WO2021254416A1 - Indanone compound and use thereof - Google Patents

Abstract

A compound as represented by formula (I), a composition and formulation comprising such compound, and a method for using and preparing such compound. The compound is used for treating diseases mediated by HIF-2α.

Description

Indanone compounds and their applications Technical field

The present invention relates to an indanone compound, a composition and preparation containing such a compound, and methods of using and preparing such a compound.

Background technique

HIFs (Hypoxia inducible factors) are members of the transcription factor family and are a pathway through which the body senses changes in oxygen. They are also called hypoxia-inducible factors. They mediate cellular hypoxia responses by controlling more than 40 downstream hypoxia-adapting genes. It is mainly composed of HIFα (HIF-1α, HIF-2α, HIF-3α) and HIF-1β. HIF-1β is always in the nucleus, while HIFα is located in the cytoplasm. Under sufficient oxygen conditions, HIFα will undergo PHD prolyl hydroxylase hydroxylation, VHL (Von Hippel-Lindau Syndrome) ubiquitinase ubiquitination and other pathways, and finally be degraded by the proteasome. However, when hypoxia or metabolic pathways are abnormal, HIFα cannot be degraded, so it accumulates in the nucleus and combines with HIF-1β to form a heterodimer, which activates the hypoxia response element (HRE) in the downstream gene promoter, and then Regulate the transcription of related genes so that cells can still survive under hypoxic conditions. These genes are involved in tumor angiogenesis, cell proliferation, survival, metabolism, invasion and metastasis, drug resistance, inflammation and immunity. Among them, HIF-2α mediates chronic hypoxia, which is continuously activated under physiological hypoxic conditions, and plays a more critical role in the occurrence and development of tumors.

Current studies have shown that the mechanisms of HIF-2α mediating tumor occurrence and development mainly include: 1. Under conditions such as hypoxia or VHL mutations, the metabolic pathway of HIF-2α is blocked, accumulates into the nucleus, and forms heterodimers with HIF-1β. It then activates the hypoxia response element (HRE), regulates the up-regulation of downstream VEGFA, CXCR4, Cyclin D1 and other cancer-related genes, and promotes tumor angiogenesis; 2. HIF-2α also participates in the conduction of immunosuppressive signals by up-regulating the expression of CD73, so it is targeted HIF-2α can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells and NK cells.

The activation of HIF-2α pathway is closely related to the occurrence and development of renal cell carcinoma, glioma, neuroblastoma and pheochromocytoma. VHL protein is an important part of E3 ubiquitin ligase, which mediates protein degradation by the proteasome. VHL gene has a 57% high mutation rate or 98% loss of heterozygosity in renal cell carcinoma (RCC), which leads to pseudohypoxia and induces the activation of HIF-2α into the nucleus. Among them, clear cell renal cell carcinoma (ccRCC) accounts for 70%-75% of primary renal cell malignancies, and more than 90% of ccRCC patients have VHL protein defects. When gliomas are not vascularized, the unstable blood supply leads to a hypoxic microenvironment, which induces high local expression of HIF-2α and promotes tumor growth. In pheochromocytoma and paraganglioma, the mutation rate of AA at positions 529-532 of HIF-2α is as high as 81%, which directly affects the hydroxylation and degradation of HIF-2α and makes HIF-2α continue to be activated.

The activation of HIF-2α and the formation of a heterodimer with HIF-1β are the key factors leading to downstream activation, and the PAS binding domain of the two is the binding site for the formation of heterodimers. Peloton’s R&D team developed HIF based on this PT2977, a small molecule inhibitor of -2α, exerts an anti-tumor effect by inhibiting the binding of HIF-2α and HIF-1β.

Based on the close relationship between HIF-2α pathway and tumorigenesis and migration, it is very necessary to develop more high-efficiency new molecular entities.

Summary of the invention

The present invention first provides a compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,

in,

R ₁ and R ₂ may be independently selected from hydrogen, deuterium, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or,

R ₁ and R ₂ and the C atom to which they are connected together form a substituted or unsubstituted C ₃ cycloalkyl or C ₃ heterocyclic group;

R _{3 is} selected from hydrogen, halogen, hydroxyl, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ haloalkoxy, C _3- C ₅ cycloalkyl;

R _{4 is} selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ haloalkoxy, C ₆ -C ₁₀ aryl, C ₅ -C ₁₈ heteroaryl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocyclic group; wherein, the C ₅ -C ₁₈ heteroaryl group and C ₃ -C ₁₀ heterocyclic group optionally contain 1, 2 Or 3 heteroatoms each independently selected from N, O and S; said R _{4 is} optionally substituted with one or more groups independently selected from R ₅ ;

R _{5 is} selected from H, halogen, hydroxyl, amino, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ haloalkoxy, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ heterocyclic group.

In some embodiments, the R ₁ and/or R ₂ are halogen.

In some embodiments, the R ₁ and/or R ₂ are F.

In some embodiments, the R ₁ and R ₂ and the C atom to which they are connected together form a substituted or unsubstituted C ₃ cycloalkyl or C ₃ heterocyclic group.

In some embodiments, the R _{3 is} selected from halogen, cyano or C ₁ -C ₅ haloalkyl.

