d,J=3.9Hz,1H),5.71(d,J=4.0Hz,1H),5.40(t,J=3.9Hz,1H)。
实施例152b:(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇:LCMS(ESI,m/z):264.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.29–8.22(m,2H),7.83(d,J=0.7Hz,1H),7.44(dd,J=7.5,1.0Hz,1H),7.40(dt,J=7.5,1.0Hz,1H),7.32–7.27(m,1H),7.21(td,J=7.5,1.2Hz,1H),6.96(s,1H),6.91–6.86(m,2H),6.35(d,J=3.9Hz,1H),5.72(d,J=4.0Hz,1H),5.40(t,J=3.9Hz,1H)。
实施例152c:(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇:LCMS(ESI,m/z):264.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.46–8.41(m,2H),7.59(d,J=0.6Hz,1H),7.48(dt,J=7.5,1.0Hz,1H),7.35–7.28(m,1H),7.20–7.12(m,4H),7.04(s,1H),6.30(d,J=4.6Hz,1H),5.64(d,J=5.5Hz,1H),5.12(t,J=5.1Hz,1H)。
实施例152d:(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇:LCMS(ESI,m/z):264.1[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.46–8.41(m,2H),7.60(t,J=0.6Hz,1H),7.48(dt,J=7.7,1.0Hz,1H),7.35–7.29(m,1H),7.21–7.12(m,4H),7.04(s,1H),6.30(d,J=4.6Hz,1H),5.65(d,J=5.5Hz,1H),5.12(t,J=5.1Hz,1H)。
实施例153:1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
步骤1:
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
在-40℃向5H-咪唑并[5,1-a]异吲哚(2g,12.81mmol)在无水THF中的溶液中添加n-BuLi(5.12mL,12.81mmol,2.5M在己烷中的溶液)且在-40℃搅拌1小时。在-40℃缓慢添加1-氰基环丙烷-1-甲酸乙酯(1.78g,12.81mmol)在无水THF(5mL)中的溶液且反应经4小时逐渐温热至0℃。反应通过冷却至-40℃和添加甲醇(10mL)淬灭。反应温热至0℃且添加NaBH4(1g)。将反应搅拌2小时同时将其缓慢温热至室温。粗产物进一步在Combi-Flash上纯化且进一步通过制备型HPLC分离以得到2种异构体,为对映异构体混合物。所有异构体的构型任意指定。
实施例153a:1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈:LCMS(ESI,m/z):252.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(t,J=0.7Hz,1H),7.67–7.58(m,2H),7.46–7.37(m,1H),7.30–7.22(m,1H),7.14(s,1H),6.46(s,1H),5.48(d,J=5.3Hz,1H),3.71(d,J=5.3Hz,1H),1.08–0.86(m,3H),0.73(dd,J=3.9,2.7Hz,1H)。
实施例153b:1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈:LCMS(ESI,m/z):252.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.88(t,J=0.7Hz,1H),7.67(dd,J=7.7,0.9Hz,1H),7.64–7.59(m,1H),7.45–7.40(m,1H),7.29(d,J=1.2Hz,1H),7.14(s,1H),6.52(s,1H),5.42(d,J=7.2Hz,1H),3.26(d,J=7.3Hz,1H),1.34–1.22(m,2H),1.01(d,J=6.8Hz,1H),0.77(s,1H)。
实施例154:(1-氟环丙基)(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
步骤1:
(R)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(S)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(R)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
在-78℃向5H-咪唑并[5,1-a]异吲哚(300mg,1.92mmol)在无水THF(10mL)中的溶液中添加n-BuLi溶液(0.92mL,2.3mmol)且搅拌1小时。将1-氟环丙烷-1-甲醛(237mg,2.69mmol)在无水THF(2.0mL)中的溶液滴加至反应混合物。反应在-78℃再保持30分钟且温热至室温。反应在室温再保持2hrs且用饱和NH4Cl溶液(20mL)淬灭。将混合物用20%2,2,2-三氟乙醇在DCM中的溶液(3x20ml)萃取且将有机相合并,用Na2SO4干燥,且浓缩。产物通过CombiFlash分离且用DCM:MeOH=96:4洗脱。最终产物进一步通过手性分离进行分离以得到4种异构体且各异构体的立体化学任意指定。
实施例154a:(R)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):245[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.83(d,J=0.7Hz,1H),7.64(dq,J=7.7,0.9Hz,1H),7.58(dt,J=7.5,1.0Hz,1H),7.38(tdd,J=7.6,1.1,0.6Hz,1H),7.24(td,J=7.6,1.1Hz,1H),7.11(s,1H),6.01(d,J=5.4Hz,1H),5.49(d,J=5.9Hz,1H),3.87(dt,J=20.5,5.6Hz,1H),0.98–0.80(m,2H),0.66–0.52(m,2H)。
实施例154b:(S)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):245[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.83(q,J=0.6Hz,1H),7.66–7.61(m,1H),7.58(dt,J=7.6,1.0Hz,1H),7.38(tdd,J=7.5,1.1,0.6Hz,1H),7.24(td,J=7.6,1.2Hz,1H),7.11(s,1H),6.00(d,J=5.5Hz,1H),5.49(d,J=5.9Hz,1H),3.87(dt,J=20.6,5.7Hz,1H),0.98–0.80(m,2H),0.66–0.52(m,2H)。
实施例154c:(S)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):245[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.82(s,1H),7.63–7.57(m,2H),7.42–7.36(m,1H),7.26(td,J=7.6,1.2Hz,1H),7.12(s,1H),5.92(d,J=5.8Hz,1H),5.50(d,J=6.3Hz,1H),3.60(dt,J=22.0,6.0Hz,1H),1.17–0.99(m,2H),0.77–0.70(m,1H),0.70–0.60(m,1H)。
实施例154d:(R)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇:LCMS(ESI,m/z):245[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.83(d,J=0.7Hz,1H),7.60(ddt,J=6.7,5.9,0.8Hz,2H),7.42–7.35(m,1H),7.26(td,J=7.6,1.3Hz,1H),7.12(s,1H),5.92(d,J=5.8Hz,1H),5.50(d,J=6.3Hz,1H),3.61(dt,J=21.9,6.1Hz,1H),1.18–0.99(m,2H),0.81–0.71(m,1H),0.71–0.61(m,1H)。
实施例155:3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(S)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
步骤1:3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙腈
在-40℃向5H-咪唑并[5,1-a]异吲哚(0.5g,3.20mmol)在无水THF中的溶液中添加n-BuLi(1.28mL,3.2mmol,2.5M在己烷中的溶液)且在-40℃搅拌1小时。在-40℃缓慢添加2-氰基-2-甲基丙酸乙酯(0.45g,3.2mmol)在无水THF(1mL)中的溶液且反应经4小时逐渐温热至0℃。反应通过将其冷却至-40℃和添加饱和NH4Cl溶液淬灭。粗产物使用DCM萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):254.2[M+H]+.
步骤2:
(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
(S)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
向3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙腈(200mg,0.79mmol)在甲醇中的溶液中添加NaOH(315mg,7.90mmol)和过氧化氢(0.8mL,7.9mmol)。将反应混合物搅拌3天。粗产物使用2,2,2-三氟乙醇萃取。粗产物进一步在Combi-Flash上纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。所有异构体的绝对构型任意指定
实施例155a:(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺:LCMS(ESI,m/z):272.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.83(t,J=0.7Hz,1H),7.55(dt,J=7.6,1.0Hz,1H),7.48(dq,J=7.7,0.9Hz,1H),7.36–7.31(m,1H),7.20(td,J=7.6,1.2Hz,1H),7.10(d,J=8.5Hz,2H),6.92(s,1H),5.36(d,J=2.9Hz,1H),4.34(d,J=3.0Hz,1H),0.98(s,3H),0.97(s,3H)。
实施例155b:(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺:LCMS(ESI,m/z):272.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.55(d,J=7.7Hz,1H),7.47(d,J=1.0Hz,1H),7.34(s,1H),7.20(d,J=1.2Hz,1H),7.09(s,2H),6.93(s,1H),5.67(d,J=6.0Hz,1H),5.36(d,J=2.9Hz,1H),4.34(dd,J=6.0,3.0Hz,1H),0.98(s,3H),0.97(s,3H)。
实施例155c:(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺:LCMS(ESI,m/z):272.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.67(d,J=0.7Hz,1H),7.54(s,2H),7.38–7.32(m,1H),7.26(d,J=1.2Hz,2H),7.12(s,1H),7.07(s,1H),5.32–5.18(m,1H),4.17(d,J=2.1Hz,1H),1.26(s,3H),1.21(s,3H)。
实施例155d:(S)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺:LCMS(ESI,m/z):272.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.54(ddt,J=6.5,5.7,0.9Hz,2H),7.38–7.32(m,1H),7.29–7.23(m,2H),7.12(s,1H),7.07(s,1H),5.44(d,J=6.7Hz,1H),5.29–5.24(m,1H),4.17(dd,J=6.7,2.0Hz,1H),1.26(s,3H),1.21(s,3H)。
实施例156:4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并
[1,5-a]吡啶-3-甲腈
步骤1:4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮
该标题化合物通过合成151a-b的通用步骤合成。
步骤2:3-碘-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮
向4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮(600mg,4.41mmol)在乙腈(30mL)中的溶液中添加I2(667mg,2.628mmol)和CAN(2.880g,5.23mmol)。所得溶液在室温搅拌1天。该反应然后通过添加饱和NaS2O3溶液(100mL)淬灭。所得溶液用EtOAc(2x100mL)萃取且合并有机层。残余物通过硅胶柱纯化用EtOAc/石油醚(30:70)洗脱。这得到600mg(52%)3-碘-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮,其为黄色固体:LCMS(ESI,m/z):263.2[M+H]+.
步骤3:4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
将3-碘-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮(900mg,3.43mmol)和CuCN(900mg,10.05mmol)在DMF(50mL)中的混合物在150℃搅拌1h。将固体过滤出。溶液用水(200mL)稀释。所得溶液用EtOAc(2x200mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(42:58)洗脱。这得到570mg(粗物质)4-氧代-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-3-甲腈,其为棕色固体:LCMS(ESI,m/z):162.2[M+H]+.
步骤4:(E)-4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
该标题化合物通过合成146c-d的通用步骤合成。
步骤5:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
该标题化合物通过合成146c-d的通用步骤合成。
步骤6:
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
该标题化合物通过合成146c-d的通用步骤合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge Shield RP18 OBD柱,5um,19x150mm;流动相,水(0.05%NH3H2O)和ACN(13.0%ACN至40.0%在7min内);检测器,UV220nm.
2.柱,Chiralpak IC,2x25cm,5um;流动相,Hex—HPLC和乙醇-HPLC(保持50%乙醇--HPLC在25min内);检测器,UV 220/254nm.
3.柱,CHIRALPAK IA,2.12x15cm,5um;流动相,己醇和乙醇-(保持50.0%乙醇-在10min内);检测器,UV 220/254nm.
所有异构体156a-e的绝对构型任意指定。
实施例156a:(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(22.4mg,11%),其为白色固体:LCMS(ESI,m/z):318.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.09(s,1H),7.92(s,1H),7.66-7.60(m,2H),7.48-7.34(m,2H),7.18(s,1H),5.68(s,1H),5.49(d,J=3.6Hz,1H),4.24-4.18(m,1H),3.95-3.84(m,1H),2.84-2.80(m,1H),2.06-1.87(m,1H),1.31-1.29(m,1H)。tR=2.082分钟(修复的手性IC,0.46x10cm;5um,MeOH(0.1%DEA):EtOH=70:30,1ml/min)。156a和156b为对映异构体。
实施例156b:(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(23.0mg,12%),其为白色固体:LCMS(ESI,m/z):318.2[M+H]+.tR=2.784分钟(修复的手性IC,0.46x10cm;5um,MeOH(0.1%DEA):EtOH=70:30,1ml/min)。156a和156b为对映异构体。
实施例156c:(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(4.1mg,2%),其为白色固体:LCMS(ESI,m/z):318.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.06(s,1H),7.90(s,1H),7.75-7.66(m,2H),7.51-7.39(m,1H),7.32(td,J=7.6,1.2Hz,1H),7.20(s,1H),5.63(d,J=5.2Hz,1H),5.21(d,J=3.5Hz,1H),4.21-4.15(m,1H),4.03-1.00(m,1H),2.60-2.58(m,1H),2.42-2.39(m,1H),2.08-2.05(m,1H)。tR=4.180分钟(手性Cellulose-SB,0.46x15cm;5um,Hex(0.1%IPAmine):EtOH=50:50,1ml/min)。156c和156d为对映异构体。
实施例156d:(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(3.8mg,2%),其为白色固体:LCMS(ESI,m/z):318.2[M+H]+.tR=5.039分钟(手性Cellulose-SB,0.46x15cm;5um,Hex(0.1%IPAmine):EtOH=50:50,1ml/min)。156c和156d为对映异构体。
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
该标题化合物通过合成146e-f的通用步骤合成。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge Shield RP18 OBD柱,5um,19x150mm;流动相,水(0.05%NH3H2O)和ACN(13%ACN至40%在7min内);检测器,UV 220nm.
