WO2023160552A1 - Composé spiro et son utilisation - Google Patents

Composé spiro et son utilisation Download PDF

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WO2023160552A1
WO2023160552A1 PCT/CN2023/077464 CN2023077464W WO2023160552A1 WO 2023160552 A1 WO2023160552 A1 WO 2023160552A1 CN 2023077464 W CN2023077464 W CN 2023077464W WO 2023160552 A1 WO2023160552 A1 WO 2023160552A1
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PCT/CN2023/077464
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Chinese (zh)
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刘希乐
张鹏涛
张路
胡利红
丁照中
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南京明德新药研发有限公司
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Publication of WO2023160552A1 publication Critical patent/WO2023160552A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a class of spirocyclic compounds and their application, and their application in the preparation of medicines for treating related diseases, in particular to the compound represented by formula (III), its stereoisomer or its pharmaceutically acceptable salt.
  • VHL clear cell renal cell carcinoma
  • HIF-2 ⁇ hypoxia-inducible factor-2 ⁇
  • the VHL protein is a member of the E3 ubiquitin ligase complex, which mediates the degradation of specific proteins by the proteasome.
  • the main role of VHL is to degrade and regulate the hypoxia-inducible factor (HIF) family of transcription factors consisting of HIF-1 ⁇ , HIF-2 ⁇ and HIF-3 ⁇ .
  • HIF-2 ⁇ is a member of the HIF transcription factor family, and its abnormal activity is a key oncogenic driver of cancers such as clear cell renal cell carcinoma (ccRCC).
  • the activity of HIF-2 ⁇ is controlled by oxygen-dependent hypoxia-inducible factors prolyl hydroxylases (PHDs). When oxygen availability is high (normal oxygen), these enzymes hydroxylate specific proline residues on the oxygen-dependent domain, forming the substrate recognition site for pVHL.
  • PBDs oxygen-dependent hypoxia-inducible factors
  • HIF-2 ⁇ Under hypoxic conditions, PHDs do not have sufficient oxygen substrates to catalyze the hydroxylation of HIF-2 ⁇ , and pVHL cannot bind unmodified HIF-2 ⁇ . Thereby, HIF-2 ⁇ accumulates and translocates into the nucleus, where it heterodimerizes with constitutively expressed aryl hydrocarbon receptor nuclear transporter (ARNT, also known as HIF-1 ⁇ ) to form an active transcription factor complex.
  • the complex recognizes the hypoxia response element (HRE) on DNA, leading to increased expression of several proteins, such as EPO, VEGF, etc., and coordinates the regulation of angiogenesis, proliferation, migration and immune escape, thereby leading to the occurrence and development of tumors.
  • HRE hypoxia response element
  • HIF-2 ⁇ Deletion of pVHL in most ccRCC patients leads to accumulation and transcriptional activation of HIF-2 ⁇ even under normoxic conditions. Therefore, the transcriptional activity of HIF-2 ⁇ can be inhibited by blocking the protein-protein interaction between HIF-2 ⁇ and ARNT, so as to achieve the purpose of tumor suppression.
  • Belzutifan is a small molecule inhibitor of HIF-2 ⁇ and has been approved for the treatment of renal cell carcinoma (RCC) and other tumors associated with Hippel-Lindau syndrome (VHL syndrome). It is very necessary to develop new and more effective HIF-2 ⁇ inhibitors.
  • the present invention provides a compound of formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 R;
  • R 22 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D , F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 21 , R 22 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 31 , R 32 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 12 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 4-5 membered heterocycloalkyl group
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D , F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • X is selected from N and CRx ;
  • T is selected from N and CR4 ;
  • R x , R 4 , R 5 , R 6 , R 7 , R 8 and R are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, C 1-3 Haloalkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl;
  • n is selected from 0 and 1.
  • the present invention provides compounds of formula (II) and (III-1), stereoisomers or pharmaceutically acceptable salts thereof,
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 R;
  • R 22 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 21 , R 22 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 31 , R 32 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 12 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 4-5 membered heterocycloalkyl group
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • X is selected from N and CRx ;
  • T is selected from N and CR4 ;
  • R x , R 4 , R 5 , R 6 , R 7 , R 8 and R are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, C 1-3 Haloalkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl;
  • n is selected from 0 and 1.
  • the present invention provides a compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 R;
  • R 22 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 21 , R 22 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 31 , R 32 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 12 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 4-5 membered heterocycloalkyl group
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D , F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • X is selected from N and CRx ;
  • R x , R 4 , R 5 , R 6 , R 7 , R 8 and R are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, C 1-3 Haloalkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl;
  • n is selected from 0 and 1.
  • the present invention provides compounds of formulas (II-1), (I), (III-1-1) and (III-1-2), stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • X, T, R x , R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the claims.