In some embodiments, the R _{3 is} selected from C ₁ -C ₅ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments, the R _{4 is} selected from C ₆ -C ₈ aryl, C ₅ -C ₈ heteroaryl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ heterocyclyl; wherein, the The C ₅ -C ₈ heteroaryl group and the C ₃ -C ₈ heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the R _{4 is} optionally substituted by one or Multiple groups independently selected from R ₅ are substituted.

In some embodiments, the compound is represented by formula (II),

In some embodiments, the R _{4 is} selected from a C ₆ -C ₈ aryl group, a C ₅ -C ₈ heteroaryl group; wherein the C ₅ -C ₈ heteroaryl group optionally contains 1, 2, or 3, respectively Heteroatoms independently selected from N, O and S; said R _{4 is} optionally substituted with one or more groups independently selected from R ₅ .

In some embodiments, the R _{4 is} selected from a benzene ring, a pyridine ring and a pyrimidine ring.

In some implementations, the R _{4 is} selected from a benzene ring or a pyridine ring.

In some embodiments, the R _{5 is} selected from H, halogen, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₃ -C ₅ cycloalkyl, or C ₃ -C ₅ heterocycle base.

In some embodiments, the R _{5 is} selected from H, halogen, cyano, or C ₁ -C ₅ haloalkyl.

Preferably, the R ₂ is halogen.

Preferably, the R ₃ is halogen or cyano, difluoromethyl or trifluoromethyl.

Preferably, the R ₃ is difluoromethyl.

Preferably, the R _{4 is} selected from

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, and the compound refers to:

1) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyrimidin-5-oxy)-2,3-dihydro-1H-inden-1-one;

2) 3-Fluoro-5-((1,2,2,4-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile;

3) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydro-1H-inden-1-one;

4) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyrimidin-2-oxy)-2,3-dihydro-1H-inden-1-one;

5) 3-((4-Cyclopropyl-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluoro Benzonitrile

6) 3-Fluoro-5-(((1,2,2-tetrafluoro-3-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)oxy基)benzonitrile;

7) 3-((4-Chloro-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile ；

8) 3-Fluoro-5-(((1,1,2,2-tetrafluoro-4-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy) Benzonitrile

9) 5-(3-cyano-5-methylphenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile ；

10) 5-(3-Chloro-5-cyanophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

11) 5-(3,3-Difluorocyclobutoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

12) 5-((4-cyano-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)nicotinonitrile;

13) 5-(3,5-Difluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

14) 3-chloro-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-2,3-dihydro-1H-indenyl-1- ketone;

15) 4'-(Difluoromethyl)-5'-(3,5-Difluorophenoxy)-2',2'-Difluorospiro[cyclopropane-1,1'-indan]-3 '(2'H)-ketone;

16) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-3,3-dimethyl-2,3-dihydro-1H-indene 1-ketone;

17) 3-((1-chloro-4-(difluoromethyl)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)- 5-fluorobenzonitrile;

18) 6-(3-Bromo-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1 -ketone;

19) 6-(3-Cyclopropyl-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

20) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy) Phthalonitrile

21) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzyl Nitrile;

22) 6-(cyclohexyloxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1-one;

23) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(3-fluoro-5-(trifluoromethyl)phenoxy)-2,3-dihydro-1H -Indenyl-1-one;

24) 3-Fluoro-5-((1,2,2,4-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile;

25) 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indene-1- ketone;

26) 3-chloro-5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl) (Oxy)benzonitrile;

27) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) -5-p-fluorobenzonitrile;

28) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(3-fluorophenoxy)-2,3-dihydro-1H-indenyl-1-one;

29) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1- ketone;

30) 6-((5-Bromopyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

31) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

32) 6-(3-chlorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1-one;

33) 6-((5-chloropyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

34) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Nicotinic acid nitrile;

35) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

36) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-phenoxy-2,3-dihydro-1H-indenyl-1-one;

37) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridin-3-yloxy)-2,3-dihydro-1H-indenyl-1-one;

38) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((3-fluoropyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

39) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridin-4-yloxy)-2,3-dihydro-1H-indenyl-1-one;

40) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-fluoropyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

41) 3-bromo-5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl )Oxy)benzonitrile;

42) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Pyridine-1-oxide;

43) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H- Indenyl-1-one;

44) 6-((5-chloropyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

45) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-methylpyridin-4-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

46) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-methoxypyridin-4-yl)oxy)-2,3-dihydro-1H- Indenyl-1-one;

47) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((4-methylpyridin-2-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

48) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridazin-4-yloxy)-2,3-dihydro-1H-indenyl-1-one ；

49) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-hydroxypyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

50) 5-(3-cyanophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile;

51) 6-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Picolinonitrile

52) 6-((2-Bromopyridin-4-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

53) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)-2,3-dihydro -1H-indenyl-1-one;

54) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Pyridine carboxaldehyde;

55) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((6-hydroxypyridin-3-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

56) 4-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Picolinonitrile

57) 1,1,2,2-Tetrafluoro-5-(3-p-fluorophenoxy)-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

58) 6-((4-cyano-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy)picolinonitrile;

59) 5-(3-Bromo-5-p-fluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile ；

60) 5-(3,3-Difluorocyclobutoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

61) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridazin-3-yloxy)-2,3-dihydro-1H-indenyl-1-one ;or

62) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((6-fluoropyridin-2-yl)oxy)-2,3-dihydro-1H-indenyl -1-ketone.

