[go: up one dir, main page]

WO2024067566A1 - Dérivé cyclique saturé, composition pharmaceutique le comprenant et son utilisation pharmaceutique - Google Patents

Dérivé cyclique saturé, composition pharmaceutique le comprenant et son utilisation pharmaceutique Download PDF

Info

Publication number
WO2024067566A1
WO2024067566A1 PCT/CN2023/121492 CN2023121492W WO2024067566A1 WO 2024067566 A1 WO2024067566 A1 WO 2024067566A1 CN 2023121492 W CN2023121492 W CN 2023121492W WO 2024067566 A1 WO2024067566 A1 WO 2024067566A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
alkyl
substituted
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/121492
Other languages
English (en)
Chinese (zh)
Inventor
刘治国
吴杰
叶阳亮
王昊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Alphama Biotechnology Co Ltd
Original Assignee
Suzhou Alphama Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Alphama Biotechnology Co Ltd filed Critical Suzhou Alphama Biotechnology Co Ltd
Publication of WO2024067566A1 publication Critical patent/WO2024067566A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • 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
    • A61K31/407—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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • C07D487/10—Spiro-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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a saturated ring derivative, and specifically relates to a saturated ring derivative used as a 2 ⁇ type hypoxia inducible factor (HIF-2 ⁇ ) inhibitor, and its use.
  • HIF-2 ⁇ hypoxia inducible factor
  • Kidney cancer also known as renal cell carcinoma, is one of the 10 most common cancers worldwide and one of the most lethal tumors of the urinary system. Histopathology divides kidney cancer into three main subtypes: clear cell renal cell carcinoma (ccRCC, 70-75%), papillary renal cell carcinoma (pRCC, 10-16%), and pheochromocytic renal cell carcinoma (chRCC, 5%). Each subtype is associated with a separate genetic syndrome, and therefore the treatment is also different.
  • ccRCC clear cell renal cell carcinoma
  • pRCC papillary renal cell carcinoma
  • chRCC pheochromocytic renal cell carcinoma
  • Clear cell renal cell carcinoma is the most common malignant tumor of the kidney, accounting for about 90% of renal cancer. According to the American Cancer Society, there are 403,000 new cases of renal cancer and 175,000 deaths worldwide each year; in China, there are about 66,800 new patients and 23,400 deaths each year. According to statistics from the National Cancer Spectrum of China, the incidence of kidney disease has increased at an average annual rate of 6.5% over the past 20 years, surpassing bladder cancer to rank first in urinary system tumor-related deaths. Kidney cancer can occur in people of all ages, with the high-incidence age mainly between 50 and 70 years old. Due to the relatively hidden location of the kidney and the lack of obvious clinical symptoms in the early stages of renal cancer, most renal cancer patients already have metastasis at the time of diagnosis.
  • renal cancer metastasizes (late stage), the prognosis is often poor, with a 5-year survival rate of less than 10%.
  • prostate cancer, bladder cancer, etc. it is not sensitive to radiotherapy and chemotherapy, which has become the biggest challenge in the treatment of renal cancer in the past. Therefore, it is a significant task to discover novel and confirmed specific drug targets for the treatment of renal cancer.
  • HIF Hypoxia-inducible factor
  • HIF family members include HIF-1 ⁇ , HIF-1 ⁇ , HIF-2 ⁇ , HIF-2 ⁇ , HIF-3 ⁇ , and HIF-3 ⁇ .
  • Abnormal HIF-2 ⁇ activity is a key carcinogenic driver of cancers such as clear cell renal cell carcinoma (ccRCC).
  • ccRCC clear cell renal cell carcinoma
  • PBDs prolyl hydroxylases
  • pVHL VHL complex
  • polyubiquitinate HIF-2 ⁇ mediate its degradation, so that HIF-2 ⁇ in the cell maintains a low expression level.
  • HIF-2 ⁇ Under hypoxic conditions, HIF-2 ⁇ cannot be hydroxylated, which makes it unable to recognize pVHL, so it accumulates and forms dimers with HIF-1 ⁇ , and then transfers to the nucleus, interacts with cofactors such as CBP/p300 and Pol II complex in the nucleus, and binds to HRE (hypoxia response element), thereby activating the expression of downstream target genes (VEGF-promotes angiogenesis; GLUT1 (glucose transporter-1)-activates glucose transport; LDHA (lactate dehydrogenase)-participates in the glycolysis pathway; and Epo-induces erythropoiesis, etc.).
  • VEGF-promotes angiogenesis VEGF-promotes angiogenesis
  • GLUT1 glucose transporter-1
  • LDHA lactate dehydrogenase
  • HIF-2 ⁇ inhibitors can treat/prevent diseases caused by overexpression of HIF-2 ⁇ , such as renal cell carcinoma.
  • Belzutifan (PT2977) is a HIF-2 ⁇ inhibitor approved by the U.S. FDA in 2021 for the treatment of adult patients with Hippel-Lindau syndrome.
  • a compound having a structure shown in the following formula (I) has good 2 ⁇ -type hypoxia-inducible factor inhibitory activity in a drug screening model at the cellular level.
  • the present invention provides a saturated cyclic compound shown in the following formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof,
  • Y 1 is N or CR 1
  • Y 2 is CR 2 R 3 , NR 4 or is absent
  • Y 3 and Y 4 are each independently selected from CR 2 R 3 , NR 4 , O, SO 2 ; any two of R 2 to R 4 can be connected to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl;