2.柱,Chiralpak IC,2x25cm,5um;流动相,Hex--HPLC和乙醇-HPLC(保持50%乙醇--HPLC在25min内);检测器,UV 220/254nm。所有异构体156e-f的绝对构型任意指定。
实施例156e:(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(10.9mg,4%),其为白色固体:LCMS(ESI,m/z):318.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.07(s,1H),7.90(s,1H),7.71-7.68(m,1H),7.56-7.37(m,3H),7.25(s,1H),5.87(d,J=2.5Hz,1H),5.29(d,J=10.7Hz,1H),4.15-4.08(m,1H),4.00-3.90(m,1H),2.71-2.61(m,1H),1.39-1.30(m,2H)。tR=3.016分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=60:40,1ml/min)。156e和156f为对映异构体。
实施例156f:(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈(10.0mg,4%),其为白色固体:LCMS(ESI,m/z):318.2[M+H]+.tR=1.875分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=60:40,1ml/min)。156e和156f为对映异构体。
实施例157:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
步骤1:5,6-二氢-1H-吲唑-7(4H)-酮
向1H-吲唑-7-醇(4.0g,22.37mmol)在EtOH(30mL)中的溶液中添加10%Pd/C(1.0g)。混合物在20巴氢气下在80℃氢化16h。将混合物过滤,且将滤液蒸发。残余物通过快速色谱法纯化(PE-EtOAc 7:3)以得到1.5g(43%)4,5,6,7-四氢-1H-吲唑-7-酮,其为棕色油状物:LCMS(ESI,m/z):137.2
步骤2:(E)-6-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-5,6-二氢-1H-吲唑-7(4H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤3:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6-二氢-1H-吲唑-7(4H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤4:
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
向6-[5H-咪唑并[4,3-a]异吲哚-5-基]-4,5,6,7-四氢-1H-吲唑-7-酮(800mg,2.77mmol)在MeOH(20mL)中的溶液中添加NaBH4(314mg,8.30mmol)。所得溶液在室温搅拌20分钟。该反应然后通过添加水(100mL)淬灭。所得溶液用EtOAc(2x100mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(80:10)洗脱。粗产物通过prep-HPLC纯化且进一步通过手性分离进行分离。所有异构体157a-h的绝对构型任意指定。
实施例157a:(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(18.1mg,2%),其为白色固体:LCMS(ESI,m/z):293.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.05(s,1H),7.75-7.59(m,2H),7.53-7.24(m,4H),5.94-5.86(m,1H),5.14(d,J=10.2Hz,1H),2.69-2.53(m,1H),2.52-2.30(m,2H),1.04(m,2H)。tR=1.872分钟(CHIRALPAKIC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。157a和157b为对映异构体。
实施例157b:(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(20.7mg,3%),其为白色固体:LCMS(ESI,m/z):293.3[M+H]+.tR=2.812分钟(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。157a和157b为对映异构体。
实施例157c:(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(24.2mg,4%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.1H NMR(300MHz,CD3OD)δ8.00(s,1H),7.73-7.63(m,1H),7.56-7.26(m,4H),7.23(s,1H),5.87(s,1H),5.18-5.08(m,1H),2.55-2.31(m,3H),1.15-1.03(m,1H),0.96(m,1H)。tR=0.680分钟(SFC,CHIRALPAK AD-33x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157c和157g为对映异构体。
实施例157d:(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(128.4mg,14%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.1H NMR(300MHz,CD3OD)δ8.13(s,1H),7.61(m,2H),7.50-7.28(m,3H),7.21-7.12(m,1H),5.61(s,1H),5.23(d,J=3.6Hz,1H),2.59(m,2H),2.36-2.19(m,1H),1.53(m,1H),1.00(m,1H)。tR=0.599分钟(SFC,CHIRALPAK AD-3 3x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157d和157e为对映异构体。
实施例157e:(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(167.1mg,16%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.tR=1.086分钟(SFC,CHIRALPAK AD-3 3x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157d和157e为对映异构体。
实施例157f:(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(35.8mg,4%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.1H NMR(300MHz,CD3OD)δ8.07(s,1H),7.77(d,J=7.7Hz,1H),7.65(d,J=7.6Hz,1H),7.49-7.24(m,3H),7.17(s,1H),5.53(d,J=5.7Hz,1H),4.91(s,1H),2.77(d,J=16.2Hz,1H),2.45(m,1H),2.25(d,J=11.0Hz,1H),2.06(m,1H),1.90(m,1H)。tR=1.505分钟(SFC,CHIRALPAK AD-33x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157f和157h为对映异构体。
实施例157g:(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(68.2mg,8%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.tR=1.910分钟(SFC,CHIRALPAK AD-3 3x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157c和157g为对映异构体。
实施例157h:(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇(50.5mg,6%),其为白色固体:LCMS(ESI,m/z):293.1[M+H]+.tR=2.961分钟(SFC,CHIRALPAK AD-3 3x100mm,3um,CO2:IPA(0.1%DEA)50%,2.0ml/min)。157f和157h为对映异构体。
实施例158a:3-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁烷-1,2-二醇
该产物的立体化学未确定。
步骤1:2-(苄基氧基)环丁酮
向苯基甲醇(2.5mL,23.35mmol)在HCl/1,4-二噁烷(200mL,4.0M)中的溶液中添加三甲基([2-[(三甲基甲硅烷基)氧基]环丁-1-烯-1-基]氧基)硅烷(5.0g,21.70mmol)。所得溶液在油浴中在80℃搅拌4h。所得混合物真空浓缩。所得溶液用EtOAc(500mL)稀释。所得混合物用饱和碳酸氢钠(2x100mL)和盐水(1x100mL)洗涤。有机层真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(0-30%)洗脱。这得到2.2g(58%)2-(苄基氧基)环丁-1-酮,其为无色油状物。1H NMR(300MHz,CDCl3)δ7.41-7.34(m,5H),4.81-4.72(m,2H),4.68-4.62(m,1H),2.83-2.74(m,2H),2.40-2.27(m,1H),2.05-1.92(m,1H)。
步骤2:(E)-2-(苄基氧基)-4-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)环丁酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤3:2-(苄基氧基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁酮
向(4E)-2-(苄基氧基)-4-([2-[1-(三苯基甲基)-1H-咪唑-4-基]苯基]亚甲基)环丁-1-酮(1.7g,2.97mmol)在DCM(20mL)中的溶液中添加三氟乙酸(10mL)。所得溶液在室温搅拌40分钟。所得溶液用水(50mL)稀释。溶液的pH值用碳酸钾调节至10。所得溶液用DCM萃取(3x100mL)。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱用DCM/MeOH(0-5%)纯化。这得到900mg(92%)2-(苄基氧基)-4-[5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-酮,其为淡黄色固体:LCMS(ESI,m/z):331.2[M+H]+.
步骤4:3-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁烷-1,2-二醇
向2-(苄基氧基)-4-[5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇(1.2g,3.61mmol)和甲酸铵(3.0g,47.58mmol)在MeOH(60mL)中的溶液中添加钯碳(1.6g,10%)。所得溶液在油浴中在80℃搅拌4h。将固体过滤出。将滤液真空浓缩。将残余物使用Prep-HPLC纯化,使用以下条件:
柱:XBridge BEH130 Prep C18 OBD柱19x150mm 5um 13nm;流动相A:水(0.05%NH3H2O),流动相B:ACN;流速:20mL/min;梯度:15%B至27%B在10min内;254/220nm.
实施例158a:3-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁烷-1,2-二醇(21.3mg,2.5%),其为白色固体:LCMS(ESI,m/z):243.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.60(d,J=7.2Hz,1H),7.39-7.34(m,2H),7.25-7.21(m,1H),7.11(s,1H),5.47(d,J=5.2Hz,1H),5.33(d,J=8.1Hz,1H),5.04(d,J=8.0Hz,1H),4.37-4.32(m,1H),4.00-3.95(m,1H),2.44-2.36(m,2H),1.86-1.77(m,1H)。
实施例159:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并
[1,5-a]吡啶-4-醇
步骤1:3-甲基-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
在氮气下,向3-碘-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮(1.3g,4.96mmol)在二噁烷(100mL,1.18mol)中的溶液中添加三甲基-1,3,5,2,4,6-三氧杂三硼杂环己烷(3.71g,14.77mmol,50%在THF中),Pd(PPh3)4(570mg,0.493mmol)和碳酸钾(1.35g,9.80mmol)。所得溶液在100℃油浴中搅拌2h。将混合物用水(100mL)稀释。所得溶液用EtOAc萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(40:60)洗脱。这得到700mg(94%)3-甲基-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮,其为棕色固体:LCMS(ESI,m/z):151.1[M+H]+.
步骤2:(E)-3-甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤3:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤4:
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成的通用步骤合成146c-d。粗产物通过prep-HPLC和手性HPLC纯化,使用以下条件:
1.柱,XBridge BEH130 Prep C18 OBD柱,19x150mm 5um 13nm;流动相,水(0.05%NH3H2O)和ACN(21.0%ACN至31.0%在10min内);检测器,uv 254/220nm.
2.柱,Lux 5u Cellulose-4,AXIA Packed,2.12x25cm,5um;流动相,Hex(0.2%DEA)和乙醇(保持50.0%乙醇-在14min内);检测器,UV220/254nm。所有异构体159a-b的绝对构型任意指定。
实施例159a:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(21.7mg,14%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.16(dd,J=1.5,0.8Hz,1H),7.66-7.60(m,2H),7.47-7.32(m,3H),7.19(s,1H),5.66(s,1H),5.32(dd,J=3.6,1.2Hz,1H),4.18-4.13(m,1H),3.83-3.73(m,1H),2.73-2.66(m,1H),2.19(s,3H),1.98-1.87(m,1H),1.22(d,J=13.7Hz,1H)。tR=1.436分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。159a和159b为对映异构体。
实施例159b:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(24.4mg,16%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=2.115分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。159a和159b为对映异构体。
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成146e-f的通用步骤合成。粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge BEH130 Prep C18 OBD柱,19x150mm 5um 13nm;流动相,水(0.05%NH3H2O)和ACN(17.0%ACN至30.0%在7min内);检测器,uv 254/220nm.
2.柱,Phenomenex Lux 5u Cellulose-4 AXIA Packed,2.12x25cm,5um;流动相,Hex和乙醇(保持30.0%乙醇-在16min内);检测器,UV 254/220nm.所有异构体159c-d的绝对构型任意指定。
实施例159c:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(37.5mg,8%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1H NMR(300MHz,CD3OD)δ8.40(d,J=6.3Hz,1H),7.78-7.76(m,1H),7.60-7.44(m,4H),7.27(s,1H),5.97(d,J=1.6Hz,1H),5.12(d,J=10.1Hz,1H),4.03-3.85(m,2H),2.71-2.64(m,1H),2.22(s,3H),1.44-1.31(m,2H)。tR=1.603分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=70:30,1ml/min)。159c和159d为对映异构体。
实施例159d:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(38.0mg,8%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=1.603分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=70:30,1ml/min)。159c和159d为对映异构体。
实施例160:3-氯-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,
5-a]吡啶-4-醇
步骤1:3-氯-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
向4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮(1.7g,12.49mmol)在DMF(100mL)中的溶液中添加NCS(1.7g,12.73mmol)。所得溶液在100℃搅拌2h在油浴中。该反应用水(200mL)稀释。所得溶液用EtOAc(2x200mL)萃取。合并有机层,用无水硫酸钠干燥,且真空浓缩。残余物通过硅胶柱纯化,用EtOAc/石油醚(1:1)洗脱。这得到2.3g(粗物质)3-氯-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-4-酮,其为黄色固体:LCMS(ESI,m/z):171.3[M+H]+.
步骤2:(E)-3-氯-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤3:3-氯-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢吡唑并[1,5-a]吡啶-4(5H)-酮
该标题化合物通过合成146c-d的通用步骤合成。
步骤4:
(4S,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成146c-d的通用步骤合成。粗产物通过prep-HPLC和手性HPLC纯化,使用以下条件:
1.柱,XBridge BEH130 Prep C18 OBD柱,19x150mm 5um 13nm;流动相,水(0.05%NH3H2O)和ACN(22%ACN至30%在10min内);检测器,uv254/220nm.
2.柱,Chiralpak IC,2x25cm,5um;流动相,Hex(0.1%DEA)--HPLC和乙醇-HPLC(保持50%乙醇--HPLC在19min内);检测器,UV 220/254nm.所有异构体160a-d的绝对构型任意指定。
实施例160a:(4S,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(51.4mg,29%),其为白色固体:LCMS(ESI,m/z):327.3[M+H]+.1HNMR(300MHz,CD3OD)δ8.15(d,J=0.8Hz,1H),7.65-7.60(m,2H),7.50-7.33(m,3H),7.18(d,J=0.6Hz,1H),5.65(d,J=1.6Hz,1H),5.36(dd,J=3.5,1.2Hz,1H),4.22-4.16(m,1H),3.87-3.77(m,1H),2.75-2.68(m,1H),2.05-1.91(m,1H),1.27-1.22(m,1H)。tR=1.340min(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。160a和160b为对映异构体。
实施例160b:(4R,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(49.8mg,28%),其为白色固体:LCMS(ESI,m/z):327.2[M+H]+.tR=1.770min(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。160a和160b为对映异构体。
实施例160c:(4S,5R)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(14.0mg,8%),其为白色固体:LCMS(ESI,m/z):307.3[M+H]+.1HNMR(300MHz,CD3OD)δ8.07(t,J=0.7Hz,1H),7.79-7.77(m,1H),7.68-7.66(m,1H),7.47-7.31(m,3H),7.19(s,1H),5.59(d,J=5.2Hz,1H),5.07(dd,J=3.0,1.3Hz,1H),4.36-4.30(m,1H),4.00-3.91(m,1H),2.52-2.41(m,2H),2.13-2.07(m,1H)。tR=1.593min(CHIRALPAKIC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。160c和160d为对映异构体。
实施例160d:(4R,5S)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(12.5mg,7%),其为白色固体:LCMS(ESI,m/z):307.2[M+H]+.tR=2.068min(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。160c和160d为对映异构体。
(4R,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过合成146e-f的通用步骤合成。
粗产物通过prep-HPLC纯化且进一步通过手性分离使用以下条件进行分离:
1.柱,XBridge BEH130 Prep C18 OBD柱,19x150mm 5um 13nm;流动相,水(0.05%NH3H2O)和ACN(22.0%ACN至30.0%在10min内);检测器,uv 254/220nm.
2.柱,CHIRALPAK IF,2x25cm,5um;流动相,Hex 0.1%DEA和乙醇(保持50.0%乙醇-在17min内);检测器,UV 220/254nm.
