WO2025252099A1 - Composé cyclique aromatique à six chaînons pyrrolo, son procédé de préparation et son utilisation - Google Patents

Composé cyclique aromatique à six chaînons pyrrolo, son procédé de préparation et son utilisation

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Publication number
WO2025252099A1
WO2025252099A1 PCT/CN2025/098939 CN2025098939W WO2025252099A1 WO 2025252099 A1 WO2025252099 A1 WO 2025252099A1 CN 2025098939 W CN2025098939 W CN 2025098939W WO 2025252099 A1 WO2025252099 A1 WO 2025252099A1
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Prior art keywords
methyl
indole
propyl
independently
ethyl
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PCT/CN2025/098939
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English (en)
Chinese (zh)
Inventor
薛晓纤
李潮
郑剑刚
钟凤霞
文原梅
李硕
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Huayao Jiyuan Shenzhen Pharmaceutical Co Ltd
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Huayao Jiyuan Shenzhen Pharmaceutical Co Ltd
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Publication of WO2025252099A1 publication Critical patent/WO2025252099A1/fr
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    • 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
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly 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
    • C07D209/30—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
    • 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
    • C07D209/30—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
    • 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
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention belongs to the pharmaceutical field and relates to a pyrrolo-6-membered aromatic ring compound, its preparation method, and its application in the pharmaceutical field.
  • HIF hypoxia-inducible factor
  • HIF is a heterodimer composed of ⁇ and ⁇ subunits.
  • the ⁇ subunit is a functional subunit, highly sensitive to and regulated by changes in intracellular oxygen concentration, playing a role in regulating HIF activity.
  • the ⁇ subunit is a structural subunit, also known as the aryl hydrocarbon acceptor nuclear transporter (ARNT), which is stably expressed intracellularly, and its mRNA transcription and protein expression levels are unaffected by changes in oxygen concentration.
  • NNT aryl hydrocarbon acceptor nuclear transporter
  • Both the ⁇ and ⁇ subunits of HIF belong to the basic helical-loop-helical transcription factor superfamily.
  • Human HIF ⁇ has three isotypes: HIF-1 ⁇ , HIF-2 ⁇ , and HIF-3 ⁇ .
  • HIF-1 ⁇ is widely distributed in vivo and plays an important role in angiogenesis induced by local tissue ischemia or hypoxia, but has little effect on iron metabolism.
  • HIF-2 ⁇ is locally distributed and plays an important role in the expression and synthesis of EPO (erythropoietin) genes in renal tissue. Furthermore, it enhances iron absorption in the intestine by upregulating the expression of cytochrome P450 and divalent metal transporter-1 in the duodenum, and also reduces the expression of hepatic bactericidal peptides, playing a dominant role in iron metabolism.
  • HIF-3 ⁇ has a different structure from other subtypes, lacking a DNA-binding region and therefore does not affect gene expression.
  • HIF-3 ⁇ may have a negative regulatory effect on HIF-mediated gene expression. Therefore, HIF-1 ⁇ and HIF-2 ⁇ play a certain role in hypoxia responses.
  • changes in HIF-2 ⁇ are more important than those in HIF-1 ⁇ .
  • Both the HIF-2 ⁇ subunit and the ARNT subunit belong to the Per-ARNT-Sim (PAS) subfamily within the basic helix-loop-helix (bHLH) family.
  • the two subunits have similar structures, primarily consisting of an N-terminal bHLH (DNA Bonding Domain, DBD) and two adjacent PASA and PASB domains (Ligand Bonding Domain, LBD).
  • DBD DNA Bonding Domain
  • PASB domain of the HIF-2 ⁇ subunit contains approximately [missing information - likely a specific structure or feature].
  • HIF-2 ⁇ when combined with regulators, can influence the heterodimerization of the HIF-2 ⁇ and ARNT subunits, thereby blocking or activating DNA binding and the transcription of target genes.
  • Downstream target genes of HIF-2 ⁇ include vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glycolytic enzymes, which are associated with chronic kidney disease, renal anemia, cardiovascular disease, infection, and cancer.
  • VEGF vascular endothelial growth factor
  • EPO erythropoietin
  • glycolytic enzymes which are associated with chronic kidney disease, renal anemia, cardiovascular disease, infection, and cancer.
  • HIF-2 ⁇ protein Diseases regulated by HIF-2 ⁇ protein, including but not limited to: treatment of hematopoietic disorders, such as renal anemia, primary anemia, and anemia associated with cancer (especially chemotherapy-induced anemia); anemia due to blood loss, iron deficiency anemia, vitamin deficiency anemia, developmental and aplastic anemia, or hemolytic anemia; anemia due to iron utilization disorders (iron loss anemia) or other endocrine disorders (e.g., hypothyroidism); postoperative surgical ischemic states and their continuous symptoms, especially cardiac interventions using a cardiopulmonary bypass machine (e.g., shunt surgery, heart valve transplantation), carotid artery intervention, aortic intervention, and interventions using instruments to open or penetrate the skull; surgical wound healing; chronic kidney disease, such as primary glomerulonephritis, hypertensive nephrotic arteriosclerosis, diabetic nephropathy, and secondary glomerulonephritis.