  • the present invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 R;
  • R 22 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D , F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 21 , R 22 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 21 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 31 , R 32 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D , F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3-5 ring Alkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R;
  • R 12 , R 31 and the C atoms connected to them together form a C 3-5 cycloalkyl group or a 4-5 membered heterocycloalkyl group
  • R 11 , R 21 , R 22 and R 32 are independently is independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, said C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2 , 3 or 4 R;
  • X is selected from N and CRx ;
  • R x , R 4 , R 5 , R 6 , R 7 , R 8 and R are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, C 1-3 Haloalkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl.
  • R 12 , R 21 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 22 , R 31 and R 32 independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R, and other variables are as defined in the present invention.
  • R 12 , R 21 and the C atom connected to them together form a C 3 cycloalkyl group
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 3 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions
  • other variables are as defined in the present invention.
  • R 12 , R 21 and the C atom connected to them together form a C 4 cycloalkyl group
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 4 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions
  • other variables are as defined in the present invention.
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 5 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions
  • other variables are as defined in the present invention.
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 3-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 4-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 12 , R 21 and the C atom connected to them together form a 5-membered heterocycloalkyl group
  • R 11 , R 22 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 5-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 22 , R 31 and the C atom connected to them together form a C 3-5 cycloalkyl group or a 3-5 membered heterocycloalkyl group
  • R 11 , R 12 , R 21 and R 32 independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R, and other variables are as in the present invention defined.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 3 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions
  • other variables are as defined in the present invention.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 4 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions, other variables are as defined in the present invention.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C 5 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions
  • other variables are as defined in the present invention.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 3-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 4-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 11 , R 12 , R 21 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the 5-membered heterocycloalkyl is optionally Substituted by 1, 2, 3 or 4 R, other variables are as defined herein.
  • R 12 , R 22 and the C atom connected to them together form a C 3 cycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 12 , R 22 and the C atom connected to them together form a C 4 cycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 4 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 12 , R 22 and the C atom connected to them together form a C 5 cycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 5 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 12 , R 22 and the C atom connected to them together form a 3-membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkane
  • the 3-membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 R;
  • R 12 , R 22 and the C atom connected to them together form a 4-membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 4-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 12 , R 22 and the C atom connected to them together form a 5-membered heterocycloalkyl group
  • R 11 , R 12 , R 31 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 5-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 4 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 5 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 3-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 4-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 11 , R 12 , R 21 and R 22 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 5-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 3 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl
  • the C Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R;
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F, Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the C 5 cycloalkyl is optionally replaced by 1 , 2, 3 or 4 R substitutions;
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 4-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • R 11 , R 21 , R 22 and R 32 are independently selected from H, D, F , Cl, Br, CN, NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 haloalkyl and -OC 1-3 haloalkyl, the 5-membered heterocycloalkyl is optionally replaced by 1, 2, 3 or 4 R;
  • the above-mentioned X is selected from N, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from CR x , and other variables are as defined in the present invention.
  • T is selected from N, and other variables are as defined in the present invention.
  • the above T is selected from CR 4 , and other variables are as defined in the present invention.
  • the above-mentioned R x is selected from H, D, F, Cl, Br, CN, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 and -OCF 3 , other variables are as defined in the present invention.
  • R x is selected from H, D, F and Cl, and other variables are as defined in the present invention.
  • R x is selected from H, and other variables are as defined in the present invention.
  • R x is selected from Cl, and other variables are as defined in the present invention.
  • R 4 is selected from H, D, F, Cl and CN, and other variables are as defined in the present invention.
  • R 4 is selected from H, and other variables are as defined in the present invention.
  • R 4 is selected from Cl, and other variables are as defined in the present invention.
  • R 5 is selected from H, D, F, Cl, Br, CN, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 and -OCF 3 , other variables are as defined in the present invention.
  • R 5 is selected from H, D, F and Cl, and other variables are as defined in the present invention.
  • R 5 is selected from H, and other variables are as defined in the present invention.
  • R 5 is selected from D, and other variables are as defined in the present invention.
  • the above-mentioned R 6 is selected from H, D, F, Cl, Br, CN, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 and -OCF 3 , other variables are as defined in the present invention.
  • R 6 is selected from H, and other variables are as defined in the present invention.
  • R 6 is selected from D, and other variables are as defined in the present invention.
  • R 7 is selected from H, D, F, Cl, Br, CN, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 and -OCF 3 , other variables are as defined in the present invention.
  • R 7 is selected from -OCHF 2 , and other variables are as defined in the present invention.
  • the above-mentioned R 8 is selected from H, D, F, Cl, Br, CN, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 and -OCF 3 , other variables are as defined in the present invention.
  • R 8 is selected from -CF 3 , and other variables are as defined in the present invention.
