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WO2023078369A1 - 双环化合物及其应用 - Google Patents

双环化合物及其应用 Download PDF

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Publication number
WO2023078369A1
WO2023078369A1 PCT/CN2022/129643 CN2022129643W WO2023078369A1 WO 2023078369 A1 WO2023078369 A1 WO 2023078369A1 CN 2022129643 W CN2022129643 W CN 2022129643W WO 2023078369 A1 WO2023078369 A1 WO 2023078369A1
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Prior art keywords
difluoro
tetrahydro
indol
difluoromethyl
sulfonyl
Prior art date
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PCT/CN2022/129643
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English (en)
French (fr)
Inventor
杨荣文
孙云
张健
伊学刚
马腾
王钰
王萍萍
丁列明
兰宏
王家炳
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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Priority to JP2024526002A priority Critical patent/JP2024540259A/ja
Priority to AU2022382762A priority patent/AU2022382762A1/en
Priority to KR1020247017046A priority patent/KR20240122434A/ko
Priority to CA3237020A priority patent/CA3237020A1/en
Priority to US18/706,666 priority patent/US20250042853A1/en
Priority to IL312530A priority patent/IL312530A/en
Priority to EP22889390.5A priority patent/EP4428125A4/en
Priority to CN202280069641.5A priority patent/CN118119601A/zh
Publication of WO2023078369A1 publication Critical patent/WO2023078369A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
    • C07D243/36—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings containing an indole or hydrogenated indole ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to bicyclic compounds, compositions and formulations comprising such compounds, and methods of using and preparing such compounds.
  • HIFs Hypoxia inducible factors
  • HIFs are members of the transcription factor family and are a pathway for the body to sense changes in oxygen, also known as hypoxia-inducible factors, which mediate cellular hypoxic responses by controlling more than 40 downstream hypoxia-adaptive genes. It is mainly composed of HIF ⁇ (HIF-1 ⁇ , HIF-2 ⁇ , HIF-3 ⁇ ) and HIF-1 ⁇ , in which HIF-1 ⁇ is always in the nucleus, while HIF ⁇ is located in the cytoplasm.
  • HIF ⁇ Under the condition of sufficient oxygen, HIF ⁇ will go through the hydroxylation of PHD prolyl hydroxylase, the ubiquitination labeling of VHL (Von Hippel-Lindau Syndrome) ubiquitinase and other pathways, and finally be degraded by the proteasome.
  • VHL Volt-Lindau Syndrome
  • HIF ⁇ cannot be degraded, so it accumulates in the nucleus, combines with HIF-1 ⁇ to form a heterodimer, activates the hypoxia response element (HRE) in the promoter of downstream genes, and then Regulate the transcription of related genes, so that cells can still survive in hypoxic conditions.
  • HRE hypoxia response element
  • HIF-2 ⁇ is mediated by chronic hypoxia, which can be continuously activated under physiological hypoxia conditions, and plays a more critical role in the occurrence and development of tumors.
  • HIF-2 ⁇ mediates tumorigenesis and development mainly include: 1. Under conditions such as hypoxia or VHL mutation, the metabolic pathway of HIF-2 ⁇ is blocked, accumulates into the nucleus, and forms a heterodimer with HIF-1 ⁇ . Then activate the hypoxia response element (HRE), up-regulate the downstream VEGFA, CXCR4, Cyclin D1 and other cancer-related genes, and promote tumor angiogenesis; 2. HIF-2 ⁇ also participates in the transmission of immunosuppressive signals by up-regulating the expression of CD73, so it targets HIF -2 ⁇ can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells and NK cells.
  • HRE hypoxia response element
  • VHL protein is an important part of E3 ubiquitin ligase, which mediates the degradation of protein by proteasome.
  • the VHL gene has a high mutation rate of 57% or loss of heterozygosity of 98% in renal cell carcinoma (RCC), resulting in pseudohypoxia and induction of HIF-2 ⁇ activation into the nucleus.
  • RCC renal cell carcinoma
  • ccRCC clear cell renal cell carcinoma
  • HIF-2 ⁇ In the absence of vascularization in glioma, the unstable blood supply leads to a hypoxic microenvironment, which induces local high expression of HIF-2 ⁇ and promotes tumor growth.
  • the 529-532 AA mutation rate of HIF-2 ⁇ is as high as 81%, which directly affects the hydroxylation degradation of HIF-2 ⁇ , and makes HIF-2 ⁇ continuously activated.
  • heterodimers between HIF-2 ⁇ activation and HIF-1 ⁇ is the key factor leading to downstream activation, and the PAS binding domain of the two is the binding site for the formation of heterodimers.
  • Peloton’s R&D team developed HIF based on this -2 ⁇ small molecule inhibitor PT2977 exerts anti-tumor effect by inhibiting the combination of HIF-2 ⁇ and HIF-1 ⁇ .
  • the present invention firstly provides the compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C or N, and at least one of X 1 , X 2 , X 3 , and X 4 is N;
  • W is selected from C, N, O or S;
  • R 1 is selected from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl, 5-18 membered hetero Aryl, C 5 -C 10 cycloalkyl, 5-10 membered heterocyclic group; wherein, the 5-18 membered heteroaryl and 5-10 membered heterocyclic group contain 1, 2 or 3 independently selected A heteroatom from N, O and S; said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 6 -C 10 Aryl, 5-18 membered heteroaryl, C 5 -C 10 cycloalkyl and 5-10 membered heterocyclyl can be optionally replaced by one or more members selected from H, halogen, -OH, -CN, oxo radical, amino, C 1 -C 6 al
  • R 4 and R 5 are independently selected from H, halogen, -NO 2 , -NR a R b , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclyl; said C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclyl can be optionally replaced by one or more selected from H, halogen, -CN, -OH, amino, oxo, C 1 -C 5 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl
  • R 6 is selected from H, -CN, halogen, -NO 2 , -OH, -NO 2 , -NR a R b , oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclyl; said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclyl can Optionally replaced by one or more selected from H, halogen, -CN, -OH, amino, oxo, C 1 -C 5 alkyl, C 1 -C 6 alkoxy
  • R 6 and R 5 together with the C atom they are connected to form a substituted or unsubstituted C 3 -C 4 cycloalkyl
  • R f is selected from nonexistent, H, -CN, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 10 cycloalkyl, oxo, -NR a R b ;
  • the C 1 -C 10 alkyl, C 1 -C 10 haloalkyl and C 3 -C 10 cycloalkyl can optionally be selected from one or more of H, halogen, -CN, -OH, amino, C 1 -C 5 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl or C 1 -C 5 haloalkyl substituents;
  • R a and R b are independently selected from H, CN, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 2 - C 10 alkynyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • R c is selected from C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 6 cycloalkyl and -NR a R b , said C 1 -C 10 alkyl, C 1 -C 10 alkoxy and C 3 -C 6 cycloalkyl can be optionally replaced by one or more selected from H, halogen, CN, -NH 2 , oxo, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 3 -C 6 cycloalkyl substituents;
  • n 0 or 1
  • n 0, 1, 2, 3 or 4;
  • the compound is shown in formula (II-1) or formula (II-2):
  • R 3 is selected from H, deuterium, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and the C 1 -C 10 alkyl and C 2 -C 10 alkenyl can be optionally Substituted by one or more substituents selected from H, halogen, -CN, -OH, amino, C 1 -C 5 haloalkyl.
  • R 3 is selected from H, deuterium, C 1 -C 3 alkyl, C 2 -C 5 alkenyl, and the C 1 -C 3 alkyl and C 2 -C 5 alkenyl can be optionally Substituted by one or more substituents selected from H, halogen, -CN, -OH, amino, C 1 -C 5 haloalkyl.
  • R 3 is selected from H, deuterium or C 1 -C 3 alkyl, and the C 1 -C 3 alkyl can be optionally replaced by one or more selected from H, halogen, -CN, -OH , Amino, C 1 -C 5 haloalkyl substituents are substituted.
  • R 3 is selected from H, deuterium or C 1 -C 3 alkyl.
  • R 3 is H or deuterium.
  • R 3 is H.
  • R 4 and R 5 are independently selected from H, halogen or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl can be optionally selected from one or more of H, halogen , -CN, -OH, amino or oxo substituents.
  • R 4 and R 5 are each independently selected from H, halogen or C 1 -C 6 alkyl.
  • R 4 and R 5 are each independently selected from H or halogen.
  • R4 and R5 are each independently selected from H or F.
  • R f is selected from H, -CN, -NH 2 , halogen, -NO 2 , C 1 -C 3 alkyl, cyclopropyl or C 1 -C 3 haloalkyl, and the C 1 -C 3 alkyl, cyclopropyl or C 1 -C 3 haloalkyl can optionally be replaced by one or more selected from H, halogen, -CN, -OH, amino, C 1 -C 3 alkyl, C 2 -C Substituents of 4 alkenyl, C 1 -C 3 haloalkyl.
  • the R f is selected from H, -CN, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • Rf is H, -CN, or halo.
  • Rf is H or halo.
  • Rf is H, -CN, -F, -Cl, -Br, or -CF3 .
  • Rf is H.
  • the W is C or O.
  • the W is C.
  • R 6 is H, -CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl may be optionally substituted by one or more substituents selected from H, halogen, -CN, -OH, oxo, amino.
  • R 6 is H, halogen, or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl can optionally be selected from one or more of H, halogen, -CN, -OH, Substituents of oxo and amino groups.
  • R 6 is H, halogen or C 1 -C 6 alkyl.
  • R 6 is H, halogen or C 1 -C 3 alkyl.
  • R 6 is H or halo.
  • R 6 is H, F, Cl or Br.
  • R 6 is H or F.
  • R 1 is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 -C 10 cycloalkyl or 5-10 membered heterocyclic group, the 5-10 membered heteroaryl And the 5-10 membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O and S, the C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 - C 10 cycloalkyl or 5-10 membered heterocyclic group can be optionally replaced by one or more selected from halogen, -OH, -CN, oxo, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 haloalkyl, -C 1 -C 6 alkylene -OR c , Substituents of -C 1 aryl, 5
  • R 1 is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 -C 10 cycloalkyl or 5-10 membered heterocyclic group, the 5-10 membered heteroaryl and 5-10 membered heterocyclic group containing 1 or 2 N heteroatoms, said C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 -C 10 cycloalkyl or 5-10 membered heterocyclic
  • the group can be optionally substituted by one or more selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 6 haloalkyl, cyano Substituents of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl substituted by cyano or C 1 -C 6 haloalkoxy.
  • R 1 is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 -C 10 cycloalkyl or 5-10 membered heterocyclic group, the 5-10 membered heteroaryl and 5-10 membered heterocyclic group containing 1 or 2 N heteroatoms, said C 6 -C 10 aryl, 5-10 membered heteroaryl, C 5 -C 10 cycloalkyl or 5-10 membered heterocyclic
  • the group can be optionally substituted by one or more selected from halogen, cyano, C 1 -C 6 haloalkyl substituted by cyano, C 1 -C 6 alkyl substituted by cyano, or C 1 -C 6 haloalkyl base replaced.
  • R is phenyl, pyridyl, naphthyl, 10-membered heteroaryl, C 8- C 10 cycloalkyl or 8-10-membered heterocyclyl, and the 10-membered heteroaryl and 8-
  • the 10-membered heterocyclic group contains 1 or 2 N heteroatoms, and the phenyl, pyridyl, naphthyl, 10-membered heteroaryl, C 8 -C 10 cycloalkyl or 8-10-membered heterocyclic group can optionally is substituted by one or more substituents selected from halogen, cyano or C 1 -C 6 haloalkyl.
  • the R 1 is phenyl, and the phenyl may be optionally substituted by one or more substituents selected from halogen, -CN or C 1 -C 6 haloalkyl.
  • the R 1 is phenyl, and the phenyl can be optionally replaced by one or more selected from halogen, -CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 or -CH 2 CF 3 substituents.
  • the R c is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and -NH 2 , and the C 1 -C 6 alkyl , C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl can optionally be replaced by one or more selected from H, halogen, CN, -NH 2 , C 1 -C 4 haloalkyl, C 3 - C 6 cycloalkyl substituents are substituted.
  • the R c is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and -NH 2 , and the C 1 -C 6 alkyl and C 1 -C 6 alkoxy Can be optionally substituted with one or more substituents selected from H, halogen, CN, —NH 2 , C 1 -C 4 haloalkyl.
  • the R c is selected from C 1 -C 6 alkyl, and the C 1 -C 6 alkyl may be optionally substituted by one or more substituents selected from H, halogen, CN.
  • the R a is selected from H, CN or C 1 -C 4 alkyl.
  • the R b is selected from H, CN or C 1 -C 4 alkyl.
  • the Rj is selected from
  • the R j is selected from
  • the compound is shown in formula (III-1), formula (III-2), formula (III-3) or formula (III-4):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R j , m, n, and W are as described in the above embodiments.
  • the compound is shown in formula (VI-1):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R c , X 1 , X 2 , X 3 , X 4 , m, n, and W are as described in the above embodiments.
  • the compound is shown in formula (VI-2):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R a , R c , X 1 , X 2 , X 3 , X 4 , m, n, and W are as described in the above embodiments.
  • the compound is shown in formula (VII-1), formula (VII-2), formula (VII-3) or formula (VII-4):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R j , m, and n are as described in the above embodiments.
  • the compound is shown in formula (VIII-1), formula (VIII-2), formula (VIII-3) or formula (VIII-4):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R c , R a , m, and n are as described in the above embodiments.
  • the compound is shown in formula (VIII-5), formula (VIII-6), formula (VIII-7) or formula (VIII-8):
  • R 1 , R 3 , R 4 , R 5 , R 6 , R f , R c , m, and n are as described in the above embodiments.
  • the compound is shown in formula (IX-1) or formula (IX-2):
  • R 1 , R 4 , R 5 , R 6 , R f , R c , R a , m are as described in the above embodiments.
  • the compound is such as formula (X-1), formula (X-2), formula (X-3), formula (X-4), formula (X-5), formula (X-6) , formula (X-7) or formula (X-8):
  • R 1 , R 6 , R j , and m are as described in the above embodiments.
  • the compound is shown in formula (XI-1) or formula (XI-2),
  • R 4 , R 5 , R 6 , R f , R c , R a , m are as described in the above embodiments;
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, the compound refers to:
  • the present invention also provides the preparation method of compound, the compound described in formula (I) of the present invention or the compound described in specific embodiment all can use commercially available starting material, known compound in the literature, or by easy
  • the prepared intermediates can be obtained by adopting organic synthesis techniques known to those skilled in the art, or according to the contents described herein, and can be obtained by using similar preparation methods to the specific examples.
  • the present invention relates to a method for preparing a compound represented by general formula (IX-1), comprising using a compound represented by formula (A-1) to react with a reducing agent,
  • R 1 , R 4 , R 5 , R 6 , R f , R c , R a , and m are as defined in the foregoing embodiments.
  • the present invention relates to a method for preparing a compound represented by the general formula (IX-2), comprising using a compound represented by the formula (A-2) to react with a reducing agent,
  • R 1 , R 4 , R 5 , R 6 , R f , R c , R a , m are as defined in the foregoing embodiments; further, the R 1 is The R x and R z are as defined in the foregoing embodiments.
  • the reducing reagent can be conventional reducing reagents such as sodium borohydride, lithium borohydride; formula (IX-1) compound and formula (IX-2) compound can pass through formula ( A-1) compound and compound of formula (A-2) can be obtained by chiral reduction (eg Noyori asymmetric reduction, CBS asymmetric reduction, etc.).
  • formula (IX-1) compound and formula (IX-2) compound can pass through formula ( A-1) compound and compound of formula (A-2) can be obtained by chiral reduction (eg Noyori asymmetric reduction, CBS asymmetric reduction, etc.).
  • the reducing agent used in the chiral reduction is [(R,R)-Ts-DPEN]RuCl(p-cymene)].
  • the compound of formula (A-1) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , R a , m are as defined in the previous embodiments ,
  • the compound shown in formula (B-1) can be prepared with NH 2 -R a (such as cyanamide, etc.) under the conditions of oxidizing agent (such as iodobenzene diacetate) to obtain the compound shown in formula (B-2), the formula (B The compound represented by -2) is oxidized to obtain the compound represented by formula (A-1).
  • oxidizing agent such as iodobenzene diacetate
  • the compound represented by formula (A-1) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , R a , m are as described above As defined by the scheme,
  • the compound shown in formula (B-1) obtains the compound shown in formula (B-3) through oxidation reaction (such as m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, etc.), shown in formula (B-3)
  • oxidation reaction such as m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, etc.
  • an oxidizing agent such as iodobenzene diacetate
  • the compound reacts with an imidization reagent (such as ammonium carbamate, trifluoroacetamide, etc.) to prepare a compound shown in formula (B-4), formula (B-4 )
  • an imidization reagent such as ammonium carbamate, trifluoroacetamide, etc.
  • the compounds shown in ) can be alkylated by
  • the compound represented by formula (A-2) can be prepared by the following method,
  • R 1 , R 4 , R 5 , R 6 , R f , R c , and m are as defined in the preceding embodiments, further, the R 1 is The R x and R z are as defined in the foregoing embodiments.
  • the compound shown in formula (B-1) can obtain the compound shown in formula (A-2) by oxidation reaction, wherein oxygenant comprises m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, ruthenium trichloride/periodine sodium chloride system, ruthenium trichloride/sodium hypochlorite system, etc.
  • the compound represented by formula (A-2) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments , X is a halogen;
  • the compound shown in formula (C-1) is prepared by coupling with corresponding sulfinic acid salt (such as methyl sulfinic acid sodium salt, etc.) under metal catalysis (such as cuprous salt) to obtain the formula (A-2) the indicated compounds.
  • sulfinic acid salt such as methyl sulfinic acid sodium salt, etc.