  • hematopoietic disorders such as
  • Nephritis tubulointerstitial nephropathy (chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, drug-induced nephropathy, etc.), ischemic nephropathy, hereditary nephropathy (polycystic kidney disease, hereditary nephritis); cardiovascular diseases, especially heart failure, coronary artery disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary, pulmonary and malignant hypertension and peripheral arterial occlusive disease; infections, especially HIV infection; inflammatory diseases, such as rheumatoid arthritis; cancer and damage to health conditions that occur during cancer treatment, especially after the use of cytosolic inhibitors, antibiotics and radiation therapy; diseases of the rheumatic form and other forms of diseases considered autoimmune diseases, especially damage to health conditions that occur during drug treatment of such diseases; continuous symptoms of acute and prolonged cerebral ischemia (e.g.
  • This invention provides a novel pyrrolo-6-membered aromatic ring compound, its preparation method, and its application in the pharmaceutical field.
  • This compound or its pharmaceutical composition can be effectively used to prepare drugs for the prevention, treatment, or alleviation of HIF-2 ⁇ -mediated diseases such as hematopoietic disorders, wound healing disorders, kidney diseases, cardiovascular diseases, infections, and inflammatory diseases.
  • the present invention provides a compound.
  • the present invention provides pharmaceutical compositions comprising the compounds described in the first aspect.
  • the present invention provides the use of the compound described in the first aspect or the pharmaceutical composition described in the second aspect.
  • the present invention provides a drug combination, a drug combination kit, or a compound preparation.
  • the present invention provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.
  • X1 is either N or CR7 ;
  • A is a C6-12 aryl or a 5-12 heteroaryl group
  • C4 -haloalkyl such as C2 -haloalkenyl, C3 -haloalkenyl, C4 -haloalkenyl
  • C2-4 -haloalkynyl such as C2 -haloalkynyl, C3 -haloalkynyl, C4 -haloalkynyl
  • C2-4 alkenyl e.g., C2 - alkynyl, C3 -alkynyl, C4-alkynyl
  • C3-6 cycloalkyl e.g., C3- cycloalkyl, C4 -cycloalkyl, C5 - cycloalkyl, C6-cycloalkyl
  • 3-6 membered heterocyclic e.g., 3- membered heterocyclic, 4 -membered heterocyclic, 5 -membered heterocyclic, 6 -membered heterocyclic
  • C1-4 haloalkyl e.g., C1 -haloalkyl, C2-haloalkyl, C3 -haloalkyl, C4 -haloalkyl, -CF3, CHF2
  • C2-4 haloalkenyl e.g., C2-haloalkenyl, C3- haloalkenyl , C4-haloalken
  • R6 can be H, D, F, Cl, Br, I, OH, CN, NH2 , NO2 , C1-4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl), C2-4 alkenyl (e.g., C2 alkenyl, C3 alkenyl, C4 alkenyl), C2-4 ynyl (e.g., C2 alkenyl, C3 alkenyl, C4 alkenyl), C1-4 haloalkyl (e.g., C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, C4 haloalkyl, -CF3 , CHF2 ), C2-4 haloalkenyl (e.g., C2 haloalkenyl, C3 haloalkenyl, C4 haloalkenyl), or C2-4 haloynyl (e.g.
  • Each R7 is independently H, D, C1-4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl), C2-4 alkenyl (e.g., C2 alkenyl, C3 alkenyl, C4 alkenyl), C2-4 ynyl (e.g., C2 alkenyl, C3 alkenyl, C4 alkenyl), C3-6 cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl), 3-6 membered heterocyclic (e.g., 3 - membered heterocyclic, 4- membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic), C1-4 haloalkyl (e.g., C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, C4 hal
  • C5 cycloalkyl, C6 cycloalkyl C3-6 membered heterocyclic (e.g., C3 cycloalkyl, C4 cycloalkyl, -CF3, CHF2 ), C2-4 membered heterocyclic (e.g., C2 haloalkenyl, C3 haloalkenyl, C4 cycloalkyl), C3-6 membered heterocyclic (e.g., C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, C4 cycloalkyl), C3-6 membered heterocyclic (e.g., C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, C4 cycloalkyl), C3-6 membered heterocyclic (e.g., C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, C4 cycloalkyl), C3-6 member
  • Each Ra and Rb is independently H, D, C1-4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl), C1-4 alkoxy (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy), C2-4 alkenyl (e.g., C2 alkenyl, C3 alkenyl, C4 alkenyl), C2-4 ynyl (e.g., C2 ynyl, C3 ynyl, C4 ynyl), C3-6 cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl), 3-6 membered heterocyclic (e.g., 3- membered heterocyclic, 4 - membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic), C1-4 halo
  • n 0, 1, 2, or 3.
  • A is selected from 5-membered aryl, 6-membered aryl, 5-part 5-membered aryl, 5-part 6-membered aryl or 6-part 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-part 5-membered heteroaryl, 5-part 6-membered heteroaryl or 6-part 6-membered heteroaryl;
  • At least two of R3, R4, R5, and R6 are H; or two or three of R3, R4, R5, and R6 are H, and the rest are not H.
  • A is selected from phenyl, imidazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuran, benzimidazole, indolyl, or quinolinyl; preferably, A is selected from phenyl or pyridyl.
  • the compounds of the present invention have structures as shown in formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), or (II-12), or stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof.