  • the compounds are shown in formulas (I-1), (I-4), (I-5), (II-1-1) and (II-1-2),
  • Ring A, ring D, ring F and ring G are selected from C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl
  • ring E is selected from C 3-5 cycloalkyl and 4-5 membered heterocycloalkyl
  • the C 3-5 cycloalkyl, 3-5 membered heterocycloalkyl and 4-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R
  • X, R 11 , R 12 , R 21 , R 22 , R 32 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • ring A, ring B, ring C and ring D are selected from C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl
  • ring E is selected from C 3-5 cycloalkyl and 4-5 membered heterocyclic Alkyl
  • the C 3-5 cycloalkyl, 3-5 membered heterocycloalkyl and 4-5 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R, and other variables are as described in the present invention definition.
  • X, R 11 , R 12 , R 21 , R 22 , R 32 , R 4 , R 5 , R 6 , R 7 , R 8 and R are as defined in the present invention.
  • n is selected from 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • X, R 11 , R 12 , R 21 , R 22 , R 32 , R 4 , R 5 , R 6 , R 7 , R 8 and R are as defined in the present invention.
  • X, R 11 , R 12 , R 21 , R 22 , R 32 , R 4 , R 5 , R 6 , R 7 , R 8 and R are as defined in the present invention.
  • X, R 11 , R 12 , R 21 , R 32 , R 4 , R 5 , R 6 and R are as defined in the present invention.
  • X, R 11 , R 12 , R 21 , R 22 , R 32 , R 4 , R 5 , R 6 and R are as defined in the present invention.
  • the present invention provides the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present invention provides the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present invention also provides the following synthetic method synthetic method 1:
  • the compound of the invention has good inhibitory activity on HIF-2 ⁇ , and is expected to be used for carcinogenesis caused by VHL abnormality.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • any variable such as R
  • its definition in each case is independently of.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the linking group L is -MW-, at this time -MW- can be connected to ring A and ring A in the same direction as the reading order from left to right to form It can also be formed by linking loop A and loop A in the opposite direction to the reading order from left to right
  • Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site is connected with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in represents the nitrogen atom through the group The two ends are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-3 haloalkyl denotes monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms.
  • the C 1-3 haloalkyl includes C 1-2 , C 2-3 , C 3 , C 2 and C 1 haloalkyl and the like.
  • Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • C 3 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 carbon atoms, which is a monocyclic ring system, and which can be monovalent, divalent or multivalent.
  • C 4 cycloalkyl means a saturated cyclic hydrocarbon group composed of 4 carbon atoms, which is a monocyclic ring system, which may be monovalent, divalent or multivalent
  • C 5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 5 carbon atoms, which is a monocyclic ring system, which may be monovalent, divalent or multivalent
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-5 membered heterocycloalkyl group includes 4-5 membered, 4-membered, and 5-membered heterocycloalkyl groups and the like.
  • Examples of 3-5 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuryl (including tetrahydrofuryl Hydrofuran-2-yl, etc.) etc.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 4-5 membered heterocycloalkyl group includes 4-membered and 5-membered heterocycloalkyl groups.
  • Examples of 4-5 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) and the like.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is from n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-member
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the compounds of the present invention can confirm the structure by conventional methods well known to those skilled in the art, if the present invention relates to the absolute structure of the compound
  • the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method is ⁇ / ⁇ scanning.
  • the direct method is further adopted (Shelxs97) By analyzing the crystal structure, the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations: aq stands for water
  • Figure 1 The tumor growth curve of the human renal cell carcinoma 786-O cell subcutaneous xenograft tumor model in the tumor-bearing mice after administration of the compound;
  • Fig. 2 The body weight change curve of tumor-bearing mice in the subcutaneous xenograft tumor model of human renal cell carcinoma 786-O cells during the administration process.
  • potassium tert-butoxide (576.32 mg, 5.14 mmol) was added to a solution of methyltriphenylphosphine bromide (1.83 g, 5.14 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was heated at 20 After stirring at °C for 15 minutes, a solution of compound 1-5 (650 mg, 4.11 mmol) in tetrahydrofuran (1 mL) was added dropwise to the mixture at 0 °C. The reaction solution was stirred at 20°C for 2 hours. Water (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 2 times).
  • reaction solution was dispersed in dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL), and the mixture was extracted with dichloromethane (15 mL ⁇ 2 times).
  • compound 1-8 120 mg, 690.41 micromole
  • bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] 15.71 mg, 20.76 ⁇ mol
  • magnesium oxide (128.04 mg, 3.18 mmol
  • diacetoxyiodobenzene (445.62 mg, 1.38 mmol) in dichloromethane (10 mL) was stirred at 45°C for 16 hours.
  • reaction solution was dispersed in dichloromethane (20 ml) and saturated sodium bicarbonate solution (20 ml), the mixture was filtered, the filtrate was extracted with dichloromethane (15 ml x 2 times), and the combined organic phases were concentrated under reduced pressure to obtain compound 1-9.
  • compound 2-11 (660 mg, 2.61 mmol), bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (99 mg, 130.87 ⁇ mol), magnesium oxide (484.37 mg, 12.01 mmol) and diacetoxyiodobenzene (2.36 g, 7.31 mmol) in dichloromethane (20 mL) was stirred at 45°C for 16 hours.