The present invention also provides a method for preparing the compound. The compound described in formula (I) or the compound described in the specific examples of the present invention can be prepared by using known organic synthesis techniques.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose. In some compositions, the weight ratio of the compound to the excipient is about 0.001-10.

In addition, the present invention also provides a method for treating a subject suffering from a disease or disorder mediated by HIF-2α, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In certain aspects, the disease or condition is selected from VHL syndrome, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, renal disorders, viral infections, and obesity. In certain aspects, the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs. In certain aspects, the disease or condition is cancer, including hematological cancers, lymphomas, multiple myeloma, tumors of the digestive system, tumors of the reproductive system, brain tumors, tumors of the nervous system.

In certain aspects, the disease or disorder is permeaglioma, pheochromocytoma, paraganglioma, colon, rectum, prostate (e.g., castrate resistant prostate cancer), lung cancer (e.g., non-small Cell lung cancer and/or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (e.g. basal or basal-like breast cancer and/or triple negative breast cancer), skin (e.g. melanoma) , Nervous system (including brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma and medulloblastoma) tumors or cancer.

In certain aspects, the disease or condition is VHL syndrome. In certain aspects, the disease or condition is kidney cancer. In certain aspects, the subject is a human.

In certain aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.

The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases or disorders mediated by HIF-2α.

The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treatment. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject suffering from a disease or condition mediated by HIF-2α.

The present invention can be implemented in other specific forms without departing from its spirit or basic attributes. The invention covers all combinations of the preferred aspects of the invention mentioned herein. It should be understood that the subject matter disclosed in the "Summary of the Invention" does not exhaustively or completely disclose the full scope of the technology of the present invention or any of its embodiments, and any and all embodiments of the present invention can be used in combination with any other one or more embodiments. Additional embodiments are described. It should also be understood that each individual element of the embodiment is its own independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe a further embodiment.

In the present invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups refer to fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, the term "alkyl" includes linear, branched or cyclic saturated monovalent hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, the "C _{1-6 "in the C 1-6} alkyl group refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched chain.

The term "alkoxy" refers to an oxyether formed from the above-mentioned linear, branched or cyclic alkyl group.

The term "alkylene" refers to a divalent alkyl linking group. Formally, alkylene refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound. Similarly, the "C _{1-4 "in the C 1-4} alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.

The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced by a halogen atom. The term "haloalkoxy" refers to the group -O-haloalkyl.

The term "oxo" or "oxo" refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when connected to a heteroatom group.

In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocyclic ring" means having aromatic characteristics (having (4n+2) non-localized π electrons, where n is Integer) carbocyclic or heterocyclic polyunsaturated ring.

The term "aryl" is a substituted or unsubstituted, stable, 6 to 10 ring carbon atom aromatic hydrocarbon group, which may contain one aromatic ring or multiple aromatic rings (for example, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.

The term "heteroaryl" refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl and the like.

The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. _{The "C 3-10} "in the term C _3-10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, fused rings, etc.). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused to a cyclized alkyl ring. Part, such as benzo or thienyl derivatives of cyclohexane, etc.

The term "cycloalkenyl" refers to a ring system having at least one cyclized alkenyl group with one or more carbon-carbon double bonds in the cycloalkenyl group. _{The "C 3-10} "in the term C _3-10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkenyl groups can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl also includes those having one or more fused rings with cyclized alkenyl Part of the aromatic ring, such as benzo or thienyl derivatives of the cyclohexene ring.

The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, and the heteroatom is selected from N, O and/or S. The heterocyclic group may include a single ring or a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. The definition of the heterocyclic group also includes moieties having one or more aromatic rings fused with a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. . In some embodiments, heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc. .

The term "composition" in the present invention is intended to include products containing specific amounts of specific components, as well as any products obtained directly or indirectly from specific amounts of specific components. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound are also the content of the present invention. Moreover, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.

The prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, the term "administration" in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or the prodrug compound disclosed in the present invention that can be converted in vivo after administration to a subject although it is not clearly disclosed. The conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select the substituent or substituted form of the compound of the present invention through the existing technical means and the method described in the present invention to provide a chemically stable and easy-to-synthesize compound.

The compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of using racemization or epimerization methods known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compound represented by formula (I) and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can all be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium, and sodium. Non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol and so on.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).

The pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Then, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. The gas carrier includes carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In consideration of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compressing or molding one or more auxiliary components or adjuvants together. The active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. A suitable surfactant such as hydroxypropyl cellulose may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Further, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. Using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above-mentioned compound to prepare an emulsion or ointment having the desired consistency.

The pharmaceutical composition provided by the present invention can be made into a form that takes a solid as a carrier and is suitable for rectal administration. The preferred dosage form is a suppository in which the mixture forms a unit dose. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or molten excipients, then cooling and moulding.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc. In addition, other adjuvants can also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or a concentrated solution.