  • metal catalysis such as cuprous salt
  • the compound represented by formula (A-2) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments , X is a halogen;
  • the compound shown in formula (C-1) can be introduced into the compound shown in formula (D-1) by the coupling reaction introduction sulfinic acid group, perhaps its halogen atom X is transformed into negative ion and the sulfur dioxide equivalent that produces sulfur dioxide in situ (such as potassium pyrosulfite, 1,4-diazabicyclo[2.2.2]octane-1,4-dium-1,4-disulfinic acid, etc.) reaction to introduce sulfinic acid groups to obtain formula ( The compound shown in D-1);
  • the compound shown in formula (D-1) can carry out nucleophilic reaction with electrophile (such as Togni's reagent, methyl iodide, trifluoroiodomethane etc.)
  • electrophile such as Togni's reagent, methyl iodide, trifluoroiodomethane etc.
  • M + is any monovalent positive ion that can form a salt, such as Na + , K + , Mg
  • the compound represented by formula (B-1) can be prepared by the following method,
  • R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the preceding embodiments, X is halogen, R 101 is C 1-10 alkyl; further, said R 1 is The R x and R z are as defined in the foregoing embodiments.
  • the compound shown in formula (C-1) and mercaptopropionate alkyl ester (such as mercaptopropionate methyl ester, mercaptopropionate ethyl ester, mercaptopropionate tert-butyl ester etc.) coupling reaction can obtain formula (C-2) Shown compound, formula (C-2) compound under alkaline conditions (potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide etc.) methane, trifluoroiodomethane, bromoacetonitrile, bromofluoromethyl diethyl phosphate, etc.) to introduce the corresponding Rc group on the sulfur atom to prepare the compound shown in formula (B-1).
  • alkaline conditions potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide etc.
  • methane trifluoroiodomethane
  • bromoacetonitrile bromofluoromethyl
  • the compound represented by formula (B-1) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments , X is a halogen;
  • the compound represented by formula (C-1) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , m are as defined in the previous embodiments, and X is Halogen, X 1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 alkyl or two R 102 and the O atom connected to it together form a 5-membered compound containing two oxygen atoms and one boron atom Heterocycle, the 5-membered heterocycle can be optionally substituted by 1 or more C 1-3 alkyl groups;
  • the compound shown in formula (F-1) obtains the compound shown in formula (F-2) by electrophilic halogenating reagent (such as NIS) in pyrrole 3 for introducing the halogen atom, the compound shown in formula (F-2) is in base Under neutral conditions (such as LiHDMS, LDA, etc.) the proton at the ortho position of the carbonyl is taken away and the electrophile (such as NFSI, Selectfluor, etc.) is reacted to introduce R4 and R5 groups to obtain the compound shown in the formula (F-4), the formula (F The compound represented by -4) is deprotected to obtain the compound represented by the formula (F-5), and then the compound represented by the formula (C-1) is obtained through a coupling reaction.
  • electrophilic halogenating reagent such as NIS
  • pyrrole 3 for introducing the halogen atom
  • the compound shown in formula (F-2) is in base Under neutral conditions (such as LiHDMS, LDA, etc.) the proton at
  • the compound of formula (F-1) can introduce R and R groups at the ortho-position of carbonyl with an electrophile under basic conditions earlier to obtain the compound of formula (F-3), and then the compound of formula (F-3) and the corresponding
  • the electrophilic halogenating reagent introduces a halogen atom at the 3-position of pyrrole to obtain a compound represented by formula (F-4).
  • the compound represented by formula (B-1) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments , X 1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 alkyl or two R 102 and the O atom connected to it together form a 5-membered heterogeneous compound containing two oxygen atoms and one boron atom ring, the 5-membered heterocyclic ring can be optionally substituted by 1 or more C 1-3 alkyl groups;
  • Compound shown in formula (F-1) reacts with electrophilic reagent (such as sinking reagent, N-(trifluoromethylthio) phthalimide etc.) to carry out the electrophilic substitution of pyrrole 3 to prepare formula (E -1) the compound shown in, then under basic conditions carbonyl ortho-position deprotonation introduces R 4 and R 5 groups to obtain the compound shown in the formula (E-3), the compound shown in the formula (E-3) is deprotonated After protection, the compound represented by formula (E-4) is obtained, and then the compound represented by formula (B-1) is obtained through coupling reaction.
  • electrophilic reagent such as sinking reagent, N-(trifluoromethylthio) phthalimide etc.
  • the compound of formula (F-1) can be deprotonated at the ortho-position of the carbonyl under basic conditions and introduces R 4 and R 5 groups to obtain the compound of formula (F-3), and then the compound of formula (F-3) can be deprotonated under basic conditions Under electrophilic substitution, the compound represented by formula (E-3) is obtained.
  • the compound represented by formula (A-2) can be prepared by the following method, wherein R 1 , R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments , X 1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 alkyl or two R 102 and the O atom connected to it together form a 5-membered heterogeneous compound containing two oxygen atoms and one boron atom ring, the 5-membered heterocyclic ring can be optionally substituted by 1 or more C 1-3 alkyl groups;
  • the compound shown in the formula (F-1) can be deprotonated at the ortho-position of the carbonyl under basic conditions to introduce R 4 and R 5 groups to obtain the compound shown in the formula (F-3), and then the compound shown in the formula (F-3)
  • the shown compound is electrophilicly substituted with a sulfonylation reagent (such as trifluoromethanesulfonic anhydride, etc.) to introduce a sulfonyl group under basic conditions to obtain a compound shown in formula (G-4).
  • a sulfonylation reagent such as trifluoromethanesulfonic anhydride, etc.
  • the compound represented by formula (G-5) can be prepared by the following method, wherein R 4 , R 5 , R 6 , R f , R c , m are as defined in the previous embodiments, and X is Halogen, X 2 is -Boc or benzenesulfonyl;
  • the compound shown in formula (H-1) can carry out N atom protection by the compound shown in formula (F-0), then obtain through halogenation reaction, formula (H-1) compound is by coupling reaction and nucleophilic sulfur reagent - SRc (such as silver trifluoromethyl mercaptide, copper trifluoromethyl mercaptide, etc.) is reacted to obtain the compound shown in formula (H-2), and the compound shown in formula (H-2) is oxidized to obtain formula (H-3) The shown compound is then subjected to a deprotection reaction to finally obtain the compound shown in formula (G-5).
  • nucleophilic sulfur reagent - SRc such as silver trifluoromethyl mercaptide, copper trifluoromethyl mercaptide, etc.
  • Another aspect of the present invention also provides intermediates for the preparation of compounds shown in formula (IX-1) and formula (IX-2), which are selected from the following structures:
  • R 1 , R 4 , R 5 , R 6 , R f , R c , R a , m are as described in the previous embodiments,
  • X is halogen
  • X 1 is selected from -TIPS, -Trt or -TBDPS
  • X 2 is -Boc or benzenesulfonyl
  • R 101 is C 1-3 alkyl.
  • R 1 , R 4 , R 5 , R 6 , R f , R c , Ra , R x , R z , m are as described in the previous embodiments, X is halogen, and X 1 is selected from TIPS-, Trt- , X 2 is -Boc, R 101 is C 1-10 alkyl.
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of at least one of the above-mentioned compounds and a pharmaceutically acceptable excipient, such as hydroxypropylmethylcellulose.
  • a pharmaceutically acceptable excipient such as hydroxypropylmethylcellulose.
  • the weight ratio of the compound to the excipient is about 0.001-10.
  • the present invention also provides a method for treating a subject suffering from a disease or condition mediated by HIF-2 ⁇ , comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease or condition is selected from VHL syndrome, autoimmune disease, cancer, inflammatory disease, neurodegenerative disease, cardiovascular disorder, renal disorder, viral infection, and obesity.
  • the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs.
  • the disease or condition is cancer selected from malignant solid tumors and hematological tumors.
  • the cancer includes, but is not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, uterine cancer, cervical cancer, endometrial cancer, lymphoma tumor, esophageal cancer, colon cancer, rectal cancer, thyroid cancer, prostate cancer, sarcoma, leukemia, bladder cancer, kidney cancer, glioma, perithelial cystadenoma, squamous cell carcinoma, pheochromocytoma, lung cancer, pancreatic cancer , liver cancer, kidney cancer, breast cancer, meningioma, neurocytoma, paraganglioma, blastoma, endocrine tumor, meningioma, and medulloblastoma.
  • the disease or condition is VHL syndrome.
  • the disease or disorder is renal cancer; further, the disease is renal cell carcinoma; and the disease is clear cell renal carcinoma.
  • the subject is a human.
  • the compound is administered intravenously, intramuscularly, parenterally, nasally or orally. In one aspect, the compound is administered orally.
  • the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by HIF-2 ⁇ .
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in treatment.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Preferred halo groups refer to fluorine, chlorine and bromine.
  • alkyl includes straight-chain or branched saturated monovalent hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1 -C 6 in C 1 -C 6 alkyl means a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
  • alkoxy refers to an oxygen ether formed from the above linear, branched or cyclic alkyl groups.
  • alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the point of attachment of the alkylene to the rest of the compound. Similarly, “C 1 -C 4 " in C 1 -C 4 alkylene refers to an alkylene group containing 1, 2, 3 or 4 carbon atoms.
  • haloalkyl refers to an alkyl group in which one or more H has been replaced by a halogen atom.
  • haloalkoxy refers to the group -O-haloalkyl.
  • oxo or "oxo” refers to an oxygen atom in the form of a dimethyl substituent which, when attached to C, forms a carbonyl group, which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
  • aromatic ring refers to an aromatic character (having (4n+2) delocalized ⁇ electrons, where n is integer) carbocyclic or heterocyclic polyunsaturated ring.
  • aryl refers to a substituted or unsubstituted stable aromatic hydrocarbon group of 6 to 10 ring carbon atoms, which may contain 1 aromatic ring or multiple aromatic rings (eg, fused bicyclic rings). Said aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
  • heteroaryl refers to a monocyclic or polycyclic (eg fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S.
  • the "5-18 membered” in the 5-18 membered heteroaryl refers to a heteroaryl group consisting of 5-18 carbon atoms or N, O or S ring atoms. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuryl, and the like.
  • cycloalkyl refers to a ring system having at least one cycloalkyl group.
  • C 3 -C 10 in the term C 3 -C 10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro, fused, etc.).
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused to cyclized alkyl rings Moieties, such as benzo or thienyl derivatives of cyclohexane, etc.
  • cycloalkenyl refers to a ring system having at least one cycloalkenyl group having one or more carbon-carbon double bonds therein.
  • C 3 -C 10 in the term C 3 -C 10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkenyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl groups also include cycloalkenyl groups with one or more rings fused to cycloalkenyl Parts of aromatic rings, such as benzo or thienyl derivatives of cyclohexene rings, etc.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom selected from N, O and/or S.
  • the heterocyclyl group may include monocyclic or polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • a heterocyclyl group can be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocyclyl moieties having one or more aromatic rings fused to a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. .
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepane, dihydrobenzofuranyl, and the like .
  • composition as used herein is intended to include a product containing the specified ingredients in the specified amounts, and also any product obtained directly or indirectly from the specified amounts of the specified ingredients. Accordingly, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and processes for preparing the compounds are also within the scope of the present invention. Furthermore, some of the crystalline forms of the compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
  • Compounds of the present invention include compounds of formula (I), and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers isomers (including diastereomers, enantiomers and racemates), geometric isomers, isotopically labeled compounds, tautomers, prodrugs, or any mixture of all of the above.
  • the “enantiomers” are a pair of non-superimposable stereoisomers that are mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the conventional RS system eg (1S,2S) designates a single stereoisomer with two chiral centers of known relative and absolute configuration.
  • Optically active (R)- and (S)-isomers can be prepared using synthesis of optically active starting materials or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC columns ).
  • the “diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.
  • the stereochemistry at each chiral carbon can be designated by R or S when the compound is a pure enantiomer.
  • Resolved compounds of unknown absolute configuration can be named (+) or (-) according to the direction in which they rotate plane-polarized light (dextrorotation or levorotation) at the wavelength of the sodium D line.
  • resolved compounds can be defined by the corresponding retention times of the corresponding enantiomers/diastereoisomers by chiral HPLC.
  • the compounds of the present invention may contain one or more chiral centers and that diastereoisomers and optical isomers may thereby arise.
  • the above formula (I) does not exactly define the stereostructure of a certain position of the compound, so it may exist in different isomeric forms.
  • the present invention includes all possible stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof, such as racemic mixtures, optically pure forms and mixtures of isomers in any proportion .
  • mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization procedures well known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.
  • prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Therefore, the term "administering" in the treatment methods provided by the present invention includes administering the compound disclosed in the present invention, or the prodrug compound disclosed in the present invention which can be converted into the prodrug compound disclosed in the present invention after administration to the subject although not explicitly disclosed. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
  • any substituent or variable at a particular position in a molecule is defined independently of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substitution forms of the compounds in the present invention by means of the prior art and the methods described in the present invention to provide chemically stable and easy-to-synthesize compounds.
  • any substituent or variable at a particular position in one molecule is independent of the definition of any substituent or variable at a particular position in another molecule. It is easy to understand that the compounds of the present invention can select suitable substituents or substitution forms according to the prior art of this subject to provide chemically stable and easy to prepare and synthesize by the prior art of this subject or the methods described in the present invention.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent forming a solvate is not particularly limited as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone, and the like can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc, and the like. Particular preference is given to the ammonium, calcium, magnesium, potassium and sodium salts.
  • Nontoxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • Other pharmaceutically acceptable non-toxic organic bases capable of forming salts including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine , lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, triprop
  • the compound provided by the present invention is a base
  • its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoro
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.
  • a substantially pure form for example, at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% is weight ratio ).
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • a pharmaceutically acceptable excipient or other optional therapeutic components or Accessories.
  • the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and prepared by any methods of preparation well known in the art of pharmacy.
  • the compound represented by formula (I) of the present invention can be used as active components and mixed with drug carriers to form a drug combination thing.
  • the pharmaceutical carrier can take a wide variety of forms depending on the mode of administration desired, for example, oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets containing predetermined doses of the active ingredient.
  • the pharmaceutical composition of the present invention may be in the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by controlled release and/or delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include a step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical compositions are prepared by uniform and intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers or a mixture of both. The product can then be conveniently prepared to the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active compounds are also included in the pharmaceutical composition of the present invention.
  • the pharmaceutical carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier.
  • Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil and water.
  • Gas carriers including carbon dioxide and nitrogen.
  • any convenient pharmaceutical medium may be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
  • oral liquid preparations such as suspensions, elixirs, and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral formulations, where solid pharmaceutical carriers are used.
  • tablets may be coated using standard aqueous or non-aqueous formulation techniques.
  • Tablets containing a compound or pharmaceutical composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be obtained by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be obtained by wetting the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine.
  • each tablet contains about 0.05 mg to 5 g of active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • dosage forms intended for oral administration to humans contain from about 0.5 mg to about 5 g of the active ingredient compounded with suitable and conveniently measured auxiliary materials comprising from about 5% to about 95% of the total pharmaceutical composition.
  • Unit dosage forms generally contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active component into water to prepare an aqueous solution or a suspension.
  • Suitable surfactants such as hydroxypropylcellulose may be included.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
  • the above pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion.
  • the final injectable form must be sterile and, for easy syringability, must be fluid.
  • the pharmaceutical composition must be stable during manufacture and storage. Accordingly, preservation against contamination by microorganisms, such as bacteria and fungi, is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Furthermore, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • These preparations can be prepared by using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods.
  • a cream or ointment is prepared by adding a hydrophilic material and water to about 5% to 10% by weight of the above compound to produce a cream or ointment having the desired consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with solid as carrier.
  • a preferred dosage form is the mixture to form unit dose suppositories.
  • Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories are conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and moulding.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional auxiliary components, such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants and preservatives (including antioxidants), etc.
  • additional auxiliary components such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants and preservatives (including antioxidants), etc.
  • other adjuvants may also include penetration enhancers that adjust the isotonic pressure of the drug and blood.
  • the pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can also be prepared in the form of powder or concentrated solution.
  • the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per day per patient.
  • the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concomitant drug use, and acceptance. The severity of the particular disease being treated.
  • DIEA N,N-Diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • K 2 CO 3 potassium carbonate
  • LDA lithium diisopropylamide
  • LiHMDS lithium bis(trimethylsilyl)amide
  • m-CPBA m-chloroperoxybenzoic acid
  • Na 2 SO 4 sodium sulfate
  • NBS N-bromosuccinimide
  • NFSI N-fluorobisbenzenesulfonamide
  • NIS N-iodosuccinimide
  • NMP N-methylpyrrolidone
  • PE petroleum ether
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl 2 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • TMSC 2 F 5 (pentafluoroethyl)trimethylsilane
  • TBAF Tetrabutylammonium fluoride
  • TEA triethylamine
  • THF Tetrahydrofuran
  • Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
  • compound M1-1 (13.5g) was dissolved in acetonitrile (100mL), NIS (11.5g) was added in batches, reacted at room temperature for 5 hours, the reaction was cooled, the precipitated solid was filtered and rinsed with methanol (50mL*2) After washing and drying, the target compound M1-2 (15.4 g) was obtained.
  • Example 7 and Example 8 (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl yl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A13, assumed) and (S)-3-((R)-(difluoromethane base)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indole-4 -alcohol Synthesis of compound A14, hypothetical)
  • Compound A3-1 is replaced by compound A13-11, referring to the method in step 2 of Example 4, to obtain compound 13-12.
  • Compound 13-1 can be obtained by replacing compound A3-2 with compound 13-11 and referring to the method in step 3 of Example 4.
  • Potassium peroxymonosulfonate (0.7 g) was added to compound A21-1 (150 mg), acetonitrile (5 mL) and water (5 mL), stirred at 60°C for 2 h, and the reaction was completed.