  • each m is independently 1, 2, or 3;
  • the compounds of the present invention have structures as shown in formula (III-1), (III-2), (III-3) or (III-4), or stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof.
  • Each A1 is independently a 5-membered heteroaryl, a 5-membered 5-membered heteroaryl, a 5-membered 6-membered heteroaryl, or a 6-membered 6-membered heteroaryl;
  • each A1 is independently imidazolyl, pyrazolyl, thiophenyl, thiazolyl, pyrimidinyl, pyrazinyl, benzofuran, benzimidazole, indolyl, or quinolinyl.
  • R6 is H, D, F, Cl, Br, I, OH, -CF3 , CHF2 , CN, NH2, NO2 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, or propargyl.
  • each R 7 is independently H, D, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, propynyl, propyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each Ra and Rb is independently H, D, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C1-4 alkyl groups may be C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl
  • C1-4 hydroxy-substituted alkyl groups may be C1 hydroxy-substituted alkyl, C2 hydroxy-substituted alkyl, C3 hydroxy-substituted alkyl, or C4 hydroxy-substituted alkyl
  • C2-4 alkenyl groups may be C2 alkenyl, C3 alkenyl, or C4 alkenyl
  • C2-4 ynyl groups may be C2 alkenyl, C3 alkenyl, or C4 alkenyl
  • C3-6 cycloalkyl groups may be C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl
  • 3-6 membered heterocyclic groups may be 3-membered heterocyclic groups, 4-membered heterocyclic groups, 3-membere
  • the present invention provides a compound having one of the following structures, or a stereoisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.
  • the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be any one of tablets, pills, capsules, or injections.
  • the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of medicaments for the prevention, treatment or relief of HIF-2 ⁇ -mediated diseases.
  • HIF-2 ⁇ -mediated related diseases are selected from hematopoietic disorders, such as renal anemia, primary anemia, and anemia associated with neoplastic diseases (especially chemotherapy-induced anemia); anemia due to blood loss, iron deficiency anemia, vitamin deficiency anemia, developmental and aplastic anemia, or hemolytic anemia; anemia due to iron utilization disorders (iron loss anemia) or due to other endocrine disorders (e.g., hypothyroidism); surgical-related ischemic states and their continuous symptoms after surgery, especially cardiac interventions using a cardiopulmonary bypass machine (e.g., shunt surgery, heart valve transplantation), carotid artery intervention, aortic intervention, and interventions using instruments to open or penetrate the skull cap; surgical wound healing; chronic kidney diseases, such as primary glomerulonephritis, hypertensive nephrotic arteriosclerosis, diabetic nephropathy, and secondary glomerulonephritis.
  • hematopoietic disorders such as renal anemia
  • tubulointerstitial nephropathy chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, drug-induced nephropathy, etc.
  • ischemic nephropathy hereditary nephropathy (polycystic kidney disease, hereditary nephritis); cardiovascular diseases, especially heart failure, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary, pulmonary and malignant hypertension and peripheral arterial occlusive disease; infections, especially HIV infection; inflammatory diseases, such as rheumatoid arthritis; cancer and damage to health conditions that occur during cancer treatment, especially after the use of cytosolic inhibitors, antibiotics and radiation therapy; rheumatic forms of disease and other forms of disease considered autoimmune diseases, especially damage to health conditions that occur during drug treatment of such diseases; continuous symptoms of acute and prolonged cerebral ischemia (e.g. stroke, childbirth
  • the HIF-2 ⁇ -mediated related diseases include any of the following:
  • the anemia includes: renal anemia, primary anemia, tumor-related anemia, chemotherapy-induced anemia, blood loss anemia, iron deficiency anemia, vitamin deficiency anemia, developmental anemia, aplastic anemia, hemolytic anemia, iron utilization disorder anemia, or endocrine disorder-related anemia.
  • the procedure includes: cardiac intervention using a cardiopulmonary bypass machine, carotid artery intervention, aortic intervention, or intervention requiring an opening or penetration of the skull.
  • the chronic kidney disease includes: primary glomerulonephritis, hypertensive arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial nephropathy, ischemic nephropathy, or hereditary nephropathy.
  • the tubulointerstitial lesions include chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, or drug-induced nephropathy; and/or
  • the hereditary kidney disease includes polycystic kidney disease or hereditary nephritis.
  • the cardiovascular disease includes: heart failure, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, essential hypertension, pulmonary hypertension, malignant hypertension, or peripheral arterial occlusive disease.
  • the infection includes HIV infection.
  • the inflammatory disease includes rheumatoid arthritis.
  • the health impairment resulting from cancer treatment includes impairment of health status occurring during the treatment of a rheumatic form of disease or a drug treatment of such disease following the use of cell inhibitors, antibiotics, and radiation therapy, or impairment of health status occurring during the treatment of other disease forms considered to be autoimmune diseases or their drug treatment.
  • the continuous symptoms include stroke or birth asphyxia.
  • HIF-2 ⁇ -mediated disease is associated with surgical wound healing.
  • HIF-2 ⁇ -mediated diseases are kidney diseases, such as primary glomerulonephritis, hypertensive nephrosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial diseases (chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, drug-induced nephropathy, etc.), ischemic nephropathy, and hereditary kidney diseases (polycystic kidney disease, hereditary nephritis).