  • R 1 is selected from one of H, halogen, hydroxyl, CN, NO 2 , -NR a R b , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC1-4 alkyl, and C3-8 cycloalkyl;
  • E is a chemical bond or is selected from a substituted or unsubstituted saturated or partially unsaturated aliphatic C3-10 cycloalkylene group, a substituted or unsubstituted saturated or partially unsaturated aliphatic 3-10 membered heterocyclylene group, a substituted or unsubstituted C6-12 arylene group, or a substituted or unsubstituted C6-12 heteroarylene group;
  • R9 and R10 are independently selected from the group consisting of H, halogen, CN, NO2 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 hydroxyhaloalkyl, C1-4 alkoxyC1-4 alkyl, C3-8 cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O) 2 R a , and C1-6 alkylene-C3-8 cycloalkyl, C1-6 alkylene-S(O) 2 R a , C1-6 alkylene-S(O) 2 R a , C1-6 alkylene-C(O)R a , C1-6 alkylene-C(O)OR a , C1-6 alkylene-C(O)NR a R
  • R9 and R10 are linked together to form a substituted or unsubstituted C3-8 cycloalkyl, or a substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
  • R 9 or R 10 and Y 4 are linked together to form a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted 3-membered to 6-membered heterocycloalkyl, a substituted or unsubstituted C6-12 arylene, or a substituted or unsubstituted C6-12 heteroarylene;
  • each of Ra and Rb is independently selected from the group consisting of H, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy and C1-8 hydroxyalkyl,
  • the saturated cyclic compound represented by formula (I) has the structure described by the following formula (II):
  • W 1 and W 2 are each independently a chemical bond, N or CR c R d , and W 3 and W 4 are each independently selected from one of CR c R d , NR c , CO, O, S, SO, and SO 2 ;
  • R 11 is independently selected from H, halogen, hydroxyl, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkyloxy and -C(O)R c
  • R 12 and R 13 are independently selected from H, halogen, C1-4 alkyl, C3-8 cycloalkyl and -C(O)R c ;
  • R c and R d is independently selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy and C1-3 hydroxyalkyl.
  • E is a chemical bond or a substituted or unsubstituted divalent group:
  • connection site is any position on the ring structure that can form a bond.
  • R 5 is H, halogen, cyano, C1-6 haloalkyl, C1-6 alkyl, or C1-6 halohydroxyalkyl.
  • W 1 is a chemical bond
  • W 2 is a chemical bond or CH 2
  • W 4 is NH or CH 2 ,
  • W 3 is one selected from CH 2 , C(Hal) 2 , CO, O, S, SO, SO 2 ,
  • R 11 is a hydroxyl group
  • R 12 and R 13 are Hal
  • Hal represents a halogen atom.
  • the present invention also provides a pharmaceutical composition, which comprises a preventive or therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof, and a pharmaceutically acceptable carrier, and the pharmaceutical composition is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and the oral dosage form includes capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures; the injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile injectable solution for re-dissolving.
  • the present invention provides the use of the above-mentioned compounds and pharmaceutical compositions for treating or preventing cancer, inflammatory diseases, and immune-related diseases. These diseases are closely related to type 2 ⁇ hypoxia-inducible factor, and regulating type 2 ⁇ hypoxia-inducible factor has therapeutic prospects for these diseases.
  • the cancer is the following cancer: prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), mesothelial cancer, leukocyte cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer, adrenal cancer, thyroid cancer, kidney or bone; glioblastoma cancer, mesothelioma cancer, renal cell carcinoma, clear cell renal cell carcinoma, gastric cancer, sarcoma, Kaposi's sarcoma, choriocarcinoma, basal cell carcinoma of the skin or testicular seminoma; the inflammation is selected from pneumonia, enteritis, nephritis, arthritis, traumatic infection; the metabolic disease is selected from obesity, dyslipidemia, hyperlipidemia.
  • the compounds of the present invention are particularly suitable for the treatment of renal cell carcinoma and clear cell renal cell carcinoma.
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, for example 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as " haloalkyl " ) (e.g., CH2F , CHF2 , CF3 , CCl3 , C2F
  • C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound may exist in the pure E (enthafen) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonon
  • the cycloalkyl has 3 to 15 carbon atoms.
  • the so-called " C3-6 cycloalkyl” refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring-forming carbon atoms, which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.
  • cycloalkylene group refers to a saturated (i.e., “cycloalkylene group” and “cycloalkyl group”) or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.
  • heterocyclyl As used herein, the so-called “heterocyclyl”, “heterocyclylene” and “heterocycle” refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and/or triple bonds in the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.