  • VEGFA ELISA detection (IC 50 )
  • the 786-O cells grown in the logarithmic phase were inoculated in a 96-well plate with a cell concentration of 65,000 cells per milliliter of culture medium and 180ul per well. Dilute the compound to the corresponding concentration, and add 20ul of different concentrations of the compound solution to the corresponding cell wells, so that the final concentration of the compound is (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After culturing for 24 hours, the cell culture supernatant was taken, and the concentration of VEGFA was measured using an ELISA kit (purchased from abcam). Finally, the reaction was terminated.
  • the light absorbance of each well was measured at a wavelength of 450 nm using a microplate reader, and the IC 50 was calculated by GraphPad Prism. At the same time, CellTiter-Glo reagent was used to measure cell viability.
  • the IC 50 data of the exemplary embodiments are provided in Table 1, wherein, A indicates IC 50 ⁇ 0.5 ⁇ M; B indicates 0.5 ⁇ M ⁇ IC 50 ⁇ 1.5 ⁇ M; C indicates 1.5 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M, and D indicates IC 50 > 10 ⁇ M.
  • Example number IC50 ( ⁇ M) Example number IC50 ( ⁇ M) 1 A 33 0.041 2 0.0083 34 A 3 0.003 35 0.018 4 0.098 36 0.108 5 0.072 37 A 6 0.011 39 0.140 9 0.047 40 A 10 A 41 A 11 0.027 42 0.074 12 0.010 43 A 13 B 44 A 14 0.040 45 A 15 B 46 A 16 0.537 47 0.008 17 A 48 1.621 18 A 49 0.099
  • the luciferase LUC gene was stably transfected into 786-O cells (purchased from ATCC) with Lipofectamine 3000 transfection reagent (purchased from Invitrogen), and constructed as HIF2 ⁇ reporter gene cells (786-O-HIF2 ⁇ -Luc cells).
  • the experiment was carried out when the 786-O-HIF2 ⁇ -Luc cells were in the logarithmic growth phase, the medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, and PBS was rinsed three times; trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells , stop digestion with culture medium, 10% fetal bovine serum, 1% penicillin, streptomycin.
  • the cells were collected by centrifugation, washed twice with PBS, the phenol red in the medium was removed, the cells were resuspended to an appropriate concentration, and the cell density and viability were tested to ensure that the cell viability was above 90% before being used in the experiment.
  • Use Echo550 non-contact acoustic wave pipetting system, purchased from Labcyte
  • 384 wells 25 nl/well
  • 4500 cells/well 25 ⁇ l medium
  • the concentrations were 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively.
  • the cells were cultured at 37°C, 5% CO 2 for 18-20 hours; Steady-Glo TM luciferase assay system (purchased from Promega) was added to a 384-well plate, 25 ⁇ l/well; the luminescence value was detected with Envision.
  • the % inhibition rate was calculated according to the RLU (Record Luminescence) signal value of each well, and then the IC 50 of the corresponding compound was calculated by Graphpad 8.0 fitting.
  • the IC 50 data of the exemplary embodiments are provided in Table 2, wherein A indicates IC 50 ⁇ 0.1 ⁇ M; B indicates 0.1 ⁇ M ⁇ IC 50 ⁇ 0.5 ⁇ M; C indicates IC 50 >0.5 ⁇ M.

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Abstract

本发明涉及如式(I)所示的化合物。本发明也提供包含这类化合物的组合物和制剂，及使用和制备这样的化合物的方法。

Description

双环化合物及其应用 技术领域
本发明涉及一种双环化合物，包含这样化合物的组合物和制剂，及使用和制备这样的化合物的方法。
背景技术
HIFs(Hypoxia inducible factors)属于转录因子家族成员，是机体感受氧气变化的一个通路，又称缺氧诱导因子，通过控制下游40多个缺氧适应基因而介导细胞缺氧反应。它主要由HIFα(HIF-1α，HIF-2α，HIF-3α)与HIF-1β两部分组成，其中HIF-1β始终在细胞核内，而HIFα位于细胞质。HIFα在氧气充足的条件下，会经过PHD脯氨酰羟化酶羟基化、VHL(Von Hippel—Lindau Syndrome)泛素酶泛素化标记等途径，最后被蛋白酶体降解。但当缺氧或代谢途径异常时，HIFα无法被降解，因而蓄积入核，与HIF-1β结合形成异二聚体，激活下游基因启动子中缺氧反应元件(Hypoxia response element，HRE)，进而调控相关基因转录，让细胞在缺氧条件仍然可以存活。这些基因涉及肿瘤血管生成，细胞增殖、生存、代谢、侵袭转移，耐药、炎症和免疫等。其中HIF-2α介导的是慢性缺氧，在生理缺氧条件下即可持续激活，对肿瘤的发生发展具有更关键作用。
目前的研究表明HIF-2α介导肿瘤发生发展的机制主要包括：1、在缺氧或VHL突变等条件下，HIF-2α代谢途径受阻，蓄积进入细胞核，与HIF-1β形成异二聚体，进而激活缺氧反应原件(HRE)，上调下游VEGFA、CXCR4、Cyclin D1等癌症相关基因，促进肿瘤血管生成；2、HIF-2α还通过上调CD73表达参与免疫抑制性信号的传导，因此靶向HIF-2α可恢复或增强成熟DC细胞、活化B细胞及NK细胞的抗肿瘤免疫功能。
HIF-2α通路的激活与肾细胞癌、胶质瘤、神经母细胞瘤与嗜铬细胞瘤等发生发展有密切关系。VHL蛋白是E3泛素连接酶的重要组成部分，介导蛋白酶体对蛋白质的降解。VHL基因在肾癌细胞(renal cell carcinoma；RCC)中有57％的高突变率或98％的杂合性缺失，导致假性缺氧并诱导HIF-2α活化入核。其中， 透明细胞肾细胞癌(Clear cell renal cell carcinoma；ccRCC)占原发性肾细胞恶性肿瘤的70％-75％，而超过90％的ccRCC患者存在VHL蛋白缺陷。胶质瘤在不血管化的情况下，血液供应不稳定导致低氧微环境，从而诱导HIF-2α局部高表达，促进肿瘤生长。在嗜铬细胞瘤及副神经节瘤中，HIF-2α的529-532位AA突变率高达81％，直接影响HIF-2α的羟基化降解，使HIF-2α持续激活。
HIF-2α活化与HIF-1β形成异二聚体是导致下游激活的关键因素，而二者的PAS结合域是其形成异二聚体的结合位点，Peloton公司的研发团队基于此开发了HIF-2α小分子抑制剂PT2977，通过抑制HIF-2α与HIF-1β结合，从而发挥抗肿瘤效果。
基于HIF-2α通路与肿瘤发生和迁移有非常重要的密切关系，开发更多的高效新分子实体是非常必要的。
发明内容
本发明首先提供了式(I)所示的化合物或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，
Figure PCTCN2022129643-appb-000001
其中，
Figure PCTCN2022129643-appb-000002
代表单键或双键；
X 1、X 2、X 3、X 4分别独立地选自C或N，且X 1、X 2、X 3和X 4至少有一个为N；
W选自C、N、O或S；
R 1选自C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、C 5-C 10环烷基、5-10元杂环基；其中，所述5-18元杂芳基和5-10元杂环基含有1、2或3个分别独立地选自N、O和S的杂原子；所述C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、 C 5-C 10环烷基和5-10元杂环基可任选地被一个或多个选自H、卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 3-C 5环烷基、C 2-C 6炔基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、-C 1-C 6亚烷基-OR c、-C 1-C 6亚烷基-C＝O-R c、-NO 2、-OR c、-SR c、-NR aR b、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-NC(＝O)R c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR aR b、-S(＝O)(＝NR a)R b、-P(＝O)R aR b或-P(＝S)R aR b的取代基所取代；
R 3选自H、氘、卤素、-NO 2、-CN、-OH、C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基或C 2-C 10炔基，所述C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基、C 2-C 10炔基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；
R 4和R 5分别独立地选自H、卤素、-NO 2、-NR aR b、-OH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基；所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、氧代基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；或R 4和R 5共同形成氧代基；或R 4和R 5与连同其所连接的C原子共同形成取代或未被取代的环丙基；
R 6选自H、-CN、卤素、-NO 2、-OH、-NO 2，-NR aR b、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基；所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、氧代基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；或两个R 6一起连同其所连接的C原子共同形成取代或未取代的C 3-C 5环烷基或3-5元杂环基；
或R 6与R 5连同其所连接的C原子共同形成取代或未取代的C 3-C 4环烷基；
R f选自不存在、H、-CN、卤素、C 1-C 10烷基、C 1-C 10卤代烷基、C 3-C 10环烷基、氧代基、-NR aR b；所述C 1-C 10烷基、C 1-C 10卤代烷基和C 3-C 10环烷基可 任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；
R j选自-C 1-C 6亚烷基-C(＝O)R c、-C 1-C 6亚烷基-C(＝O)OR c、-C 2F 5、-C(＝O)R c、-C(＝O)OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c，其中，所述C 1-C 6亚烷基可任选地被一个或多个选自H，卤素，氰基，C 1-C 4烷基，C 2-C 4烯基，C 2-C 4炔基，C 1-C 4卤代烷基，C 1-C 4烷氧基和C 1-C 4卤代烷氧基的取代基所取代；
R a和R b分别独立地选自H、CN、C 1-C 10烷基、C 1-C 10卤代烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 10环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基；
R c选自C 1-C 10烷基、C 1-C 10烷氧基、C 3-C 6环烷基和-NR aR b，所述C 1-C 10烷基、C 1-C 10烷氧基和C 3-C 6环烷基可任选地被一个或多个选自H、卤素、CN、-NH 2、氧代基、C 1-C 4卤代烷基、C 1-C 4卤代烷氧基、C 3-C 6环烷基的取代基所取代；
n为0或1；
m为0、1、2、3或4；
条件是，所述化合物不为：
3-氟-5-(4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
1-(3-氯-5-氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
3-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈；
3-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈；
1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
1-(3-氯-5-氟苯基)-5,6-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
(S)-5-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
1-(3-氯-5-氟苯基)-5,5-二氟-3-((S)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇；
1-(3-氯-5-氟苯基)-5,5-二氟-3-((R)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇；
3-氟-5-(5-氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈(193)；
(S)-1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-2-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
2-氯-5-(5,5-二氟-4-羟基-3-(甲基磺酰基)-5,6-二氢环戊[b]吡咯-1(4H)-基)苯甲腈；和
1-(3-氯-5-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-1,4,5,6-四氢环戊并[b]吡咯-4-醇。
一些实施方案中，所述化合物如式(II-1)或式(II-2)所示：
Figure PCTCN2022129643-appb-000003
一些实施方案中，R 3选自H、氘、C 1-C 10烷基、C 2-C 10烯基，所述C 1-C 10烷基和C 2-C 10烯基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基的取代基所取代。
一些实施方案中，R 3选自H、氘、C 1-C 3烷基、C 2-C 5烯基，所述C 1-C 3烷基和C 2-C 5烯基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基的取代基所取代。
一些实施方案中，R 3选自H、氘或C 1-C 3烷基，所述C 1-C 3烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基的取代基所取代。
一些实施方案中，R 3选自H、氘或C 1-C 3烷基。
一些实施方案中，R 3为H或氘。
一些实施方案中，R 3为H。
一些实施方案中，R 4和R 5分别独立地选自H、卤素或C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基或氧代基的取代基所取代。
一些实施方案中，R 4和R 5分别独立地选自H、卤素或C 1-C 6烷基。
一些实施方案中，R 4和R 5分别独立地选自H或卤素。
一些实施方案中，R 4和R 5分别独立地选自H或F。
一些实施方案中，R f选自H、-CN、-NH 2、卤素、-NO 2、C 1-C 3烷基、环丙基或C 1-C 3卤代烷基，所述C 1-C 3烷基、环丙基或C 1-C 3卤代烷基可任选地被一 个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 3烷基、C 2-C 4烯基、C 1-C 3卤代烷基的取代基所取代。
一些实施方案中，所述R f选自H、-CN、卤素、C 1-C 3烷基或C 1-C 3卤代烷基。
一些实施方案中，R f为H、-CN或卤素。
一些实施方案中，R f为H或卤素。
一些实施方案中，R f为H、-CN、-F、-Cl、-Br或-CF 3。
一些实施方案中，R f为H。
一些实施方式中，所述W为C或O。
一些实施方式中，所述W为C。
一些实施方案中，R 6为H、-CN、卤素、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基，所述C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氧代基、氨基的取代基所取代。
一些实施方案中，R 6为H、卤素或C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氧代基、氨基的取代基所取代。
一些实施方案中，R 6为H、卤素或C 1-C 6烷基。
一些实施方案中，R 6为H、卤素或C 1-C 3烷基。
一些实施方案中，R 6为H或卤素。
一些实施方案中，R 6为H、F、Cl或Br。
一些实施方案中，R 6为H或F。
一些实施方案中，R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基，所述5-10元杂芳基和5-10元杂环基含有1、2或3个分别独立地选自N、O和S的杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或多个选自卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基、-C 1-C 6亚烷基-OR c、-C 1-C 6亚烷基-C＝O-R c、-NO 2、C(＝O)OR c或-S(＝O) 2R c的取代基所取代。
一些实施方案中，R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基，所述5-10元杂芳基和5-10元杂环基含有1或2个N杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或 多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 5环烷基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基或C 1-C 6卤代烷氧基的取代基所取代。
一些实施方案中，R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基，所述5-10元杂芳基和5-10元杂环基含有1或2个N杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或多个选自卤素、氰基、氰基取代的C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基或C 1-C 6卤代烷基的取代基所取代。
一些实施方案中，R 1为苯基、吡啶基、萘基、10元杂芳基、C 8-C 10环烷基或8-10元杂环基，所述10元杂芳基和8-10元杂环基含有1或2个N杂原子，所述苯基、吡啶基、萘基、10元杂芳基、C 8-C 10环烷基或8-10元杂环基可任选地被一个或多个选自卤素、氰基或C 1-C 6卤代烷基的取代基所取代。
一些实施方案中，所述R 1为苯基，所述苯基可任选地被一个或多个选自卤素、-CN或C 1-C 6卤代烷基的取代基所取代。
一些实施方案中，所述R 1为苯基，所述苯基可任选地被一个或多个选自卤素、-CN、-CH 2F、-CHF 2、-CF 3、-CH 2CHF 2或-CH 2CF 3的取代基所取代。
一些实施方案中，所述R j选自-C 1-C 6亚烷基-C(＝O)R c、-C 1-C 6卤代亚烷基-C(＝O)R c、-C 1-C 6卤代亚烷基-C(＝O)OR c、-C 2F 5、-C 1-C 6氰基取代亚烷基-C(＝O)R c、-C(＝O)R c、-C(＝O)OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c。
一些实施方案中，所述R j选自-C 2F 5、-C 1-C 6卤代亚烷基-C(＝O)R c、-C 1-C 6卤代亚烷基-C(＝O)OR c、-C(＝O)OR c、-C(＝O)R c、-SR c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c。
一些实施方案中，所述R j为-SR c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c。
一些实施方式中，所述R c选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基和-NH 2，所述C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 6环烷基可任选地被一个或多个选自H、卤素、CN、-NH 2、C 1-C 4卤代烷基、C 3-C 6环烷基的取代基所取代。
一些实施方式中，所述R c选自C 1-C 6烷基、C 1-C 6烷氧基和-NH 2，所述C 1-C 6烷基和C 1-C 6烷氧基可任选地被一个或多个选自H、卤素、CN、-NH 2、C 1-C 4卤代烷基的取代基所取代。
一些实施方式中，所述R c选自C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、CN的取代基所取代。
一些实施方式中，所述R a选自H、CN或C 1-C 4烷基。
一些实施方式中，所述R b选自H、CN或C 1-C 4烷基。
一些实施方案中，所述R j选自
Figure PCTCN2022129643-appb-000004
Figure PCTCN2022129643-appb-000005
一些实施方案中，所述R j选自
Figure PCTCN2022129643-appb-000006
Figure PCTCN2022129643-appb-000007
一些实施方案中，所述化合物如式(III-1)、式(III-2)、式(III-3)或式(III-4)所示：
Figure PCTCN2022129643-appb-000008
其中，R 1、R 3、R 4、R 5、R 6、R f、R j、m、n、W如上述实施方案所述。
一些实施方案中，所述化合物如式(VI-1)所示：
Figure PCTCN2022129643-appb-000009
其中，R 1、R 3、R 4、R 5、R 6、R f、R c、X 1、X 2、X 3、X 4、m、n、W如上述实施方案所述。
一些实施方案中，所述化合物如式(VI-2)所示：
Figure PCTCN2022129643-appb-000010
其中，R 1、R 3、R 4、R 5、R 6、R f、R a、R c、X 1、X 2、X 3、X 4、m、n、W如上述实施方案所述。
一些实施方案中，所述化合物如式(VII-1)、式(VII-2)、式(VII-3)或式(VII-4)所示：
Figure PCTCN2022129643-appb-000011
其中，R 1、R 3、R 4、R 5、R 6、R f、R j、m、n如上述实施方案所述。
一些实施方案中，所述化合物如式(VIII-1)、式(VIII-2)、式(VIII-3)或式(VIII-4)所示：
Figure PCTCN2022129643-appb-000012
其中，R 1、R 3、R 4、R 5、R 6、R f、R c、R a、m、n如上述实施方案所述。
一些实施方案中，所述化合物如式(VIII-5)、式(VIII-6)、式(VIII-7)或式(VIII-8)所示：
Figure PCTCN2022129643-appb-000013
其中，R 1、R 3、R 4、R 5、R 6、R f、R c、m、n如上述实施方案所述。
一些实施方案中，所述化合物如式(IX-1)或式(IX-2)所示：
Figure PCTCN2022129643-appb-000014
其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如上述实施方案所述。