  • kidney diseases such as primary glomerulonephritis, hypertensive nephrosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial diseases (chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, drug-induced nephropathy, etc.), ischemic nephropathy, and her
  • HIF-2 ⁇ -mediated diseases are cardiovascular diseases, particularly heart failure, coronary artery disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary and pulmonary hypertension, and peripheral arterial occlusive disease.
  • the HIF-2 ⁇ -mediated disease is infection, particularly HIV infection.
  • HIF-2 ⁇ -mediated inflammatory diseases such as rheumatoid arthritis; cancer and damage to health status that occurs during cancer treatment, particularly after the use of cytosolic inhibitors, antibiotics and radiation therapy; rheumatic forms of disease and other forms of disease considered autoimmune diseases, especially damage to health status that occurs during drug treatment of such diseases.
  • HIF-2 ⁇ -mediated diseases are continuous symptoms of acute and prolonged cerebral ischemia, such as stroke and childbirth asphyxia.
  • the HIF-2 ⁇ -mediated disease is disease-related respiratory distress syndrome.
  • the present invention provides a drug combination for treating diseases related to HIF-2 ⁇ activity, wherein the drug combination is a combination of the compound or pharmaceutical composition described in the present invention and a proline hydroxylase inhibitor.
  • the compound or pharmaceutical composition of the present invention and the proline hydroxylase inhibitor are physically separated or mixed together in the drug combination kit.
  • the drug combination, drug combination kit, or combination preparation is used to prevent, treat, or alleviate diseases associated with HIF-2 ⁇ activity.
  • the diseases associated with HIF-2 ⁇ activity include HIF-2 ⁇ -mediated diseases as described in the present invention.
  • references to terms such as “one embodiment,” “some embodiments,” “example,” “specific example,” or “some examples,” etc. indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention.
  • the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example.
  • the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.
  • those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.
  • the term “patient” refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a person.
  • the structural formulas and compounds described in this invention include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, compounds of the present invention that are individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs are also within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.
  • the compounds of this invention can be independently and optionally substituted by one or more substituents.
  • substituents independently and optionally substituted by one or more substituents.
  • substituted means that one or more hydrogen atoms in the given structure are substituted by a specific substituent.
  • an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.
  • room temperature refers to the ambient temperature, which can be 10°C-35°C, 15°C-30°C, or 20°C-30°C.
  • C q1-q2 represents the number of carbon atoms in the described group.
  • C 1-6 alkyl represents an alkyl group containing 1-6 carbon atoms
  • C 3-6 cycloalkyl represents a cycloalkyl group containing 3-6 carbon atoms.
  • q3-q4-membered or “composed of q3-q4 atoms” indicate the number of cyclic atoms in the described ring.
  • a 3-6-membered heterocyclic group indicates a heterocyclic group containing 3-6 cyclic atoms.
  • alkyl refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms. In another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; and in still another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-Bu, -CH( CH3 ) CH2CH3 ), tert-butyl, n-pentyl, 2-pentyl , etc.
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis” and “tans", or the orientation of "E” and "Z".
  • the alkenyl group contains 2-10 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 carbon atoms.
  • alkynyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention.
  • the alkynyl group contains 2-6 carbon atoms; in another embodiment, the alkynyl group contains 2-10 carbon atoms; the alkynyl group contains 2-4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propynyl ( -CH2C ⁇ CH ), 1-propynyl (-C ⁇ C- CH3 ), etc.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C1-6 hydroxyalkyl group, i.e., a C1-6 alkyl group substituted with one or more hydroxyl groups; preferably, C1-6 hydroxyalkyl refers to an alkyl group substituted with one hydroxyl group. In some embodiments, hydroxyalkyl refers to a C1-4 hydroxyalkyl group.
  • hydroxyalkyl refers to a C1-3 hydroxyalkyl group .
  • hydroxyalkyl groups include, but are not limited to, CH2OH- , CH2OHCH2CH2CH2- , CH2OHCH2- , CH2OHCH2CHOHCH2- , CH( CH3 ) OHCH2CHOHCH2- , etc.
  • halogenated alkyl means that an alkyl group is replaced by one or more halogen atoms. Examples of such substitutions include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.
  • halogen refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine), and halogenation means replacing the corresponding hydrogen with a halogen.
  • alkoxy group indicates that an alkyl group is attached to the rest of the molecule via an oxygen atom.
  • the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2CH3 ), 1-propoxy ( n -PrO, n -propoxy, -OCH2CH2CH3 ) , 2-propoxy (i-PrO, i-propoxy, -OCH( CH3 ) 2 ), 1-butoxy ( n -BuO, n - butoxy , -OCH2CH2CH2CH3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH ( CH3 ) 2 ), etc.
  • heterocyclic group refers to a monovalent, non-aromatic, saturated or partially unsaturated monocyclic system having 3-12 ring atoms, comprising at least one carbon atom and one, two, or three heteroatoms selected from O, N, and S. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(O)-.
  • the sulfur atom of the ring may optionally be oxidized to an S-oxide, and the nitrogen atom of the ring may optionally be oxidized to an N-oxide.
  • the heterocycle contains 4-7 ring atoms, representing a 4-7 membered heterocycle; in other embodiments, the heterocycle contains 4-7 ring atoms, representing a 4-7 membered heterocycle.
  • heterocycles include, but are not limited to: ethylene oxide, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl
  • heterocyclic groups where the -CH2- group is substituted with -C(O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, and 3,5-dioxopyridine.