  • compound 2-12 400 mg, 1.60 mmol
  • compound 1-10 620 mg, 2.51 mmol
  • cuprous thiophene-2-carboxylate 17.78 mg, 93.23 micromol
  • cesium carbonate (1.04 g, 3.19 mmol) in dimethyl sulfoxide (6 ml) was stirred at 80°C for 12 hours.
  • Compound 2 was passed through preparative SFC, using Daicel Chiralcel OD (250mm*30mm, 10 ⁇ m), mobile phase was 20% ethanol (0.1% ammonia water) and 80% liquid carbon dioxide, and the flow rate was 50 g/min to obtain two groups of enantiomers. Constructs 2A and 2B.
  • Compound 2A was prepared by preparative SFC using Daicel Chiralpak AD (250mm*30mm, 10 ⁇ m), the mobile phase was 30% isopropanol (0.1% ammonia water) and 70% liquid carbon dioxide, and the flow rate was 60 g/min to obtain compound 2A-1 and 2A-2.
  • Analysis method column: Daicel Chiralpak AD (50mm*4.6mm ID, 3 ⁇ m), mobile phase: isopropanol (0.05% diethylamine) in carbon dioxide from 5% to 40%, flow rate is 3 ml/min.
  • Compound 2B was passed through preparative SFC, using Daicel Chiralpak AD (250mm*30mm, 10 ⁇ m), the mobile phase was 25% isopropanol (0.1% ammonia water) and 75% liquid carbon dioxide, and the flow rate was 50 g/min to obtain a single isomer 2B-1 and 2B-2.
  • compound 3-2 (8 g, 26.01 mmol), 2-2 (11.45 g, 52.02 mmol), palladium acetate (200.00 mg, 890.82 micromol), n-butyl-bis(1-adamant
  • reaction solution was filtered with diatomaceous earth, water (200 ml) was added to the filtrate, extracted with ethyl acetate (100 ml x 2 times), the organic phases were combined, washed with saturated brine (200 ml x 1 time), anhydrous sulfuric acid Sodium drying, filtration, and the filtrate was spin-dried to obtain the crude product.
  • compound 3-10 (370 mg, 1.55 mmol), bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (70.92 mg, 93.02 ⁇ mol), magnesium oxide (299.88 mg, 7.44 mmol) and diacetoxyiodobenzene (1.40 g, 4.34 mmol) in dichloromethane (15 mL) was stirred at 45°C for 16 hours.
  • compound 3-11 (210 mg, 887.37 micromol), compound 1-A (329.50 mg, 1.33 mmol), cuprous thiophene-2-carboxylate (33.83 mg, 177.42 micromol) and cesium carbonate (579.98 mg, 1.78 mmol) in dimethyl sulfoxide (10 mL) was stirred at 80°C for 16 hours.
  • Compound 3 was passed through preparative SFC, using REGIS (R, R) WHELK-O1 (250mm*25mm, 10 ⁇ m), the mobile phase was 35% isopropanol (0.1% ammonia water) and 65% liquid carbon dioxide, and the flow rate was 65 ml/ Min, two sets of enantiomers 3A and 3B and 3C and 3D were obtained.
  • Analysis method Column: (SS) Whelk-O1 (50 ⁇ 4.6mm ID, 3.5 ⁇ m), mobile phase: isopropanol (0.05% diethylamine) in carbon dioxide from 5% to 40%, flow rate is 3 ml/ minute.
  • isopropyllithium chloride (2.0 mol/L, 26.00 ml, 53.92 mmol) was added dropwise to a solution of compound 4-1 (10.0 g, 49.02 mmol) in tetrahydrofuran (100 ml) at 0°C. ), after stirring for 1 hour, a solution of methyl 3-oxocyclobutanecarboxylate (6.91 g, 53.92 mmol) in tetrahydrofuran (20 ml) was added at -65 ° C, and the reaction solution was stirred for 1 hour and then slowly warmed to 27 ° C and then stirred 16 hours.
  • lithium hydroxide monohydrate (10.06 g, 239.70 mmol) was added to a solution of compound 4-3 (7.60 g, 39.95 mmol) in tetrahydrofuran (38 ml) at 0°C, and the reaction solution was stirred at 27°C 4 hours.
  • compound 4-8 (900 mg, 4.14 mmol), bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (180 mg, 236.07 ⁇ mol), magnesium oxide (764.90 mg, 18.98 mmol) and diacetoxyiodobenzene (3.74 g, 11.6 mmol) in dichloromethane (20 mL) was stirred at 45°C for 16 hours.
  • Compound 4 was passed through preparative SFC using DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m), the mobile phase was 20% ethanol (0.1% ammonia water) and 80% liquid carbon dioxide, and the flow rate was 50 ml/min to obtain two groups of enantiomers. Constructs 4A and 4B.