一些实施方案中，所述化合物如式(X-1)、式(X-2)、式(X-3)、式(X-4)、式(X-5)、式(X-6)、式(X-7)或式(X-8)所示：
Figure PCTCN2022129643-appb-000015
其中，R 1、R 6、R j、m如上述实施方案所述。
一些实施方案中，所述化合物如式(XI-1)或式(XI-2)所示，
Figure PCTCN2022129643-appb-000016
其中，R 4、R 5、R 6、R f、R c、R a、m如上述实施方案所述；
R x和R z分别独立地任选自卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基、-C 1-C 6亚烷基-OR c、-C 1-C 6亚烷基-C＝O-R c、-NO 2、-C(＝O)OR c和-S(＝O) 2R c。
本发明进一步提供了一种化合物或其药学上可接受的盐，所述化合物是指：
1)5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2,3-二氟苯腈；
2)5,5-二氟-1-(4-氟-3-(氟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
3)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
4)(S)-5-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
5)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
6)(S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
7)(S)-3-((S)-(二氟甲基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
8)(S)-3-((R)-(二氟甲基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
9)5-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
10)(S)-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
11)(S)-5-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
12)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
13)(S)-2-((5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)乙腈；
14)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
15)2-(1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酰胺；
16)(S)-3-(乙基磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
17)5-(3-(氰基二氟甲基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
18)N-(((S)-1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(甲基)(氧代)-16-亚磺基)氰胺；
19)(S)-2-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)乙腈；
20)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
21)(S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
22)(S)-5-(3-((二氟甲基)磺酰基)-2,5,5-三氟醚-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
23)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
24)1-(3-氯-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
25)1-(3-氯-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
26)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
27)(S)-2-氯-5-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
28)(S)-2-氯-5-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
29)(S)-4-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
30)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
31)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
32)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
33)(S)-1-(3-氯-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
34)(S)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
35)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
36)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
37)(S)-1-(3-氯-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
38)(S)-4-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
39)(S)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
40)(S)-2-氯-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
41)4-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
42)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
43)(S)-2-(二氟甲基)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
44)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
45)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
46)(S)-4-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
47)2-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2-氟乙腈；
48)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酸乙酯；
49)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙腈；
50)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酰胺；
51)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(噻唑-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
52)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
53)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(恶唑-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
54)(S)-2-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2,2-二氟乙腈；
55)2-(((S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2-氟乙腈；
56)(S)-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)二甲基氧化膦甲基；
57)2-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)丙腈；
58)(S)-1-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)环丙烷-1-腈；
59)N-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(甲基)(氧代)-16-亚磺基)氰胺；
60)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-羧酸乙酯；
61)(R)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
62)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-甲酰胺；
63)(4S,5R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5-氟-4,5,6,7-四氢-1H-吲哚-4-醇；
64)(4S,5S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5-氟-4,5,6,7-四氢-1H-吲哚-4-醇；
65)(R)-2-(二氟甲基)-4-(4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
66)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-3-氟苯腈；
67)(4S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)亚磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
68)(S)-1-((R)-6,8-二氟-1,2,3,4-四氢萘-1-基-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
69)(S)-1-((S)-6,8-二氟-1,2,3,4-四氢萘-1-基-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
70)(S)-1-(2,4-二氟苄基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
71)(S)-2-((5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)甲基)-5-氟苯腈；
72)(S)-1-(2,4-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
73)N-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(氧基)(三氟甲基)-l6-亚磺基)氰胺；
74)N-((二氟甲基)((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(氧代)-16-亚磺基)氰胺；
75)(S)-2-(5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯基)乙腈；
76)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(氟甲基)苯甲腈；
77)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
78)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
79)(S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
80)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
81)(S)-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-5,6-二氢环戊二烯[b]吡咯-1(4H)-基)-基2-氟苯腈；
82)(S)-3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢吲哚-8-醇；
83)(S)-3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇；
84)(7R,8S)-3-(3-(二氟甲基)-4-氟苯基)-7-氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢吲哚嗪-8-醇；
85)1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-1,4,5,7-四氢吡喃[3,4-b]吡咯-4-醇；
86)2-(二氟甲基)-4-((4S,5R)-3-((二氟甲基)磺酰基)-5-氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
87)2-(二氟甲基)-4-((4S,5R)-5-氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
88)(S)-5,5-二氟-1-(咪唑并[1,2-a]吡啶-8-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
89)(4S,5R)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
90)(S)-8-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟-1-萘腈；
91)(S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(4-氟-5,6,7,8-四氢萘-1-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
92)(S)-5,5-二氟-1-(喹啉-8-基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
93)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
94)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
95)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
96)1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
97)(4S)-1-(5,7二氟-2,3-二氢-1H-茚-1-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
98)(4S)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
99)(4S)-5,5-二氟-3-(甲磺酰基)-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
100)5,5-二氟-3-((氟甲基)磺酰基)-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
101)(4S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
102)(4S)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
103)2-(二氟甲基)-4-(5-氟-4-羟基-3-((三氟甲基)硫代)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；
104)2-(二氟甲基)-4-(5-氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；
105)2-氟-5-(5-氟-4-羟基-3-(三氟甲基)-4,7-二氢吡喃[3,4-b]吡咯-1(5H)-基)苄腈；
106)2-氟-5-(2,5,5-三氟-4-羟基-3-(噻吩-2-基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；或
107)2-(二氟甲基)-4-(5-氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈。
本发明还提供了化合物的制备方法，本发明式(I)所述的化合物或具体实施例所述的化合物都可使用可商购获得的起始物料，文献中已知的化合物，或由容易制备的中间体，通过采用本领域技术人员已知的，或根据本文记载内容 对本领域技术人员已知的有机合成技术制备获得，可以采用与具体实施例相类似的制备方法而得。
具体而言，在另一实施方案中，本发明涉及制备通式(IX-1)所示的化合物的方法，包括使用式(A-1)所示的化合物经还原试剂反应得到，
Figure PCTCN2022129643-appb-000017
其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如前述实施方案所定义。
在另一实施方案中，本发明涉及制备通式(IX-2)所示的化合物的方法，包括使用式(A-2)所示的化合物经还原试剂反应得到，
Figure PCTCN2022129643-appb-000018
其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如前述实施方案所定义；进一步地，所述R 1为
Figure PCTCN2022129643-appb-000019
所述R x、R z如前述实施方案所定义。
其中，所述还原试剂可以为硼氢化钠，硼氢化锂等常规还原试剂；式(IX-1)化合物和式(IX-2)化合物在骨架结构羟基位置相应的手性单体可以通过式(A-1)化合物和式(A-2)化合物的手性还原得到(例如Noyori不对称还原，CBS不对称还原等)。
在一些实施方式中，所述手性还原所应用的还原试剂为[(R,R)-Ts-DPEN]RuCl(p-cymene)]。
在另一些实施方案中，式(A-1)化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、R a、m如前述实施方案所定义，
Figure PCTCN2022129643-appb-000020
Figure PCTCN2022129643-appb-000021
式(B-1)所示的化合物可以与NH 2-R a(例如氰胺等)在氧化剂(例如二乙酸碘苯)条件下制备得到式(B-2)所示的化合物，式(B-2)所示的化合物经过氧化制备得到式(A-1)所示的化合物。
在另一些实施方案中，式(A-1)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、R a、m如前述实施方案所定义，
Figure PCTCN2022129643-appb-000022
式(B-1)所示的化合物经过氧化反应(例如间氯过氧苯甲酸，过氧单磺酸钾等)获得式(B-3)所示的化合物，式(B-3)所示的化合物在氧化剂(例如二乙酸碘苯)的存在下与亚胺化试剂(例如氨基甲酸铵，三氟乙酰胺等)反应制备得到式(B-4)所示的化合物，式(B-4)所示的化合物可以通过烷基化
(例如碘甲烷，碘乙烷等)引入Ra，或者偶联反应引入Ra(例如与氰化亚铜偶联)得到式(A-1)所示的化合物。在另一些实施方案中，式(A-2)所示的化合物可以通过如下方法制备得到，
Figure PCTCN2022129643-appb-000023
其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，进一步地，所述R 1为
Figure PCTCN2022129643-appb-000024
所述R x、R z如前述实施方案所定义。
式(B-1)所示的化合物可以通过氧化反应得到式(A-2)所示的化合物，其中氧化剂包括间氯过氧苯甲酸、过氧单磺酸钾、三氯化钌/高碘酸钠体系，三氯化钌/次氯酸钠体系等。
在另一些实施方案中，式(A-2)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X为卤素；
Figure PCTCN2022129643-appb-000025
式(C-1)所示的化合物与相应的亚磺酸盐(例如甲基亚磺酸钠盐等)在金属催化下(例如亚铜盐)偶联制备可获得式(A-2)所示的化合物。
在另一些实施方案中，式(A-2)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X为卤素；
Figure PCTCN2022129643-appb-000026
式(C-1)所示的化合物可通过偶联反应引入亚磺酸基团得到式(D-1)所示的化合物，或者将其卤原子X转变成负离子与原位产生二氧化硫的二氧化硫等价物(例如焦亚硫酸钾，1,4-二氮杂双环[2.2.2]辛烷-1,4-二鎓-1,4-二亚磺酸等)反应引入亚磺酸基团得到式(D-1)所示的化合物；式(D-1)所示的化合物可以与亲电试剂(例如Togni’s试剂，碘甲烷，三氟碘甲烷等)进行亲核反应制备得到式(A-2)所示的化合物，其中M +为任意可以成盐的一价正离子，例如Na +，K +，MgBr +等。
在另一些实施方案中，式(B-1)所示的化合物可以通过如下方法制备得到，
Figure PCTCN2022129643-appb-000027
其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X为卤素，R 101为C 1-10烷基；进一步地，所述R 1为
Figure PCTCN2022129643-appb-000028
所述R x、R z如前述实施方案所定义。
式(C-1)所示的化合物与巯基丙酸烷基酯(例如巯基丙酸甲酯，巯基丙酸乙酯，巯基丙酸叔丁酯等)偶联反应可以得到式(C-2)所示的化合物，式(C- 2)化合物在碱性条件下(碳酸钾，碳酸铯，磷酸钾，叔丁醇钾等)与相应的烷基化或亲电试剂(例如碘甲烷，氟碘甲烷，三氟碘甲烷，溴乙腈，溴氟甲基磷酸二乙酯等)在硫原子上引入相应的Rc基团制备得到式(B-1)所示的化合物。
在另一些实施方案中，式(B-1)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X为卤素；
Figure PCTCN2022129643-appb-000029
可以通过亲核硫试剂 -SRc(例如三氟甲硫醇银，三氟甲硫醇铜等)与式(C-1)所示的化合物进行偶联反应，得到式(B-1)所示的化合物。
在另一些实施方案中，式(C-1)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、m如前述实施方案所定义，X为卤素，X 1为-TIPS，-Trt或-TBDPS，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
Figure PCTCN2022129643-appb-000030
式(F-0)所示的化合物可以通过市售途径获得(例如1,5,6,7-四氢-4H-吲哚-4-酮)，式(F-0)所示化合物在碱性条件下进行N原子保护反应，即得式(F- 1)所示的化合物。式(F-1)所示化合物通过亲电的卤化试剂(例如NIS)在吡咯3为引入卤原子获得式(F-2)所示的化合物，式(F-2)所示的化合物在碱性条件下(如LiHDMS，LDA等)夺去羰基邻位的质子与亲电试剂(例如NFSI，Selectfluor等)反应引入R4和R5基团得到式(F-4)所示的化合物，式(F-4)所示化合物脱保护后得到式(F-5)所示化合物，然后经偶联反应得到式(C-1)所示的化合物。
式(F-1)化合物可以先在碱性条件下与亲电试剂在羰基邻位引入R 4和R 5基团，得到式(F-3)化合物，然后式(F-3)化合物与相应的亲电的卤化试剂在吡咯3位引入卤原子得到式(F-4)所示的化合物。
在另一些实施方案中，式(B-1)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X 1为-TIPS，-Trt或-TBDPS，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
Figure PCTCN2022129643-appb-000031
式(F-1)所示化合物与亲电试剂(例如沈试剂，N-(三氟甲硫基)邻苯二甲酰亚胺等)反应进行吡咯3位的亲电取代制备得到式(E-1)所示的化合物，然后在碱性条件下羰基邻位去质子化引入R 4和R 5基团得到式(E-3)所示的化合物，式(E-3)所示化合物脱保护后得到式(E-4)所示化合物，然后经偶联反应得到式(B-1)所示的化合物。
式(F-1)化合物可以先在碱性条件下羰基邻位去质子化引入R 4和R 5基团，得到式(F-3)化合物，然后式(F-3)化合物在碱性条件下亲电取代得到式(E-3)所示的化合物。
在另一些实施方案中，式(A-2)所示的化合物可以通过如下方法制备得到，其中R 1、R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X 1为-TIPS，-Trt或-TBDPS，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
Figure PCTCN2022129643-appb-000032
式(F-1)所示化合物与磺酰化试剂(例如三氟甲磺酸酐等)亲电取代引入磺酰基得到式(G-2)所示的化合物，然后在碱性条件下羰基邻位去质子化引入R 4和R 5基团得到式(G-4)所示的化合物，式(G-4)所示化合物脱保护后得到式(G-5)所示化合物，然后经偶联反应得到式(A-2)所示化合物。
式(F-1)所示化合物可以先在碱性条件下羰基邻位去质子化引入R 4和R 5基团，得到式(F-3)所示化合物，然后式(F-3)所示化合物在碱性条件下与磺酰化试剂(例如三氟甲磺酸酐等)亲电取代引入磺酰基得到式(G-4)所示化合物。
在另一些实施方案中，式(G-5)所示的化合物可以通过如下方法制备得到，其中R 4、R 5、R 6、R f、R c、m如前述实施方案所定义，X为卤素，X 2为-Boc或苯磺酰基；
Figure PCTCN2022129643-appb-000033
式(H-1)所示的化合物可以通过式(F-0)所示化合物进行N原子保护，然后经过卤代反应得到，式(H-1)化合物通过偶联反应与亲核性硫试剂 -SRc(例如三氟甲硫醇银，三氟甲硫醇铜等)反应得到式(H-2)所示化合物，式(H-2)所示化合物进行氧化反应得到式(H-3)所示化合物，然后进行脱保护反应最终得到式(G-5)所示化合物。