In general, to treat the conditions or discomforts shown above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. However, it is understood that the specific dosage level for any particular patient will depend on many factors, including age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs and acceptance The severity of the specific disease being treated.

detailed description

In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with examples. These examples are only illustrative and are not limited to the scope of application of the present invention. Specific experimental methods not mentioned in the following examples, It is usually carried out in accordance with conventional experimental methods.

Unless otherwise stated, all parts and percentages are calculated by weight, and all temperatures are in degrees Celsius.

The following abbreviations are used in the examples:

DAST: Diethylaminosulfur trifluoride;

Dess-Martin: Dess-Martin oxidant;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

DIBAL-H: Diisobutyl aluminum hydride

EA: ethyl acetate;

ESI-MS: Electrospray ionization mass spectrometry;

IBX: 2-iodoyl benzoic acid;

LDA: lithium diisopropylamide;

Prep-TLC: Preparative thin layer chromatography;

THF: Tetrahydrofuran;

¹ H NMR: Proton nuclear magnetic resonance spectrum;

h: hour;

min: minutes.

Example 1 Preparation of 7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyrimidin-5-oxy)-2,3-dihydro-1H-inden-1-one (Compound 1)

Under the protection of nitrogen, 7-(difluoromethyl)-2,2,3,3,6-pentafluoroindol-1-one (80mg), DMF (2mL), 5-hydroxypyrimidine ( 36 mg), cesium carbonate (143 mg), and the reaction mixture was heated to 50° C. to react for 4 hours. The reaction system was diluted with EA (50 mL), the mixed solution was washed 3 times with water, once with brine, the organic phase was spin-dried, and purified by Prep-TLC to obtain 75 mg of target compound 1.

MS[M+H] ⁺ :349.12.

¹ H NMR (500MHz, DMSO) δ9.11 (s, 1H), 8.78 (s, 2H), 8.44 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.78 ( s, 0.34H), 7.68 (s, 0.52H), 7.57 (s, 0.34H).

Example 2 Preparation of 3-fluoro-5-((1,2,2,4-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile (Compound 2)

Step 1: Synthesis of compound 2-1

Under the protection of nitrogen, add 2-bromo-3,4-difluorobenzoic acid (2.8g) and THF (5mL) to the reaction flask successively, cool down in an ice-water bath, add borane-tetrahydrofuran solution (2M, 50mL), and react at room temperature for 4 After hours, the reaction mixture was spin-dried, diluted with dichloromethane (50mL), saturated sodium carbonate solution was added dropwise, the organic phase was separated, the organic phase was washed with water, 1N hydrochloric acid and saturated sodium chloride aqueous solution, and dried and concentrated to obtain 2g of the target compound. 2-1.

ESI-MS m/z: 440.10 [M+H] ⁺ .

Step 2: Synthesis of compound 2-2

Under the protection of nitrogen, compound 2-1 (2g) and dichloromethane (10mL) were sequentially added to the reaction flask, and Dess-Martin (5.71g) was added to the reaction flask to cool down in an ice-water bath, and react at room temperature overnight. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was washed with an aqueous solution of sodium thiosulfate, washed with saturated brine, and then dried and concentrated to obtain 1.9 g of the target compound 2-2.

Step 3: Synthesis of compound 2-3

Under the protection of nitrogen, add 3-fluoro-5-hydroxybenzonitrile (1.3g), compound 2-2 (1.9g), cesium carbonate (2.95g) and DMF (15mL) to the reaction flask in sequence, and heat to 60℃ and stir for 1 Hour. The temperature was cooled in an ice water bath, the reaction was quenched by adding water, extracted with ethyl acetate once, the organic phase was washed 3 times with water, washed with saturated brine, dried and concentrated, and purified by column chromatography to obtain 2.0 g of the target compound 2-3.

Step 4: Synthesis of compound 2-4

Under the protection of nitrogen, add tetrahydrofuran (10mL) and zinc powder (567mg) to the reaction flask successively, add 2-bromo-2,2-difluoroethyl acetate (1.80g) dropwise under the water bath, stir for 20min after the addition is complete, dropwise A THF solution (5 mL) of compound 2-3 (2g) was added, and the temperature was raised to 50° C. to react overnight. The reaction system was diluted with EA (50 mL), filtered, the filtrate was spin-dried, and purified by column chromatography to obtain 1 g of target compound 2-4.

¹ H NMR(500MHz,DMSO)δ7.73(d,J=8.1Hz,1H),7.55(s,1H),7.52-7.46(m,2H),7.39-7.35(m,1H),7.02(d , J = 6.1 Hz, 1H), 5.55 (dt, J = 18.7, 5.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Step 5: Synthesis of compound 2-5

Under the protection of nitrogen, compound 2-4 (1g) and dichloromethane (5mL) were sequentially added to the reaction flask, DAST (348mg) was added dropwise at -40°C, and the addition was completed and stirred at room temperature for 1 hour. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate, saturated brine, dried and concentrated, and purified by column chromatography to obtain 0.9 g of the target compound 2-5.

¹ H NMR(500MHz,DMSO)δ7.75(d,J=7.7Hz,1H), 7.63(s,1H), 7.60–7.55(m,1H), 7.46–7.38(m,2H), 6.46(ddd , J=41.8, 15.4, 5.4 Hz, 1H), 4.46-4.34 (m, 2H), 1.33-1.24 (m, 3H).