  • a “3-10 membered heterocyclic (ene) group” is a saturated or partially unsaturated heterocyclic (ene) group having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • heterocyclyl and heterocyclic examples include, but are not limited to: (sub) oxirane, (sub) aziridine, (sub) azetidinyl, (sub) oxetanyl, (sub) tetrahydrofuranyl, (sub) dioxolyl (dioxolinyl), (sub) pyrrolidinyl, (sub) pyrrolidonyl, (sub) imidazolidinyl, (sub) pyrazolidinyl, (sub) pyrrolinyl, (sub) tetrahydropyranyl, (sub) piperidinyl, (sub) morpholinyl, (sub) dithianyl (dithianyl), (sub) thiomorpholinyl, (sub) piperazinyl or (sub) trithianyl (trithianyl).
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3,9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, etc.).
  • the heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.
  • the so-called “(ylidene)aryl” and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • the so-called “C 6-10 (ylidene)aryl” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • heteroaryl or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is an sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described herein, wherein specific examples include, but are not limited to, vinyl, allyl, and butylene, etc. Alkenyl may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • Bridged cycloalkyl refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl.
  • the heterocyclyl may be optionally substituted or unsubstituted.
  • spiro heterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multi-spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monospiro heterocyclyl.
  • spiro heterocyclyl include, but are not limited to:
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic group include, but are not limited to:
  • bridged heterocyclic groups include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner.
  • the so-called “aryl” includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl is a C 6 -C 10 aryl, more preferably, the aryl is phenyl and naphthyl, and most preferably, phenyl.
  • the aryl may be substituted or unsubstituted.
  • the "aryl” may be fused with a heteroaryl, a heterocyclic group, or a cycloalkyl group, wherein the aryl ring is connected to the parent structure, and non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • the embodiment of “heteroaryl” includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quino
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-), wherein alkyl is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Benzyl refers to -CH 2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Acetyl refers to -C(O)CH 3 or Ac.
  • Carboxylate refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • halo or halogen groups are defined to include F, Cl, Br, or I.
  • substitution is meant that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • an "effective amount" of a compound refers to an amount sufficient to down-regulate or agonize a corresponding target.
  • the "therapeutically effective dose” of a compound refers to an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease, or negatively regulate or stimulate a corresponding target. This dose can be used as a single dose or taken according to a regimen to be effective.
  • treating means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.
  • amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition refers to any reduction, whether permanent or temporary, lasting or transient, attributable to or associated with the administration of that composition.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present invention.
  • Diastereoisomers can be separated into individual diastereomers on the basis of their physical chemical differences by methods such as chromatography, crystallization, distillation or sublimation.
  • Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active forms i.e., they have the ability to rotate the plane of plane polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to name the sign of rotation of the plane of polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different.
  • Stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the so-called “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that can be interconverted through a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in humans or animals. Salts of compounds can be obtained by using a sufficient amount of base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, etc.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts.
  • bases include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.
  • esters refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity, which when administered into or onto the body can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit/risk ratio within the scope of reasonable medical judgment.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • sterile liquids such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • water is an exemplary carrier.
  • Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, Ethanol, etc.
  • the composition may also contain a small amount of a wetting agent, an emulsifier or a pH buffer as needed.
  • Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, local, in the form of ophthalmic preparations or by inhalation.
  • suitable routes for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, local, in the form of ophthalmic preparations or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in suitable dosage forms.
  • the dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include (but are not limited to): one or more of saline, buffer, glucose, water, glycerol, ethanol, powder, etc.
  • the pharmaceutical preparation should match the administration method.