  • heterocyclic groups where the nitrogen atom is oxidized to an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine.
  • aryl refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a carbon atom of an aromatic ring.
  • aryl groups can include phenyl, naphthyl, and anthracene.
  • heteromatic ring refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring consisting of 5-7 atoms.
  • the 5-10 membered heteroaryl group comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • heteroaryl refers to a heteroaromatic group containing 5 ring atoms or a 5-membered heteroaryl group, comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl.
  • 5-pyrimidinyl pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl 1,2,3-Thiodiazolyl, 1,3,4-Thiodiazolyl, 1,2,5-Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl,
  • prodrug refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues.
  • the prodrug compounds of this invention can be esters; in existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic ( C1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters.
  • a compound in this invention contains a hydroxyl group, meaning it can be acylated to obtain the prodrug form.
  • Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound.
  • Methodabolic products refer to the products obtained from the metabolism of a specific compound or its salt in vivo.
  • the metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc.
  • this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.
  • pharmaceutically acceptable salts refers to the organic and inorganic salts of the compounds of this invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts obtained by other methods described in the literature, such as ion exchange.
  • inorganic acid salts formed by reactions with amino groups such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates
  • organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts obtained by other methods described in the literature, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, gluconate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropylprop
  • Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + ( C1-4 alkyl) 4 salts.
  • This invention also envisions the formation of quaternary ammonium salts from any compound containing an N-group. Water-soluble or oil-soluble or dispersed products can be obtained via quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates.
  • the compounds disclosed in this invention can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • their solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.
  • solvent refers to an association formed by one or more solvent molecules with the compound of this invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed when the solvent molecules are water.
  • treatment refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, “treatment” means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, “treatment” means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, “treatment” means preventing or delaying the onset, occurrence, or worsening of the disease or condition.
  • Combination refers to a fixed combination or portion of a cassette for combined administration in the form of a single dose unit, wherein the compounds disclosed in this invention and their combination partners can be administered independently at the same time or separately at time intervals, particularly to enable the combination partners to exhibit cooperative, e.g., synergistic, effects.
  • co-administration or “combination administration” as used herein are intended to encompass administering a selected combination partner to a single individual (e.g., a patient) in need of it, and are intended to include treatment regimens in which the substances do not necessarily take place via the same route of administration or are administered simultaneously.
  • drug combination refers to a product obtained by mixing or combining one or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients.
  • fixed combination means that the active ingredient, such as a compound disclosed herein, and its conjugate are administered simultaneously to a patient as a single entity or dose.
  • non-fixed combination means that the active ingredient, such as a compound disclosed herein, and its conjugate are administered to a patient simultaneously, jointly, or sequentially as separate entities, wherein this administration provides therapeutically effective levels of both compounds in the patient.
  • cocktail therapies such as the administration of three or more active ingredients.
  • v:v indicates a volume ratio.
  • DCM dichloromethane
  • PE petroleum ether
  • EA ethyl acetate
  • Figure 1A is a statistical graph showing the downregulation of ⁇ -SMA gene and protein expression by the compound detected by real-time quantitative PCR in the TGF- ⁇ 1-induced rat renal fibroblast activation experiment in Example 114 of the present invention.
  • relative mRNA level refers to the relative level of mRNA.
  • Figure 1B is a statistical graph showing the downregulation of Collagen III gene and protein expression by real-time quantitative PCR in the TGF- ⁇ 1-induced rat renal fibroblast activation experiment in Example 114 of the present invention.
  • relative mRNA level refers to the relative level of mRNA.
  • Figure 2A is a statistical graph showing the upregulation of the transcription of the HIF-2 downstream target gene VEGF by the compound detected by real-time quantitative PCR in 786-O cells in Example 115 of the present invention.
  • relative mRNA level relative mRNA level.
  • Figure 2B is a statistical graph showing the upregulation of the transcription of the HIF-2 downstream target gene NDRG1 by the compound detected by real-time quantitative PCR in 786-O cells in Example 115 of the present invention.
  • relative mRNA level relative mRNA level.
  • Figure 2C is a statistical graph showing the upregulation of the transcription of the HIF-2 downstream target gene EPO by the compound detected by real-time quantitative PCR in 786-O cells in Example 115 of the present invention.
  • relative mRNA level relative mRNA level.
  • Figure 3 is a statistical graph showing the upregulation of the transcription of the HIF-2 downstream target gene EPO by the compound combined with roxadustat in Hep3B cells using real-time quantitative PCR in Example 116 of this invention.
  • relative mRNA level refers to the relative level of mRNA.
  • Figure 4A shows the detection results of compound 16 significantly improving renal edema in the aristolochic acid-induced kidney injury zebrafish model of Example 117.
  • control normal control group
  • model model control group
  • aristolochic acid-induced model aristolochic acid-induced model.
  • Figure 4B shows the detection results of compound 16 significantly improving glomerular filtration capacity in the aristolochic acid-induced kidney injury zebrafish model of Example 117.
  • control normal control group
  • model model control group
  • aristolochic acid-induced model aristolochic acid-induced model.
  • Figure 4C shows the detection results of compound 16 significantly increasing the signal intensity of cardiac erythrocytes in the aristolochic acid-induced kidney injury zebrafish model of Example 117.