本发明另一方面还提供了制备式(IX-1)和式(IX-2)所示化合物的中间体，其选自如下结构：
Figure PCTCN2022129643-appb-000034
Figure PCTCN2022129643-appb-000035
其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如前述实施方案所述，X为卤素，X 1选自-TIPS，-Trt或-TBDPS，X 2为-Boc或苯磺酰基，R 101为C 1-3烷基。
进一步地，本发明还提供了制备式(XI-1)和式(XI-2)所示化合物的中间体，其选自如下结构：
Figure PCTCN2022129643-appb-000036
Figure PCTCN2022129643-appb-000037
其中，R 1、R 4、R 5、R 6、R f、R c、R a、R x、R z、m如前述实施方案所述，X为卤素，X 1选自TIPS-、Trt-，X 2为-Boc，R 101为C 1-10烷基。
本发明还提供了一种药物组合物，包含治疗有效量的至少一种上述化合物和药学上可接受的辅料，例如羟丙基甲基纤维素。在一些组合物中，所述化合物与所述辅料的重量比大约为0.001～10。
此外，本发明还提供一种治疗患有对HIF-2α介导疾病或病症的受试者的方法，包括给药治疗有效量的式(I)的化合物或其可药用盐。
在某些方面，疾病或病症选自VHL综合征、自身免疫疾病、癌症、炎性疾病、神经变性疾病、心血管障碍、肾病症、病毒感染和肥胖。
在某些方面，所述疾病或病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、银屑病、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性阻塞性气道病、肺炎、皮炎、脱发、肾炎、血管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥反应。
在某些方面，所述疾病或病症是癌症，所述癌症选自恶性实体肿瘤和血液学肿瘤。
在某些方面，所述癌症包括但不限于骨癌、胰腺癌、皮肤癌、头颈癌恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、胃癌、子宫癌、宫颈癌、子宫内膜癌、 淋巴瘤、食道癌、结肠癌、直肠癌、甲状腺癌、前列腺癌、肉瘤、白血病、膀胱癌、肾癌、胶质瘤、外皮囊腺瘤、鳞状细胞癌、嗜铬细胞瘤、肺癌、胰腺癌、肝癌、肾癌、乳腺癌、脑脊膜瘤、神经细胞瘤、副神经节瘤、母细胞瘤、内分泌瘤、脑膜瘤和髓母细胞瘤。
在某些方面，所述疾病或病症为VHL综合征。
在某些方面，所述疾病或病症为肾癌；更进一步的，所述疾病为肾细胞癌；所述疾病为透明细胞肾癌。
在在某些方面，所述受试者是人类。
在某些方面，所述化合物是静脉内、肌内、胃肠外、鼻或口服给药的。在一个方面，所述化合物是口服给药的。
本发明还提供式(I)的化合物或其可药用盐在制备用于治疗由HIF-2α介导的疾病或病症的药物中的用途。
本发明还提供用于治疗的式(I)所示化合物或其可药用盐。进一步提供用于治疗患有由HIF-2α介导的疾病或病症的受试者的式(I)的化合物或其可药用盐。
本发明可以在不脱离其精神或基本属性的情况下以其他特定形式实施。本发明涵盖本文提到的本发明的优选方面的所有组合。应理解，发明内容中公开的主题没有穷尽或完整地公开了本发明技术或其任意实施方案的全部范围，可以采用本发明的任何和所有实施方案结合任何其他一个或多个实施方案来描述另外的实施方案。还应理解，实施方案的每个单独要素是其本身的独立实施方案。此外，实施方案的任何要素意在与来自任何实施方案中的任何和所有其他要素组合来描述另外的实施方案。
本发明中，除另有说明，术语“卤素”(halogen)是指氟、氯、溴或碘。优选的卤素基团是指氟、氯和溴。
本发明中，除另有说明，术语“烷基”包括直链或支链的饱和单价烃基。例如，烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似的，C 1-C 6烷基中的“C 1-C 6”是指含有1、2、3、4、5或6个碳原子以直链或支链形式排列的基团。
术语“烷氧基”是指由上述的直链、支链或环状烷基所形成的氧醚。
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的，C 1-C 4亚烷基中的“C 1-C 4”是指含有1、2、3或4个碳原子的亚烷基。
术语“卤代烷基”是指一个或多个H已经被卤素原子置换的烷基。术语“卤代烷氧基”是指-O-卤代烷基的基团。
术语“氧代”或“氧代基”是指呈二甲取代基形式的氧原子，其与C连接时形成羰基，其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。
本发明中，除另有说明，术语“芳香环”、“芳香族环”或“芳香族杂环”即为具有芳香族特征(具有(4n+2)个非定域π电子，其中n为整数)的多不饱和环的碳环或杂环。
术语“芳基”为取代或未取代的稳定的6到10个环碳原子的芳香族烃基，其可以包含1个芳香环或多个芳香环(例如稠和双环)。所述的芳香环不含有杂原子。芳基的实施例包括但不限于，苯基、萘基、茚基等。
术语“杂芳基”是指具有至少一个杂原子环成员的单环或多环(例如稠合双环)芳香族杂环，所述杂原子选自N、O和/或S。5-18元杂芳基中的“5-18元”是指含有5-18个碳原子或N、O或S的成环原子组成的杂芳基。此类杂芳基的实例包括但不限于，吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯并咪唑、苯并噻吩基、苯并呋喃基等。
术语“环烷基”是指具有至少一个环化烷基的环系统。术语C 3-C 10环烷基中的“C 3-C 10”是指环烷基可以具有3、4、5、6、7、8、9或10个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环，螺环、并环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等；在一些实施例中环烷基还包括具有一个或多个与环化烷基环稠合的芳香族环的部分，例如环己烷的苯并或噻吩基衍生物等。
术语“环烯基”是指具有至少一个环化烯基的环系统，所述环烯基中具有一个或多个碳碳双键。术语C 3-C 10环烯基中的“C 3-C 10”是指环烯基可以具有3、4、5、6、7、8、9或10个成环原子。环烯基可以包括单环和多环(例如具有2、3或4个稠合环，螺环、桥环等)。一些实施例中环烯基包括但不限于环己烯基、环己二烯、环庚三烯基等；在一些实施例中环烯基还包括具有一个或多个与环化烯基环稠合的芳香族环的部分，例如环己烯环的苯并或噻吩基衍生物等。
术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环系统，所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环，螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。所述杂环基的定义中还包括具有一个或多个与环化烷基或环化烯基环稠合的芳香族环的部分，例如哌啶、吗啉等的苯并或噻吩基衍生物。在一些实施方案中，杂环基包括但不限于吡咯烷基、吡咯啉基、四氢噻吩基、四氢呋喃基、哌啶基、吗啉基、氮杂环庚烷、二氢苯并呋喃基等。
本发明中术语“组合物”旨在包括含有特定数量的特定组分的产品，也包括任何由特定数量的特定组分直接或间接得到的产品。因此，包含本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法也是本发明的内容。而且，一些化合物的晶型可以多晶型形式存在，这些也包括在本发明中。此外，一些化合物与水(如水合物)或普通有机溶剂形成溶剂化物，这些溶剂化物也包含在本发明中。
本发明所述化合物”包括式(Ⅰ)的化合物，及其所有药学上可接受的形式。这些药学上可接受的形式包括盐、溶剂化物、非共价复合物、螯合物、立体异构体(包括非对映异构体、对映异构体和外消旋体)、几何异构体、同位素标记的化合物、互变异构体、前体药物、或上述所有形式的任意混合物。
所述“对映异构体”是一对彼此不可重叠、互为镜像的立体异构体，一对对映异构体的1:1混合物是一种“外消旋”混合物。当指定本发明化合物的立体化学时，使用常规RS系统(例如(1S,2S)指定具有两个手性中心的已知相对和绝对构型的单一立体异构体)。光学活性(R)-和(S)-异构体可以使用光学活性的原料合成来制备或手性试剂来制备，或者使用常规技术来拆分(例如，在手性SFC或HPLC色谱柱上分离)。
所述“非对映异构体”是具有至少两个不对称原子的立体异构体，但其不是彼此的镜像。当化合物为纯对映体时，每个手性碳上的立体化学可以由R或S指定。
绝对构型未知的拆分化合物可以根据他们在钠D线的波长处旋转平面偏振光的方向(右旋或左旋)命名为(+)或(-)。或者，拆分的化合物可以通过手性HPLC的相应对应异构体/非对应异构体的相应保留时间来定义。
本领域技术人员将认识到，本发明化合物可能含有一个或多个手性中心，并可能由此产生非对映异构体和光学异构体。上述式(I)没有确切定义该化合物某一位置的立体结构，因此可以以不同的异构形式存在。除非另有说明，否则本发明包括式(I)所示化合物的所有可能的立体异构体及其药学上可接受的盐，例如外消旋混合物、光学纯形式和任意比例的异构体混合物。进一步地，立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中，或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中，制得的产品可以是立体异构体的混合物。
本发明化合物的药物前体(前药)包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需要的化合物的功能性衍生物。因此，本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物，或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的前药化合物。有关选择和制备合适药物前体衍生物的常规方法，已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
显然的，一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解，本领域普通技术人员可以通过现有技术手段及本发明中所述的方法，选择本发明中的化合物的取代基或取代形式，以提供化学上稳定且容易合成的化合物。
显然的，一个分子中任何取代基或特定位置的变量的定义，与其他分子中的任何取代基或特定位置的变量的定义是无关的。很容易理解，本发明中的化合物可以根据本学科现有技术选择合适的取代基或取代形式，以提供化学上稳定且容易用本学科现有技术或本发明中所述的方法进行制备合成。
当式(I)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之 类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。由于式(I)所示化合物将作为药物应用，所以优选使用基本上纯的形式，例如，至少60％纯度，更适当地至少75％的纯度，特别地至少98％的纯度(％是重量比)。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
实际上，根据常规的药物混合技术，本发明式(I)所示化合物，或药物前体，或代谢物，或药学上可接受的盐，可以作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，这取决于期望采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式，如包含预定剂量的活性组分的胶囊剂、 扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液，或油包水型乳液形式。另外，除了上述提到的常见的剂型，式(I)所示化合物或其药学上可接受的盐，也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切的混合制得。然后，该产品可以方便地制备成所需要的外观。
因此，本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其药学上可接受的盐。式(I)所示化合物或其药学上可接受的盐，与其他一种或多种具有治疗活性的化合物也包括在本发明的药物组合物中。
本发明采用的药物载体可以是，例如，固体载体、液体载体或气体载体。固体载体，包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体，包括糖浆、花生油、橄榄油和水。气体载体，包括二氧化碳和氮气。制备药物口服制剂时，可以使用任何方便的制药学上的介质。例如，水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂；而载体，如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用，口服制剂首选片剂和胶囊，在此应用固体药学载体。可选地，片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过，任选一种或多种辅助组分或辅药一起压制或成型制备。活性组分以自由流动的形式如粉末或颗粒，与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合，在适当的机器中，通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物，然后在适当的机器中，通过成型可以制得模制片。较优地，每个片剂含有大约0.05mg到5g的活性组分，每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如，拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分，与合适且方便计量的辅助材料复合，该辅助材料约占药物组合物总量的5％至95％。单位剂型一般包含约1mg到约2g的活性组分，典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇，及其在油中的混合物，也可以制得分散体系。进一步地，防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射的药物组合物，包括无菌水溶液或分散体系。进一步地，上述药物组合物可以制备成可用于即时配制无菌注射液或分散液的无菌粉末的形式。无论如何，最终的注射形式必须是无菌的，且为了易于注射，必须是易于流动的。此外，所述药物组合物在制备和储存过程中必须稳定。因此，优选抗微生物如细菌和真菌污染的保存。载体可以是溶剂或分散介质，例如，水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。
本发明提供的药物组合物，可以是适于局部用药的形式，例如，气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。进一步地，本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(I)所示化合物，或其药学上可接受的盐，通过常规的加工方法，可以制备这些制剂。作为一个例子，乳剂或软膏剂的制备是通过在约5wt％到10wt％的上述化合物中加入亲水性材料和水，制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物，可以制成以固体为载体，适用于直肠给药的形式。优选的剂型为混合物形成单位剂量的栓剂。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备，首先药物组合物与软化或熔化的辅料混合，然后冷却和模具成型而制得。
除了上述提到的载体组分外，上述药学制剂还可以包括，适当的，一种或多种附加的辅料组分，如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。此外，其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含式(I)所示化合物，或其药学上可接受的盐的药物组合物，也可以制备成粉剂或浓缩液的形式。
一般情况下，治疗上述所示的状况或不适，药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重，或者每个病人每天0.5mg到7g。但是，可以理解，任何特定病人的具体剂量水平将取决于多种因素，包括年龄、体重、综 合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。
具体实施方案
为使本发明更加容易理解，下面将结合实施例来详细说明本发明，这些实施例仅起说明性作用，并不局限于本发明的应用范围。本发明中的实验方法，如无特殊说明，均为常规方法。本发明中所用的实验材料如无特殊说明，均为市场购买得到。
除另有说明，所有的部分和百分数均以重量计算，所有的温度均为摄氏度。
实施例中使用了下列缩略语：
CuI：碘化亚铜；
DAST：二乙胺基三氟化硫；
DCM：二氯甲烷；
DIEA：N,N-二异丙基乙基胺；
DMF：N,N-二甲基甲酰胺；
DMSO：二甲基亚砜；
EA：乙酸乙酯；
ESI-MS：电喷雾电离质谱；
K 2CO 3：碳酸钾；
NaH：氢化钠；
LDA：二异丙基氨基锂；
LiHMDS：双(三甲基硅基)胺基锂；
m-CPBA：间氯过氧苯甲酸；
MtBE：甲基叔丁基醚；
Na 2SO 4：硫酸钠；
NaBH 4：硼氢化钠；
NBS：N-溴代琥珀酰亚胺；
NFSI：N-氟代双苯磺酰胺；
NIS：N-碘代丁二酰亚胺；
NMP：N-甲基吡咯烷酮；
PE：石油醚；
Pd 2(dba) 3：三(二亚苄基丙酮)二钯；
Pd(dppf)Cl 2：1,1'-双(二苯基膦基)二茂铁]二氯化钯；
Pd(PPh 3) 4：四(三苯基膦)钯；
Prep-TLC：制备薄层色谱；
TMSC 2F 5：(五氟乙基)三甲基硅烷；
TBAF：四丁基氟化铵；
TEA：三乙胺；
THF：四氢呋喃；
Xantphos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；
TLC：薄层色谱；
ESI-MS：电喷雾质谱；
LCMS或LC-MS：液相色谱质谱联用；
1H NMR：核磁共振氢谱；
[(R,R)-Ts-DPEN]RuCl(p-cymene)：氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)。
中间体M1的合成(5,5-二氟-3-碘-1,5,6,7-四氢-4H-吲哚-4-酮)
Figure PCTCN2022129643-appb-000038
步骤1:化合物M1-1的合成
氮气保护下，将6,7‐二氢‐1H‐吲哚‐4(5H)‐酮(13.5g)悬浮于THF(100mL)中，室温下缓慢滴加DBU(33.44g)和三异丙基氯硅烷(21.2g)。室温搅拌3小时，在反应液中加入MTBE(100mL)和10％柠檬酸水溶液(100mL)后分液，有机相用无水硫酸钠干燥，过滤，浓缩后得到目标化合物M1-1(20.3g)，直接用于下一步。
ESI-MS m/z:292.10[M+H] +。
步骤2：化合物M1-2的合成
氮气保护下，将化合物M1-1(13.5g)溶于乙腈(100mL)中，分批加入NIS(11.5g)，室温反应5小时，将反应冷却，析出固体过滤并用甲醇(50mL*2)淋洗，干燥后得目标化合物M1-2(15.4g)。
ESI-MS m/z:418.10[M+H]+。
步骤3：化合物M1的合成
将化合物M1-2(4.2g)和NFSI(7.9g)悬浮于THF(100mL)中，冷却至-78℃，缓慢滴入1.0M的LiHMDS四氢呋喃溶液(28.2mL)，在-60℃下搅拌2小时后，反应液中加入饱和氯化铵的水溶液(200mL)，用乙酸乙酯萃取两次，饱和食盐水洗涤两次，干燥，浓缩得粗产物，粗产物用甲醇淋洗，得到目标化合物M1(2.1g)。
ESI-MS m/z:297.99[M+H] +。
1H NMR(500MHz,DMSO-d6)：δ12.05(s,1H),7.12(d,J＝2.3Hz,1H),2.98(t,J＝6.2Hz,2H),2.60-2.53(m,2H)。
中间体M2的合成(5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮)
Figure PCTCN2022129643-appb-000039
将M1(12g)、碘化亚铜(7.8g)，氟磺酰基二氟乙酸甲酯(24g)加入NMP(120mL)，氮气置换保护加热到120℃，反应过夜，TLC和LCMS显示无原料剩余，降温冷却，乙酸乙酯稀释，有机相饱和食盐水洗涤，硫酸钠干燥，浓缩得粗产物，柱层析(EA/PE＝1：5)纯化，得目标化合物M2(8.4g)。
ESI-MS m/z:238.00[M-H] -。
1H NMR(500MHz,DMSO)δ12.37(s,1H),7.56(s,1H),3.03(t,J＝6.1Hz,2H),2.68–2.55(m,2H)。
中间体M3的合成(5-氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮)
Figure PCTCN2022129643-appb-000040
步骤1：化合物M3-1的合成
在50mL单口瓶中依次加入化合物M1-2(834mg)，碘化亚铜(380mg)，NMP(20mL)和氟磺酰基二氟乙酸甲酯(1.15g)，升温至120℃，反应6h，反应混合液经EA稀释，用水洗涤三次，饱和食盐水洗涤一次，干燥，浓缩得粗产物，粗产物经柱层析(DCM＝100％)纯化，得到目标化合物M3-1(264mg)。
ESI-MS m/z:204.08[M+H +] +。
步骤2：化合物M3的合成
方法一：
在氮气保护下，将化合物M3-1(264mg)溶于超干四氢呋喃(20mL)中，冷却至-78℃，缓慢滴入1.0M的LDA四氢呋喃溶液(2.5mL)，搅拌半小时后，滴入NFSI(491mg)的四氢呋喃溶液(5mL)，继续保持在-78℃下搅拌两小时。向反应混合物中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取两次，饱和食盐水洗涤两次，干燥，浓缩得粗产物，粗产物经柱层析(DCM＝100％)纯化，得到目标化合物M3(147mg)。
方法二：
在氮气保护下，将化合物M3-1(200mg)溶于甲醇(3mL)，加入NFSI(465mg)，70℃回流过夜，反应完毕，浓缩柱层析(DCM＝100％)纯化得目标化合物M3(173mg)。
ESI-MS m/z:222.12[M+H +] +。
中间体M4(3-溴-7-氟-1-(三氟甲基)-6,7-二氢吲哚嗪-8(5H)-酮)和中间体M5 (3-溴-7,7-二氟-1-(三氟甲基)-6,7-二氢吲哚嗪-8(5H)-酮)的合成
Figure PCTCN2022129643-appb-000041
步骤1:化合物M4-1的合成
氮气保护下，将3-溴-1H-吡咯-2-羧酸甲酯(20.4g)和4-溴代丁酸甲酯(19.8g)溶于DMF(100mL)中，加入碳酸铯(65.2g)，室温搅拌4小时后，将反应液倒入冰水(500mL)混合物中，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:10)纯化，得目标化合物M4-1(28.3g)。
ESI-MS m/z:304.10[M+H] +。
步骤2：化合物M4-2的合成
氮气保护下，将化合物M4-1(15.2g)溶于THF(100mL)中，冰浴下缓慢滴入1.0M的叔丁醇钾四氢呋喃溶液(60mL)，0℃下搅拌3小时后冷却至-78℃，滴入NFSI(18.9g)的四氢呋喃溶液(50mL)，-78℃下继续反应1小时，加入饱和氯化铵的水溶液淬灭反应后，用乙酸乙酯萃，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:5)纯化，得到目标化合物M4-2(9.1g)。
ESI-MS m/z:277.15[M+H] +。
步骤3：化合物M4-3的合成
在氮气保护下，将化合物M4-2(8.3g)溶于DMF(100mL)中，加入醋酸钯(3.3g)，CuI(11.4g)和氟磺酰基二氟乙酸甲酯(23g)，100℃搅拌3小时，乙酸乙酯萃取，有机层用盐水洗涤，经Na 2SO 4干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:4)纯化，得目标化合物M4-3(4.23g)。
ESI-MS m/z:279.20[M+H] +。
步骤4：化合物M4-4的合成
将化合物M4-3(4.23g)溶于乙醇(20mL)和6M的盐酸水溶液(20mL)的混合溶剂中，反应回流3小时。减压浓缩旋掉乙醇，残余物用乙酸乙酯(100mL*2)萃取，有机层用盐水(100mL*2)洗涤，经Na 2SO 4干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:4)纯化，得到目标化合物M4-4(2.1g)。
ESI-MS m/z:221.20[M+H] +。
步骤5：化合物M4的合成
将化合物M4-4(2.1g)溶于乙腈(20mL)，室温下加入NBS(1.8g)，将反应液回流4小时，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸 钠干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化，得到目标化合物M4(2.5g)。
ESI-MS m/z:300.10[M+H] +。
步骤6：化合物M5的合成
将化合物M4(1.3g)溶于THF(50mL)中，冷却至-78℃，缓慢滴入1.0M的LiHMDS四氢呋喃溶液(6mL)，搅拌半小时后，滴入NFSI(1.5g)的四氢呋喃溶液(10mL)，继续搅拌两小时，加入饱和氯化铵的水溶液淬灭反应后，用乙酸乙酯萃取两次，饱和食盐水洗涤两次，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化，得到目标化合物M5(0.8g)。
实施例1 5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2,3-二氟苯 腈的合成(化合物B1)
Figure PCTCN2022129643-appb-000042
步骤1：化合物B1-1的合成
将醋酸钾(0.76g)，1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷复合物(0.21g)，联硼酸频那醇酯(1.31g)，5-溴-2,3-二氟苯腈(0.56g)溶于二氧六环(6mL)和二甲亚砜(0.05mL)中，氮气置换，95℃搅拌过夜，反应完毕后，加入乙酸乙酯和水，分液，饱和食盐水洗涤，干燥浓缩得粗品B1-1(0.7g)直接用于下一步。
步骤2：化合物B1-2的合成
将醋酸铜(0.31g)，4A分子筛(0.5g)，化合物M2(0.47g)和化合物B1-1(0.7g)置于反应瓶中，加入DMF(1mL)和三乙胺(0.71mL)，氧气置换，80℃搅拌过夜，冷却至室温，过滤，乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物B1-2(0.07g)。
步骤3：化合物B1的合成
将化合物B1-2(0.07g)溶于甲醇(1mL)和四氢呋喃(1mL)中，冰水浴冷却，加入硼氢化钠(0.02g)，室温搅拌过夜，反应完毕后向反应液中加入 乙酸乙酯和水，饱和食盐水洗涤，干燥，浓缩，Prep-TLC得目标化合物B1(0.07g)。
ESI-MS m/z:423.21[M+HCOO -] -。
实施例2 5,5-二氟-1-(4-氟-3-(氟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4- 醇的合成(化合物B2)