  • the pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under aseptic conditions.
  • the pharmaceutical composition of the present invention can also be prepared in powder form for aerosol inhalation.
  • the dosage of the active ingredient is a therapeutically effective amount, for example, about 1 ⁇ g/kg body weight to about 50 mg/kg body weight per day; preferably, about 5 ⁇ g/kg body weight to about 10 mg/kg body weight; further preferably, about 10 ⁇ g/kg body weight to about 5 mg/kg body weight.
  • the compounds of the present invention can also be used together with other therapeutic agents.
  • composition of the present invention can be administered to a desired subject (such as a human or non-human mammal) in a conventional manner, and representative administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, and the like.
  • a safe and effective amount of the drug is administered to a mammal, wherein the safe and effective amount is usually at least about 10 micrograms/kg body weight, and in most cases does not exceed about 50 milligrams/kg body weight, preferably, the dose is about 10 micrograms/kg body weight to about 20 milligrams/kg body weight.
  • the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician.
  • the so-called “effective amount” refers to the amount of the compound that, after being administered, will alleviate one or more symptoms of the treated condition to a certain extent. Specifically, as used herein, the “effective amount” of the compound refers to an amount sufficient to inhibit type 2 ⁇ hypoxia-inducible factor or inhibit cancer. As used herein, the “therapeutically effective dose” of the compound refers to an amount sufficient to improve or reduce symptoms in some way, stop or reverse the progression of the disease, or inhibit type 2 ⁇ hypoxia-inducible factor. This dose can be used as a single dose or taken according to a regimen, so as to be effective.
  • An important aspect of the present invention is to provide the use of the above-mentioned saturated ring derivatives provided by the present invention in the preparation of a drug for treating a disease selected from cancer, inflammation, and metabolic diseases
  • a disease selected from cancer, inflammation, and metabolic diseases
  • the cancer is selected from cancers of the head, neck, eyes, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and hematogenous tumors, glioblastoma, renal cell carcinoma (RCC) and clear cell renal cell carcinoma (ccRCC);
  • the inflammation is selected from pneumonia, enteritis, nephritis, arthritis, and traumatic infection
  • the metabolic disease is selected from obesity, dyslipidemia
  • the present invention also provides a method for treating cancer using a saturated ring derivative used as an inhibitor, which is carried out by administering an effective amount of the compound to a subject suffering from cancer.
  • the so-called “effective amount” means an amount of a compound or composition sufficient to significantly and positively alter the symptoms and/or condition to be treated (e.g., provide a positive clinical response).
  • the effective amount of the active ingredient used in a pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent treatment, the specific active ingredient(s) used, the pharmaceutically acceptable excipient(s)/carrier(s) used, and similar factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of formula (I) for use in cancer treatment is an amount sufficient to symptomatically alleviate the symptoms of cancer in a human, to slow the progression of cancer, or to reduce the risk of worsening symptoms in a patient with cancer.
  • the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • the mass spectrum was obtained by LC/MS using ESI as the ionization method.
  • HPLC model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); flow rate: 1.0 mL/min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Rf The ratio of the distance from the origin to the center of the spot in thin layer chromatography to the distance from the origin to the solvent front.
  • Hydrogen atmosphere refers to a hydrogen balloon with a volume of about 1L connected to the reaction bottle.
  • the solution in the reaction refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C-30°C.
  • the reaction progress in the embodiments is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction
  • the column chromatography eluent system used for purifying the compound or the developing solvent system of thin layer chromatography includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added for adjustment, such as acetic acid or triethylamine.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and anhydrous sodium sulfate was added to prepare a saturated solution. It was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and anhydrous sodium sulfate was added. The mixture was dried and concentrated. The crude product was slurried with petroleum ether (100 mL), filtered with suction, and the filter cake was dried to obtain the title compound IN-1c (6.9 g, yield 91%) as a yellow solid.
  • reaction solution was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-2f (605 mg, yield 93%) as a gray solid.
  • reaction solution was cooled to room temperature, concentrated to remove ethanol, and ice water (50 mL) was added and stirred in an ice bath for 30 minutes.
  • the reaction solution was filtered and the filter cake was dried to obtain the title compound IN-4b (7.2 g, yield 95%) as a silvery white flaky solid.