  • control normal control group
  • model model control group
  • aristolochic acid-induced model aristolochic acid-induced model.
  • Figure 5A shows the staining results of compounds 16 and 76HE (A) (40x magnification) in a kidney injury model caused by unilateral ureteral obstruction in Example 118.
  • Figure 5B shows the results of Masson trichrome staining (B) (20x magnification) of compounds 16 and 76 in a kidney injury model caused by unilateral ureteral obstruction in Example 118.
  • Figure 5C is a statistical graph showing the semi-quantitative analysis results of renal tubular damage in HE-stained section (C) of Figure 5A.
  • Paller scores serum CREA
  • UREA UREA
  • Compound (Ia) can be prepared by the synthetic method of synthetic scheme (I), wherein R1 , R2 , R3 , R4 , R5 and R6 each have the definitions described in this invention.
  • Compound (Ia-1) is coupled with brominated/iodinated compound (Ia-2) under suitable conditions (e.g., reacting at 135°C for 2 hours in the presence of N,N'-dimethyl-1,2-cyclohexanediamine, cuprous iodide and potassium carbonate, with N,N'-dimethylformamide as solvent, or refluxing at 110°C for 24 hours in the presence of N,N'-dimethyl-1,2-cyclohexanediamine, cuprous iodide and potassium phosphate, with toluene as solvent) to obtain compound (Ia).
  • Compound Ia can undergo functional group transformation through different chemical reactions to obtain the final product.
  • Step 2 Preparation of methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 6-fluoro-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 6-chloro-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-fluoro-5-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method was the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-iodo-3-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-chloro-5-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-chloro-5-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-methoxypyridine.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-methoxypyridin-4-yl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-iodo-3,5-dimethoxybenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3,5-dimethoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method was the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3,5-dimethoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1,3-dichloro-5-iodobenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3,5-dichlorophenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3,5-dichlorophenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-fluoropyridine.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-fluoropyridin-4-yl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-(trifluoromethyl)benzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethyl)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethyl)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-(trifluoromethoxy)benzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethoxy)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethoxy)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 2-bromo-1,4-dimethoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2,5-dimethoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate is replaced with methyl 1-(2,5-dimethoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-2-methylphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-3-fluoro-2-methoxypyridine.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-2-methoxypyridin-4-yl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-1-fluoro-2-methoxybenzene.
  • the synthesis method was the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(4-fluoro-3-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-methoxy-1-nitrobenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-methoxy-4-nitrophenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-2-fluoro-3-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-fluoro-3-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-hydroxy-3-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-3-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-1-fluoro-2-methoxybenzene.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-3-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-2-fluoro- 3 -methoxybenzene.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-3-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-fluoro-5-methoxybenzene.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-3-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-methoxypyridine.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-fluoro-3-methoxyphenyl)-1H-indole-3-carboxylate.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(methylsulfonyl)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(2-chloro-3-methoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-fluoro-5-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method was the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-5-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-fluoro-5-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-indole-5-carboxylate.
  • the synthesis method was the same as in Example 4, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-fluoro-5-methoxyphenyl)-1H-indole-5-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-(difluoromethoxy)benzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-(difluoromethoxy)phenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-ethoxybenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-ethoxyphenyl)-1H-indole-4-carboxylic acid.
  • the synthesis method is the same as step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-ethoxy-5-fluorobenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-ethoxy-5-fluorophenyl)-1H-indole-4-carboxylic acid.
  • the synthesis method is the same as step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-ethoxypyridine.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(2-ethoxypyridin-4-yl)-1H-indole-4-carboxylic acid.
  • the synthesis method is the same as step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-propoxybenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-propoxyphenyl)-1H-indole-4-carboxylate.
  • the synthesis method is the same as step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-(2,2,2-trifluoroethoxy)benzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-indole-4-carboxylic acid.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-ethylbenzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(3-ethylphenyl)-1H-indole-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-2-fluoro-3-(trifluoromethyl)benzene.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(2-fluoro-3-(trifluoromethyl)phenyl)-1H-indole-4-carboxylic acid.
  • the synthesis method is the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid is replaced with methyl 1-(2-chloro-3-(trifluoromethyl)phenyl)-1H-indole-4-carboxylic acid.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-indole-4-carboxylic acid, and 1,3-difluoro-5-iodobenzene is replaced with 2-bromo-6-(trifluoromethyl)phenol.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-trifluoromethylbenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-1-fluoro-2-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid was replaced with methyl 1-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-trifluoromethoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylate was replaced with methyl 1-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid was replaced with methyl 1-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid was replaced with methyl 1-(2-hydroxy-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 4-bromo-2-methoxypyridine.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid was replaced with methyl 1-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.
  • the synthesis method follows step 1 of Example 1, except that 4-bromo-1H-indole is replaced with methyl 3-chloro-1H-indole-4-carboxylate, and 1,3-difluoro-5-iodobenzene is replaced with 1-bromo-3-fluoro-5-methoxybenzene.
  • the synthesis method was the same as in Example 3, except that methyl 1-(3,5-difluorophenyl)-1H-indole-4-carboxylic acid was replaced with 3-chloro-1-(3-fluoro-5-methoxyphenyl)-1H-indole- 4 -carboxylic acid.