  • lithium diisopropylamide (2.0 mol/L, 136.37 ml, 272.75 mmol) was diluted in tetrahydrofuran (257 ml), and compound 5-1 (48.6 g, 252.55 mmol) was added at -60°C ) in tetrahydrofuran (122 ml), after stirring for 2 hours, add iodine (67.30 g, 265.17 mmol) in tetrahydrofuran (122 ml) at -60°C, stir the reaction solution for 0.5 hour, and disperse the reaction solution in sodium thiosulfate (5%, 100 ml) and ethyl acetate (100 ml), the mixture was extracted with ethyl acetate (300 ml ⁇ 3), the combined organic phase was washed with saturated brine (300 ml ⁇ 1), anhydrous sodium sulfate The organic phase was dried, filtered, and the filtrate
  • compound 5-10 (130 mg, 483.86 micromol), compound 1-10 (179.67 mg, 725.79 micromol), cuprous thiophene-2-carboxylate (18.45 mg, 96.74 micromol) and cesium carbonate (316.25 mg, 970.62 micromole) in dimethyl sulfoxide (6 mL) was stirred at 80°C for 16 hours.
  • Compound 5 was passed through preparative SFC, using Daicel Chiralcpak IC (250mm*30mm, 10 ⁇ m), the mobile phase was 35% isopropanol (0.1% ammonia water) and 65% liquid carbon dioxide, and the flow rate was 65 ml/min to obtain two groups of pairs Enantiomers 5A and 5B.
  • reaction solution was dispersed in dichloromethane (30 mL) and saturated sodium bicarbonate solution (30 mL), and the mixture was extracted with dichloromethane (30 mL ⁇ 2 times).
  • the combined organic phases were washed with saturated brine (50 mL ⁇ 1 time), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was added to petroleum ether/ethyl acetate (10:1, 10 mL) In the mixed solvent, stirred at 25° C. for 0.5 hour, the mixture was filtered, and the filter cake was spin-dried under reduced pressure to obtain compound 6-9A.
  • compound 6-10A 250 mg, 872.11 micromol
  • compound 1-A 323.84 mg, 1.31 mmol
  • cuprous thiophene-2-carboxylate 33.25 mg, 174.37 micromol
  • cesium carbonate 570.00 mg, 1.75 mmol
  • dimethyl sulfoxide 7.5 mL
  • Compound 6A was passed through preparative SFC, using Daicel Chiralcpak IC (250mm*30mm, 5 ⁇ m), the mobile phase was 30% isopropanol (0.1% ammonia water) and 70% liquid carbon dioxide, and the flow rate was 65 ml/min to obtain two pairs of pairs Enantiomers 6A-1 and 6A-2.
  • the reaction solution was filtered with celite, the filtrate was dispersed in dichloromethane (10 ml) and saturated sodium bicarbonate solution (20 ml), extracted with dichloromethane (10 ml x 5 times), and the combined organic phase was washed with Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product is subjected to preparative HPLC, using Phenomenex luna C18 (150*40mm*15 ⁇ m), the mobile phase is acetonitrile and water (formic acid), and the content of acetonitrile is from 19% to 49%. , with a flow rate of 60 ml/min, compound 6-10B was obtained.
  • compound 6-10B (260 mg, 906.99 micromol), compound 1-A (336.79 mg, 1.36 mmol), cuprous thiophene-2-carboxylate (34.58 mg, 181.34 micromol) and cesium carbonate (592.80 mg, 1.82 mmol) in dimethyl sulfoxide (7.8 mL) was stirred at 80°C for 16 hours.
  • Compound 6B was passed through preparative SFC, using Daicel Chiralcpak IC (250mm*30mm, 5 ⁇ m), the mobile phase was 30% isopropanol (0.1% ammonia water) and 70% liquid carbon dioxide, and the flow rate was 65 ml/min to obtain two groups of pairs Enantiomers 6B-1 and 6B-2.
  • Analysis method column: Chiralpak IC-3 (50mm*4.6mm ID, 3 ⁇ m), mobile phase: isopropanol (0.05% diethylamine) in carbon dioxide from 5% to 40%, flow rate is 3 ml/min.
  • lithium chloride (2.22 g, 52.35 mmol) and zinc chloride 1M diethyl ether solution (52.38 ml, 52.38 mmol) were dissolved in tetrahydrofuran (84 ml), and slowly added dropwise to the mixture at 10-15°C Allylmagnesium bromide 1M solution in tetrahydrofuran (157.50 mL, 157.50 mmol). The reaction solution was stirred at 15°C for 0.5 hours.
  • Compound 7-1 (7 g, 26.17 mmol) was dissolved in tetrahydrofuran solution (28 ml) and added dropwise to the cloudy solution, and the reaction solution was stirred at 25° C. for 0.5 hour.