所有异构体160e-f的绝对构型任意指定。
实施例160e:(4R,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(6.0mg,1%),其为白色固体:LCMS(ESI,m/z):327.3[M+H]+.1H NMR(300MHz,CD3OD)δ7.96(s,1H),7.70-7.67(m,1H),7.56-7.37(m,4H),7.23(s,1H),5.86(d,J=1.4Hz,1H),5.24(d,J=9.8Hz,1H),4.00-3.86(m,2H),2.70-2.61(m,1H),1.38-1.17(m,2H)。tR=2.208min(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):IPA=50:50,1.0ml/min)。160e和160f为对映异构体。
实施例160f:(4S,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇(24.0mg,3%),其为白色固体:LCMS(ESI,m/z):327.2[M+H]+.tR=1.515分钟(Lux 3u Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=70:30,1ml/min)。160e和160f为对映异构体。
实施例161:2-氨基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并
[1,5-a]吡啶-4-醇
(4R,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
步骤1:((E)-(4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-基)氨基甲酸叔丁酯
该标题化合物通过合成Int-2的通用步骤合成。LCMS(ESI,m/z):648.3[M+H]+
步骤2:(5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-基)氨基甲酸叔丁酯
该标题化合物通过合成Int-3的通用步骤合成。LCMS(ESI,m/z):406.3[M+H]+
步骤3:2-氨基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
在-10℃向(5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-基)氨基甲酸叔丁酯(1.4g,3.45mmol)在MeOH(30mL)中的溶液中分批添加NaBH4(391mg,10.36mmol)且溶液在室温搅拌1hr。反应通过饱和氯化铵(10mL)淬灭。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x30mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=94:6洗脱。向该醇(1g,2.45mmol)在DCM(15mL)中的溶液中添加TFA(~5mL,61.35mmol)在室温且搅拌4小时。4h后,在减压下去除溶剂且将饱和NaHCO3(20mL)缓慢添加至残余物,然后添加DCM(20mL)。收集有机层且水层用具有三氟乙醇的DCM萃取(2x20mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其使用combi flash纯化:LCMS(ESI,m/z):308.2[M+H]+。混合物通过手性分离方法分离且异构体的构型任意指定。
(4R,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5S)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
实施例161b:(4S,5S)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.63(d,J=7.5Hz,1H),7.50(d,J=6.9Hz,1H),7.42(t,J=7.4Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.18(s,1H),5.98(d,J=7.3Hz,1H),5.72(s,1H),5.51(s,1H),4.88(dd,J=10.4,7.3Hz,1H),4.50(s,2H),3.64(dd,J=10.9,4.1Hz,1H),3.49(td,J=11.6,5.8Hz,1H),2.48–2.31(m,1H),1.06–0.88(m,2H)。
实施例161c:(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.62(d,J=7.7Hz,1H),7.59(d,J=7.5Hz,1H),7.39(t,J=7.5Hz,1H),7.29(td,J=7.6,1.0Hz,1H),7.12(s,1H),5.94(d,J=5.4Hz,1H),5.49(d,J=2.1Hz,1H),5.44(s,1H),5.07–4.92(m,1H),4.52(s,2H),3.81–3.64(m,1H),3.49(td,J=12.1,4.8Hz,1H),2.49–2.45(m,1H),1.79(tq,J=12.3,5.7Hz,1H),1.12(d,J=13.8Hz,1H)。
实施例161d:(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.71(d,J=7.7Hz,1H),7.61(d,J=7.5Hz,1H),7.39(t,J=7.5Hz,1H),7.24(td,J=7.6,1.1Hz,1H),7.13(s,1H),5.68(d,J=5.4Hz,1H),5.42(d,J=5.4Hz,1H),5.38(s,1H),4.81(d,J=5.3Hz,1H),4.50(s,2H),3.85(dd,J=11.3,4.3Hz,1H),3.69–3.45(m,1H),2.32–2.09(m,2H),1.81(d,J=10.9Hz,1H)。
实施例161e:(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.62(d,J=7.6Hz,1H),7.59(d,J=7.5Hz,1H),7.39(t,J=7.5Hz,1H),7.29(td,J=7.6,1.0Hz,1H),7.12(s,1H),5.94(d,J=5.4Hz,1H),5.49(d,J=2.1Hz,1H),5.44(s,1H),5.05–4.96(m,1H),4.52(s,2H),3.81–3.62(m,1H),3.49(td,J=12.1,4.8Hz,1H),2.47(d,J=2.9Hz,1H),1.79(tq,J=12.3,5.8Hz,1H),1.12(d,J=13.0Hz,1H)。
实施例161f:(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.71(d,J=7.7Hz,1H),7.62(d,J=7.5Hz,1H),7.39(t,J=7.4Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.13(s,1H),5.68(d,J=5.4Hz,1H),5.43(d,J=5.4Hz,1H),5.39(s,1H),4.81(d,J=5.4Hz,1H),4.50(s,2H),3.85(dd,J=11.3,4.3Hz,1H),3.66–3.50(m,1H),2.33–2.11(m,2H),1.82(d,J=10.7Hz,1H)。
实施例161g:(4R,5R)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.63(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),7.32(td,J=7.5,1.0Hz,1H),7.18(s,1H),5.98(d,J=7.3Hz,1H),5.73(s,1H),5.51(s,1H),4.88(dd,J=10.3,7.4Hz,1H),4.50(s,2H),3.64(dd,J=10.7,4.0Hz,1H),3.49(td,J=11.5,5.8Hz,1H),2.49–2.28(m,1H),1.05–0.85(m,2H)。
实施例161h:(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):308.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.64(d,J=7.6Hz,1H),7.57(d,J=7.7Hz,1H),7.41(t,J=7.5Hz,1H),7.27(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.98(d,J=6.7Hz,1H),5.72(d,J=3.1Hz,1H),5.47(s,1H),4.81(dd,J=10.5,6.4Hz,1H),4.49(s,2H),3.65(dd,J=12.2,4.2Hz,1H),3.52(td,J=12.0,4.7Hz,1H),2.65–2.54(m,1H),1.06(tq,J=12.5,5.9Hz,1H),0.93(d,J=13.7Hz,1H)。
实施例162:4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢
苯并[d]噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
步骤1:3-溴环己烷-1,2-二酮
向1,2-环己烷二酮(5.1g,45.5mmol)在乙醚(46mL)在0℃中的溶液中经10分钟滴加Br2(2.34mL,45.5mmol)。当添加完成后,将反应恢复至室温且搅拌15分钟,此时反应混合物在减压下浓缩。所得深色油状物倒入2.5%MeOH/CHCl3且运行通过硅胶垫,用相同溶剂混合物洗脱。溶剂然后在减压下去除且所得黄色固体用冷乙醚(15mL)研磨。将产物过滤且干燥。1HNMR(400MHz,氯仿-d)δ6.45(s,1H),2.90(td,J=6.0,5.6,0.6Hz,2H),2.54–2.61(m,2H),2.05–2.13(m,2H)。
步骤2:4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酸乙酯
将3-溴环己烷-1,2-二酮3(10.76g,56.32mmol)和2-氨基-2-硫代乙酸乙酯(5.0g,37.55mmol)在乙醇(150mL)中的混合物加热至回流且搅拌15h。将混合物冷却至室温。在减压下去除溶剂且产物通过CombiFlash分离。产物用EtOAc:己烷=50:50洗脱:LCMS(ESI,m/z):226.2[M+H]+.
步骤3:N-甲基-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
在室温向4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酸乙酯(2.0g,8.88mmol)在乙醇(13.5mL)中的溶液中添加甲基胺(2.0M)在THF(13.3mL,26.64mmol)中的溶液。所得混合物在室温搅拌3小时。TLC指示起始材料完全消耗。在减压下去除溶剂且产物通过CombiFlash分离。所需产物用MeOH:DCM=3:97洗脱:LCMS(ESI,m/z):211.2[M+H]+.
步骤4:(E)-N-甲基-4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2.45g,5.91mmol)和N-甲基-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺(1.49g,7.09mmol)在乙醇(40mL)中的溶液中添加吡咯烷(388mL,4.73mmol)。将混合物在95℃搅拌5hrs。在减压下去除溶剂且产物通过CombiFlash分离。所需产物用EtOAc:Hex=60:40洗脱:LCMS(ESI,m/z):607.3[M+H]+.
步骤5:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
E)-N-甲基-4-氧代-5-(2-(1-三苯甲基-1H-咪唑-4-基)亚苄基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺(2.59g,4.27mmol)在甲醇(20mL)和乙酸(5mL)中在90℃搅拌2h。冷却至室温后,在减压下去除溶剂且添加饱和NaHCO3(20mL)以淬灭乙酸。水层用DCM萃取(3x30mL)。合并的有机层用Na2SO4干燥且溶剂在减压下蒸发以得到粗产物,其通过使用CombiFlash纯化且用DCM:MeOH=95:5洗脱:LCMS(ESI,m/z):365.2[M+H]+.
步骤6:
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
在0℃向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4-氧代-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺(1.02g,2.80mmol)在甲醇(20mL)中的溶液中分批添加硼氢化钠(212mg,5.60mmol)。混合物温热至室温且再搅拌1小时。该反应用饱和氯化铵溶液(20mL)淬灭。水层用20%2,2,2-三氟乙醇在DCM中的溶液(3x20mL)萃取。合并的有机萃取物用(Na2SO4)干燥且在减压下浓缩以得到粗产物。粗物质通过CombiFlash纯化且产物用DCM:MeOH=95:5洗脱。最终产物进一步通过手性分离进行分离以得到8种异构体且各异构体的立体化学任意指定。
实施例162a:(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.53(q,J=4.8Hz,1H),7.90(s,1H),7.64(dd,J=7.6,1.0Hz,1H),7.55(dd,J=7.7,1.0Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.90(d,J=7.3Hz,1H),5.77(d,J=3.2Hz,1H),5.00(dd,J=9.4,7.4Hz,1H),2.81(d,J=4.8Hz,3H),2.70–2.60(m,3H),0.99(dt,J=9.8,6.9Hz,2H)。
实施例162b:(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.56(q,J=4.7Hz,1H),7.93(s,1H),7.64(dt,J=7.5,0.9Hz,1H),7.52–7.46(m,1H),7.46–7.39(m,1H),7.33(td,J=7.5,1.1Hz,1H),7.18(s,1H),5.87(d,J=7.7Hz,1H),5.78(d,J=1.8Hz,1H),5.04(t,J=8.7Hz,1H),2.81(d,J=4.7Hz,3H),2.73–2.56(m,2H),1.03–0.88(m,2H)。
实施例162c:(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.56(q,J=4.7Hz,1H),7.93(s,1H),7.64(dt,J=7.6,0.9Hz,1H),7.49(dq,J=7.6,0.9Hz,1H),7.42(tt,J=7.5,0.8Hz,1H),7.33(td,J=7.5,1.1Hz,1H),7.18(s,1H),5.87(d,J=7.8Hz,1H),5.78(d,J=1.8Hz,1H),5.04(t,J=8.6Hz,1H),2.81(d,J=4.7Hz,3H),2.73–2.56(m,2H),1.03–0.88(m,2H)。
实施例162d:(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.53(q,J=4.5Hz,1H),7.90(s,1H),7.64(d,J=7.6Hz,1H),7.55(d,J=7.7Hz,1H),7.40(t,J=7.5Hz,1H),7.25(td,J=7.6,1.1Hz,1H),7.17(s,1H),5.90(d,J=7.3Hz,1H),5.77(d,J=3.2Hz,1H),5.05–4.96(m,1H),2.80(d,J=4.8Hz,3H),2.70–2.61(m,3H),1.03–0.93(m,2H)。
实施例162e:(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.70(q,J=4.7Hz,1H),7.99(s,1H),7.65(dq,J=7.6,0.9Hz,1H),7.60(dt,J=7.5,0.9Hz,1H),7.39(tt,J=7.6,0.9Hz,1H),7.29(td,J=7.5,1.2Hz,1H),7.13(s,1H),5.95(d,J=7.1Hz,1H),5.52(d,J=2.4Hz,1H),5.11(dd,J=7.1,3.5Hz,1H),2.92–2.84(m,1H),2.80(d,J=4.8Hz,3H),2.60–2.51(m,2H),1.55(qd,J=12.7,5.5Hz,1H),1.04(d,J=6.7Hz,1H)。
实施例162f:(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.66(q,J=4.7Hz,1H),7.97(s,1H),7.78(dq,J=7.7,0.9Hz,1H),7.62(dt,J=7.5,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.74(d,J=7.1Hz,1H),5.46(d,J=5.7Hz,1H),4.92(dd,J=7.2,3.3Hz,1H),2.98(ddd,J=17.4,5.5,1.6Hz,1H),2.66(ddd,J=17.5,11.9,5.8Hz,1H),2.28–2.19(m,1H),1.96(qd,J=12.7,5.5Hz,1H),1.76–1.66(m,1H)。
实施例162g:(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.70(q,J=4.7Hz,1H),7.99(s,1H),7.65(dq,J=7.6,0.9Hz,1H),7.60(dt,J=7.5,0.9Hz,1H),7.39(tt,J=7.6,0.8Hz,1H),7.29(td,J=7.5,1.1Hz,1H),7.13(s,1H),5.95(d,J=7.1Hz,1H),5.55–5.47(m,1H),5.11(dd,J=7.1,3.5Hz,1H),2.92–2.84(m,1H),2.80(d,J=4.8Hz,3H),2.60–2.51(m,2H),1.55(qd,J=12.7,5.5Hz,1H),1.04(d,J=7.3Hz,1H)。
实施例162h:(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺:LCMS(ESI,m/z):367.5[M+H]+;1HNMR(500MHz,DMSO-d6)δ8.66(q,J=4.7Hz,1H),7.97(s,1H),7.78(dd,J=7.7,1.0Hz,1H),7.66–7.58(m,1H),7.39(dd,J=8.0,7.0Hz,1H),7.25(td,J=7.6,1.2Hz,1H),7.14(s,1H),5.74(d,J=7.1Hz,1H),5.46(d,J=5.7Hz,1H),4.92(dd,J=7.2,3.3Hz,1H),2.98(ddd,J=17.4,5.6,1.7Hz,1H),2.78(d,J=4.8Hz,3H),2.66(ddd,J=17.5,11.9,5.8Hz,1H),2.24(ddt,J=12.0,5.9,2.9Hz,1H),1.96(qd,J=12.7,5.5Hz,1H),1.72(d,J=7.2Hz,1H)。
实施例163:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]
噁二唑-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
步骤1:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢苯并[c][1,2,5]噁二唑-4(5H)-酮
向2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2g,4.82mmol)和6,7-二氢苯并[c][1,2,5]噁二唑-4(5H)-酮(749.76mg,5.43mmol)在甲醇(130mL)中的溶液中添加吡咯烷(0.98mL,2.41mmol)且反应回流过夜。将乙酸(7mL)添加至反应混合物且回流4小时。甲醇和乙酸在旋转式蒸发器上蒸发且将粗物质溶于水,分批添加固体碳酸钠以中和剩余乙酸。粗物质然后使用DCM(2X30mL)萃取,其进一步通过Combi-Flash纯化。LCMS(ESI,m/z):293.2.2[M+H]+
步骤2:
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
在0℃向5-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢苯并[c][1,2,5]噁二唑-4(5H)-酮(800mg,2.74mmol)在甲醇(30mL)中的溶液中添加硼氢化钠(0.31g,8.21mmol)。反应烧瓶然后从冰浴移除且将反应搅拌2小时。反应通过缓慢添加饱和NH4Cl淬灭。所得混合物真空浓缩且粗产物使用DCM中的10%TFE萃取。合并的有机层蒸发以得到粗产物,其进一步通过Combi-Flash纯化且进一步通过手性分离进行分离以得到8种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例163a:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.73(dd,J=7.8,0.9Hz,1H),7.62(d,J=7.6Hz,1H),7.42–7.35(m,1H),7.29–7.22(m,1H),7.14(s,1H),6.36(d,J=5.7Hz,1H),5.55(d,J=4.9Hz,1H),5.22(d,J=2.4Hz,1H),3.06–2.91(m,1H),2.73–2.61(m,1H),1.95(qd,J=12.8,5.6Hz,1H),1.68(dd,J=13.4,6.2Hz,1H),0.90–0.78(m,1H)。
实施例163b:(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(ddt,J=7.7,6.6,0.9Hz,2H),7.40(tt,J=7.7,0.8Hz,1H),7.30(td,J=7.5,1.2Hz,1H),7.13(s,1H),6.69(d,J=5.7Hz,1H),5.62–5.55(m,1H),5.46(dd,J=5.9,3.5Hz,1H),2.91(ddd,J=17.4,5.6,1.9Hz,1H),2.68(dq,J=12.6,2.7,Hz,1H),2.55(ddd,J=17.4,12.6,6.3Hz,1H),1.56(qd,J=12.9,5.6Hz,1H),1.06–0.95(m,1H)。
实施例163c:(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.60(tt,J=7.3,0.9Hz,2H),7.40(tt,J=7.5,0.8Hz,1H),7.30(td,J=7.5,1.2Hz,1H),7.13(s,1H),6.69(d,J=5.5Hz,1H),5.62–5.55(m,1H),5.46(t,J=4.5Hz,1H),2.91(ddd,J=17.4,5.6,1.8Hz,1H),2.68(dq,J=12.5,2.6Hz,1H),2.55(ddd,J=17.4,12.6,6.2Hz,1H),1.61–1.50(m,1H),1.06–0.98(m,1H)。
实施例163d:(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.64(dt,J=7.7,1.0Hz,1H),7.52–7.46(m,1H),7.43(tt,J=7.6,0.9Hz,1H),7.33(td,J=7.6,1.1Hz,1H),7.19(s,1H),6.69(d,J=7.2Hz,1H),5.80–5.71(m,1H),5.26(dd,J=11.0,7.3Hz,1H),2.78(dt,J=17.3,3.8Hz,1H),2.65–2.53(m,2H),0.96(dtd,J=11.2,6.4,3.9Hz,2H)。
实施例163e:(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.65(d,J=7.5Hz,1H),7.61(dd,J=7.7,0.9Hz,1H),7.44–7.38(m,1H),7.28(td,J=7.6,1.2Hz,1H),7.18(s,1H),6.71(d,J=6.9Hz,1H),5.78(d,J=3.2Hz,1H),5.17(dd,J=11.1,6.8Hz,1H),2.80–2.68(m,2H),2.66–2.56(m,1H),0.89-1.04(m,2H)。
实施例163f:(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.64(dt,J=7.6,0.9Hz,1H),7.52–7.47(m,1H),7.46–7.40(m,1H),7.33(td,J=7.6,1.1Hz,1H),7.19(s,1H),6.68(d,J=7.3Hz,1H),5.80–5.76(m,1H),5.25(dd,J=11.1,7.3Hz,1H),2.78(dt,J=17.3,3.8Hz,1H),2.65–2.53(m,2H),1.01–0.91(m,2H)。
实施例163g:(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.65(d,J=7.5Hz,1H),7.61(dd,J=7.7,1.0Hz,1H),7.41(d,J=0.8Hz,1H),7.28(dd,J=7.6,1.1Hz,1H),7.18(s,1H),6.71(d,J=6.7Hz,1H),5.78(d,J=3.2Hz,1H),5.17(dd,J=11.1,6.5Hz,1H),2.83–2.69(m,2H),2.66–2.57(m,1H),1.06–0.94(m,1H),0.81–0.93(m,1H)。
实施例163h:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇:LCMS(ESI,m/z):295.4[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.73(dd,J=7.7,0.9Hz,1H),7.63(d,J=7.6Hz,1H),7.40(t,J=0.8Hz,1H),7.25(d,J=1.2Hz,1H),7.14(s,1H),6.36(d,J=5.8Hz,1H),5.55(d,J=4.8Hz,1H),5.22(dd,J=5.9,3.3Hz,1H),3.00(ddd,J=17.5,5.6,1.9Hz,1H),2.68(ddd,J=17.4,12.3,6.3Hz,1H),1.95(qd,J=12.8,5.6Hz,1H),1.68(dd,J=13.4,6.2Hz,1H),1.22-1.26(m,1H)。
实施例164:1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
向5H-咪唑并[5,1-a]异吲哚(0.866g,5.55mmol)在无水THF(25mL)在-40℃中的溶液中添加n-BuLi(2.22mL,5.55mmol,2.5M在己烷中的溶液)。在-40℃搅拌1.0hr后,添加2,2-二甲基环己烷-1-酮(350mg,2.77mmol)且将反应温热至-10℃且搅拌3小时。反应通过添加饱和NH4Cl(10mL)和水(20mL)淬灭,产物用CH2Cl2(3x35mL)萃取。合并的有机萃取物用Na2SO4干燥且在减压下浓缩以得到粗混合物。粗产物通过CombiFlash纯化且进一步通过手性分离进行分离以得到2种异构体,为白色固体,立体化学任意指定:LCMS(ESI,m/z):283.23[M+H]+.