  • the culture medium was discarded, and 20 ⁇ L of firefly luciferase reporter gene cell lysis buffer (RG126M, Beyotime) was added to each well.
  • the 96-well plate was placed on a microplate shaker and shaken for 10 min. After shaking, 10 ⁇ L of the lysis buffer was transferred to a white opaque plate, and then 10 ⁇ L of Steady-LumiTM firefly luciferase assay reagent (RG058S, Beyotime) was added to each well. Finally, the plate was placed in an Agilent SynergyNeo2 microplate reader for luminescence detection. To characterize the activity of the agonist, the effective concentration of the compound that produces a 50% detection signal ( EC50 ) was calculated using Graphpad software.
  • Table 1 lists the compounds with agonistic activity, where “A” refers to EC 50 less than or equal to 1 ⁇ M, “B” refers to EC 50 between 1 ⁇ M and 5 ⁇ M, and “C” refers to EC 50 between 5 ⁇ M and 20 ⁇ M.
  • Table 1 show that the compounds of the present invention have good agonistic activity at the HIF-2 ⁇ protein transcription level.
  • Example 114 In the experiment of TGF- ⁇ 1-induced fibrosis in rat renal fibroblasts, the regulatory effect of the compound on renal fibrosis genes was determined.
  • TGF- ⁇ 1 Transforming growth factor (TGF- ⁇ 1) is a major driver of fibrosis, promoting the transformation of fibroblasts into myofibroblasts and also promoting the differentiation of myofibroblasts into pro-fibrotic phenotypes.
  • TGF- ⁇ 1 stimulates rat renal fibroblasts (NRK-49F), thereby increasing the upregulation of pro-fibrotic genes such as ⁇ -smooth muscle actin ( ⁇ -SMA) and type III collagen.
  • Rat kidney fibroblasts were seeded into 12-well plates. After 24 hours, the culture medium was aspirated, and fresh medium containing 0.5% FBS was added, followed by 2 ng/mL of TGF- ⁇ 1 (dissolved in DMEM). After 6 hours, the test compound was added to a final concentration of 10 ⁇ M, and incubation continued for another 24 hours.
  • RNA extraction was performed using TRIZOL reagent.
  • cDNA transcription was performed using the All-in-one TM First-Strand cDNA Synthesis Kit (see instruction manual for detailed operating procedures). Signal labeling was performed using SYBR reagent, with ⁇ -actin as an internal control.
  • qRT-PCR primers were:
  • Drug screening results showed that compounds 16, 20, 25, 47, 56, 60, 76, 85, 93, 103, 105, 107, 110, and 112 significantly inhibited TGF- ⁇ 1-induced upregulation of the ⁇ -SMA gene (P ⁇ 0.05–P ⁇ 0.001); meanwhile, compounds 16, 17, 20, 22, 25, 28, 31, 34, 36, 39, 47, 48, 56, 57, 60, 76, 85, 87, 89, 91, 93, 95, 101, and 103 significantly reduced Collagen III gene expression levels (P ⁇ 0.05–P ⁇ 0.001).
  • Experimental data were statistically analyzed using GraphPad Prism software (version 8.0). Compared with the 2 ng/mL TGF- ⁇ 1 treatment group, a two-tailed detection method was used, and the significance level was set as *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Example 115 Determining the regulatory effect of the compound on the renal anemia gene in 786-O cells.
  • the 786-O cell line is a cell model derived from renal cell carcinoma, characterized by the deletion of the VHL gene.
  • the deletion of the VHL gene allows HIF-2 ⁇ to remain stable and undegraded under normoxic conditions. This characteristic makes 786-O cells an ideal tool for studying HIF-2 ⁇ transcriptional activity and related signaling pathways.
  • Epidermal growth factor (VEGF) is a key pro-angiogenic factor that plays a central role in various physiological and pathological processes.
  • N-Myc downstream regulatory gene 1 (NRDG1) is a multifunctional regulatory gene that plays an important role in biological processes such as cell differentiation, proliferation, apoptosis, iron metabolism, and hypoxia response.
  • NRDG1 may play a role in iron homeostasis by regulating the expression of hepcidin, thereby affecting iron absorption and utilization. Furthermore, upregulation of NRDG1 expression under hypoxic conditions may promote angiogenesis.
  • Erythropoietin (EPO) also known as erythrocyte-stimulating factor, is an endogenous glycoprotein hormone in the human body that stimulates erythrocyte production.
  • M1002 is an agonist of HIF-2 ⁇ and is used here as a positive control.
  • Renal cell carcinoma cells 786-O were seeded into 12-well plates. After 24 hours, 2 ⁇ M of the test compound was added, and the cells and compound were co-incubated for 24 hours.
  • RNA extraction was performed using TRIZOL reagent.
  • cDNA transcription was performed using the All-in-one TM First-Strand cDNA Synthesis Kit (see instruction manual for detailed operating procedures). Signal labeling was performed using SYBR reagent, with GAPDH as an internal control.
  • qRT-PCR primers were:
  • GAPDH_fwd GCACCGTCAAGGCTGAGAAC
  • Example 116 Determination of the regulatory effect of the compound in combination with roxadustat on the renal anemia gene.