Step 6: Synthesis of compound 2-6

Under the protection of nitrogen, compound 2-5 (0.9g), THF (2mL), ethanol (2mL) and lithium hydroxide (139mg) were sequentially added to the reaction flask, stirred at room temperature for 1 hour, and adjusted to pH 5-6 with 1N hydrochloric acid. It was extracted with ethyl acetate three times, and the organic phases were combined, dried, and concentrated to obtain 0.8 g of the target compound 2-6.

¹ H NMR(500MHz,DMSO)δ7.73(d,J=7.6Hz,1H), 7.61(s,1H), 7.60-7.55(m,1H),7.43-7.38(m,1H), 6.36(ddd , J=42.8, 16.0, 5.3 Hz, 1H).

Step 7: Synthesis of compound 2

Under the protection of nitrogen, compound 2-6 (0.24g), THF (2mL) were sequentially added to the reaction flask, n-butyllithium (0.6mL, 2.5M n-hexane solution) was added at -78°C, and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by Prep-TLC to obtain 50 mg of target compound 2.

¹ H NMR (500MHz, DMSO) δ 7.96 (s, 1H), 7.84 (s, 1H), 7.75-7.72 (m, 1H), 7.61-7.58 (m, 2H), 6.47 (dd, J = 52.5, 8.3Hz, 1H).

Example 3 of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydro-1H-inden-1-one Preparation (Compound 3)

Step 1: Synthesis of compound 3-1

Under the protection of nitrogen, add 2-bromo-4-p-fluorobenzonitrile (3g) and THF (20mL) to the reaction flask, cool to -78°C, add LDA (7.5mL, 2M THF solution), and stir at low temperature for 1 hour. Then DMF (1.16 mL) was added, stirred at low temperature for 1 hour, and heated to -15°C and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with EA (50 mL*3), and the organic phases were combined, washed with brine, dried, concentrated, and purified by column chromatography to obtain 1.5 g of target compound 3-1.

Step 2: Synthesis of compound 3-2

Under the protection of nitrogen, compound 3-1 (2g) and dichloromethane (20mL) were sequentially added to the reaction flask, and DAST (3.53g) was added to the reaction flask while cooling in an ice-water bath, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dichloromethane (100mL) was dissolved and diluted, saturated sodium bicarbonate solution was added under ice bath to make it alkaline, the organic phase was separated, washed with water and saturated brine successively, dried and concentrated, and purified by column chromatography to obtain 2g Target compound 3-2.

Step 3: Synthesis of compound 3-3

Under the protection of nitrogen, compound 3-2 (0.5 g) and dichloromethane (10 mL) were sequentially added to the reaction flask, DIBAL-H (1.5 mL, 1.5 M toluene solution) was added to the reaction flask while cooling in an ice water bath, and stirred at room temperature for 2 hours. The reaction mixture was quenched with 1N hydrochloric acid, extracted with dichloromethane, the organic phase was dried, concentrated, and purified by Prep-TLC to obtain 200 mg of the target compound 3-3.

Step 4: Synthesis of compound 3-4

Under the protection of nitrogen, 3,5-difluorophenol (925mg), compound 3-3 (1.5g), cesium carbonate (3.87g) and DMF (15mL) were sequentially added to the reaction flask, and stirred at 80°C for 3 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, diluted with ethyl acetate, and the organic phase was separated. The organic phase was washed with water and saturated brine in turn, dried, concentrated, and purified by column chromatography to obtain 1.5 g of target compound 3-4.

Step 5: Synthesis of compound 3-5

Under the protection of nitrogen, tetrahydrofuran (10mL), zinc powder (270mg), 1,2-dibromoethane (51.74mg) were added to the reaction flask successively, and ethyl 2-bromo-2,2-difluoroacetate was added dropwise under the water bath. (838mg), stir for 20 min after the addition is complete, add compound 3-4 (1g) in tetrahydrofuran solution (5 mL) dropwise, and warm to 50° C. to react overnight. The reaction system was diluted with EA (100 mL), filtered, the filtrate was concentrated, and purified by column chromatography to obtain 250 mg of target compound 3-5.

Step 6: Synthesis of compound 3-6

Under the protection of nitrogen, compound 3-5 (250 mg) and dichloromethane (5 mL) were sequentially added to the reaction flask, DAST (124 mg) was added dropwise at -60°C, and the addition was completed and stirred at room temperature for 1 hour. The reaction solution was concentrated, diluted with dichloromethane (50 mL), and the organic phase was separated. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried, concentrated, and purified by column chromatography to obtain 200 mg of target compound 3-6.

Step 7: Synthesis of compound 3

Under the protection of nitrogen, compound 3-6 (0.24g), THF (5mL) were sequentially added to the reaction flask, n-butyllithium (0.25mL, 2.5M n-hexane solution) was added at -78°C, and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by Prep-TLC to obtain 30 mg of target compound 3.

¹ H NMR (500MHz, CDCl ₃ ) δ 7.87-7.82 (m, 1H), 7.67 (s, 0.23H), 7.56 (s, 0.50H), 7.47-7.40 (m, 1.35H), 6.66-6.60 ( m, 1H), 6.55-6.50 (m, 2H), 5.83 (dd, J = 53.7, 10.8 Hz, 1H).