实施例164a:(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):283.23[M+H]+.1H NMR(DMSO-d6,500MHz):δ(ppm)7.90(s,1H),7.66–7.53(m,2H),7.37(tt,J=7.5,0.8Hz,1H),7.21(td,J=7.6,1.2Hz,1H),7.11(s,1H),5.12(s,1H),5.11(s,1H),2.40–2.26(m,1H),1.87–1.69(m,3H),1.56(d,J=11.9Hz,1H),1.43–1.20(m,2H),0.65(d,J=13.1Hz,1H),0.19(s,3H),0.13(s,3H)。
实施例164b:(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇:LCMS(ESI,m/z):283.23[M+H]+.1H NMR(DMSO-d6,500MHz):与164a相同.
实施例165:1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
步骤1:
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
1-((R)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
1-((S)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
向1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈(800mg,3.18mmol)在甲醇中的溶液中添加NaOH(1.27g,31.84mmol)和过氧化氢(2.49mL,31.84mmol,30%水溶液)。将反应混合物搅拌3天。粗产物使用5%2,2,2-三氟乙醇在DCM中的溶液萃取且在Combi-Flash上纯化且进一步通过手性分离进行分离以得到4种异构体,其为白色固体。所有异构体的绝对构型任意指定。
实施例165a:1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺:LCMS(ESI,m/z):270.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.76(s,1H),7.66–7.62(m,1H),7.56(dt,J=7.5,0.9Hz,1H),7.41–7.33(m,1H),7.29-7.17(m,3H),7.09(s,1H),5.94(d,J=5.1Hz,1H),5.48(d,J=6.9Hz,1H),1.02-0.95(m,2H),0.73–0.65(m,1H),0.52–0.42(m,1H)。
实施例165b:1-((R)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺:LCMS(ESI,m/z):270.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.57(dt,J=7.5,0.9Hz,1H),7.51(dd,J=7.6,0.9Hz,1H),7.40–7.35(m,1H),7.32-7.21(m,3H),7.10(s,1H),6.05(s,1H),5.57(d,J=7.3Hz,1H),1.10(ddd,J=9.4,6.8,4.2Hz,1H),0.97(ddd,J=9.4,6.4,4.1Hz,1H),0.78(ddd,J=9.4,6.8,4.2Hz,1H),0.40(ddd,J=9.4,6.5,4.2Hz,1H)。
实施例165c:1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺:LCMS(ESI,m/z):270.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.76(s,1H),7.64(dd,J=7.7,1.0Hz,1H),7.59–7.54(m,1H),7.37(t,J=7.4Hz,1H),7.23(td,J=7.6,1.2Hz,3H),7.09(s,1H),5.94(d,J=5.8Hz,1H),5.48(d,J=6.9Hz,1H),1.00-0.97(q,2H),0.72–0.66(m,1H),0.51–0.43(m,1H)。
实施例165d:1-((S)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺:LCMS(ESI,m/z):270.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.83(s,1H),7.57(dt,J=7.5,0.9Hz,1H),7.51(dd,J=7.6,0.9Hz,1H),7.40–7.35(m,1H),7.32-7.21(m,3H),7.10(s,1H),6.05(s,1H),5.57(d,J=7.3Hz,1H),1.10(ddd,J=9.4,6.8,4.2Hz,1H),0.97(ddd,J=9.4,6.4,4.1Hz,1H),0.78(ddd,J=9.4,6.8,4.2Hz,1H),0.40(ddd,J=9.4,6.5,4.2Hz,1H)。
实施例166:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并
[1,5-a]吡啶-4-醇
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
该标题化合物通过与实施例96相同的方法合成。
异构体的构型任意指定。
实施例166a:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.97(s,1H),7.64(dt,J=7.6,0.9Hz,1H),7.50(dq,J=7.6,1.0Hz,1H),7.42(tt,J=7.4,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.19(s,1H),6.10(d,J=5.6Hz,1H),6.08(s,1H),5.75(d,J=1.8Hz,1H),4.97(dd,J=10.5,5.1Hz,1H),3.89–3.82(m,1H),3.69(td,J=12.0,5.4Hz,1H),2.49–2.43(m,1H),2.12(s,3H),1.08–1.00(m,2H)。166a和166b为对映异构体。
实施例166b:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇:LCMS(ESI,m/z):307.2[M+H]+;1HNMR(500MHz,DMSO-d6)δ7.97(s,1H),7.64(dt,J=7.6,0.9Hz,1H),7.50(dq,J=7.6,1.0Hz,1H),7.42(tt,J=7.4,0.9Hz,1H),7.32(td,J=7.5,1.1Hz,1H),7.19(s,1H),6.10(d,J=5.6Hz,1H),6.08(s,1H),5.75(d,J=1.8Hz,1H),4.97(dd,J=10.5,5.1Hz,1H),3.89–3.82(m,1H),3.69(td,J=12.0,5.4Hz,1H),2.49–2.43(m,1H),2.12(s,3H),1.08–1.00(m,2H)。166a和166b为对映异构体。
实施例167:6-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-
醇
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
该标题化合物通过与实施例88相同的方法合成。
异构体的构型任意指定。
实施例167a:(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.97(s,1H),7.97(s,1H),7.75(dd,J=7.7,1.0Hz,1H),7.61(d,J=7.5Hz,1H),7.38(dd,J=8.0,7.1Hz,1H),7.24(td,J=7.6,1.1Hz,1H),7.13(s,1H),5.87(d,J=6.7Hz,1H),5.47(d,J=5.5Hz,1H),5.07(dd,J=6.8,3.6Hz,1H),2.82(dd,J=16.8,3.9Hz,1H),2.57(ddd,J=16.9,11.7,5.9Hz,1H),2.37–2.28(m,1H),1.94(qd,J=12.6,5.3Hz,1H),1.69(d,J=12.6Hz,1H)。167a和167f为对映异构体。
实施例167b:(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.94(d,J=0.7Hz,1H),7.92(s,1H),7.63(ddd,J=14.2,7.7,1.0Hz,2H),7.41(ddd,J=7.5,6.9,0.9Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.17(s,1H),6.37(d,J=6.4Hz,1H),5.76(d,J=3.0Hz,1H),5.15(s,1H),2.60–2.52(m,2H),1.06–0.82(m,3H)。167b和167g为对映异构体。
实施例167c:(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.96(d,J=0.8Hz,1H),8.00(s,1H),7.66–7.62(m,1H),7.49(dq,J=7.7,1.0Hz,1H),7.44–7.41(m,1H),7.33(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.34(d,J=7.6Hz,1H),5.76(s,1H),5.20(t,J=8.6Hz,1H),2.64–2.57(m,1H),2.46–2.33(m,2H),0.96–0.84(m,2H)。167c和167d为对映异构体。
实施例167d:(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.96(d,J=0.7Hz,1H),8.00(s,1H),7.64(d,J=7.5Hz,1H),7.52–7.47(m,1H),7.42(t,J=7.5Hz,1H),7.33(td,J=7.5,1.1Hz,1H),7.18(s,1H),6.33(d,J=7.6Hz,1H),5.76(s,1H),5.20(t,J=8.7Hz,1H),2.59(s,1H),2.43(t,J=10.6Hz,2H),0.99–0.84(m,2H)。167c和167d为对映异构体。
实施例167e:(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),7.94(s,1H),7.61(ddt,J=12.0,7.7,0.9Hz,2H),7.39(tt,J=7.5,0.9Hz,1H),7.29(td,J=7.5,1.2Hz,1H),7.12(s,1H),6.16(d,J=6.6Hz,1H),5.53(d,J=1.5Hz,1H),5.25(dd,J=6.6,3.9Hz,1H),2.76–2.68(m,1H),2.62–2.55(m,1H),2.48–2.42(m,1H),1.52(qd,J=12.7,5.6Hz,1H),1.01–0.93(m,1H)。167e和167h为对映异构体。
实施例167f:(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.97(s,1H),7.97(s,1H),7.75(dd,J=7.7,1.0Hz,1H),7.61(d,J=7.5Hz,1H),7.41–7.36(m,1H),7.24(td,J=7.6,1.2Hz,1H),7.13(s,1H),5.87(d,J=6.7Hz,1H),5.47(d,J=5.6Hz,1H),5.07(dd,J=6.7,3.7Hz,1H),2.85–2.79(m,1H),2.57(ddd,J=17.0,11.7,5.8Hz,1H),2.33(ddd,J=12.9,5.8,3.0Hz,1H),1.94(qd,J=12.6,5.5Hz,1H),1.69(d,J=11.3Hz,1H)。167a和167f为对映异构体。
实施例167g:(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.94(d,J=0.7Hz,1H),7.92(s,1H),7.63(dd,J=15.0,7.6Hz,2H),7.41(dd,J=7.9,7.1Hz,1H),7.26(td,J=7.6,1.2Hz,1H),7.17(s,1H),6.35(d,J=7.3Hz,1H),5.76(d,J=2.9Hz,1H),5.14(t,J=8.6Hz,1H),2.61–2.54(m,2H),1.06–0.79(m,3H)。167b和167g为对映异构体。
实施例167h:(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇:LCMS(ESI,m/z):310.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),7.94(s,1H),7.61(ddt,J=12.1,7.7,1.0Hz,2H),7.39(tt,J=7.6,0.9Hz,1H),7.29(td,J=7.5,1.2Hz,1H),7.12(s,1H),6.16(d,J=6.6Hz,1H),5.53(d,J=1.7Hz,1H),5.25(dd,J=6.6,3.9Hz,1H),2.76–2.69(m,1H),2.62–2.55(m,1H),2.47–2.41(m,1H),1.52(qd,J=12.6,5.5Hz,1H),1.01–0.94(m,1H)。167e和167h为对映异构体。
实施例168:5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁
唑-4-醇。
步骤1:2-重氮基环己烷-1,3-二酮
将环己烷-1,3-二酮(5.0g,44.6mmol)溶于80g 11%对甲苯-磺酰基叠氮化物(44.6mmol)在甲苯且填充三甲基胺(18.6mL,134mmol)。在室温搅拌过夜后,溶液用500mLEtOAc和500mL水稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩。粗残余物然后通过硅胶色谱法纯化(EtOAc中的15-50%庚烷)以得到2-重氮基环己烷-1,3-二酮(5.1g,83%产率)LCMS(ESI,m/z):139.1(M+H)。
步骤2:2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮
将2-重氮基环己烷-1,3-二酮(300mg,2.2mmol)溶于10ml ACN且添加四乙酸二铑(88mg,0.2mmol)。在60℃加热混合物过夜后,将混合物用50mL EtOAc和50mL水稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩。粗残余物然后通过硅胶色谱法纯化(1–15%MeOH在DCM中)以得到2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮(210mg,64%产率)。LCMS(ESI,m/z):152.1(M+H)。
步骤3:(E)-2-甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)苯乙烯基)-6,7-二氢苯并[d]噁唑-4(5H)-酮
将二异丙基胺(1.3mL,9.3mmol)溶于5mL无水THF,冷却至0℃,且添加2.5M己烷中的正丁基锂(3.7mL,9.3mmol)。溶液然后在0℃搅拌15分钟且冷却至-78℃。在单独的烧瓶中,将2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮(1.4g,9.3mmol)溶于5ml无水THF且在-78℃滴加至二异丙基胺/正丁基锂在THF中的上述混合物中。在单独的烧瓶中,将2-(1-三苯甲基-1H咪唑-4-基)苯甲醛(3.5g,8.4mmol)溶于20mL无水THF,然后在-78℃滴加至上述混合物。溶液然后在室温搅拌过夜。溶液用500mL EtOAc和500mL水稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩。粗残余物然后通过硅胶色谱法纯化(EtOAc中的15-50%庚烷)以得到(E)-2-甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)苯乙烯基)-6,7-二氢苯并[d]噁唑-4(5H)-酮(3.3g,71%产率)LCMS(ESI,m/z):562.2(M+H)。
步骤4:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮
将(E)-2-甲基-5-(2-(1-三苯甲基-1H-咪唑-4-基)苯乙烯基)-6,7-二氢苯并[d]噁唑-4(5H)-酮(3.0g,5.5mmol)溶于10mL AcOH和30mL MeOH且在80℃加热2小时。溶液然后真空浓缩且通过硅胶色谱法纯化(1-15%MeOH在DCM中)以得到5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮(1.1g,66%产率)。LCMS(ESI,m/z):306.1(M+H)。
步骤5:5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇
将5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-6,7-二氢苯并[d]噁唑-4(5H)-酮(1.1g,3.6mmol)溶于10mL THF,冷却至-78℃,且添加L-Selectride(1.0M在THF中,20mL,20mmol)。在-78℃搅拌30分钟后,添加2mL AcOH。溶液然后用100mL EtOAc和100mL水稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩。粗残余物然后通过硅胶色谱法纯化(1-15%MeOH在DCM中)以得到5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇(800mg,72%产率)。LCMS(ESI,m/z):308.1(M+H)。
步骤6:4-硝基苯甲酸5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-基酯
将5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇(230mg,0.74mmol)溶于3ml THF且添加叠氮基甲酸二-叔丁基酯(861mg,3.7mmol)、4-硝基-苯甲酸(188mg,1.1mmol)和三丁基膦(930uL,3.7mmol)。在室温搅拌过夜后,溶液真空浓缩。粗残余物然后添加10mL 1.0M柠檬酸和10mL EtOAc。丢弃有机层且水层用10mL 1.0M碳酸氢钠处理。水性物质然后用EtOAc萃取两次且将有机物合并且真空浓缩。残余物然后通过硅胶色谱法纯化以得到4-硝基苯甲酸5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-基酯(200mg,59%产率)。LCMS(ESI,m/z):457.1(M+H)
步骤7:(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇
将4-硝基苯甲酸5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-基酯(100mg,0.21mmol)溶于1mL THF且填充600uL 1MLiOH(aq)。在室温搅拌30分钟后,溶液然后用10mL EtOAc和5mL水稀释。丢弃水性物质且有机物用水洗涤一次,用Na2SO4干燥,过滤,且真空浓缩。粗残余物然后通过硅胶色谱法纯化(1–15%MeOH在DCM中)以得到5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇(40mg,62%产率)。LCMS(ESI,m/z):308.1(M+H)
(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇通过手性SFC纯化(甲醇w/0.1%NH4OH,等度洗脱@10%MeOH,Cellulose-3(150x21mm,5um))以得到绝对构型未确定的单一立体异构体。实施例168a和168b为彼此的对映异构体。绝对构型任意指定。
实施例168a:(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇。LCMS(ESI,m/z):308.1(M+H)。1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.63(dt,J=7.5,1.0Hz,1H),7.49–7.37(m,2H),7.32(td,J=7.5,1.2Hz,1H),7.17(s,1H),5.72(m,J=6.9Hz,2H),4.89(m,1H),2.43–2.26(m,5H),0.99–0.78(m,2H)。tR=0.39分钟(纤维素3,甲醇w/0.1%NH4OH,1.5ml/min)。
实施例168b:(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇。LCMS(ESI,m/z):308.1(M+H)。1H NMR与168a相同。tR=0.59分钟(Cellulose 3,甲醇w/0.1%NH4OH,1.5ml/min)。
实施例169:8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5S,6S)-6-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
(5R,6R)-6-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
该标题化合物通过与实施例096相同的方法合成。产物通过手性分离进行分离以得到2种异构体,为白色固体。各异构体的立体化学任意指定。
实施例169a:(5S,6S)-6-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):322.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.35(ddd,J=4.7,1.8,0.7Hz,1H),8.01(s,1H),8.00–7.97(m,1H),7.53(ddd,J=9.6,6.4,3.7Hz,2H),7.27(dd,J=7.8,4.7Hz,1H),7.23(s,1H),7.14(ddd,J=9.6,8.4,2.5Hz,1H),6.21(d,J=7.5Hz,1H),5.80(s,1H),4.97(dd,J=10.6,7.6Hz,1H),2.68(dd,J=8.8,4.0Hz,2H),2.47–2.38(m,1H),1.02–0.82(m,2H)。
实施例169b:(5R,6R)-6-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇:LCMS(ESI,m/z):322.3[M+H]+;1H NMR与实施例122g相同。
实施例170:3-(9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3R,4R)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
(3S,4S)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
该标题化合物通过与实施例69相同的方法合成。
异构体的构型任意指定。
实施例170a:(3R,4R)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):261.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.45–7.33(m,2H),7.28(ddt,J=9.0,8.2,0.8Hz,1H),7.13(s,1H),5.81–5.77(m,1H),5.48(d,J=5.7Hz,1H),3.94(tt,J=10.4,5.0Hz,1H),3.77(dd,J=11.6,4.7Hz,1H),3.26–3.15(m,1H),3.03–2.96(m,1H),2.39(t,J=11.2Hz,1H),2.25(tt,J=10.8,3.5Hz,1H),1.96–1.88(m,1H),1.62–1.50(m,1H)。170a和170b为对映异构体。
实施例170b:(3S,4S)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):261.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.45–7.33(m,2H),7.28(t,J=8.8Hz,1H),7.13(s,1H),5.79(d,J=2.5Hz,1H),5.48(d,J=5.6Hz,1H),3.94(tt,J=10.3,4.9Hz,1H),3.77(dd,J=11.7,4.7Hz,1H),3.20(td,J=12.2,2.1Hz,1H),2.99(dd,J=11.5,4.0Hz,1H),2.39(t,J=11.2Hz,1H),2.25(tt,J=10.7,3.5Hz,1H),1.92(ddt,J=12.6,4.2,2.0Hz,1H),1.56(tdd,J=12.5,10.5,4.8Hz,1H)。170a和170b为对映异构体。
实施例170c:(3R,4R)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):261.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.06(s,1H),7.41(dq,J=7.6,0.9Hz,1H),7.38–7.33(m,1H),7.33–7.23(m,1H),7.12(s,1H),5.73(d,J=3.5Hz,1H),5.29(d,J=5.2Hz,1H),3.79(qd,J=13.2,11.7,4.7Hz,2H),3.17(td,J=12.0,2.3Hz,1H),3.02–2.95(m,1H),2.61(t,J=11.2Hz,1H),2.41(ddt,J=10.7,6.9,3.8Hz,1H),1.87–1.79(m,1H),1.57–1.45(m,1H)。170c和170d为对映异构体。
实施例170d:(3S,4S)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇:LCMS(ESI,m/z):261.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.06(t,J=0.7Hz,1H),7.41(dd,J=7.6,1.0Hz,1H),7.38–7.33(m,1H),7.33–7.24(m,1H),7.11(s,1H),5.73(d,J=3.5Hz,1H),5.29(s,1H),3.78(ddd,J=21.3,10.9,4.4Hz,2H),3.17(td,J=12.0,2.2Hz,1H),2.99(dd,J=11.3,3.9Hz,1H),2.61(t,J=11.2Hz,1H),2.41(tt,J=10.8,3.8Hz,1H),1.87–1.79(m,1H),1.57–1.45(m,1H)。170c和170d为对映异构体。
实施例171:4-(8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3S,4R)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
(3R,4S)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
该标题化合物通过与实施例69相同的方法合成。
异构体的构型任意指定。
实施例171a:(3S,4R)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.45–7.39(m,2H),7.16(s,1H),7.12–7.06(m,1H),5.54(d,J=4.1Hz,1H),5.22(d,J=4.6Hz,1H),4.26(dq,J=5.7,4.1Hz,1H),3.71(dd,J=9.2,8.1Hz,1H),3.57(dd,J=9.2,5.6Hz,1H),3.42(dd,J=9.2,4.0Hz,1H),3.16(dd,J=9.2,6.3Hz,1H),2.81(ddt,J=8.1,6.3,4.0Hz,1H),2.36(d,J=0.8Hz,3H)。171a和171b为对映异构体。
实施例171b:(3R,4S)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.06(s,1H),7.46–7.40(m,2H),7.19(s,1H),7.10(ddd,J=7.8,1.7,0.8Hz,1H),5.55(d,J=4.1Hz,1H),5.22(d,J=4.6Hz,1H),4.25(dd,J=5.6,4.0Hz,1H),3.72(dd,J=9.2,8.1Hz,1H),3.58(dd,J=9.2,5.7Hz,1H),3.41(dd,J=9.2,4.1Hz,1H),3.18(dd,J=9.2,6.3Hz,1H),2.81(ddt,J=8.0,6.2,4.0Hz,1H),2.38–2.34(m,3H)。171a和171b为对映异构体。
实施例171c:(3S,4R)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),7.50–7.46(m,1H),7.43(d,J=7.8Hz,1H),7.28(s,1H),7.15(ddd,J=7.9,1.7,0.8Hz,1H),5.54(d,J=4.7Hz,1H),5.03(d,J=4.8Hz,1H),4.00(dd,J=9.3,7.7Hz,1H),3.87(s,1H),3.80(dd,J=9.3,5.5Hz,1H),3.44–3.37(m,2H),2.75(dtd,J=8.1,5.3,3.1Hz,1H),2.38(s,3H)。171c和171d为对映异构体。
实施例171d:(3R,4S)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇:LCMS(ESI,m/z):257.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.50–7.45(m,1H),7.42(d,J=7.8Hz,1H),7.26(s,1H),7.14(ddd,J=7.8,1.7,0.8Hz,1H),5.53(d,J=4.7Hz,1H),5.03(d,J=4.7Hz,1H),4.00(dd,J=9.3,7.7Hz,1H),3.87(d,J=4.7Hz,1H),3.79(dd,J=9.3,5.5Hz,1H),3.40(qd,J=9.3,4.5Hz,2H),2.75(dtd,J=8.0,5.3,3.1Hz,1H),2.37(s,3H)。171c和171d为对映异构体。
实施例179:8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺
[4.5]癸-1-醇
步骤1:
1-羟基-2-(5H-咪唑并[4,3-a]异吲哚-5-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):396.2[M+H]+。四对外消旋化合物混合物通过Prep-HPLC分离且各对分别运至下一步。
异构体的构型任意指定。
步骤2:
(1S,2R)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
(1R,2S)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
向(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯和(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(150mg,0.38mmol)在DCM(8mL)中的外消旋化合物混合物添加TFA(2ml)。所得溶液在室温搅拌1h。然后蒸发溶剂。所得混合物溶于DCM(10ml)。在0℃添加TEA(0.419mL,3.03mmol)和甲磺酰氯(43mg,0.38mmol)。将混合物在室温搅拌1h。溶液用DCM(50mL)稀释。溶液用水洗涤(50mL),用硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用DCM/MeOH(97:3)洗脱。粗产物进一步通过Prep-HPLC和手性分离而分离。179a和179b的绝对构型任意指定。
实施例179a:(1S,2S)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(21.7mg,31%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.63-7.57(m,2H),7.40-7.24(m,2H),7.15(s,1H),5.43(d,J=6.9Hz,1H),5.32(d,J=6.3Hz,1H),4.08(dd,J=7.9,6.2Hz,1H),3.37-3.31(m,1H),3.28-3.24(m,1H),2.95-2.69(m,5H),2.52-2.47(m,1H),1.74-1.54(m,4H),1.45-1.41(m,1H),0.95(t,J=10.4Hz,1H)。tR=2.862分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。179a和179b为对映异构体。
实施例179b:(1R,2R)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(24.1mg,34%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.63-7.57(m,2H),7.40-7.24(m,2H),7.15(s,1H),5.43(d,J=6.9Hz,1H),5.32(d,J=6.4Hz,1H),4.08(dd,J=7.9,6.3Hz,1H),3.34-3.32(m,1H),3.32-3.24(m,1H),2.91-2.69(m,5H),1.74-1.54(m,4H),1.43(d,J=13.5Hz,1H),0.95(t,J=10.5Hz,1H)。tR=4.216分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1ml/min)。179a和179b为对映异构体。
步骤3:
(1R,2R)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
该标题化合物通过合成179a和179b的通用步骤合成。异构体的构型任意指定。
实施例179c:(1R,2R)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(43.8mg,31%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.61(dd,J=7.2,1.5Hz,1H),7.39(t,J=7.5Hz,2H),7.28-7.23(m,2H),7.14(s,1H),5.41(d,J=8.6Hz,1H),5.26(d,J=6.7Hz,1H),3.98(t,J=7.2Hz,1H),3.37-3.27(m,2H),2.94-2.77(m,5H),2.36-2.30(m,1H),1.86(dd,J=11.0,9.5Hz,1H),1.72-1.45(m,5H)。tR=1.119min(CHIRALPAK IA-3,0.46x5cm;3um,(Hex:DCM=5:1):EtOH=50:50,1.0ml/min)。179c和179d为对映异构体。
实施例179d:(1S,2S)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(49.5mg,35%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.67(d,J=7.5Hz,1H),7.59(d,J=7.5Hz,1H),7.41-7.36(m,1H),7.30-7.25(m,1H),7.13(s,1H),5.40(d,J=4.0Hz,1H),5.38(d,J=5.6Hz,1H),3.92-3.89(m,1H),3.39-3.35(m,1H),3.22-3.17(m,1H),3.93-2.86(m,1H),2.80(s,3H),2.35-2.28(m,1H),1.75-1.52(m,6H),1.35-1.24(m,2H)。tR=2.995min(CHIRALPAK IA-3,0.46x5cm;3um,(Hex:DCM=5:1):EtOH=50:50,1.0ml/min)。179c和179d为对映异构体。
步骤4:
(1R,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
(1S,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
该标题化合物通过合成179a和179b的通用步骤合成。
异构体的构型任意指定。
实施例179e:(1R,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(19.1mg,6.2%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.70-7.58(m,2H),7.48-7.24(m,2H),7.14(d,J=2.9Hz,1H),5.76(d,J=5.5Hz,1H),5.47(d,J=8.7Hz,1H),4.12(dd,J=9.0,4.8Hz,1H),3.32-2.92(m,4H),2.83(s,1H),2.67-2.52(m,1H),1.94-1.79(m,3H),1.60(t,J=5.8Hz,3H)。tR=1.836min(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。179e和179f为对映异构体。
实施例179f:(1S,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(21.3mg,7%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.65-7.58(m,2H),7.40-7.24(m 2H),7.14(s,1H),5.75(d,J=5.5Hz,1H),5.47(d,J=8.7Hz,1H),4.13(td,J=6.3,3.0Hz,1H),3.19-2.95(m,4H),2.83(s,3H),2.61-2.51(m,1H),1.94-1.75(m,3H),1.60(t,J=5.8Hz,3H)。tR=2.941min(CHIRALPAK IC-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1.0ml/min)。179e和179f为对映异构体。
步骤5:
(1R,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
(1S,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇
该标题化合物通过合成179a和179b的通用步骤合成。
异构体的构型任意指定。
实施例179g:(1R,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(24.4mg,52%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.63-7.60(m,1H),7.41-7.36(m,2H),7.26-7.20(m,1H),7.13(s,1H),5.79(d,J=6.0Hz,1H),5.42(d,J=10.6Hz,1H),4.08(td,J=5.9,2.9Hz,1H),3.20-2.98(m,4H),2.85(s,3H),2.35-2.19(m,2H),1.95-1.61(m,5H)。tR=2.279min(LuxCellulose-4,0.46x5cm;3um,:Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。179g和179h为对映异构体。
实施例179h:(1S,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇(22.7mg,48%),其为白色固体:LCMS(ESI,m/z):374.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.63-7.60(m,1H),7.42-7.36(m,2H),7.26-7.20(m,1H),7.14(s,1H),5.79(d,J=6.0Hz,1H),5.42(d,J=10.7Hz,1H),4.08(td,J=6.1,3.0Hz,1H),3.20-2.98(m,4H),2.85(s,3H),2.35-2.19(m,2H),1.95-1.61(m,5H)。tR=3.761min(LuxCellulose-4,0.46x5cm;3um,:Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。179g和179h为对映异构体。
实施例180:8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺
[4.5]癸-1-醇
步骤1:
1-羟基-2-(5H-咪唑并[4,3-a]异吲哚-5-基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
该标题化合物通过合成Int-5的通用步骤合成:LCMS(ESI,m/z):410.2[M+H]+。两对外消旋化合物混合物通过Prep-HPLC分离,且各对分别运至下一步。外消旋化合物异构体的构型任意指定。
步骤2:
(1S,2S)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2R)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
向(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯和(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(506mg,1.246mmol)在DCM(20mL)的外消旋化合物混合物添加TFA(1mL)。所得溶液在室温搅拌2h且真空去除溶剂。向所得残余物在DCM中的溶液(20mL)添加TEA(1.2mL,8.72mmol)。然后在0℃添加甲磺酰氯(185mg,1.62mmol)。将混合物在室温搅拌1h。溶液用二氯甲烷(100mL)稀释。溶液用水(50mL)洗涤,用硫酸钠干燥且真空浓缩。残余物通过硅胶柱纯化,用MeOH/DCM(0%-10%)洗脱。粗产物进一步通过prep-HPLC和手性分离纯化。
180a和180b的绝对构型任意指定。
实施例180a:(1S,2S)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(4.8mg,5%),其为白色固体:LCMS(ESI,m/z):388.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.93(s,1H),7.60(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.41-7.37(m,1H),7.29-7.25(m,1H),7.11(s,1H),5.45(d,J=4.0Hz,1H),5.08(d,J=5.6Hz,1H),3.60-3.57(m,1H),3.44-3.35(m,2H),2.82(s,3H),2.81-2.64(m,3H),1.73-1.58(m,3H),1.35-1.04(m,4H),0.88-0.85(m,1H)。tR=4.843分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。180a和180b为对映异构体。
实施例180b:(1R,2R)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(8.3mg,8%),其为白色固体:LCMS(ESI,m/z):388.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.93(s,1H),7.60(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.41-7.37(m,1H),7.29-7.25(m,1H),7.11(s,1H),5.45(d,J=4.0Hz,1H),5.08(d,J=5.6Hz,1H),3.60-3.57(m,1H),3.44-3.35(m,2H),2.82(s,3H),2.81-2.64(m,3H),1.73-1.58(m,3H),1.35-1.04(m,4H),0.88-0.85(m,1H)。tR=1.690分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。180a和180b为对映异构体。
步骤3:
(1S,2S)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
(1R,2R)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
该标题化合物通过合成180a和180b的通用步骤合成。异构体的构型任意指定。
实施例180c:(1S,2S)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(56.1mg,24%),其为白色固体:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.67(d,J=7.5Hz,1H),7.59(d,J=7.5Hz,1H),7.41-7.36(m,1H),7.30-7.25(m,1H),7.13(s,1H),5.40(d,J=4.0Hz,1H),5.38(d,J=5.6Hz,1H),3.92-3.89(m,1H),3.39-3.35(m,1H),3.22-3.17(m,1H),3.93-2.86(m,1H),2.80(s,3H),2.35-2.28(m,1H),1.75-1.52(m,6H),1.35-1.24(m,2H)。tR=2.258分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。180c和180d为对映异构体。
实施例180d:(1R,2R)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇(29.9mg,13%),其为白色固体:LCMS(ESI,m/z):388.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.67(d,J=7.5Hz,1H),7.59(d,J=7.5Hz,1H),7.41-7.36(m,1H),7.30-7.25(m,1H),7.13(s,1H),5.40(d,J=4.0Hz,1H),5.38(d,J=5.6Hz,1H),3.92-3.89(m,1H),3.39-3.35(m,1H),3.22-3.17(m,1H),3.93-2.86(m,1H),2.80(s,3H),2.35-2.28(m,1H),1.75-1.52(m,6H),1.35-1.24(m,2H)。tR=3.315分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。180c和180d为对映异构体。
实施例181:1-羟基-2-(5H-咪唑并[4,3-a]异吲哚-5-基)-7-氮杂螺[3.5]壬烷-7-
磺酰胺
步骤1:
N-[(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰基]氨基甲酸叔丁酯和N-[(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰基]氨基甲酸叔丁酯的外消旋化合物混合物
向(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯和(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(600mg,1.52mmol)在DCM(20mL)中的外消旋化合物混合物中添加TFA(4mL)。所得溶液在室温搅拌0.5h。所得混合物真空浓缩。这得到2-[5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬-1-醇,其为黄色油状物。在0℃向[(氯磺酰基)亚氨基]甲酮(214mg,1.51mmol)在DCM(10mL)中的溶液添加叔丁醇(336mg,4.533mmol)。所得溶液在0℃搅拌0.5h。将粗物质2-[5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬-1-醇和TEA(1.68mL,12.06mmol)溶于DCM(10mL),然后搅拌0.5h。然后,在0℃将[(氯磺酰基)亚氨基]甲酮的混合物添加至2-[5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬-1-醇的混合物。所得溶液在室温搅拌0.5h。该反应然后通过添加水淬灭。所得溶液用EA萃取且合并有机层。残余物通过硅胶柱纯化,用DCM/MeOH(96:4)洗脱。这得到630mg(76%)N-(1-羟基-2-[5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰基)氨基甲酸叔丁酯,其为黄色固体:LCMS(ESI,m/z):475.2[M+H]+
步骤2:
(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
向N-(1-羟基-2-{5H-咪唑并[4,3-a]异吲哚-5-基}-7-氮杂螺[3.5]壬烷-7-磺酰基)氨基甲酸叔丁酯(510mg,1.074mmol)在DCM(20mL)中的溶液中添加TFA(5mL)。将混合物在室温搅拌30分钟。溶液真空浓缩。粗产物进一步通过Prep-HPLC和手性分离分离。异构体的构型任意指定。
实施例181a:(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(38.0mg,19%),其为白色固体:LCMS(ESI,m/z):375.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.93(s,1H),7.61-7.58(m,2H),7.41-7.25(m,2H),7.18(s,1H),6.64(s,2H),5.43(d,J=7.3Hz,1H),5.29(d,J=6.7Hz,1H),4.06(t,J=7.2Hz,1H),3.32-3.15(m,2H),2.73-2.51(m,4H),2.50-2.43(m,1H),1.73-1.39(m,5H),1.04(t,J=10.4Hz,1H)。tR=8.881分钟(CHIRALPAK IG-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1ml/min)。181a和181b为对映异构体。
实施例181b:(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(33.8mg,17%),其为白色固体:LCMS(ESI,m/z):375.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.96(s,1H),7.61(d,J=7.5Hz,2H),7.47-7.26(m,2H),7.20(s,1H),6.65(s,2H),5.44(d,J=7.4Hz,1H),5.29(d,J=6.6Hz,1H),4.06(t,J=6.8Hz,1H),3.20-3.16(m,2H),2.73-2.54(m,4H),2.50-2.41(m,1H),1.73-1.43(m,5H),1.05(t,J=10.5Hz,1H)。tR=11.147分钟(CHIRALPAK IG-3,0.46x5cm;3um,Hex(0.1%DEA):IPA=70:30,1ml/min)。181a和181b为对映异构体。
步骤3:
(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
该标题化合物通过合成181a-b的通用步骤合成。异构体的构型任意指定。
实施例181c:(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(74.9mg,34%),其为白色固体:LCMS(ESI,m/z):375.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.62(d,J=7.5Hz,1H),7.43-7.38(m,2H),7.30-7.24(m,1H),7.20(s,1H),6.67(s,2H),5.43(d,J=8.7Hz,1H),5.24(d,J=6.9Hz,1H),3.97(t,J=7.1Hz,1H),3.26-3.18(m,2H),2.75-2.60(m,2H),2.35-2.29(m,1H),1.86-1.64(m,3H),1.58-1.47(m,3H);tR=1.297min(Lux Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。181c和181d为对映异构体。
实施例181d:(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(66.8mg,31%),其为白色固体:LCMS(ESI,m/z):375.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.99(s,1H),7.61(d,J=7.5Hz,1H),7.43-7.37(m,2H),7.28-7.23(m,1H),7.16(s,1H),6.67(s,2H),5.41(d,J=8.7Hz,1H),5.24(d,J=7.0Hz,1H),3.96(t,J=7.2Hz,1H),3.26-3.19(m,1H),2.75-2.60(m,2H),2.38-2.26(m,1H),1.86-1.64(m,3H),1.58-1.47(m,3H)。tR=3.276min(Lux Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。181c和181d为对映异构体。
步骤4:
(1R,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
(1S,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
该标题化合物通过合成181a-b的通用步骤合成。异构体的构型任意指定。
实施例181e:(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(76.3mg,31%),其为白色固体:LCMS(ESI,m/z):375.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.86(s,1H),7.65-7.58(m,2H),7.40-7.35(m,1H),7.29-7.24(m,1H),7.14(s,1H),6.69(s,2H),5.76(d,J=5.7Hz,1H),5.46(d,J=8.9Hz,1H),4.09(td,J=6.2,2.9Hz,1H),3.08-2.98(m,2H),2.88-2.76(m,2H),2.63-2.50(m,1H),1.93(t,J=10.4Hz,1H),1.79-1.73(m,2H),1.60(t,J=5.5Hz,3H)。tR=3.997min(CHIRALPAK IF-3,0.46x5cm;3um,Hex(8mMNH3):EtOH=80:20,1.0ml/min)。181e和181f为对映异构体。
实施例181f:(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(72.2mg,29%),其为白色固体:LCMS(ESI,m/z):375.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.86(s,1H),7.65-7.58(m,2H),7.40-7.35(m,1H),7.29-7.24(m,1H),7.14(s,1H),6.69(s,2H),5.77(d,J=5.6Hz,1H),5.46(d,J=8.9Hz,1H),4.09(td,J=6.1,2.8Hz,1H),3.08-2.98(m,2H),2.88-2.76(m,2H),2.63-2.50(m,1H),1.93(t,J=10.4Hz,1H),1.79-1.73(m,2H),1.60(t,J=5.5Hz,3H)。tR=5.326分钟(CHIRALPAK IF-3,0.46x5cm;3um,Hex(8mMNH3):EtOH=80:20,1.0ml/min)。181e和181f为对映异构体。
步骤5:
(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺
该标题化合物通过合成181a-b的通用步骤合成。异构体的构型任意指定。
实施例181g:(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(17.0mg,29%),其为白色固体:LCMS(ESI,m/z):375.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.89(s,1H),7.62(d,J=7.6Hz,1H),7.42-7.36(m,2H),7.26-7.21(m,1H),7.15(s,1H),6.71(s,2H),5.79(d,J=6.1Hz,1H),5.42(d,J=10.7Hz,1H),4.06(td,J=6.4,3.2Hz,1H),3.20-2.98(m,2H),2.89-2.85(m,2H),2.41-2.28(m,1H),2.22(t,J=10.3Hz,1H),1.92-1.76(m,2H),1.68-1.61(m,3H)。tR=2.075min(Lux Cellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。181g和181h为对映异构体。
实施例181h:(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺(17.4mg,29%),其为白色固体:LCMS(ESI,m/z):375.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ7.89(s,1H),7.62(d,J=7.5Hz,1H),7.42-7.36(m,2H),7.26-7.21(m,1H),7.15(s,1H),6.71(s,2H),5.80(d,J=6.1Hz,1H),5.42(d,J=10.6Hz,1H),4.06(td,J=6.0,2.9Hz,1H),3.20-2.98(m,2H),2.89-2.85(m,2H),2.54(s,6H),2.44-2.29(m,1H),2.22(t,J=10.3Hz,1H),1.92-1.76(m,2H),1.68-1.61(m,3H)。tR=3.203min(LuxCellulose-4,0.46x5cm;3um,Hex(0.1%DEA):EtOH=50:50,1.0ml/min)。181g和181h为对映异构体。
实施例182:8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺
[4.5]癸-1-醇
(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺
(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺
该标题化合物通过合成181a-h的通用步骤合成。异构体的构型任意指定。
实施例182a:(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺(11.3mg,14%),其为白色固体:LCMS(ESI,m/z):389.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.62(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.42-7.30(m,1H),7.29-7.25(m,1H),7.16(s,1H),6.63(s,2H),5.47(d,J=4.0Hz,1H),5.07(d,J=5.6Hz,1H),3.60-3.55(m,1H),3.28-3.25(m,2H),2.68-2.51(m,2H),2.49-2.45(m,1H),1.74-1.68(m,2H),1.55-1.54(m,1H),1.33-1.01(m,4H),0.86-0.85(m,1H)。tR=1.314分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(8mMNH3):EtOH=50:50,1.0ml/min)。182a和182b为对映异构体。
实施例182b:(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺(11.0mg,14%),其为白色固体:LCMS(ESI,m/z):389.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.62(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.42-7.30(m,1H),7.29-7.25(m,1H),7.16(s,1H),6.63(s,2H),5.47(d,J=4.0Hz,1H),5.07(d,J=5.6Hz,1H),3.60-3.55(m,1H),3.28-3.25(m,2H),2.68-2.51(m,2H),2.49-2.45(m,1H),1.74-1.68(m,2H),1.55-1.54(m,1H),1.33-1.01(m,4H),0.86-0.85(m,1H)。tR=2.846分钟(CHIRALPAK IA-3,0.46x5cm;3um,Hex(8mMNH3):EtOH=50:50,1.0ml/min)。182a和182b为对映异构体。