Figure PCTCN2022129643-appb-000043
将5,5-二氟-1-(4-氟-3-(羟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇(100mg)溶于二氯甲烷(2mL)，冰水浴冷却，加入DAST(48mg)，冰水浴搅拌1小时后，向反应液中加入饱和碳酸氢钠，二氯甲烷稀释，分液，有机相饱和食盐水洗涤，干燥，浓缩，Prep-TLC制备得目标化合物B2(10mg)。
ESI-MS m/z:350.10[M+H 2O-H +] +。
实施例3(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟 甲基)苯甲腈的合成(化合物B3)
Figure PCTCN2022129643-appb-000044
步骤1：化合物B3-1的合成
将醋酸钾(224mg)，1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷复合物(42mg)，联硼酸频那醇酯(305mg)，4-溴-2-(二氟甲基)苯腈(265mg)溶于二氧六环(6mL)，氮气保护，80℃搅拌过夜，反应完毕后，向反应液中加入乙酸乙酯和水，分液，饱和食盐水洗涤，干燥浓缩得粗品，粗品经柱层析纯化得化合物B3-1(165mg)。
步骤2：化合物B3-2的合成
向醋酸铜(92mg)，4A分子筛(100mg)，化合物M2(61mg)和化合物B3-1(50mg)的混合物中加入DCM(5mL)和二异丙基乙基胺(0.13mL)，氧气置换，室温搅拌过夜，过滤，浓缩，柱层析纯化得目标化合物B3-2(64mg)。
步骤3：化合物B3的合成
向化合物B3-2(64mg)的二氯甲烷溶液中，加入三乙胺(0.05mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)和甲酸(23mg)，室温搅拌过夜，浓缩，柱层析纯化得目标化合物B3(35mg)。
ESI-MS m/z:437.24[M+HCOO -] -。
实施例4(S)-5-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1- 基)-2-氟苯腈的合成(化合物A3)
Figure PCTCN2022129643-appb-000045
步骤1：化合物A3-1的合成
向化合物M2(0.9g)的DCM(50mL)溶液中加入醋酸铜(0.55g)，3-氰基-4-氟苯硼酸(1.0g)和TEA(1.2g)，室温搅拌过夜。反应混合液用二氯甲烷稀释，饱和食盐水洗涤两次，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:5)纯化，得目标化合物A3-1(0.92g)。
步骤2：化合物A3-2的合成
将化合物A3-1(1.26g)，3-巯基丙酸甲酯(0.73g)，Xantphos(0.35g),三(二亚苄基丙酮)二钯(0.28g)，DIEA(1.5mL)和甲苯(40mL)的混合物于70℃搅拌过夜，反应完毕，浓缩得粗产物，粗产物经柱层析纯化得目标化合物A3-2(1.10g)。
步骤3：化合物A3-3的合成
于-78℃条件下，向化合物A3-2(0.40g)的四氢呋喃(10mL)溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(1.5mL)，搅拌10分钟后加入溴氟甲基膦酸二乙酯(0.40g)，搅拌2小时后加入水淬灭反应，反应液升至室温继续搅拌过夜，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1：3)纯化得目标化合物A3-3(0.18g)。
步骤4：化合物A3-4的合成
向化合物A3-3(0.15g)，乙腈(1mL)，二氯甲烷(1mL)和水(2mL)的混合物中加入三氯化钌(0.01g)和高碘酸钠(0.5g)，室温搅拌2h，反应完毕，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A3-4(0.1g)。
步骤5：化合物A3的合成
向化合物A3-4(0.12g)的二氯甲烷溶液中加入三乙胺(0.08mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(0.04g)和甲酸(0.04g)，室温搅拌过夜，反应液加入二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A3(0.09g)。
ESI-MS m/z:451.16[M+HCOO -] -。
实施例5(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-4,5,6,7-四氢- 1H-吲哚-4-醇的合成(化合物A4)
Figure PCTCN2022129643-appb-000046
步骤1：化合物A4-1的合成
将(4-氟-3-甲酰基苯基)硼酸(2.0g)，化合物M2(3.5g)，醋酸铜(2.5g)和三乙胺(5.0mL)分别加入二氯甲烷(40mL)中，氧气氛围下，室 温搅拌过夜，反应完毕后，反应液加入二氯甲烷稀释，饱和食盐水洗涤两次，干燥，过滤，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A4-1(1.8g)。
ESI-MS m/z:420.0[M+H] +。
步骤2：化合物A4-2的合成
向化合物A4-1(500mg)的二氯甲烷(10mL)溶液中加入DAST(700mg)，室温搅拌过夜，反应完毕，反应液加入二氯甲烷稀释，饱和碳酸氢钠淬灭，有机相水洗，干燥，过滤，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A4-2(150mg)。
ESI-MS m/z:442.0[M+H] +。
步骤3：化合物A4-3的合成
将化合物A4-2(0.88g)，3-巯基丙酸甲酯(0.36g)，Xantphos(0.23g),三(二亚苄基丙酮)二钯(0.18g)，DIEA(0.66mL)和甲苯(5mL)的混合物于70℃搅拌过夜，反应完毕，浓缩得粗产物，粗产物经柱层析纯化得目标化合物A4-3(0.8g)。
ESI-MS m/z:434.0[M+H] +。
步骤4：化合物A4-4的合成
将化合物A4-3(0.30g)溶于四氢呋喃(10mL)中，降至-78℃搅拌半小时，然后加入1.0M叔丁醇钾的四氢呋喃溶液(1.0mL)，搅拌10分钟后加入碘甲烷(0.09mL)，-78℃继续搅拌2小时，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A4-4(0.20g)。
ESI-MS m/z:362.0[M+H] +。
步骤5：化合物A4-5的合成
向化合物A4-4(0.2g)，乙腈(10mL)和水(2mL)的混合物中加入过氧单磺酸钾(0.71g)，60℃搅拌2h，反应完毕，反应液加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A4-5(0.18g)。
ESI-MS m/z:394.0[M+H] +。
步骤6：化合物A4的合成
向A4-5(0.06g)的二氯甲烷(3mL)溶液中加入三乙胺(0.03g)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(0.01g)和甲酸(0.02g)，室温搅拌过夜，反应液加入二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩得粗产物，粗产物经柱层析(EA/PE＝1:3)纯化得目标化合物A4(0.03g)。
ESI-MS m/z:451.16[M+H +-H 2O] +。
实施例6(S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四 氢-1H-吲哚-4-醇的合成(化合物A5)
Figure PCTCN2022129643-appb-000047
步骤1：化合物A5-1的合成
将化合物A4-3(0.20g)溶于四氢呋喃(10mL)中，降至-78℃搅拌半小时，加入1.0M的叔丁醇钾的四氢呋喃溶液(0.7mL)，搅拌10分钟后加入溴氟甲基膦酸二乙酯(0.20g)，-78℃继续搅拌2小时，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥浓缩，柱层析纯化得目标化合物A5-1(0.15g)。
ESI-MS m/z:398.0[M+H] +。
步骤2：化合物A5-2的合成
向化合物A5-1(0.15g)，乙腈(2mL)，二氯甲烷(2mL)和水(4mL)的混合物中加入三氯化钌(0.01g)和高碘酸钠(0.24g)，室温搅拌2h，反应完毕，反应液加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A5-2(0.08g)。
步骤3：化合物A5的合成
向化合物A5-2(0.08g)的二氯甲烷(3mL)溶液中加入三乙胺(0.05mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(0.01g)和甲酸(0.03g)，室温搅拌过夜，反应液加入二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A5(0.03g)。
ESI-MS m/z:414.05[M+H +-H 2O] +。
实施例7和实施例8(S)-3-((S)-(二氟甲基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲 基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇(化合物A13，假定)和(S)-3-((R)-(二氟甲 基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇(化 合物A14，假定)的合成
Figure PCTCN2022129643-appb-000048
步骤1：化合物A13-11的合成
将3-氰基-4-氟苯硼酸替换为3-三氟甲基-4-氟苯硼酸，参考实施例4步骤1的方法，即可得化合物A13-11。
步骤2：化合物A13-12的合成
将化合物A3-1替换为化合物A13-11，参考实施例4步骤2的方法，即可得到化合物13-12。
步骤3：化合物13-1的合成
将化合物A3-2替换为化合物13-11，参考实施例4步骤3的方法，即可得到化合物13-1。
步骤4：化合物A13-2的合成
向化合物A13-1(120mg)的乙腈(2mL)和水(2mL)混合溶液中加入过氧单磺酸钾(210mg)，65℃搅拌过夜，反应完毕，冷却，乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A13-2(90mg)。
ESI-MS m/z:430.0[M-H +] -。
步骤5：化合物A13和A14的合成
向A13-2(100mg)的二氯甲烷(5mL)溶液中加入氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)，三乙胺(0.06mL)和甲酸(0.03g)，室温搅拌过夜，反应液加入二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，粗品经HPLC纯化(Luna PREP C18，流动相A：水(0.1％甲酸)，流动相B：乙腈(35％到70％)，流速：40mL/min，检测波长：254nm，温度：室温)，收集前峰为目标化合物A13(20mg)，后峰为目标化合物A14(20mg)。
ESI-MS m/z:416.07[M+H +-H 2O] +。
实施例9 5-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈 的合成(化合物A10)
Figure PCTCN2022129643-appb-000049
步骤1：化合物A10-1的合成
向A3-1(130mg)，碘化亚铜(0.12g)，氟化银(0.08g)和二甲亚砜(2mL)混合溶液中加入TMSC 2F 5(0.11mL)和吡啶(0.12mL)，80℃搅拌过夜，反应液加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A10-1(100mg)。
步骤2：化合物A10的合成
将化合物A10-1(100mg)溶于甲醇(1mL)和四氢呋喃(1mL)中，冰水浴冷却至0℃，加入硼氢化钠(30mg)，室温反应过夜，反应液加水稀释，乙酸乙酯萃取，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A10(90mg)。
ESI-MS m/z:455.17[M+HCOO -] -。
实施例10(S)-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1- 基)-2-氟苯腈的合成(化合物A11)
Figure PCTCN2022129643-appb-000050
步骤1：化合物A11-1的合成
向噻吩-2-甲酸亚铜(270mg)，化合物A3-1(400mg)和三氟甲烷硫醇银(300mg)的混合物中加入N，N-二甲基乙酰胺(2mL)，100℃搅拌过夜，冷却至室温，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A11-1(210mg)。
ESI-MS m/z:389.0[M-H +] -。
步骤2：化合物A11-2的合成
向化合物A11-1(100mg)的乙腈(2mL)，二氯甲烷(2mL)和水(4mL)混合液中加入三氯化钌(0.01g)和高碘酸钠(0.22g)，室温搅拌2h，反应完毕后，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A11-2(70mg)。
ESI-MS m/z:421.0[M-H +] -。
步骤3：化合物A11的合成
向化合物A11-2(50mg)的二氯甲烷(5mL)溶液中加入氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)，三乙胺(0.03mL)和甲酸(30mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A11(10mg)。
ESI-MS m/z:469.10[M+HCOO -] -。
实施例11(S)-5-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1- 基)-2-氟苯腈的合成(化合物A16)
Figure PCTCN2022129643-appb-000051
步骤1：化合物A16-1的合成
在-78℃条件下，向化合物A3-2(120mg)的四氢呋喃(10mL)溶液中，加入1.0M的叔丁醇钾的四氢呋喃溶液(0.44mL)，搅拌10分钟后再加入氟碘甲烷(70mg)，继续搅拌2小时，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A16-1(80mg)。
ESI-MS m/z:353.0[M-H +] -。
步骤2：化合物A16-2的合成
向化合物A16-1(60mg)的乙腈(3mL)和水(3mL)混合溶液中加入过氧单磺酸钾(0.63g)，60℃搅拌过夜，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A16-2(50mg)。
ESI-MS m/z:385.0[M-H +] -。
步骤3：化合物A16的合成
向化合物A16-2(70mg)的二氯甲烷(5mL)溶液中加入三乙胺(0.05mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)和甲酸(20mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A16(30mg)。
ESI-MS m/z:433.16[M+HCOO -] -。
实施例12(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7- 四氢-1H-吲哚-4-醇的合成(化合物A17)
Figure PCTCN2022129643-appb-000052
步骤1:化合物A17-1的合成
向噻吩-2-甲酸亚铜(140mg)，化合物A4-2(220mg)和三氟甲烷硫醇银(160mg)的混合物中加入N，N-二甲基乙酰胺(5mL)，100℃搅拌过夜，冷却至室温，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A17-1(160mg)。
ESI-MS m/z:416.0[M+H +] +。
步骤2：化合物A17-2的合成
向化合物A17-1(0.17g)的乙腈(3mL)，二氯甲烷(3mL)和水(6mL)混合液中加入三氯化钌(0.01g)和高碘酸钠(0.44g)，室温搅拌过夜，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A17-2(0.07g)。
ESI-MS m/z:446.0[M-H +] -。
步骤3：化合物A17的合成
向A17-2(70mg)的二氯甲烷(5mL)溶液中加入氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)，三乙胺(0.04mL)和甲酸(0.02g)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A17(60mg)。
ESI-MS m/z:494.12[M+HCOO -] -。
实施例13(S)-2-((5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4-羟基-4,5,6,7-四氢-1H-吲 哚-3-基)磺酰基)乙腈的合成(化合物A18)
Figure PCTCN2022129643-appb-000053
步骤1：化合物A18-2的合成
在-78℃条件下，向A18-1(160mg)四氢呋喃(10mL)的溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(0.5mL)，搅拌10分钟后加入溴乙腈(60mg)，继续搅拌2小时，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A18-2(120mg)。
ESI-MS m/z:405[M+H +] +。
步骤2：化合物A18-3的合成
向化合物A18-2(120mg)于乙腈(3mL)和水(3mL)的混合液中加入过氧单磺酸钾(457mg)，60℃搅拌2h，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A18-3(100mg)。
ESI-MS m/z:435[M-H +] -。
步骤3：化合物A18的合成
向化合物A18-3(100mg)的二氯甲烷(5mL)溶液中加入三乙胺(0.06mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)和甲酸(30mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A18(50mg)。
ESI-MS m/z:437.12[M-H -] -。
实施例14(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四 氢-1H-吲哚-4-醇的合成(化合物A19)
Figure PCTCN2022129643-appb-000054
步骤1：化合物A19-1的合成
于-78℃条件下，向化合物A4-3(270mg)的四氢呋喃(10mL)溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(1.0mL)，搅拌10分钟后加入氟碘甲烷(0.15g)，维持该温度下继续搅拌2小时，反应液加水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A19-1(180mg)。
ESI-MS m/z:380[M+H +] +。
步骤2：化合物A19-2的合成
向化合物A19-1(190mg)的乙腈(4mL)/水(4mL)溶液中加入过氧单磺酸钾(1.85g),60℃搅拌3h，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A19-2(150mg)。
ESI-MS m/z:412[M+H +] +。
步骤3：化合物A19的合成
向化合物A19-2(150mg)的二氯甲烷(5mL)溶液中加入三乙胺(0.11mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(20mg)和甲酸(50mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A19(90mg)。
ESI-MS m/z:458.11[M+HCOO -] -。
实施例15 2-(1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)- 2,2-二氟乙酰胺的合成(化合物A20)
Figure PCTCN2022129643-appb-000055
步骤1：化合物A20-1的合成
向二氟溴乙酸乙酯(100mg)的二甲亚砜(1mL)溶液中加入铜粉(30mg)和化合物A3-1(100mg)，95℃搅拌过夜，冷却至室温，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A20-1(70mg)。
步骤2：化合物A20-2的合成
向化合物A20-1(70mg)的甲醇(1mL)溶液中加入7mol/L的氨甲醇溶液(0.49mL)，室温搅拌4小时，反应液浓缩得目标化合物A20-2，未经进一步纯化直接用于下一步。
ESI-MS m/z:384.1[M+H +] +。
步骤3：化合物A20的合成
将A20-2(70mg)溶于甲醇(1mL)和四氢呋喃(1mL)，冰水浴冷却后，加入硼氢化钠(20mg)，室温反应过夜，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A20(40mg)。
ESI-MS m/z:430.0[M+HCOO -] -。
实施例16(S)-3-(乙基磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢- 1H-吲哚-4-醇的合成(化合物A21)
Figure PCTCN2022129643-appb-000056
步骤1：化合物A21-1的合成
于-78℃条件下，向化合物A18-1(180mg)的四氢呋喃(10mL)溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(0.6mL)，搅拌10分钟后加入碘乙烷(90mg)，反应液搅拌2小时，反应液经水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A21-1(150mg)。
ESI-MS m/z:394[M+H +] +。
步骤2：化合物A21-2的合成
向化合物A21-1(150mg)、乙腈(5mL)和水(5mL)混合物中加入过氧单磺酸钾(0.7g),60℃搅拌2h，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A21-2(150mg)。
ESI-MS m/z:424[M-H +] -。
步骤3：化合物A21的合成
向化合物A21-2(150mg)的二氯甲烷(5mL)溶液中加入三乙胺(0.10mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(20mg)和甲酸(50mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A21(60mg)。
ESI-MS m/z:472.15[M+HCOO -] -。
实施例17 5-(3-(氰基二氟甲基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟 苯腈的合成(化合物A22)
Figure PCTCN2022129643-appb-000057
步骤1：化合物A22-1的合成
将化合物A20-2(0.7g)的二氯甲烷(2mL)溶液冷却至0℃，然后加入三乙胺(0.07mL)和三氟乙酸酐(0.07mL)，50℃搅拌过夜，浓缩得目标化合物A22-1，无需进一步纯化直接用于下一步。
步骤2：化合物A22的合成
向化合物A22-1(60mg)溶于甲醇(1mL)和四氢呋喃(1mL)的溶液中加入硼氢化钠(20mg)，室温反应过夜，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A22(20mg)。
ESI-MS m/z:412.0[M+HCOO -] -。
实施例18 N-(((S)-1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3- 基)(甲基)(氧代)-16-亚磺基)氰胺的合成(化合物A23)
Figure PCTCN2022129643-appb-000058
步骤1：化合物A23-1的合成
于-78℃条件下，向化合物A3-2(180mg)的四氢呋喃(10mL)溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(0.7mL)，搅拌10分钟后加入碘甲烷(90mg)，反应液继续搅拌2小时，反应液经水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A23-1(116mg)。
ESI-MS m/z:337[M+H +] +。
步骤2：化合物A23-2的合成
向化合物A23-1(200mg)的乙腈(5mL)溶液中加入氰胺(40mg)和二乙酸碘苯(250mg)，室温搅拌过夜，浓缩，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A23-2(120mg)。
ESI-MS m/z:377[M+H +] +。
步骤3：化合物A23-3的合成
向化合物A23-2(120mg)溶于乙腈(2mL)，二氯甲烷(2mL)和水(4mL)的混合液中加入三氯化钌(10mg)和高碘酸钠(370mg)，室温搅拌4小时，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A23-3(40mg)。
ESI-MS m/z:393.0[M+H +] +。
步骤4：化合物A23的合成
向化合物A23-3(40mg)的二氯甲烷(5mL)溶液中加入氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(10mg)，三乙胺(0.03mL)和甲酸(14mg)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A23(10mg)。
ESI-MS m/z:395.11[M+H +] +。
实施例19(S)-2-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲 哚-3-基)磺酰基)乙腈的合成(化合物A24)
Figure PCTCN2022129643-appb-000059
步骤1：化合物A24-1的合成
于-78℃条件下，向A4-3(0.86g)的四氢呋喃(20mL)溶液中加入1.0M的叔丁醇钾的四氢呋喃溶液(3.0mL)，搅拌10分钟后加入溴乙腈(0.36g)， 反应液继续搅拌2小时，反应液经水和乙酸乙酯稀释，有机相饱和食盐水洗涤，干燥，浓缩，柱层析纯化得目标化合物A24-1(0.38g)。
ESI-MS m/z:387[M+H +] +。
步骤2：化合物A24-2的合成