  • Step 4 4,4-difluoro-1-(3-methoxy-3-oxopropionamido)cyclohexane-1-carboxylic acid methyl ester IN-4e
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and a saturated solution prepared with anhydrous sodium sulfate (100 mL) was added. It was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain the yellow solid title compound IN-4f (2.0 g, yield 76%).
  • reaction solution was cooled to room temperature, concentrated to about 100 mL, cooled in an ice bath, and 1M dilute hydrochloric acid was added dropwise to adjust the pH to 1-2.
  • the mixture was filtered and the filter cake was dried to obtain the title compound IN-5b (12.3 g, yield 68%) as a white solid.
  • Step 4 3-(3-methoxy-3-oxopropionamido)tetrahydrofuran-3-carboxylic acid methyl ester IN-5e
  • reaction solution was cooled to room temperature, dried by adding a large amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the yellow oily title compound IN-5f (1.3 g, crude product), which was directly used in the next step.
  • Step 7 3,3-difluoro-4-hydroxy-7-oxa-1-azaspiro[4.4]nonen-2-one IN-5h
  • reaction solution was poured into ice water, extracted with dichloromethane (50 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 3b (460 mg, crude product) as a white solid, which was directly used in the next step.
  • the intermediate IN-1 (150 mg, 0.85 mmol) was dissolved in anhydrous dichloromethane (20 mL), and triethylamine (344 mg, 3.40 mmol) and 4-dimethylaminopyridine (104 mg, 0.85 mmol) were added. After the addition was completed, the mixture was cooled to 0°C under nitrogen protection, and compound 3b (428 mg, 2.05 mmol) was slowly added. After the addition was completed, the reaction solution was stirred at room temperature for 12 hours. TLC detected that the raw material reaction was complete.
  • 3-chloro-5-fluorophenylcarbonyl chloride 3b (981 mg, 4.7 mmol) and intermediate IN-3 (300 mg, 1.6 mmol) were used as raw materials to obtain the title compound 7 (177 mg, yield 31.0%) as a colorless oil.
  • reaction solution was quenched with water (5 mL), extracted with dichloromethane (6 mL x 2), and the organic phases were combined, washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Method 1 Dissolve isothiocyanate (1.5 eq) and triethylamine (3 eq) in dichloromethane (20 V), cool to 0°C under nitrogen protection, and slowly add the intermediate amine (1 eq). After the addition is complete, the reaction solution is stirred at 0°C for 2 hours. TLC detection shows that the reaction of the raw materials is complete. The reaction mixture was quenched by adding water (100 V), extracted with dichloromethane (150 V), and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate system) to obtain the title compound.
  • reaction solution is quenched with ice water (120 V), extracted with dichloromethane (120 V x 2), the organic phases are combined, washed with saturated brine (120 V), dried over anhydrous sodium sulfate, and concentrated.
  • the acid (2 eq) was dissolved in anhydrous N,N-dimethylacetamide (2 V), and the intermediate amine (1 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq) and N,N-diisopropylethylamine (3 eq) were added at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 16 hours. TLC detected that the reaction of the raw materials was complete. Water (20 V) was added to the reaction solution to quench, and ethyl acetate was extracted (10 V x 3).
  • Lithium hydroxide (0.083 g, 3.45 mmol) was dissolved in water (1 mL), and then compound 23c (0.26 g, 1.15 mmol) and methanol (5 mL) were added. After the addition was completed, the reaction solution was heated to 75°C for 3 hours.
  • Step 4 (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonen-1-yl)methanone 23
  • PT-2977 was used as a positive control in this experiment.
  • the compounds of the present invention have excellent HIF-2 ⁇ inhibitory activity.
  • the compound of the present invention has advantages over existing positive compounds in terms of solubility, in vivo clearance rate and bioavailability.
  • the present invention illustrates the inhibitory activity of the present invention through the above examples, thereby proving its therapeutic use in the treatment or alleviation of diseases related to overexpression.
  • the compound of the present invention has excellent solubility in water and indicates metabolic stability in vivo, and has very broad industrial application prospects.
  • the present invention is not limited to the above embodiments, which does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé suivant (I), ou un sel pharmaceutiquement acceptable, un ester, un isomère optique, un tautomère, un stéréoisomère, un polymorphe, un solvate, un N-oxyde, un composé à marquage isotopique, un métabolite, un chélate, un complexe, un clathrate ou un promédicament de celui-ci, et une composition pharmaceutique contenant le composé, et concerne en outre l'utilisation du composé en tant qu'inhibiteur du facteur induit par l'hypoxie de type 2α (HIF-2α), l'utilisation du composé dans la préparation d'un médicament contre une maladie associée à un facteur induit par l'hypoxie de type 2α, et une composition pharmaceutique correspondante.
PCT/CN2023/121492 2022-09-30 2023-09-26 Dérivé cyclique saturé, composition pharmaceutique le comprenant et son utilisation pharmaceutique Ceased WO2024067566A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211210386 2022-09-30
CN202211210386.X 2022-09-30