  • the Hep3B cell line is derived from human hepatocellular carcinoma tissue, and the liver is one of the main organs for EPO gene expression. Under physiological conditions, the liver (especially during fetal development) and kidneys are the main sites of EPO production. Although the kidneys become the primary source of EPO in adulthood, the liver can reactivate EPO expression under certain pathological conditions (such as hypoxia or anemia). Therefore, the Hep3B cell line provides a suitable model for studying the regulation of EPO gene expression in hepatocytes. Roxadustat, a proline hydroxylase inhibitor, and ZG-2033, an HIF-2 ⁇ agonist, were used as positive controls.
  • Hep3B liver cancer cells were seeded into 12-well plates. After 24 hours, 2.5 ⁇ M Roxadustat was added, and after 6 hours, 10 ⁇ M of the test compound was added, followed by incubation for another 24 hours.
  • RNA extraction was performed using TRIZOL reagent.
  • cDNA transcription was performed using the All-in-one TM First-Strand cDNA Synthesis Kit (see instruction manual for detailed operating procedures). Signal labeling was performed using SYBR reagent, with GAPDH as an internal control.
  • qRT-PCR primers were:
  • GAPDH_fwd GCACCGTCAAGGCTGAGAAC
  • Example 117 Experiment on aristolochic acid-induced kidney injury combined with renal anemia in zebrafish
  • Wild-type AB strain zebrafish (2 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Except for the normal control group, all experimental groups were treated with aristolochic acid in water to establish a zebrafish renal anemia model. After treatment at 28°C for 18 h, samples were administered in water (concentrations shown in Tables 1-2). A normal control group and a model control group were also set up, with a volume of 3 mL per well. After further treatment at 28°C for 4 h, each experimental group was intravenously injected with a fluorescent marker (Dextran tetramethylrhodamine).
  • a fluorescent marker Dextran tetramethylrhodamine
  • Wild-type AB strain zebrafish (2 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Except for the normal control group, all experimental groups were treated with aristolochic acid in water to establish a zebrafish renal anemia model. After treatment at 28°C for 18 h, the samples were administered in water, with a normal control group and a model control group included, each well containing 3 mL. After further treatment at 28°C for 30 h, the samples were stained with o-anisidine. After staining, 10 zebrafish from each experimental group were randomly selected and photographed under a dissecting microscope.
  • the glomerular filtration rate of the 1 ⁇ M compound 16 experimental group was 145%, the glomerular filtration rate of the 10 ⁇ M compound 16 experimental group was 140%, and the glomerular filtration rate of the 30 ⁇ M compound 16 experimental group was 151%, indicating that compound 16 has the function of improving glomerular filtration (Figure 4B).
  • (3) The cardiac red blood cell count in the normal zebrafish group was 100%, the cardiac red blood cell count in the aristolochic acid-induced zebrafish model group was 46%, the cardiac red blood cell count in the 10 ⁇ M compound 16 experimental group was 67%, and the cardiac red blood cell count in the 30 ⁇ M compound 16 experimental group was 79%, indicating that compound 16 has a therapeutic effect on renal anemia (Figure 4C).
  • Example 118 Experiment on renal fibrosis caused by unilateral ureteral obstruction (UUO).
  • mice Male Balb/c mice were anesthetized with isoflurane and fixed to the operating table with medical tape. A midline abdominal incision was made, and the surgical site was disinfected with 75% alcohol-iodine-alcohol. An incision was then made along the linea alba, and the incision was fixed with an abdominal fixator. The left ureter was dissected using sterile cotton swabs and small curved forceps and ligated with 3-0 suture near the upper pole of the bladder. A drop of saline was instilled into the abdominal cavity, and the abdomen was sutured. After resuscitation on a heating pad, the mice were returned to their cages and given normal food and water, and observed to complete the model establishment.
  • the sham group underwent the same procedures as the model group except for the absence of ligation.
  • Male Balb/c mice in the experimental group of the UUO model were given compound 16,76 or roxadustat orally by gavage for three consecutive days after a one-week acclimatization period. Administration continued for seven days after unilateral ureteral obstruction surgery.
  • Mice in the sham-operated group and the UUO control group were administered the solvent according to the same dosing regimen. After the last treatment, the rats were euthanized. Statistical significance was determined by one-way ANOVA, followed by Dunnett's test for comparison with the UUO control group (*P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001).
  • This invention illustrates the compounds, compositions, preparation methods, and applications of the present invention through the above embodiments.
  • the present invention is not limited to the above methods, meaning that the present invention must rely on the detailed methods described above to be implemented.
  • Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials in the products of the present invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

La présente invention relève du domaine de la médecine et concerne un composé cyclique aromatique à six chaînons, son procédé de préparation et son utilisation dans le domaine des produits pharmaceutiques. Plus particulièrement, le composé selon la présente invention a une structure représentée par la formule (I), ou un stéréoisomère, un tautomère, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé selon la présente invention et une composition pharmaceutique de celui-ci peuvent être utilisés pour préparer un médicament destiné au traitement de maladies associées à médiation par HIF-2α, telles que des troubles hématopoïétiques, la cicatrisation des plaies, les maladies rénales, les maladies cardiovasculaires, les infections, les maladies inflammatoires et le syndrome de détresse respiratoire aiguë.
PCT/CN2025/098939 2024-06-07 2025-06-04 Composé cyclique aromatique à six chaînons pyrrolo, son procédé de préparation et son utilisation Pending WO2025252099A1 (fr)

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