Using a method basically similar to that of Example 1 to Example 3, the examples in Table 1 below were prepared.

Table 1

^{The 1} HNMR data of compound 18, compound 21, compound 23, compound 25 and compound 27 are shown below:

¹ H NMR(500MHz,DMSO)δ8.42(d,J=8.6Hz,1H), 7.89(d,J=8.7Hz,1H), 7.72(s,0.25H), 7.62(s,0.50H), 7.51 (s, 0.25H), 7.48 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.22-7.16 (m, 1H). (Compound 18)

¹ H NMR(500MHz,DMSO)δ8.40(d,J=8.7Hz,1H),7.81(d,J=8.7Hz,1H),7.77–7.62(m,4H),7.54–7.52(m,1H ). (Compound 21)

¹ H NMR(500MHz,DMSO)δ8.49(d,J=8.7Hz,1H),7.99(d,J=8.7Hz,1H),7.85-7.58(m,2H),7.54(d,J=9.7 Hz, 1H), 7.50 (s, 1H). (Compound 23)

¹ H NMR(500MHz,DMSO)δ8.42(d,J=8.7Hz,1H),7.90(d,J=8.7Hz,1H),7.74-7.48(m,1H),7.36(d,J=8.6 Hz, 1H), 7.20–7.10 (m, 2H). (Compound 25)

¹ H NMR(500MHz,DMSO)δ8.45(d,J=8.7Hz,1H),7.94(d,J=8.7Hz,1H),7.77(d,J=8.2Hz,1H),7.73-7.52m ,3H). (Compound 27)

Comparative Example 1 Synthesis of 3-fluoro-5-((1,2,2,4-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)cyanobenzene

Under the protection of nitrogen, compound 2 (50mg), methanol (2mL) were added to the reaction flask successively, and sodium borohydride (11mg) was added to the reaction flask while cooling in an ice-water bath. The mixture was stirred at room temperature for 1 hour. Ester extraction, drying and concentration, and Prep-TLC purification, to obtain 9 mg of the compound of Comparative Example 1.

¹ H NMR(500MHz,DMSO)δ7.75–7.65(m,1H), 7.53(d,J=8.3Hz,1H), 7.48–7.40(m,3H), 6.71(d,J=8.2Hz,1H ), 6.13–6.05(m,0.5H), 6.00–5.95(m,0.5H), 5.28(s,1H).

Comparative Example 2 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydro-1H-indene-1-ol synthesis

Under the protection of nitrogen, add compound 3 (10mg) and methanol (2mL) to the reaction flask successively, add sodium borohydride (2.1mg) on ice-water bath cooling, react on ice-water bath for 30 minutes, add water to quench (5mL) and dilute with ethyl acetate. , Dried and concentrated, and purified by Prep-TLC to obtain 9.3 mg of the compound of Comparative Example 2.

MS[MH] ^- : 365.14.

Pharmacological experiment

Experimental Example 1 Detection of the compound of the present invention VEGFA ELISA (IC ₅₀ )

The 786-O cells grown in the logarithmic phase were seeded in a 96-well plate at a cell concentration of 65,000 cells per milliliter of culture medium, 180ul per well. Dilute the compound to the corresponding concentration, and add 20 ul of the compound solution of different concentrations to the corresponding cell wells so that the final concentration of the compound is (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After culturing for 24 hours, the cell culture supernatant was taken, and the VEGFA concentration was measured using an ELISA kit (purchased from abcam). Finally, the reaction was terminated, and the light absorption value of each well was measured with a microplate reader at 450nm wavelength, and the IC50 was calculated by GraphPadPrism. At the same time, CellTiter-Glo reagent was used to determine cell viability.

_{The IC 50} data of some examples are provided in Table 2, where A represents IC ₅₀ ≤10nM; B represents 10nM＜IC ₅₀ ≤100nM; C represents 100nM＜IC ₅₀ ≤250nM; D represents 250nM＜IC ₅₀ IC ₅₀ ≤500nM ; E represents IC _50> 500nM.

Table 2

Example number	IC 50 (nM)	Example number	IC 50 (nM)
Example 1	C	Example 32	52
Example 2	C	Example 33	15.3
Example 3	B	Example 34	23.5
Example 18	5.3	Example 36	15.6
Example 20	58.4	Example 37	1
Example 21	4.9	Example 50	8.8
Example 23	58.2	Example 51	17.8
Example 25	4.3	Example 57	10.96
Example 26	9.8	Example 58	43.7
Example 27	4.2	Example 59	69.7
Example 28	5.1	Example 62	44.3
Example 29	3.4	Comparative example 1	>1×10 4
Example 30	15.5	Comparative example 2	E
Example 31	15.2	To	To

Luciferase experiment

The luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) with Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2α reporter cells (786-O-HIF2α-Luc cells). Test when the 786-O-HIF2α-Luc cells are in the logarithmic growth phase, discard the medium (RPMI MEDIUM 1640, purchased from Invitrogen), rinse with PBS three times; add trypsin (TrypLE, purchased from Invitrogen) to digest the cells , Wash the cells with culture medium, 10% fetal bovine serum, 1% penicillin, and streptomycin to stop the digestion. Collect the cells by centrifugation, wash them twice with PBS, remove the phenol red in the culture medium, resuspend the cells to an appropriate concentration, check the cell density and viability, and ensure that the cell viability is above 90% and can be used for experiments.