Publications (1)

Publication Number Publication Date
WO2024067566A1 true WO2024067566A1 (fr) 2024-04-04

Family

ID=90418756

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/121492 Ceased WO2024067566A1 (fr) 2022-09-30 2023-09-26 Dérivé cyclique saturé, composition pharmaceutique le comprenant et son utilisation pharmaceutique

Country Status (2)

Country Link
CN (1) CN117800894A (fr)
WO (1) WO2024067566A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101765596A (zh) * 2007-05-18 2010-06-30 拜耳先灵制药股份公司 用于治疗过增生症状和与血管生成有关疾病的缺氧诱导因子(hif)抑制剂
US20100330199A1 (en) * 2008-01-11 2010-12-30 Fibrogen, Inc. Isothiazole-pyridine derivates as modulators of hif (hypoxia inducible factor) activity
CN103319468A (zh) * 2012-03-21 2013-09-25 广东东阳光药业有限公司 取代的螺双环化合物及其使用方法和用途
CN104837818A (zh) * 2012-12-07 2015-08-12 霍夫曼-拉罗奇有限公司 可用作cb2激动剂的吡啶-2-酰胺
CN110621316A (zh) * 2017-04-21 2019-12-27 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CN113149996A (zh) * 2020-05-12 2021-07-23 苏州阿尔脉生物科技有限公司 一种作为cdk9抑制剂的多环酰胺类衍生物、其制备方法及用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101765596A (zh) * 2007-05-18 2010-06-30 拜耳先灵制药股份公司 用于治疗过增生症状和与血管生成有关疾病的缺氧诱导因子(hif)抑制剂
US20100330199A1 (en) * 2008-01-11 2010-12-30 Fibrogen, Inc. Isothiazole-pyridine derivates as modulators of hif (hypoxia inducible factor) activity
CN103319468A (zh) * 2012-03-21 2013-09-25 广东东阳光药业有限公司 取代的螺双环化合物及其使用方法和用途
CN104837818A (zh) * 2012-12-07 2015-08-12 霍夫曼-拉罗奇有限公司 可用作cb2激动剂的吡啶-2-酰胺
CN110621316A (zh) * 2017-04-21 2019-12-27 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CN113149996A (zh) * 2020-05-12 2021-07-23 苏州阿尔脉生物科技有限公司 一种作为cdk9抑制剂的多环酰胺类衍生物、其制备方法及用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANDREA TESTA, XAVIER LUCAS, GUILHERME V. CASTRO, KWOK-HO CHAN, JANE E. WRIGHT, ANDREW C. RUNCIE, MORGAN S. GADD, WILLIAM T. A. HAR: "3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 140, no. 29, 25 July 2018 (2018-07-25), pages 9299 - 9313, XP055758524, ISSN: 0002-7863, DOI: 10.1021/jacs.8b05807 *
MOLLE, INGE VAN ET AL.: "Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface", CHEMISTRY & BIOLOGY, vol. 19, 26 October 2012 (2012-10-26), XP055196702, DOI: 10.1016/j.chembiol.2012.08.015 *
PAN JING; ZHANG YANMIN; RAN TING; XU ANYANG; QIAO XIN; YIN LINGFENG; ZHOU WEINENG; ZHU LU; ZHAO JUNNAN; LU TAO; CHEN YADONG; JIANG: "QSAR modeling andin silicodesign of small-molecule inhibitors targeting the interaction between E3 ligase VHL and HIF-1$$\alpha $$α", MOLECULAR DIVERSITY, SPRINGER INTERNATIONAL PUBLISHING, CHAM, vol. 21, no. 3, 8 July 2017 (2017-07-08), Cham, pages 719 - 739, XP036294969, ISSN: 1381-1991, DOI: 10.1007/s11030-017-9750-y *