向化合物A24-1(0.38g)于乙腈(6mL)和水(6mL)的混合液中加入过氧单磺酸钾(3.6g)，60℃搅拌过夜，反应完毕，反应液经乙酸乙酯稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A24-2(0.34g)。
ESI-MS m/z:417[M-H +] -。
步骤3：化合物A24的合成
向化合物A24-2(0.34g)的二氯甲烷(10mL)溶液中加入三乙胺(0.23mL)，氯{[(1R,2R)-(-)-2-氨-1,2-二苯乙基](4-甲苯磺酰)氨}(P-异丙基甲苯)钌(II)(0.08g)和甲酸(0.11g)，室温搅拌过夜，反应液经二氯甲烷稀释，水洗，饱和食盐水洗涤，干燥，浓缩，柱层析(EA/PE＝1:3)纯化得目标化合物A24(0.18g)。
ESI-MS m/z:419[M-H -] -。
采用与实施例1-实施例19基本类似的方法，制备以下实施例。
Figure PCTCN2022129643-appb-000060
Figure PCTCN2022129643-appb-000061
Figure PCTCN2022129643-appb-000062
Figure PCTCN2022129643-appb-000063
Figure PCTCN2022129643-appb-000064
Figure PCTCN2022129643-appb-000065
Figure PCTCN2022129643-appb-000066
Figure PCTCN2022129643-appb-000067
Figure PCTCN2022129643-appb-000068
Figure PCTCN2022129643-appb-000069
Figure PCTCN2022129643-appb-000070
Figure PCTCN2022129643-appb-000071
Figure PCTCN2022129643-appb-000072
Figure PCTCN2022129643-appb-000073
部分示例性化合物的 1H NMR数据如下所示：
1H NMR(500MHz,CDCl 3)δ7.91(d,J＝8.3Hz,1H),7.71(s,1H),7.56(d,J＝8.2Hz,1H),7.21(s,1H),7.00(dd,J＝70.0,38.6Hz,1H),4.93(t,J＝6.2Hz,1H),2.92–2.81(m,1H),2.74–2.64(m,1H),2.60–2.45(m,1H),2.30–2.20(m,1H)。(实施例3)
1H NMR(500MHz,CDCl 3)δ7.67(dd,J＝5.2,2.7Hz,1H),7.62(ddd,J＝8.9,4.4,2.8Hz,1H),7.50(s,1H),7.46–7.40(m,1H),6.39(t,J＝54.0Hz,1H),5.06(t,J＝6.3Hz,1H),3.11(s,1H),2.83–2.70(m,1H),2.62(ddd,J＝16.3,6.3,2.3Hz,1H),2.55–2.38(m,1H),2.31–2.19(m,1H)。(实施例4)
1H NMR(500MHz,DMSO)δ7.85–7.75(m,2H),7.65(s,1H),7.57(t,J＝9.2Hz,1H),7.23(t,J＝53.9Hz,1H),6.35(d,J＝6.0Hz,1H),4.85–4.80(m,1H),3.24(s,3H),2.80–2.70(m,1H),2.70–2.59(m,1H),2.35–2.25(m,1H),2.20–2.10(m,1H)。(实施例5)
1H NMR(500MHz,CDCl 3)δ7.62(dd,J＝5.7,2.7Hz,1H),7.58(d,J＝9.2Hz,1H),7.52–7.44(m,1H),7.35(t,J＝8.9Hz,1H),7.08–6.78(m,1H),5.03(dt,J＝7.5,3.7Hz,1H),3.02(d,J＝7.4Hz,1H),2.85–2.73(m,1H),2.67–2.43(m,2H),2.35–2.18(m,1H)。(实施例12)
1H NMR(500MHz,CDCl 3)δ7.60(dd,J＝5.8,2.7Hz,1H),7.49–7.43(m,2H),7.32(t,J＝8.9Hz,1H),6.94(dd,J＝59.6,49.5Hz,1H),5.47(dd,J＝47.2,9.8Hz,1H),5.25–5.07(m,2H),3.00(d,J＝3.4Hz,1H),2.76(ddd,J＝16.5,10.5,6.1Hz,1H),2.64(ddd,J＝16.3,6.2,2.7Hz,1H),2.55–2.37(m,1H),2.31–2.16(m,1H)。(实施例14)
1H NMR(500MHz,CDCl 3)δ7.63–7.58(m,1H),7.56(s,1H),7.51–7.42(m,1H),7.33(t,J＝8.9Hz,1H),6.94(t,J＝54.5Hz,1H),5.15(s,1H),4.63(d,J＝16.4Hz,1H),4.17(d,J＝16.4Hz,1H),2.90(s,1H),2.83–2.61(m,2H),2.53–2.16(m,2H)。(实施例19)
1H NMR(500MHz,CDCl 3)δ7.52(s,J＝6.3Hz,1H),7.28–7.24(m,1H),7.19(d,J＝0.9Hz,1H),7.02(dt,J＝8.3,2.1Hz,1H),6.39(t,J＝54.0Hz,1H),5.05(t,J＝6.4Hz,1H),3.08(s,1H),2.85–2.75(m,1H),2.70(ddd,J＝16.4,6.3,2.4Hz,1H),2.56–2.38(m,1H),2.32–2.17(m,1H)。(实施例23)
1H NMR(500MHz,CDCl 3)δ7.41(dd,J＝6.2,2.6Hz,1H),7.36(s,1H),7.29(t,J＝8.5Hz,1H),7.21(ddd,J＝8.7,4.0,2.7Hz,1H),5.14(t,J＝6.4Hz,1H),3.25(s,3H),3.21(d,J＝2.2Hz,1H),2.80–2.59(m,2H),2.55–2.35(m,1H),2.28–2.19(m,1H)。(实施例24)
1H NMR(500MHz,CDCl 3)δ7.74–7.67(m,2H),7.55(dd,J＝8.6,2.6Hz,1H),7.51(s,1H),6.38(t,J＝54.0,1H),5.10–5.02(m,1H),3.11(d,J＝3.4Hz,1H),2.85–2.75(m,1H),2.64(ddd,J＝16.3,6.2,2.4Hz,1H),2.57–2.36(m,1H),2.33–2.20(m,1H)。(实施例28)
1H NMR(500MHz,CDCl 3)δ7.96(d,J＝8.3Hz,1H),7.76(s,1H),7.61(dd,J＝8.3,2.1Hz,1H),7.47(s,1H),7.03(t,J＝67.7Hz,1H),5.22–5.15(m,1H),3.21(d,J＝3.0Hz,1H),2.92–2.82(m,1H),2.73(ddd,J＝16.2,6.0,2.9Hz,1H),2.56–2.40(m,1H),2.34–2.24(m,1H)。(实施例29)
1H NMR(500MHz,CDCl 3)δ8.00(d,J＝8.3,1H),7.81(d,J＝9.4,1H),7.79–7.68(m,1H),7.53(s,1H),5.51(dd,J＝47.2,9.9Hz,1H),5.25–5.05(m,2H),3.00 (s,1H),2.94–2.79(m,1H),2.75–2.65(m,1H),2.56–2.38(m,1H),2.31–2.22(m,1H)。(实施例45)
1H NMR(500MHz,CDCl 3)δ7.97(d,J＝8.4Hz,1H),7.78(d,J＝2.1Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.14(s,1H),4.89(t,J＝5.9Hz,1H),2.92–2.83(m,1H),2.69(dd,J＝16.1,6.4Hz,1H),2.63–2.42(m,2H),2.34–2.17(m,1H)。(实施例46)
药理实验
VEGFA ELISA检测(IC 50)
取对数期生长的786-O细胞接种于96孔板中，细胞浓度为每毫升培养液65000个细胞，180ul每孔。稀释化合物至相应浓度，取20ul不同浓度化合物溶液添加到相应细胞孔，使化合物终浓度分别为(nM)：1.5、4.6、13.7、41.2、123.5、370.4、1111.1、3333.3、10000。培养24h，取细胞培养上清液，使用ELISA试剂盒(购自abcam)测定VEGFA浓度，最后终止反应，使用酶标仪在450nm波长测量各孔的光吸收值，通过GraphPadPrism计算IC 50。同时采用CellTiter-Glo试剂测定细胞活力。
示例性实施例的IC 50数据提供于表1中，其中，A表示IC 50≤0.5μM；B表示0.5μM＜IC 50≤1.5μM；C表示1.5μM＜IC 50≤10μM，D表示IC 50＞10μM。
表1
实施例编号 IC 50(μM) 实施例编号 IC 50(μM)
1 A 33 0.041
2 0.0083 34 A
3 0.003 35 0.018
4 0.098 36 0.108
5 0.072 37 A
6 0.011 39 0.140
9 0.047 40 A
10 A 41 A
11 0.027 42 0.074
12 0.010 43 A
13 B 44 A
14 0.040 45 A
15 B 46 A
16 0.537 47 0.008
17 A 48 1.621
18 A 49 0.099
19 B 51 1.250
20 0.039 52 0.046
21 0.012 57 A
22 0.086 58 0.639
23 0.011 59 0.109
24 0.072 61 A
25 0.063 62 A
26 0.628 63 0.050
27 A 64 0.033
28 0.118 65 0.030
29 0.174 72 B
30 0.045 105 C
31 0.021 106 0.015
32 0.062 107 0.034
荧光素酶实验
将荧光素酶LUC基因用Lipofectamine 3000转染试剂(购自Invitrogen)稳定转入786-O细胞(购自ATCC)，构建为HIF2α报告基因细胞(786-O-HIF2α-Luc细胞)。在786-O-HIF2α-Luc细胞处于对数生长期时进行试验，弃去培养基(RPMI MEDIUM 1640，购自Invitrogen)，PBS润洗三遍；加入胰蛋白酶(TrypLE，购自invitrogen)消化细胞，用培养基、10％胎牛血清、1％青霉素，链霉素终止消化。离心收集细胞，用PBS吹洗两遍，去除培养基中的酚红，重悬细胞至适当的浓度，检测细胞密度和活率，保证细胞活率在90％以上方可用于实验。
用Echo550(非接触式声波移液系统，购自Labcyte)将梯度浓度化合物转移至384孔内，25nl/孔；将细胞种到384孔板中，4500细胞/孔，25μl培养基，使化合物终浓度分别为10000、3333、1111、370、123、41.1、13.7、4.6、1.5、0.5nM。将细胞至于37℃，5％CO 2环境中培养18-20h；加入Steady-Glo TM荧光素酶测定系统(购自Promega)至384孔板，25μl/孔；用Envision检测发光值。根据每孔的RLU(Record Luminescence)信号值计算抑制率％，然后通过Graphpad 8.0拟合计算相应化合物的IC 50。
示例性实施例的IC 50数据提供于表2中，其中，A表示IC 50≤0.1μM；B表示0.1μM＜IC 50≤0.5μM；C表示IC 50>0.5μM。
表2
实施例编号 IC 50(μM)
6 0.038
11 B
12 A
14 0.054
23 0.040
32 B
33 0.052
35 0.010
52 0.045
59 B
107 A
体内PK
化合物用5％DMSO、5％Solutol和90％NaCl进行配制。动物选用SD大鼠与Balb/c小鼠进行给药，静脉给药剂量为1mg/kg，口服给药剂量为5mg/kg，分别于5min、15min、30min、1h、2h、4h、7h、24h眼眶取血。采血后4000rpm离心10min，取上清，在30μL上清中加入200μL内标溶液进行沉淀，涡旋振荡后用12000rpm离心10min，取100μL上清溶液与纯净水按1:1比例进行混合进样。通过高效液质联用仪对血浆内化合物浓度进行检测，采用内标定量法对血浆样品内化合物浓度进行定量分析。测得化合物浓度后通过Winnonln软件计算包括Cmax、AUC等相关的药代动力学参数。经实验发现本发明示例性化合物具有较好的体内PK性质。

Claims (38)

  1. 一种式(I)所示的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，
    Figure PCTCN2022129643-appb-100001
    Figure PCTCN2022129643-appb-100002
    代表单键或双键；
    X 1、X 2、X 3、X 4分别独立地选自C或N，且X 1、X 2、X 3和X 4至少有一个为N；
    W选自C、N、O或S；
    R 1选自C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、C 5-C 10环烷基、5-10元杂环基；其中，所述5-18元杂芳基和5-10元杂环基含有1、2或3个分别独立地选自N、O和S的杂原子；所述C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、C 5-C 10环烷基和5-10元杂环基可任选地被一个或多个选自H、卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 3-C 5环烷基、C 2-C 6炔基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、-C 1-C 6亚烷基-OR c、-C 1-C 6亚烷基-C＝O-R c、-NO 2、-OR c、-SR c、-NR aR b、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-NC(＝O)R c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR aR b、-S(＝O)(＝NR a)R b、-P(＝O)R aR b或-P(＝S)R aR b的取代基所取代；
    R 3选自H、氘、卤素、-NO 2、-NR aR b、-CN、-OH、C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基或C 2-C 10炔基，所述C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基、C 2-C 10炔基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；
    R 4和R 5分别独立地选自H、卤素、-NO 2、-OH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基；所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、氧代基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；或R 4和R 5共同形成氧代基；或R 4和R 5与连同其所连接的C原子共同形成取代或未被取代的环丙基；
    R 6选自H、-CN、卤素、-NO 2、-OH、-NO 2，-NR aR b、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基；所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、氧代基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；或两个R 6一起连同其所连接的C原子共同形成取代或未取代的C 3-C 5环烷基或3-5元杂环基；
    或R 6与R 5连同其所连接的C原子共同形成取代或未取代的C 3-C 4环烷基；
    R f不存在或选自H、-CN、卤素、C 1-C 10烷基、C 1-C 10卤代烷基、C 3-C 10环烷基、氧代基、-NR aR b；所述C 1-C 10烷基、C 1-C 10卤代烷基和C 3-C 10环烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 1-C 6烷氧基、C 2-C 6烯基或C 1-C 5卤代烷基的取代基所取代；
    R j选自-C 1-C 6亚烷基-C(＝O)R c、-C 1-C 6亚烷基-C(＝O)OR c、-C 2F 5、-C(＝O)R c、-C(＝O)OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c，其中，所述C 1-C 6亚烷基可任选地被一个或多个选自H，卤素，氰基，C 1-C 4烷基，C 2-C 4烯基，C 2-C 4炔基，C 1-C 4卤代烷基，C 1-C 4烷氧基和C 1-C 4卤代烷氧基的取代基所取代；
    R a和R b分别独立地选自H、CN、C 1-C 10烷基、C 1-C 10卤代烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 10环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基；
    R c选自C 1-C 10烷基、C 1-C 10烷氧基、C 3-C 6环烷基和-NR aR b，所述C 1-C 10烷基、C 1-C 10烷氧基和C 3-C 6环烷基可任选地被一个或多个选自H、卤素、CN、-NH 2、氧代基、C 1-C 4卤代烷基、C 1-C 4卤代烷氧基、C 3-C 6环烷基的取代基所取代；
    n为0或1；
    m为0、1、2、3或4；
    条件是，所述化合物不为：
    3-氟-5-(4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    1-(3-氯-5-氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    3-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈；
    3-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈；
    1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    1-(3-氯-5-氟苯基)-5,6-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    (S)-5-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    1-(3-氯-5-氟苯基)-5,5-二氟-3-((S)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    1-(3-氯-5-氟苯基)-5,5-二氟-3-((R)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    3-氟-5-(5-氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    (S)-1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-2-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    2-氯-5-(5,5-二氟-4-羟基-3-(甲基磺酰基)-5,6-二氢环戊[b]吡咯-1(4H)-基)苯甲腈；和
    1-(3-氯-5-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-1,4,5,6-四氢环戊并[b]吡咯-4-醇。
  2. 根据权利要求1所述化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述化合物如式(II-1)或式(II-2)所示：
    Figure PCTCN2022129643-appb-100003
  3. 根据权利要求1所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述化合物如式(III-1)、式(III-2)、式(III-3)或式(III-4)所示
    Figure PCTCN2022129643-appb-100004
  4. 根据权利要求1-3任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 3选自H、氘、C 1-C 3烷基、C 2-C 5烯基，所述C 1-C 3烷基和C 2-C 5烯基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基的取代基所取代。
  5. 根据权利要求1-4任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 3选自H、氘或C 1-C 3烷基。
  6. 根据权利要求1-5任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 3为H或氘。
  7. 根据权利要求1-6任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 4和R 5分别独立地选自H、卤素或C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基或氧代基的取代基所取代。
  8. 根据权利要求1-7任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 4和R 5分别独立地选自H、卤素或C 1-C 6烷基。
  9. 根据权利要求1-8任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 4和R 5分别独立地选自H或卤素。
  10. 根据权利要求1-9任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 6为H、-CN、卤素、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基，所述C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氧代基、氨基的取代基所取代。
  11. 根据权利要求1-10任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 6为H、卤素或C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氧代基、氨基的取代基所取代。
  12. 根据权利要求1-11任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，R 6为H或卤素。
  13. 根据权利要求1-12任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R f选自H、-CN、-NH 2、卤素、C 1-C 3烷基、环丙基或C 1-C 3卤代烷基，所述C 1-C 3烷基、环丙基或C 1-C 3卤代烷基可任选地被一个或多个选自H、卤素、-CN、-OH、氨基、C 1-C 3烷基、C 2-C 4烯基、C 1-C 3卤代烷基的取代基所取代。
  14. 根据权利要求1-13任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R f选自H、-CN、卤素、C 1-C 3烷基或C 1-C 3卤代烷基。
  15. 根据权利要求1-14任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R f选自H、-CN或卤素。
  16. 根据权利要求1-15任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述W为C或O。
  17. 根据权利要求1-16任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基， 所述5-10元杂芳基和5-10元杂环基含有1、2或3个分别独立地选自N、O和S的杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或多个任选自卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基、-C 1-C 6亚烷基-OR c、-C 1-C 6亚烷基-C＝O-R c、-NO 2、C(＝O)OR c或-S(＝O) 2R c的取代基所取代。
  18. 根据权利要求1-17任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基，所述5-10元杂芳基和5-10元杂环基含有1或2个N杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-5环烷基、C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基、氰基取代的C 1-C 6卤代烷基或C 1-C 6卤代烷氧基的取代基所取代。
  19. 根据权利要求1-18任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 1为C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基，所述5-10元杂芳基和5-10元杂环基含有1或2个N杂原子，所述C 6-C 10芳基、5-10元杂芳基、C 5-C 10环烷基或5-10元杂环基可任选地被一个或多个选自卤素、氰基、氰基取代的C 1-C 6卤代烷基、氰基取代的C 1-C 6烷基或C 1-C 6卤代烷基的取代基所取代。
  20. 根据权利要求1-19任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R 1为苯基、吡啶基、萘基、10元杂芳基、C 8-C 10环烷基或8-10元杂环基，所述10元杂芳基和8-10元杂环基任选地含有1或2个N杂原子，所述苯基、吡啶基、萘基、10元杂芳基、C 8-C 10环烷基或8-10元杂环基可任选地被一个或多个选自卤素、氰基或C 1-C 6卤代烷基的取代基所取代。
  21. 根据权利要求1-20任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R j选自-C 1-C 6亚烷基-C(＝O)R c、-C 1-C 6卤代亚烷基-C(＝O)R c、-C 1-C 6 卤代亚烷基-C(＝O)OR c、-C 2F 5、-C 1-C 6氰基取代亚烷基-C(＝O)R c、-C(＝O)R c、-C(＝O)OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c。
  22. 根据权利要求1-21任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R j选自-C 2F 5、-C 1-C 6卤代亚烷基-C(＝O)R c、-C 1-C 6卤代亚烷基-C(＝O)OR c、-C(＝O)OR c、-C(＝O)R c、-SR c、-S(＝O) 2R c或-S(＝O)(＝NR a)R c。