  • Triethyl orthoformate 14.47 g, 97.61 mmol was added to a solution of compound 7-4 (6.3 g, 32.54 mmol) in ethylene glycol (90 mL), and the reaction solution was stirred at 60° C. for 1 hour. Saturated aqueous sodium bicarbonate (50 mL) and water (50 mL) were added to the reaction solution and extracted with ethyl acetate (70 mL ⁇ 3).
  • compound 7-13A (600 mg, 1.98 mmol), bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (84 mg, 110.16 ⁇ mol), magnesium oxide (366 mg, 9.08 mmol) and diacetoxyiodobenzene (1.79 g, 5.55 mmol) in dichloromethane (10 mL) was stirred at 45°C for 16 hours.
  • compound 7-14A (220 mg, 731.66 micromol), compound 1-10 (352 mg, 1.42 mmol), cuprous thiophene-2-carboxylate (44 mg, 230.74 micromol) and cesium carbonate ( 484 mg, 1.49 mmol) in dimethyl sulfoxide (3 mL) was stirred at 80°C for 12 hours.
  • the reaction solution was filtered through celite, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was washed with saturated brine (20 mL x 3 times).
  • Compound 7A was passed through preparative SFC, using column: DAICEL CHIRALCEL OD (250mm*30mm, 10 ⁇ m), the mobile phase was 25% ethanol (0.1% ammonia water) and 75% liquid carbon dioxide, and the flow rate was 50 ml/min to obtain two groups Enantiomers 7A-1 and 7A-2.
  • Analysis method Column: Column: Chiralpak AD-3 50 ⁇ 4.6mm ID, 3 ⁇ m, mobile phase: methanol (0.05% diethylamine) in carbon dioxide from 5% to 40%, flow rate is 3 ml/min.
  • compound 7-13B 500 mg, 1.65 mmol
  • bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] 70 mg, 91.80 ⁇ mol
  • magnesium oxide 305 mg, 7.57 mmol
  • diacetoxyiodobenzene (1.49 g, 4.63 mmol) in dichloromethane (10 mL) was stirred at 45°C for 16 hours.
  • compound 7-14B (290 mg, 964.45 micromol), compound 1-10 (464 mg, 1.87 mmol), cuprous thiophene-2-carboxylate (58 mg, 304.16 micromol) and cesium carbonate ( 638 mg, 1.96 mmol) in dimethyl sulfoxide (3 mL) was stirred at 80°C for 12 hours.
  • the reaction solution was filtered through celite, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was washed with saturated brine (20 mL x 3 times).
  • Compound 7B was passed through preparative SFC, using a chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 ⁇ m), the mobile phase was 15% ethanol (0.1% ammonia water) and 85% liquid carbon dioxide, and the flow rate was 50 ml/min to obtain two groups Enantiomers 1A and 1B.
  • Analysis method Column: Column: Chiralpak IG-3 50 ⁇ 4.6mm ID, 3 ⁇ m, mobile phase: ethanol (0.05% diethylamine) in carbon dioxide from 5% to 40%, flow rate is 3 ml/min.
  • trifluoromethyltrimethylsilane (71.01 g, 499.36 mmol) and sodium iodide were added to a solution of compound 8-4 (28.0 g, 199.74 mmol) in tetrahydrofuran (900 ml) at 19°C (14.97 g, 99.87 mmol), and the reaction solution was stirred at 80°C for 2 hours.
  • the reaction solution was cooled to 30°C, trifluoromethyltrimethylsilane (71.01 g, 499.36 mmol) was added, and the reaction solution was stirred at 80°C for 2 hours. Repeat the above addition operation three times.
  • Dess Martin oxidant (9.19 g, 21.66 mmol) was added to a solution of compound 8-12 (4 g, 10.89 mmol) in ethyl acetate (100 ml), and the suspension was stirred at 70° C. for 12 Hour.
  • the reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (50 mL).
  • the filtrate was washed with saturated sodium sulfite (40 mL ⁇ 2 times), and the combined organic phases were washed with saturated brine (20 mL).
  • Compound 8 was separated by preparative SFC to afford four isomers 8A, 8B, 8C and 8D.
  • compound 9-4 (1.2 g, 4.99 mmol), bis[( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (190.08 mg, 249.29 ⁇ mol), magnesium oxide (920.24 mg, 22.83 mmol) and diacetoxyiodobenzene (4.5 g, 13.96 mmol) in dichloromethane (20 mL) was stirred at 45° C. for 16 hours.
  • the reaction solution was dispersed into water (20 ml), extracted with ethyl acetate (20 ml x 2 times), the combined organic phases were washed with saturated brine (20 ml x 2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate Spin dry to get the crude product.
  • Compound 9 was passed through preparative SFC, using DAICEL CHIRALPAK AD-H (250mm*30mm, 5um), the mobile phase was 20% ethanol (0.1% ammonia water) and 80% liquid carbon dioxide, and the flow rate was 50 ml/min to obtain two groups of pairs Enantiomers 9A and 9B.