(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺
(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺
该标题化合物通过合成181a-h的通用步骤合成。异构体的构型任意指定。
实施例182c:(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺(104.4mg,37%),其为白色固体:LCMS(ESI,m/z):389.3[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.69(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.42-7.38(m,1H),7.31-7.28(m,1H),7.18(s,1H),6.68(s,2H),5.40(d,J=4.0Hz,1H),5.38(d,J=5.6Hz,1H),3.90-3.88(m,1H),3.23-3.20(m,1H),3.08-3.05(m,1H),2.76-2.67(m,2H),2.32-2.29(m,1H),1.78-1.34(m,8H)。tR=3.132分钟(Lux Cellulose-4,0.46x5cm;3um,Hex(8mMNH3):EtOH=50:50,1.0ml/min)。182c和182d为对映异构体。
实施例182d:(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺(102.0mg,37%),其为白色固体:LCMS(ESI,m/z):389.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.69(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.42-7.38(m,1H),7.31-7.28(m,1H),7.18(s,1H),6.68(s,2H),5.40(d,J=4.0Hz,1H),5.38(d,J=5.6Hz,1H),3.90-3.88(m,1H),3.23-3.20(m,1H),3.08-3.05(m,1H),2.76-2.67(m,2H),2.32-2.29(m,1H),1.78-1.34(m,8H)。tR=2.128分钟(Lux Cellulose-4,0.46x5cm;3um,Hex(8mMNH3):EtOH=50:50,1.0ml/min)。182c和182d为对映异构体。
TDO2生物化学测定法测量化合物抑制人重组TDO2活性的能力,所述人重组TDO2分解代谢色氨酸底物以产生产物N-甲酰基犬尿氨酸(NFK)。通过RapidFire-质谱(RF-MS)监测底物和产物浓度。
IDO1和TDO2细胞测试
NFK GreenScreenTM(NTRC,荷兰)使用结合N-甲酰基犬尿氨酸(NFK)的特异性化学探针,其是由IDO或TDO促进的色氨酸分解代谢产物,并且当在410nm激发时引起510nm处的荧光。该测定用于评估化合物对TDO和IDO的抑制(导致SW48细胞(高TDO表达细胞)中NFK水平降低),和确定化合物是否对A172+IFNg细胞(高IDO表达细胞)具有选择性,或者是否在细胞中为双重抑制剂。该测定与Cell(Promega)复合以确定化合物是否具有细胞毒性。简而言之,在生长培养基,含有10%FBS、2mM L-谷氨酰胺和1x pen/strep的RPMI1640中收获SW48或A172细胞。将细胞重悬于测定培养基中,该培养基为补充有2%透析的FBS、2mM L-谷氨酰胺和1x pen/strep的不含色氨酸的RPMI 1640。在Vi-Cell(BeckmanCoulter)上计数细胞。在测定培养基中将SW48细胞稀释至1x10^6细胞/ml。在测定培养基中将A172细胞稀释至0.24x10^6细胞/ml。将25ul细胞用Multi-Flo(Bio-Tek)分配器分配到384孔greinerμclear板(Greiner,781091),其中含有14种化合物,一式两份。用(Labcyte)将化合物分配到平板中,起始的最高浓度为25μM,并在10点滴定中稀释约3倍。将含有1.2mM色氨酸的5μl测定培养基加入SW48细胞中,每孔中终浓度为200uM色氨酸。将含有600uM色氨酸和600ng/ml IFNγ的5ul测定培养基加入到A172细胞中,每孔中终浓度为100uM色氨酸和100ng/ml IFNγ。最终的DMSO浓度为0.5%。将细胞板置于室温下的封闭的TC罩中,关闭鼓风机以使细胞沉降约30分钟。然后将平板移至设定在37℃、5%CO2的培养箱中24小时。在24小时化合物孵育后,用MultidropTM Combi分配器(Thermo Scientific)将8ul NFK green试剂加入每个孔中。将板密封并在37℃、5%CO2下孵育5小时,然后在(BMG labtech)上读数。通过归一化至DMSO和高抑制剂对照来分析数据。在读取板的NFK green后,向每个孔中加入25ul Cell(Promega),在室温下孵育15分钟,并在Envision(Perkin Elmer)上读数。通过归一化至DMSO对照来分析Cell Titer-Glo数据。使用四参数曲线拟合并报告EC50数据。
表3
TDO选择性
测试本发明的化合物对IDO相对TDO选择性。上述基于细胞的测定法用于测试TDO和IDO活性。获得以下结果:
总之,本发明涉及:
1.式(I)的化合物:
或其立体异构体,或其药学上可接受的盐,
其中
R1为C1-6烷基、C3-10环烷基、3-7元杂环基、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基;
条件是
(a)当R1为3-7元杂环基时,该3-7元杂环基中没有成员为-NH-;
(b)当R1为C1-6烷基时,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上取代有-NR2或-OH;且
(c)当R1为C1-6烷基、C3-10环烷基、3-7元杂环基、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基或-C1烷基-杂芳基时,R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-NR2或-OH。
2.实施方案1所述的化合物,其中
R1为C3-10环烷基、3-7元杂环基、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基或-C1烷基-杂芳基,
其中所述C3-10环烷基或3-7元杂环基任选稠合至芳基、杂芳基、C3-7环烷基或3-7元杂环基;或
其中所述C3-10环烷基或3-7元杂环基任选取代有=(螺-C3-7环烷基)或=(螺-(3-7元杂环基));
其中R1取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
3.实施方案1或2所述的化合物,其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上或在与键合至5H-咪唑并[5,1-a]异吲哚基的碳原子相邻的碳原子上取代有-OH且n为0或1。
4.实施方案2或3所述的化合物,其中,
环A为C3-10环烷基或3-7元杂环基;且
m为0、1、2、3或4;且
各个Ra独立地选自氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2。
5.实施方案4所述的化合物,其中环A为C3-10环烷基。
6.实施方案5所述的化合物,其中R1为
7.实施方案4所述的化合物,其中环A为3-7元杂环基。
8.实施方案7所述的化合物,其中环A为5–7元杂环基。
9.实施方案7所述的化合物,其中R1为
其中R3为甲基、乙基、丙基、丁基、-O-甲基、-O-乙基、-O-丙基或-O-丁基。
10.实施方案3所述的化合物,其中,
环A为C3-8环烷基或3-7元杂环基;
环B为芳基、杂芳基、C3-7环烷基或3-7元杂环基;
m为0、1、2、3或4;
各个Ra独立地选自氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
11.根据实施方案10的化合物,其中n为0或1。
12.实施方案2或3所述的化合物,其中,
环A和环B形成螺环体系,
环A为C3-8环烷基或3-7元杂环基;
环B为C3-7环烷基、3-7元杂环基、芳基或杂芳基;
m为0、1、2、3或4;
各个Ra独立地选自氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;且
该羟基部分键合至A环且各个Ra独立地为A环或B环的取代基。
13.根据实施方案10的化合物,其中n为0或1。
14.实施方案10或11所述的化合物,其中
环A为C3-8环烷基;
环B为芳基或杂芳基。
15.实施方案14所述的化合物,其中R1为
16.实施方案14所述的化合物,其中
环A为C3-8环烷基;
环B为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻唑基、三唑基、噁唑基或噁二唑基。
17.实施方案16所述的化合物,其中R1为
18.实施方案12或13所述的化合物,其中
环A为C3-8环烷基;
环B为C3-7环烷基或3-7元杂环基。
19.实施方案18所述的化合物,其中R1为
20.实施方案10、11、12或13的化合物,其中
环A为3-7元杂环基;
环B为3-7元杂环基或杂芳基。
21.实施方案20所述的化合物,其中R1为
22.实施方案20所述的化合物,其中R1为
其中
R3为甲基、乙基、丙基或丁基。
23.实施方案12或13所述的化合物,其中
环A为3-7元杂环基;
环B为芳基。
24.实施方案12或13所述的化合物,其中
环A为3-7元杂环基;
环B为杂芳基。
25.实施方案24所述的化合物,其中R1为
26.实施方案10–13任一项的化合物,其中
环A为3-7元杂环基;
环B为C3-7环烷基。
27.实施方案10–13任一项的化合物,其中
环A为3-7元杂环基;
环B为3-7元杂环基。
28.实施方案4、5、7、8、10–14、16、18、20、23、24和27任一项的化合物,其中m为0、1、2或3。
29.实施方案4、5、7、8、10–14、16、18、20、23、24、26和27任一项的化合物,其中m为0、1或2。
30.实施方案4、5、7、8、10–14、16、18、20、23、24、26和27任一项的化合物,其中m为1。
31.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自卤素、C1-6烷基、-OR、-S(O)2R和-S(O)2N(R)2。
32.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自C1-6烷基、-OR和-S(O)2R。
33.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自C1-6烷基、-OR和-S(O)2N(R)2。
34.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自-OR和-S(O)2R。
35.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自-OR和-S(O)2N(R)2。
36.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中各个Ra独立地选自C1-6烷基和-OR。
37.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中Ra为C1-6烷基。
38.实施方案4、5、7、8、10–14、16、18、20、23、24和26-30任一项的化合物,其中Ra为-OR。
39.实施方案4、5、7、8、10–14、16、18、20、23、24、27和27任一项的化合物,其中m为0。
40.实施方案1-39任一项的化合物,其中n为0、1、2或3。
41.实施方案1-39任一项的化合物,其中n为0、1或2。
42.实施方案1-39任一项的化合物,其中n为1。
43.实施方案1-42任一项的化合物,其中各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基或-OR。
44.实施方案1-42任一项的化合物,其中各个R2独立地为卤素、C1-6烷基或-OR。
45.实施方案1-42任一项的化合物,其中各个R2独立地为卤素或C1-6烷基。
46.实施方案1-42任一项的化合物,其中各个R2独立地为卤素。
47.实施方案1-42任一项的化合物,其中各个R2独立地为C1-6烷基。
48.实施方案1-47任一项的化合物,其中n为0。
49.实施方案1-47任一项的化合物,其为式(Ia),
或其立体异构体混合物。
50.实施方案1-47任一项的化合物,其为式(Ic)
或其立体异构体混合物。
51.实施方案1-47任一项的化合物,其为式(Id):
52.实施方案1-47任一项的化合物,其为式(Ie):
53.实施方案1-47任一项的化合物,其为式(If):
54.实施方案1-47任一项的化合物,其为式(Ig):
55.实施方案1-47任一项的化合物,其为式(Ih):
56.实施方案1-47任一项的化合物,其为式(Ii):
57.实施方案1-56任一项的化合物,其中各个R为氢或C1-6烷基。
58.根据实施方案1-56任一项的化合物,其中各个R为氢,或其药学上可接受的盐。
59.实施方案1所述的化合物,其中R1为C1-6烷基。
60.实施方案1或58的化合物,其中R1取代有1或2个独立选自以下的Ra基团:卤素、C1-6烷基、-C1-6卤代烷基、C3环烷基或-OR。
61.实施方案1或58的化合物,其中R1取代有1或2个-OH。
62.实施方案1或58的化合物,其中R1代有1个-OH。
63.实施方案1或58的化合物,其中R1代有2个-OH。
64.实施方案1所述的化合物,其中,
m为0、1、2、3或4;且
R4为-NR2或-OR。
65.实施方案1所述的化合物,其中,
环A为C3-10环烷基或3-7元杂环基;
m为0、1、2、3或4;且
R4为-NR2或-OR。
66.实施方案65所述的化合物,其中
环A为C3-10环烷基。
67.实施方案65所述的化合物,其中
环A为3-7元杂环基。
68.实施方案64-67任一项的化合物,其中R4为-OH。
69.实施方案65所述的化合物,其中R1为
70.实施方案1所述的化合物,其中,
环A为C3-10环烷基、3-7元杂环基或杂芳基;
m为0、1、2、3或4;且
R4为在A环上取代的-NR2或-OR或键合至A环的亚甲基。
71.实施方案70所述的化合物,其为式(Vc)
72.实施方案70或71所述的化合物,其中R1为
73.化合物,其为
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
7-(5H-咪唑并[4,3-a]异吲哚-5-基)-5H,6H,7H,8H-咪唑并[1,5-a]吡啶-8-醇
6-(5H-咪唑并[4,3-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇
1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
1-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮
2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
2-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
1-(乙基磺酰基)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
1-(乙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇
4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇
2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
2-(3-羟基-4-(-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-磺酰胺
9-羟基-8-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7,8,9-四氢-4H-喹嗪-4-酮
4-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-胺
4-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇
3-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺
1-(乙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇
7-羟基-6-(5H-咪唑并[1,5-b]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
3,3-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇
环丙基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
2-(4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
3-(5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇
4-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
3-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
1-(环丙基磺酰基)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇
3-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺
3-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
4-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
8-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
1-(环丙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基哌啶-1-磺酰胺
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
1-(环丙基磺酰基)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
2-(氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
4-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺
4-(9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇
4-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(氧杂环丁烷-3-基)哌啶-3-醇
5-羟基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺
8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
2,2-二氟-6-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇
8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇
2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇
4-(7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇
8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈
7-(乙基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇
7-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
3-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇
4-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
2-氨基-6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
8-羟基-7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇
3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯
1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇
1-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇
(5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇
4-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺
8-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇
4-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇
环己基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
3,3-二(氟甲基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇
3-氟-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
(5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇
1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
(1-氟环丙基)(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
3-羟基-3-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇
3-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁烷-1,2-二醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
3-氯-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
2-氨基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇
1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇
5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇
8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇
3-(9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇
4-(8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-甲酰胺
2-(二氟甲基)-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-2-甲腈
7-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-5,6,7,8-四氢异喹啉-8-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噻唑-7-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-(甲基磺酰基)-3-氮杂双环[3.1.1]庚-6-醇
5-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇
8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
1-羟基-2-(5H-咪唑并[4,3-a]异吲哚-5-基)-7-氮杂螺[3.5]壬烷-7-磺酰胺
8-(甲基磺酰基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-(甲基磺酰基)-2-氮杂螺[3.3]庚-5-醇
或其药学上可接受的盐,或其对映异构体或非对映异构体,或其外消旋混合物。
74.化合物,其为
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-5-醇,
1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮,
1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮,
1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮,
1-(3-羟基-4-(5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙-1-酮,
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
1-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮,
1-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮,
1-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮,
1-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮,
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
(3S,4R)-1-(乙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3R,4S)-1-(乙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3R,4S)-1-(乙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3S,4R)-1-(乙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-1-醇,
(1S,2S)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2S)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2R)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2R)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2S)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2S)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2R)-4,4-二氟-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,2R)-4,4-二氟-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,3-二氢-1H-茚-1-醇,
(1S,2R)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇,
(1S,2R)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇,
(1R,2S)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇,
(1R,2S)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环戊烷-1-醇,
(1R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环丁-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(1R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环戊烷-1-醇,
(1R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(1R,2S)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇,
(1S,2R)-2-[(5S)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇,
(1S,2R)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇,
(1R,2S)-2-[(5R)-8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环己烷-1-醇,
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
2-((3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
(3R,4R)-3羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺,
(3R,4R)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺,
(3S,4S)-3-羟基-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺,