Use Echo550 (non-contact sonic pipetting system, purchased from Labcyte) to transfer the gradient concentration of the compound into 384 wells, 25nl/well; seed the cells into a 384-well plate, 4500 cells/well, 25μl medium to make the compound final The concentrations are 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively. The cells were cultured at 37°C and 5% CO ₂ for 18-20 hours; Steady-Glo ^TM Luciferase Assay System (purchased from Promega) was added to a 384-well plate, 25 μl/well; the luminescence value was detected with Envision. % Inhibition is calculated according to each well RLU (Record Luminescence) signal values, and fitting calculation of IC ₅₀ through the corresponding compound Graphpad 8.0. It is found through experiments that the exemplary compounds of the present invention have better activity.

PK in vivo

The compound was formulated with 5% DMSO, 5% Solutol and 90% NaCl. SD rats and Balb/c mice were selected for administration. The intravenous dose was 1 mg/kg and the oral dose was 5 mg/kg, respectively at 5 min, 15 min, 30 min, 1h, 2h, 4h, 7h, 24h Take blood from the orbit. After blood collection, centrifuge at 4000 rpm for 10 min, take the supernatant, add 200 μL of internal standard solution to 30 μL of supernatant for precipitation, vortex and centrifuge at 12000 rpm for 10 min, take 100 μL of supernatant solution and purified water in a 1:1 ratio for mixing and injection. The compound concentration in the plasma is detected by a high performance liquid-mass spectrometer, and the compound concentration in the plasma sample is quantitatively analyzed by the internal standard quantification method. After the compound concentration is measured, Winnonln software is used to calculate related pharmacokinetic parameters including Cmax and AUC. It is found through experiments that the exemplary compounds of the present invention have better PK properties in vivo.

Claims (16)

1. The compound represented by formula (I), or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,

   

   in,

   R ₁ and R ₂ are each independently selected from hydrogen, deuterium, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or,

   R ₁ and R ₂ and the C atom to which they are connected together form a substituted or unsubstituted C ₃ cycloalkyl or C ₃ heterocyclic group;

   R _{3 is} selected from hydrogen, halogen, hydroxyl, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ haloalkoxy, C _3- C ₅ cycloalkyl;

   R _{4 is} selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ haloalkoxy, C ₆ -C ₁₀ aryl, C ₅ -C ₁₈ heteroaryl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocyclic group; wherein, the C ₅ -C ₁₈ heteroaryl group and C ₃ -C ₁₀ heterocyclic group optionally contain 1, 2 Or 3 heteroatoms each independently selected from N, O and S; said R _{4 is} optionally substituted with one or more groups independently selected from R ₅ ;

   R _{5 is} selected from H, halogen, hydroxyl, amino, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ haloalkoxy, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ heterocyclic group.
2. The compound according to claim 1, wherein the R ₁ and/or R ₂ are halogen, or the R ₁ and R ₂ and the C atom to which they are connected together form a substituted or unsubstituted C ₃ ring Alkyl group or C ₃ heterocyclic group.
3. The compound according to any one of claims 1-2, wherein the R _{3 is} selected from halogen, cyano, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ alkyl or C ₃ -C ₅ ring alkyl.
4. The compound according to any one of claims 1 to 3, wherein the R _{4 is} selected from C ₆ -C ₈ aryl, C ₅ -C ₈ heteroaryl, C ₃ -C ₅ cycloalkyl, C _3- C ₅ heterocyclic group; wherein, the C ₅ -C ₈ heteroaryl group and C ₃ -C ₈ heterocyclic group optionally contain 1, 2 or 3 heterocyclic groups independently selected from N, O and S Atom; said R _{4 is} optionally substituted with one or more groups independently selected from R ₅ .
5. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: The compound is represented by formula (II),

   
6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that the R _{4 is} selected from C ₆ -C ₈ aryl, C ₅ -C ₈ heteroaryl; wherein, the C ₅ -C ₈ heteroaryl optionally contains 1, 2 or 3 independently Heteroatoms selected from N, O and S; said R _{4 is} optionally substituted with one or more groups independently selected from R ₅ .
7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that the R _{5 is} selected from H, halogen, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₃ -C ₅ cycloalkyl or C ₃ -C ₅ heterocyclic group .
8. The compound according to any one of claims 1-7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that the R _{5 is} selected from H, halogen, cyano, methyl, ethyl, cyclopropyl, difluoromethyl or trifluoromethyl.
9. The compound of claim 1, wherein the compound is selected from:

   1) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyrimidin-5-oxy)-2,3-dihydro-1H-inden-1-one;

   2) 3-Fluoro-5-((1,2,2,4-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile;

   3) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydro-1H-inden-1-one;

   4) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyrimidin-2-oxy)-2,3-dihydro-1H-inden-1-one;

   5) 3-((4-Cyclopropyl-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluoro Benzonitrile