  • RPMI1640 medium fetal bovine serum, and penicillin/streptomycin antibiotics were purchased from Vicente.
  • Bright-Glo (Luciferase Detection System) Reagents Purchased from Promega.
  • the 786-O cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd., the 786-O/HIF-2 ⁇ cell was constructed by Wuhan Heyan, and the EnVision multi-label analyzer (PerkinElmer).
  • the 786-O/HIF-2 ⁇ cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 30,000 786-O/HIF-2 ⁇ cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the 8th concentration, that is, diluted from 2000 ⁇ M to 5.12nM with a row gun, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 ⁇ L of each well to the cell plate after mixing. Compound concentrations ranged from 10 [mu]M to 0.026 nM were transferred to the cell plate. Cell plates were cultured in a carbon dioxide incubator for 24 hours.
  • Table 1 provides the EC50 of compounds of the present invention in the 786-O cell luciferase assay.
  • the compound of the present invention has good activity in the luciferase assay of 786-O cells.
  • the compound to be tested is serially diluted with a row gun, and a double-well experiment is set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 ⁇ L of each well to the cell plate after mixing, the final concentration of the compound test is 10 ⁇ M to 0.026 nM, and the final concentration of DMSO The concentration is 0.5%, and incubated at 37 degrees for 20 hours.
  • Compound working solution preparation the compound to be tested was diluted with a row gun, and a double-well experiment was set up. Add 117 ⁇ L of medium to the middle plate, then transfer 3 ⁇ L of each well of the gradient dilution compound to the middle plate according to the corresponding position, and mix well;
  • Standard curve solution preparation use buffer A to dilute the standard curve storage solution 20ng/mL to obtain a solution with a concentration of 1500pg/mL, and then use buffer A to perform a 2-fold gradient dilution of the diluted standard curve solution.
  • ELISA plates use washing solution, 300 ⁇ L per well, wash 4 times;
  • Max well the reading value of the positive control well is 10 ⁇ M positive ginseng compound treated cell well
  • Negative control well reads as 0.5% DMSO treated cell well
  • Table 2 provides the EC50 of the compounds tested in the VEGF ELISA assay for the compounds of the present invention.
  • the compound of the present invention has good activity in the 786-O cell VEGF ELISA test.
  • the purpose of this experiment is to study the pharmacokinetics of the test compound in mice and rats after a single oral administration.
  • the plasma drug concentration data of the compounds were processed in a non-compartmental model.
  • the peak concentration (C max ) and peak time (T max ) as well as the quantifiable final time were obtained directly from the plasma concentration-time diagram.
  • the following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: half-life (T 1/2 ), apparent volume of distribution (V dss ) and clearance (Cl), area under the time-plasma concentration curve from point 0 to the terminal time point (AUC 0- last ).
  • mice single intravenous and oral administration of the pharmacokinetic parameters of the compound of the present invention
  • the compound of the present invention has better oral absorption in rats, lower clearance rate, higher exposure, and better bioavailability.
  • Cell inoculation Inoculate 10 ⁇ 10 6 786-O cells on the right side of the neck and back of each mouse, the inoculation volume is 0.2 mL, the cell suspension is PBS and Matrigel (1:1), when the average tumor volume reaches 251 mm 3 Start group dosing.
  • mice in each group 1: Number of mice in each group; 2: Administration volume parameters: 10 ⁇ L/g based on mouse body weight. If the weight loss exceeds 15%, stop the drug until the body weight returns to within 10%; 3: 10% ethanol, 30% polyethylene glycol 400, 60% (0.5% methylcellulose, 0.5% Tween 80 aqueous solution).
  • Tumor diameters were measured twice a week with vernier calipers.
  • TGI total tumor proliferation rate
  • T/C relative tumor proliferation rate
  • Relative tumor proliferation rate T/C (%) T RTV /C RTV ⁇ 100%
  • T RTV average RTV of the treatment group
  • C RTV average RTV of the negative control group
  • the tumor volume at one measurement, T RTV and C RTV take the data of the same day.
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of the solvent control group-Average at the beginning of treatment of the solvent control group Tumor volume)] ⁇ 100%.
  • the compound of the present invention has a significant anti-tumor effect in the HIF-2 ⁇ overexpression 786-O animal drug effect model.
  • the purpose of this test is to detect the potential toxicity and toxicokinetics of the test product by oral administration to rats once a day for 14 days or 28 days (TK) features.
  • the plasma drug concentration data of the compounds were processed in a non-compartmental model.
  • the peak concentration (C max ) and peak time (T max ) as well as the quantifiable final time were obtained directly from the plasma concentration-time diagram.
  • the following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: half-life (T 1/2 ), apparent volume of distribution (V dss ) and clearance (Cl), area under the time-plasma concentration curve from point 0 to the terminal time point (AUC 0- last ).