(3S,4S)-3-羟基-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]吡咯烷-1-磺酰胺,
(3R,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(3S,4S)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺,
(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺,
(3R,4R)-4-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺,
(3S,4S)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]氧杂环戊烷-3-胺,
(3R,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3S,4S)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3S,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3S,4S)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇,
(3R,4R)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(3R,4R)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-4-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基环丁-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(2S,3S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(2S,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(2R,3R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(2S,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(2R,3S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(2R,3R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇,
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物,
(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物,
(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物,
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢噻吩1,1-二氧化物,
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺,
(3R,4R)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺,
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺,
(3S,4S)-3-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-磺酰胺,
(3R,4R)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇,
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇,
(3R,4R)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇,
(3S,4S)-1-(乙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-3-醇,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(R)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(S)-4-(5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(R)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇,
(S)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇,
(R)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇,
(S)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(R)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇,
(S)-3-(5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环丁烷-3-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(R)-3,3-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(S)-3,3-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(S)-4,4-二氟-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(R)-3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(S)-3,3-二(氟甲基)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环戊烷-1-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
2-((3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4S)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3R,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
2-((3S,4R)-4-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙腈,
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇,
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇,
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4-甲基四氢-2H-吡喃-4-醇,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基四氢-2H-吡喃-4-醇,
(1R,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1R,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1S,2S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1S,2R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1S,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1S,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1R,2R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1R,2S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[3.3]庚-2-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氧杂螺[4.5]癸-1-醇,
(3R,4R)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-3-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-4-((R)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-4-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-3-((S)-6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4R)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3R,4S)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3S,4R)-1-(环丙基磺酰基)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(3R,4S)-1-(环丙基磺酰基)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-4-醇,
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-6,7-二氢-5H-环戊二烯并[c]吡啶-7-醇,
(4R,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4R,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4S,5S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4S,5R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4R,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4R,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4S,5R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(4S,5S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)螺[2.3]己-5-醇,
(3R,4R)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺,
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺(31.7mg,32%),其为白色固体,LCMS(ESI,m/z):349.2,
(3R,4R)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-4-((R)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-4-((S)-7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(1S,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1R,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1R,2R)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1S,2S)-8-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1R,2S)-8-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(3R,4R)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3S,4S)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3R,4R)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基哌啶-1-磺酰胺,
(3S,4S)-3-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基哌啶-1-磺酰胺,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇,
(3R,4R)-1-(环丙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3S,4S)-1-(环丙基磺酰基)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇,
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(2,2,2-三氟乙基)哌啶-3-醇,
(3R,4R)-4-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-1-甲基哌啶-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基哌啶-3-醇,
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2,5,5-四甲基四氢呋喃-3-醇,
(3S,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3S,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3R,4R)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3R,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3R,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基四氢呋喃-3-醇,
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氧杂环庚烷-4-醇,
(5R,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5S,6R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5S,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5R,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5R,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5S,6S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5R,6S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(5S,6R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-氧杂螺[3.3]庚-6-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7S,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-8-醇,
(3R,4R)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇,
(3S,4S)-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(异丙基磺酰基)哌啶-3-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,6,6-三甲基环己烷-1-醇,
(3S,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3R,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3R,4S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3S,4R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3R,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3S,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3S,4R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(3R,4S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)色满-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)氮杂环庚烷-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇,
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(4S,5S)-2-(氟甲基)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-2-(氟甲基)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(3S,4R)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物,
(3S,4S)-4-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)硫代色满1,1-二氧化物,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N,N-二甲基-5,6,7,8-四氢萘-2-甲酰胺,
(3R,4R)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-4-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-4-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺,
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺,
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺,
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1R,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(1S,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1,2,3,4-四氢萘-1-醇,
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(氧杂环丁烷-3-基)哌啶-3-醇,
(5R,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5R,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5S,6R)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5R,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5S,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(5S,6R)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-2-甲酰胺,
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺,
(1R,6R)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,6S)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1S,6S)-2,2-二氟-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(1R,6R)-2,2-二氟-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇,
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7S,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-3-甲腈,
(S)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇,
(R)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-1-(乙基磺酰基)氮杂环丁烷-3-醇,
(1S,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2R)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1R,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2S)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(1S,2R)-2-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇,
(3S,4R)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((R)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((S)-7-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇,
(5S,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5S,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5R,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5R,6S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(5S,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇,
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7S,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲腈,
(1S,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1S,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1R,2S)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1R,2R)-7-(乙基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1S,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1R,2R)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1S,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1R,2S)-7-(乙基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氮杂螺[3.5]壬-1-醇,
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(1S,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(1R,2S)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(1S,2R)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇,
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇,
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇,
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)吡咯烷-3-醇,
(7S,8S)-7-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(7R,8R)-7-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(3S,4R)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇,
(3R,4S)-3-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇,
(3S,4R)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇,
(3R,4S)-3-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-4-醇,
(3S,4S)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3R,4R)-4-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3R,4R)-4-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(3S,4S)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3S,4S)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(3R,4R)-4-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(5S,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6R)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6S)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5S,6R)-2-氨基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6S)-2-氨基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(7R,8R)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(7R,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(7R,8S)-8-羟基-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(7S,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(7S,8S)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹喔啉-5-醇,
(5S,6S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇,
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-5,6,7,8-四氢喹唑啉-5-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-4-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-8-醇,
(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环庚-1-醇,
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-4,4-二甲基环己烷-1-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂环庚三烯-4-醇,
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(甲基磺酰基)哌啶-3-醇,
(S)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7R,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7S,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(7R,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢吲嗪-8-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇,
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇,