   6) 3-Fluoro-5-(((1,2,2-tetrafluoro-3-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)oxy基)benzonitrile;

   7) 3-((4-Chloro-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile ；

   8) 3-Fluoro-5-(((1,1,2,2-tetrafluoro-4-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy) Benzonitrile

   9) 5-(3-cyano-5-methylphenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile ；

   10) 5-(3-Chloro-5-cyanophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

   11) 5-(3,3-Difluorocyclobutoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

   12) 5-((4-cyano-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)nicotinonitrile;

   13) 5-(3,5-Difluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

   14) 3-chloro-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-2,3-dihydro-1H-indenyl-1- ketone;

   15) 4'-(Difluoromethyl)-5'-(3,5-Difluorophenoxy)-2',2'-Difluorospiro[cyclopropane-1,1'-indan]-3 '(2'H)-ketone;

   16) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-3,3-dimethyl-2,3-dihydro-1H-indene 1-ketone;

   17) 3-((1-chloro-4-(difluoromethyl)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)- 5-fluorobenzonitrile;

   18) 6-(3-Bromo-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1 -ketone;

   19) 6-(3-Cyclopropyl-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

   20) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy) Phthalonitrile

   21) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzyl Nitrile;

   22) 6-(cyclohexyloxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1-one;

   23) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(3-fluoro-5-(trifluoromethyl)phenoxy)-2,3-dihydro-1H -Indenyl-1-one;

   24) 3-Fluoro-5-((1,2,2,4-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile;

   25) 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indene-1- ketone;

   26) 3-chloro-5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl) (Oxy)benzonitrile;

   27) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) -5-p-fluorobenzonitrile;

   28) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(3-fluorophenoxy)-2,3-dihydro-1H-indenyl-1-one;

   29) 7-(Difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1- ketone;

   30) 6-((5-Bromopyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

   31) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

   32) 6-(3-chlorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl-1-one;

   33) 6-((5-chloropyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

   34) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Nicotinic acid nitrile;

   35) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

   36) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-phenoxy-2,3-dihydro-1H-indenyl-1-one;

   37) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridin-3-yloxy)-2,3-dihydro-1H-indenyl-1-one;

   38) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((3-fluoropyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

   39) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridin-4-yloxy)-2,3-dihydro-1H-indenyl-1-one;

   40) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-fluoropyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

   41) 3-bromo-5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl )Oxy)benzonitrile;

   42) 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Pyridine-1-oxide;

   43) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H- Indenyl-1-one;

   44) 6-((5-chloropyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

   45) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-methylpyridin-4-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

   46) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-methoxypyridin-4-yl)oxy)-2,3-dihydro-1H- Indenyl-1-one;

   47) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((4-methylpyridin-2-yl)oxy)-2,3-dihydro-1H-indene 1-ketone;

   48) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridazin-4-yloxy)-2,3-dihydro-1H-indenyl-1-one ；

   49) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((2-hydroxypyridin-4-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

   50) 5-(3-cyanophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile;

   51) 6-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Picolinonitrile

   52) 6-((2-Bromopyridin-4-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-indenyl -1-one;

   53) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)-2,3-dihydro -1H-indenyl-1-one;

   54) 5-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Pyridine carboxaldehyde;

   55) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((6-hydroxypyridin-3-yl)oxy)-2,3-dihydro-1H-indenyl -1-one;

   56) 4-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy) Picolinonitrile

   57) 1,1,2,2-Tetrafluoro-5-(3-p-fluorophenoxy)-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

   58) 6-((4-cyano-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-5-yl)oxy)picolinonitrile;

   59) 5-(3-Bromo-5-p-fluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile ；

   60) 5-(3,3-Difluorocyclobutoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indenyl-4-carbonitrile;

   61) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-(pyridazin-3-yloxy)-2,3-dihydro-1H-indenyl-1-one ;or

   62) 7-(Difluoromethyl)-2,2,3,3-tetrafluoro-6-((6-fluoropyridin-2-yl)oxy)-2,3-dihydro-1H-indenyl -1-ketone.
10. A pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound according to any one of claims 1-9 and at least one pharmaceutically acceptable excipient.
11. The use of the compound of any one of claims 1-9 or the pharmaceutical composition of claim 10 in the preparation of a medicament for treating, preventing, delaying or preventing the occurrence or progression of HIF-2α-mediated diseases.
12. The application according to claim 11, wherein the HIF-2α-mediated disease is cancer, and the cancer is selected from the group consisting of hematological cancer, lymphoma, multiple myeloma, tumors of the digestive system, tumors of the reproductive system , Brain tumors, tumors of the nervous system. .
13. The use according to claim 12, wherein the cancer is selected from the group consisting of glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer , Cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neurocytoma, meningioma and medulloblastoma.
14. A method for treating and/or preventing diseases mediated by HIF-2α, characterized in that a therapeutically effective amount of the compound according to any one of claims 1-9 or the drug according to claim 10 is administered to a subject to be treated combination.
15. The method of claim 14, wherein the HIF-2α-mediated disease is cancer.
16. The method according to claim 15, wherein the cancer is selected from the group consisting of glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney Cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neurocytoma, meningioma, and medulloblastoma.