  • the in vitro test system was used to evaluate the effect of compounds on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A) of human liver microsomal cytochrome P450 (CYP).
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and compounds at different concentrations, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the samples were processed after the reaction And the concentration of the metabolite produced by the probe substrate was quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), so as to calculate the IC 50 value, as shown in Table 8.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • the compound of the present invention has weak inhibition on cytochrome P450 (CYP) isoenzyme, and the risk of drug-drug interaction is low.
  • CYP cytochrome P450
  • each selected kinase by the compound uses the Eurofins standard Kinase ProfilerTM experimental process, which follows the relevant standard operating procedures. Protein kinase (except ATM(h) and DNA-PK(h)) tests are measured by radiation dose, while lipid kinase, ATM(h), ATR/ATRIP(h) and DNA-PK(h) tests are measured by radiation dose to test.
  • All provided compounds were formulated in 100% DMSO to 50X final experimental concentration. When appropriate, the more concentrated stock solution was diluted with 100% DMSO into a 50 ⁇ working solution. If the compound powder is provided, first make a 10mM stock solution through 100% DMSO solution, and then dilute it into a 50 ⁇ liquid.
  • IC50 For the determination of IC50 , the data were analyzed using XLFit version 5.3 (ID Business Solutions), and a sigmoidal dose-response curve (variable slope) was fitted by non-linear regression analysis based on the mean value of each concentration tested. When the top and/or bottom values exceed 10% or fall below -10%, the maximum and minimum limits of the curve may be redefined as 100 and 0 if the QC criteria of R2 are met.
  • targets including 24 GPCR targets, 3 neurotransmitter transporters, 2 nuclear receptors, 7 enzyme targets and 6 ion channels were tested for the activity of the compound to further evaluate the in vitro activity of the compound. Off-target effects, so as to evaluate its safety.
  • the off-target effects of the test compounds on the selected 42 targets were detected at the cellular or molecular level in vitro, mainly using radioactive Use isotope binding methods, calcium flux detection methods, and enzymatic fluorescence or chemiluminescence techniques to evaluate the safety of test compounds against these targets.
  • the compound of the present invention has relatively weak activity on the tested targets such as kinases, receptors and ion channels, and has high selectivity.
  • UV standard solutions of 1 ⁇ M, 20 ⁇ M and 200 ⁇ M are used as standard solutions for solubility experiments.
  • the compound of the present invention has good solubility and good drug-like properties.
  • Cell inoculation 10 ⁇ 10 6 A498 cells were inoculated on the right side of the neck and back of each mouse, the inoculation volume was 0.2 mL, the cell suspension was PBS and Matrigel (1:1), and the grouping began when the average tumor volume reached 200 mm 3 medication.
  • mice in each group 1: Number of mice in each group; 2: Administration volume parameters: 10 ⁇ L/g based on mouse body weight. If the weight loss exceeds 15%, stop the drug until the body weight returns to within 10%; 3: 10% ethanol, 30% polyethylene glycol 400, 60% (0.5% methylcellulose, 0.5% Tween 80 aqueous solution).
  • Tumor diameters were measured twice a week with vernier calipers.
  • TGI total tumor proliferation rate
  • T/C relative tumor proliferation rate
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of the solvent control group-Average at the beginning of treatment of the solvent control group Tumor volume)] ⁇ 100%.
  • the compound of the present invention has a significant anti-tumor effect in the HIF-2 ⁇ overexpression A498 animal drug effect model.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé spiro et son utilisation, et en particulier, l'invention concerne un composé tel que représenté dans la formule (III), et un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/077464 2022-02-22 2023-02-21 Composé spiro et son utilisation WO2023160552A1 (fr)

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CN202210161999.2 2022-02-22
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101815718A (zh) * 2007-08-10 2010-08-25 克里斯捷诺米有限公司 吡啶衍生物及其用法
CN102459278A (zh) * 2009-06-16 2012-05-16 默沙东公司 取代的-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮
CN105530923A (zh) * 2013-09-09 2016-04-27 佩洛通治疗公司 芳基醚及其用途
WO2021217508A1 (fr) * 2020-04-29 2021-11-04 Novartis Ag COMPOSÉS ET COMPOSITIONS POUR INHIBER L'ACTIVITÉ DE HIF2α ET LEURS MÉTHODES D'UTILISATION

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101815718A (zh) * 2007-08-10 2010-08-25 克里斯捷诺米有限公司 吡啶衍生物及其用法
CN102459278A (zh) * 2009-06-16 2012-05-16 默沙东公司 取代的-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮
CN105530923A (zh) * 2013-09-09 2016-04-27 佩洛通治疗公司 芳基醚及其用途
WO2021217508A1 (fr) * 2020-04-29 2021-11-04 Novartis Ag COMPOSÉS ET COMPOSITIONS POUR INHIBER L'ACTIVITÉ DE HIF2α ET LEURS MÉTHODES D'UTILISATION

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