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇,
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇,
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-7-醇,
(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺,
(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺,
(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺,
(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲酰胺,
(R)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(S)-8-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(R)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(S)-8-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇,
(1R,2R)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(1S,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-7-(甲基磺酰基)-1,2,3,4-四氢萘-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(S)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(S)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(R)-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(R)-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-3-醇,
(1R,4r)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈,
(1R,4s)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈,
(1S,4s)-4-羟基-4-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈,
(1S,4r)-4-羟基-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-甲腈,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-[1,2,3]三唑并[1,5-a]吡啶-4-醇,
(7S,8R)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇,
(7R,8S)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇,
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇,
(7R,8R)-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-8-醇,
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(S)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇,
(R)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(1R,2R)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2R)-3,3-二(氟甲基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1R,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(1S,2S)-3,3-二(氟甲基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇,
(4R,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-3-氟-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5S)-3-氟-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈,
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈,
(R)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺,
(R)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺,
(S)-3-羟基-3-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺,
(S)-3-羟基-3-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基丙酰胺,
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲腈,
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-3-氯-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5S)-3-氯-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5S)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5S)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-2-氨基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4S,5R)-2-氨基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5R)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4S,5R)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4R,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4R,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4R,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4S,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4S,5S)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[c][1,2,5]噁二唑-4-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2,2-二甲基环己烷-1-醇,
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
1-((R)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
1-((S)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇,
(6R,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6R,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6S,7R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6S,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6R,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(6R,7S)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇,
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇,
(4R,5R)-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢苯并[d]噁唑-4-醇,
(5S,6S)-6-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(5R,6R)-6-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹啉-5-醇,
(3R,4R)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3R,4R)-3-((R)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4S)-3-((S)-9-氟-5H-咪唑并[5,1-a]异吲哚-5-基)四氢-2H-吡喃-4-醇,
(3S,4R)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3S,4R)-4-((R)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(3R,4S)-4-((S)-8-甲基-5H-咪唑并[5,1-a]异吲哚-5-基)四氢呋喃-3-醇,
(1S,2R)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1R,2S)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1R,2R)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1S,2S)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1R,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1S,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1R,2R)-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1S,2S)-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-甲磺酰基-7-氮杂螺[3.5]壬-1-醇,
(1S,2S)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1R,2R)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1S,2S)-8-(甲基磺酰基)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1R,2R)-8-(甲基磺酰基)-2-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-8-氮杂螺[4.5]癸-1-醇,
(1S,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1R,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1R,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1S,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-7-氮杂螺[3.5]壬烷-7-磺酰胺,
(1S,2S)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺,
(1R,2R)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺,
(1S,2S)-1-羟基-2-[(5S)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺,和
(1R,2R)-1-羟基-2-[(5R)-5H-咪唑并[4,3-a]异吲哚-5-基]-8-氮杂螺[4.5]癸烷-8-磺酰胺。
75.实施方案1所述的化合物,其为
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)环丁-1-醇;
5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇;
(3S,4S)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-四氢-2H-吡喃-3-醇;
(5R,6R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢喹唑啉-5-醇;
(7R,8R)-8-羟基-7-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺;或
(6S,7R)-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-7-醇。
76.实施方案1所述的化合物,其为
(7S,8S)-7-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇;
8-氟-5H-咪唑并[4,3-a]异吲哚-5-基]环丁-1-醇;
3-(-5H-咪唑并[5,1-a]异吲哚-5-基)双环[2.2.2]辛-2-醇;
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-5,6,7,8-四氢萘-2-甲酰胺;
(1R,2S)-2-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-7-氧杂螺[3.5]壬-1-醇;或
(4S,5R)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基-4,5,6,7-四氢-2H-吲唑-4-醇。
77.实施方案1所述的化合物,其为
4-(5H-咪唑并[1,5-b]异吲哚-5-基)-2,2-二甲基-环丁醇;
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇;
(R)-1-(5H-咪唑并[5,1-a]异吲哚-5-基)环己烷-1-醇;
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡啶-4-醇;
((5R,6S)-5-羟基-6-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-磺酰胺;或
(4S,5S)-4-羟基-5-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺。
78.实施方案1所述的化合物,其为
2-(5H-咪唑并[1,5-b]异吲哚-5-基)螺[3.3]庚-3-醇;
(1R,2S)-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-3,3-二甲基环丁-1-醇;
(5S,6S)-5-羟基-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢萘-2-甲酰胺;
4-羟基-5-(5H-咪唑并[5,1-a]异吲哚-5-基)氮杂环庚烷-1-磺酰胺;
(5R,6R)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢酞嗪-5-醇;或(6S,7S)-6-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-4,5,6,7-四氢-1H-吲唑-7-醇。
79.实施方案1所述的化合物,其为
(3S,4S)-1-(乙基磺酰基)-4-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-3-醇;
3-(5H-咪唑并[5,1-a]异吲哚-5-基)硫杂环丁烷-3-醇;
(4S,5S)-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-甲基-4,5,6,7-四氢-1H-吲唑-4-醇;
(7S,8S)-7-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-5,6,7,8-四氢异喹啉-8-醇;
(4S,5S)-4-羟基-5-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-2-甲酰胺;或
6-(5H-咪唑并[5,1-a]异吲哚-5-基)-3-(甲基磺酰基)-3-氮杂双环[3.1.1]庚-6-醇。
80.药物组合物,其包含根据实施方案1-79任一项的化合物和药学上可接受的稀释剂、赋形剂或载体。
81.根据实施方案80的药物组合物,其还包含第二治疗剂。
82.实施方案81所述的药物组合物,其中所述第二治疗性治疗包括抗病毒剂、化疗或其它抗癌剂、免疫增强剂、免疫抑制剂、放射、抗肿瘤或抗病毒疫苗、细胞因子治疗或酪氨酸激酶抑制剂。
83.在需要的受试者中治疗与疾病相关的色氨酸2,3-双加氧酶(TDO2)介导的免疫抑制的方法,包括给予有效的色氨酸2,3-双加氧酶抑制量的根据实施方案1-79任一项的化合物或根据实施方案80–82任一项的药物组合物。
84.在需要的受试者中治疗与疾病相关的色氨酸2,3-双加氧酶(TDO2)介导的免疫抑制的方法,包括给予有效的色氨酸2,3-双加氧酶抑制量的根据实施方案1-79任一项的化合物和第二治疗性治疗,该第二治疗性治疗包括抗病毒剂、化疗或其它抗癌剂、免疫增强剂、免疫抑制剂、放射、抗肿瘤或抗病毒疫苗、细胞因子治疗或酪氨酸激酶抑制剂。
85.实施方案83或84所述的方法,其中所述疾病为癌症。
86.实施方案85所述的方法,其中所述癌症为结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头癌、或颈癌、或淋巴瘤、白血病、或黑素瘤。
87.实施方案83或84所述的方法,其中所述给药与第二治疗性治疗同时或连续进行。
88.实施方案86所述的方法,其中所述第二治疗性治疗包括用化疗或其它抗癌剂、免疫增强剂、免疫检查点抑制剂、放射、抗肿瘤疫苗、细胞因子治疗或酪氨酸激酶抑制剂的治疗。
89.实施方案83或84所述的方法,其中所述第二治疗性治疗包括用IDO1抑制剂的治疗。
90.实施方案83或84所述的方法,其中所述第二治疗性治疗包括用阻滞或抑制PD-1或PD-L1的作用的化合物的治疗。
91.实施方案90所述的方法,其中所述化合物为派姆单抗、纳武单抗、皮地利珠单抗、BMS 936559、阿特珠单抗或阿维单抗。
92.试剂盒,其包含根据实施方案1-79任一项的化合物和第二治疗剂。
93.实施方案91的试剂盒,其中所述第二治疗剂为派姆单抗、纳武单抗、皮地利珠单抗、BMS 936559、阿特珠单抗或阿维单抗。
Claims (18)
1.式(I)的化合物:
或其立体异构体,或其药学上可接受的盐,
其中
R1为C1-6烷基、-C1烷基-C3-10环烷基、-C1烷基-3-7元杂环基或-C1烷基-杂芳基,
其中R1在键合至5H-咪唑并[5,1-a]异吲哚基的碳原子上取代有-NR2或-OH,且
R1还取代有1、2、3或4个独立选自以下的Ra基团:氧代、卤素、氰基、硝基、C1-6烷基、-C1-6卤代烷基、C1-6烷基-氰基、-OR、-NR2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR和-N(R)C(O)N(R)2;
n为0、1、2、3或4;
各个R2独立地为卤素、氰基、C1-6烷基、C3环烷基、-C1-6卤代烷基、-OR、-NR2或-SR;且
各个R独立地为氢、C1-6烷基或C1-6卤代烷基。
7.权利要求1的化合物,其中各个R为氢或C1-6烷基。
8.根据权利要求1的化合物,其中各个R为氢,或其药学上可接受的盐。
12.化合物,其为
1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇
2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇
环丙基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇
1-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇
(5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇
1-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇
环己基(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇
(5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇
1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈
(1-氟环丙基)(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇;
1-(羟基(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺
或其药学上可接受的盐,或其对映异构体或非对映异构体,或其外消旋混合物。
13.化合物,其为
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇,
(R)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇,
(S)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)丙-2-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙烷-1,2-二醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环丙基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环丙基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(四氢-2H-吡喃-4-基)乙-1-醇,
(S)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((R)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(S)-1-((S)-8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-2-甲基丙-1-醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)丙-1-醇,
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(四氢-2H-吡喃-4-基)甲醇,
(R)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(R)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(S)-1-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(S)-1-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1H-咪唑-2-基)乙-1-醇,
(R)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-环己基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-环己基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(R)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(S)-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
(R)-((R)-5H-咪唑并[5,1-a]异吲哚-5-基)(吡啶-4-基)甲醇,
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈,
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲腈,
(R)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(S)-(1-氟环丙基)((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
(R)-(1-氟环丙基)((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲醇,
1-((R)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
1-((R)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,
1-((S)-羟基((R)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺,或
1-((S)-羟基((S)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)环丙烷-1-甲酰胺。
14.药物组合物,其包含根据权利要求1-13任一项的化合物和药学上可接受的稀释剂、赋形剂或载体。
15.根据权利要求14的药物组合物,其还包含第二治疗剂。
16.根据权利要求1的化合物在制备用于治疗与疾病相关的色氨酸2,3-双加氧酶(TDO2)介导的免疫抑制的药物中的用途。
17.权利要求16所述的用途,其中所述疾病为癌症。
18.权利要求17所述的用途,其中所述癌症为结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头癌、或颈癌、或淋巴瘤、白血病、或黑素瘤。
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RU2717577C2 (ru) * | 2015-04-21 | 2020-03-24 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Производное имидазоизоиндола, способ его получения и медицинское применение |
US10800780B2 (en) * | 2015-12-24 | 2020-10-13 | Genentech, Inc. | TDO2 Inhibitors |
US11603373B2 (en) | 2017-06-28 | 2023-03-14 | Genentech, Inc. | TDO2 and IDO1 inhibitors |
SI3752501T1 (sl) | 2018-02-13 | 2023-08-31 | Gilead Sciences, Inc. | Inhibitorji pd-1/pd-l1 |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
UA126834C2 (uk) | 2018-05-01 | 2023-02-08 | Мерк Шарп Енд Доум Елелсі | Спіропіперидинові алостеричні модулятори нікотинових ацетилхолінових рецепторів |
GB201809050D0 (en) | 2018-06-01 | 2018-07-18 | E Therapeutics Plc | Modulators of tryptophan catabolism |
TWI809427B (zh) | 2018-07-13 | 2023-07-21 | 美商基利科學股份有限公司 | Pd‐1/pd‐l1抑制劑 |
WO2020086556A1 (en) | 2018-10-24 | 2020-04-30 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
EP3835432A1 (en) | 2019-12-10 | 2021-06-16 | Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts | Interleukin-4-induced gene 1 (il4i1) and respective metabolites as biomarkers for cancer |
US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
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WO2017107979A1 (en) | 2017-06-29 |
EP3394068A4 (en) | 2019-07-03 |
JP2019504039A (ja) | 2019-02-14 |
TW201730190A (zh) | 2017-09-01 |
EP3394068A1 (en) | 2018-10-31 |
US20190016726A1 (en) | 2019-01-17 |
CN110072864B (zh) | 2022-05-27 |
EP3394068B1 (en) | 2024-09-11 |
JP7227005B2 (ja) | 2023-02-21 |
US20220306635A1 (en) | 2022-09-29 |
CN110072864A (zh) | 2019-07-30 |
US10800780B2 (en) | 2020-10-13 |
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