Also Published As

Publication number Publication date
CN117800894A (zh) 2024-04-02

Similar Documents

Publication Publication Date Title
JP6391076B2 (ja) アンドロゲン受容体モジュレーターおよびその使用
CN105793253B (zh) 自分泌运动因子抑制剂化合物
CN111801318B (zh) 受体抑制剂、包含其的药物组合物及其用途
CN114375193B (zh) 甲状腺激素受体β激动剂化合物
JP7106659B2 (ja) インドール－２、３－ジオキシゲナーゼ阻害剤としてのスピロ化合物
TW202019939A (zh) 作為ｔｒｋ抑制劑的雜環化合物
CN118510758A (zh) Rxfp1激动剂
CN110049985B (zh) 作为RORγ调节剂的杂环砜类
JP2024012450A (ja) 受容体阻害剤、同阻害剤を含む医薬組成物及びその使用
CN105524053A (zh) 四氢苯并噻吩化合物
WO2018001332A1 (fr) Composé ayant une activité inhibitrice contre l'isocitrate déshydrogénase mutante, son procédé de préparation et son utilisation
CN113272315B (zh) 一类类固醇化合物及其用途
CN113754635A (zh) 稠环类化合物及其制备方法和用途
WO2024067566A1 (fr) Dérivé cyclique saturé, composition pharmaceutique le comprenant et son utilisation pharmaceutique
CN114980886A (zh) 用于治疗草酸盐相关疾病的化合物和方法
WO2023116763A1 (fr) Composé pyridazine, composition pharmaceutique et leur utilisation
WO2024067708A1 (fr) Dérivé d'oxalate d'ammonium, composition pharmaceutique le comprenant et son utilisation pharmaceutique
WO2024067463A1 (fr) Dérivé de benzo[7]annulène, composition pharmaceutique le comprenant, et utilisations médicales associées
WO2024067709A1 (fr) Dérivé de pyridinylamide, composition pharmaceutique le comprenant et utilisation médicale associée
US20030144262A1 (en) N-heterocyclyl hydrazides as neurotrophic agents
CN113735825B (zh) 1,2,3,6-四氢吡啶类化合物及其制备方法和用途
WO2024153203A1 (fr) Inhibiteur d'intégrase et son utilisation
CN110724076B (zh) 对芳基二甲酰胺类化合物、包含其的药物组合物、其制备方法及其用途
WO2023246876A1 (fr) Utilisation médicale de dérivés de formamide, dérivés de formamide et composition pharmaceutique les comprenant
WO2024099403A1 (fr) Composé thioéther ayant une propriété de médicament doux et son utilisation, composition pharmaceutique et utilisation associées

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23870795

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23870795

Country of ref document: EP

Kind code of ref document: A1