  23. 根据权利要求1-22任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R c选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基和-NH 2，所述C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 6环烷基可任选地被一个或多个选自H、卤素、CN、-NH 2、C 1-C 4卤代烷基、C 3-C 6环烷基的取代基所取代。
  24. 根据权利要求1-23任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R c选自C 1-C 6烷基，所述C 1-C 6烷基可任选地被一个或多个选自H、卤素、CN的取代基所取代。
  25. 根据权利要求1-24任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R a选自H、CN或C 1-C 4烷基。
  26. 根据权利要求1-25任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R b选自H、CN或C 1-C 4烷基。
  27. 根据权利要求1-26任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述R j选自
    Figure PCTCN2022129643-appb-100005
    Figure PCTCN2022129643-appb-100006
    Figure PCTCN2022129643-appb-100007
  28. 根据权利要求1-27任一所述的化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述化合物如式(IX-1)或式(IX-2)所示，
    Figure PCTCN2022129643-appb-100008
  29. 一种化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述化合物选自：
    1)5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2,3-二氟苯腈；
    2)5,5-二氟-1-(4-氟-3-(氟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    3)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
    4)(S)-5-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    5)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    6)(S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    7)(S)-3-((S)-(二氟甲基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    8)(S)-3-((R)-(二氟甲基)亚磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    9)5-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    10)(S)-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    11)(S)-5-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    12)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    13)(S)-2-((5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)乙腈；
    14)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    15)2-(1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酰胺；
    16)(S)-3-(乙基磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    17)5-(3-(氰基二氟甲基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    18)N-(((S)-1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(甲基)(氧代)-16-亚磺基)氰胺；
    19)(S)-2-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)乙腈；
    20)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    21)(S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    22)(S)-5-(3-((二氟甲基)磺酰基)-2,5,5-三氟醚-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈；
    23)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    24)1-(3-氯-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    25)1-(3-氯-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    26)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    27)(S)-2-氯-5-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    28)(S)-2-氯-5-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    29)(S)-4-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
    30)(S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    31)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
    32)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    33)(S)-1-(3-氯-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    34)(S)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
    35)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
    36)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈；
    37)(S)-1-(3-氯-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    38)(S)-4-(5,5-二氟-4-羟基-3-(甲基磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
    39)(S)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
    40)(S)-2-氯-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    41)4-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
    42)(S)-4-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
    43)(S)-2-(二氟甲基)-4-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    44)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-2-(二氟甲基)苯甲腈；
    45)(S)-4-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
    46)(S)-4-(5,5-二氟-4-羟基-3-(全氟乙基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二腈；
    47)2-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2-氟乙腈；
    48)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酸乙酯；
    49)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙腈；
    50)(S)-2-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)-2,2-二氟乙酰胺；
    51)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(噻唑-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    52)(R)-1-(3-(二氟甲基)-4-氟苯基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    53)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(恶唑-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    54)(S)-2-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2,2-二氟乙腈；
    55)2-(((S)-5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)-2-氟乙腈；
    56)(S)-(1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)二甲基氧化膦甲基；
    57)2-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)丙腈；
    58)(S)-1-((1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)磺酰基)环丙烷-1-腈；
    59)N-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(甲基)(氧代)-16-亚磺基)氰胺；
    60)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-羧酸乙酯；
    61)(R)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    62)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-甲酰胺；
    63)(4S,5R)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5-氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    64)(4S,5S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5-氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    65)(R)-2-(二氟甲基)-4-(4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    66)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-3-氟苯腈；
    67)(4S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)亚磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    68)(S)-1-((R)-6,8-二氟-1,2,3,4-四氢萘-1-基-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    69)(S)-1-((S)-6,8-二氟-1,2,3,4-四氢萘-1-基-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    70)(S)-1-(2,4-二氟苄基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    71)(S)-2-((5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)甲基)-5-氟苯腈；
    72)(S)-1-(2,4-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    73)N-(((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(氧基)(三氟甲基)-l6-亚磺基)氰胺；
    74)N-((二氟甲基)((S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)(氧代)-16-亚磺基)氰胺；
    75)(S)-2-(5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯基)乙腈；
    76)(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(氟甲基)苯甲腈；
    77)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((氟甲基)磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
    78)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(甲基磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
    79)(S)-1-(3-(二氟甲基)-4-氟苯基)-3-((二氟甲基)磺酰基)-5,5-二氟-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
    80)(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-1,4,5,6-四氢环戊二烯[b]吡咯-4-醇；
    81)(S)-5-(5,5-二氟-4-羟基-3-((三氟甲基)磺酰基)-5,6-二氢环戊二烯[b]吡咯-1(4H)-基)-基2-氟苯腈；
    82)(S)-3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢吲哚-8-醇；
    83)(S)-3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇；
    84)(7R,8S)-3-(3-(二氟甲基)-4-氟苯基)-7-氟-1-((三氟甲基)磺酰基)-5,6,7,8-四氢吲哚嗪-8-醇；
    85)1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-((三氟甲基)磺酰基)-1,4,5,7-四氢吡喃[3,4-b]吡咯-4-醇；
    86)2-(二氟甲基)-4-((4S,5R)-3-((二氟甲基)磺酰基)-5-氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    87)2-(二氟甲基)-4-((4S,5R)-5-氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈；
    88)(S)-5,5-二氟-1-(咪唑并[1,2-a]吡啶-8-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    89)(4S,5R)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    90)(S)-8-(5,5-二氟-3-((氟甲基)磺酰基)-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟-1-萘腈；
    91)(S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(4-氟-5,6,7,8-四氢萘-1-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    92)(S)-5,5-二氟-1-(喹啉-8-基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    93)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    94)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    95)(4S)-1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-3-((二氟甲基)磺酰基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇；
    96)1-(6,8-二氟-1,2,3,4-四氢萘-1-基)-5,5-二氟-3-((氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    97)(4S)-1-(5,7二氟-2,3-二氢-1H-茚-1-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    98)(4S)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    99)(4S)-5,5-二氟-3-(甲磺酰基)-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    100)5,5-二氟-3-((氟甲基)磺酰基)-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    101)(4S)-3-((二氟甲基)磺酰基)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    102)(4S)-5,5-二氟-1-(5,6,7,8-四氢喹啉-8-基)-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇；
    103)2-(二氟甲基)-4-(5-氟-4-羟基-3-((三氟甲基)硫代)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；
    104)2-(二氟甲基)-4-(5-氟-4-羟基-3-((三氟甲基)磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；
    105)2-氟-5-(5-氟-4-羟基-3-(三氟甲基)-4,7-二氢吡喃[3,4-b]吡咯-1(5H)-基)苄腈；
    106)2-氟-5-(2,5,5-三氟-4-羟基-3-(噻吩-2-基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈；或
    107)2-(二氟甲基)-4-(5-氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苄腈。
  30. 一种药物组合物，其特征在于，包含治疗有效量的至少一种权利要求1-29任一所述的化合物和至少一种药学上可接受的辅料。
  31. 权利要求1-29任一所述的化合物或权利要求30所述的药物组合物在制备用于治疗由HIF-2α介导的疾病的药物中的应用。
  32. 根据权利要求31所述的应用，其特征在于，所述的疾病是VHL综合征、自身免疫疾病、炎性疾病和/或癌症。
  33. 根据权利要求32所述的应用，其特征在于，所述癌症选自骨癌、胰腺癌、皮肤癌、头颈癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、胃癌、 宫颈癌、子宫内膜癌、淋巴瘤、食道癌、结肠癌、甲状腺癌、前列腺癌、肉瘤、白血病、膀胱癌、肾癌、胶质瘤、外皮囊腺瘤、鳞状细胞癌、嗜铬细胞瘤、肺癌、肝癌、乳腺癌、脑脊膜瘤、神经细胞瘤、副神经节瘤、母细胞瘤、内分泌瘤、脑膜瘤和髓母细胞瘤。
  34. 一种治疗和/或预防由HIF-2α介导的疾病的方法，其特征在于，向治疗对象施用治疗有效量的权利要求1-29任一项所述的化合物或权利要求30所述的药物组合物。
  35. 根据权利要求34所述的方法，其特征在于，所述HIF-2α介导的疾病是VHL综合征、自身免疫疾病、炎性疾病和/或癌症。
  36. 根据权利要求35所述的方法，其特征在于，所述的癌症选自骨癌、胰腺癌、皮肤癌、头颈癌、恶性黑色素瘤、卵巢癌、直肠癌、胃癌、子宫癌、宫颈癌、子宫内膜癌、淋巴瘤、食道癌、结肠癌、甲状腺癌、前列腺癌、肉瘤、白血病、膀胱癌、肾癌、胶质瘤、外皮囊腺瘤、鳞状细胞癌、嗜铬细胞瘤、肺癌、肝癌、乳腺癌、脑脊膜瘤、神经细胞瘤、副神经节瘤、母细胞瘤、内分泌瘤、脑膜瘤和髓母细胞瘤。
  37. 一种制备如权利要求28所述的化合物的方法，其特征在于，包括将中间体式(A-1)所示的化合物或式(A-2)所示的化合物进行氧化反应以形成式(IX-1)或式(IX-2)所示的化合物，
    Figure PCTCN2022129643-appb-100009
    其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如权利要求1-27任一所述；
    进一步优选地，所述方法包括通过方案1或方案2的方法制备得到式(A-1)所示的化合物，
    方案1
    Figure PCTCN2022129643-appb-100010
    Figure PCTCN2022129643-appb-100011
    其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如权利要求1-27任一所述；
    方案2
    Figure PCTCN2022129643-appb-100012
    其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如权利要求1-27任一所述；
    进一步优选地，所述方法包括通过方案3、方案4、方案5或方案6的方法制备得到式(A-2)所示的化合物，
    方案3
    Figure PCTCN2022129643-appb-100013
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述；
    方案4
    Figure PCTCN2022129643-appb-100014
    其中，R 1、R 4、R 5、R 6、R f、m如权利要求1-27任一所述，X为卤素；
    方案5
    Figure PCTCN2022129643-appb-100015
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，X为卤素；
    方案6
    Figure PCTCN2022129643-appb-100016
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，X 1为-TIPS，-Trt或-TBDPS，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
    更进一步优选地，所述方法包括通过方案7的方法制备得到式(C-1)所示的化合物，
    方案7
    Figure PCTCN2022129643-appb-100017
    其中，R 1、R 4、R 5、R 6、R f、m如权利要求1-27任一所述，X为卤素，X 1为-TIPS，-Trt或-TBDPS，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
    更进一步优选地，所述方法包括通过方案8，方案9或方案10的方法制备得到式(B-1)所示的化合物，
    方案8
    Figure PCTCN2022129643-appb-100018
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，X为卤素，R 101为C 1-10烷基；
    方案9
    Figure PCTCN2022129643-appb-100019
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，X为卤素；
    方案10
    Figure PCTCN2022129643-appb-100020
    其中，R 1、R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代；
    更进一步优选地，所述方法包括通过方案11的方法制备得到式(G-5)所示的化合物，
    方案11
    Figure PCTCN2022129643-appb-100021
    其中，R 4、R 5、R 6、R f、R c、m如权利要求1-27任一所述，X为卤素，X 2为-Boc或苯磺酰基。
  38. 一种化合物，或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物，其特征在于，所述化合物选自如下结构：
    Figure PCTCN2022129643-appb-100022
    其中，R 1、R 4、R 5、R 6、R f、R c、R a、m如权利要求1-27任一所述，X为卤素，X 1为-TIPS，-Trt或-TBDPS，X 2为-Boc或苯磺酰基，R 101为C 1-10烷基， R 102为H、C 1-3烷基或两个R 102与其相连的O原子共同形成含有两个氧原子和1个硼原子的5元杂环，所述5元杂环可任选地被1或多个C 1-3烷基所取代。
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