CN109776607A - Aryl phosphorus oxygen class and aryl phosphorus sulphur class compound and its preparation method and application - Google Patents
Aryl phosphorus oxygen class and aryl phosphorus sulphur class compound and its preparation method and application Download PDFInfo
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- CN109776607A CN109776607A CN201910135589.9A CN201910135589A CN109776607A CN 109776607 A CN109776607 A CN 109776607A CN 201910135589 A CN201910135589 A CN 201910135589A CN 109776607 A CN109776607 A CN 109776607A
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Abstract
The invention discloses aryl phosphorus oxygen classes and aryl phosphorus sulphur class compound and its preparation method and application, aryl phosphorus oxygen class of the present invention and aryl phosphorus sulphur class compound can be used as HIF-2 alpha inhibitor, are used to prepare treatment and/or prevent the drug of mammal disease relevant to Hypoxia-inducible fa ctor 2α or illness.The structural formula of the compound aryl phosphorus oxygen class and aryl phosphorus sulphur class compound is as follows:
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a new class of aryl phosphorus oxygen class with anti-tumor activity and virtue
Base phosphorus sulphur class compound and its preparation method and application.
Background technique
Kidney is initiated by the malignant tumour of kidney essence uriniferous tubule epithelial systems, and academic noun full name is clear-cell carcinoma,
Also known as Grawitz's tumor, referred to as kidney.Kidney accounts for about the 2%~3% of adult malignancies, accounts for the 80% of Adult kidney malignant tumour
~90%.Kidney disease incidence ascensional range ranks the first in malignant tumour in recent years.Clinical treatment show kidney to radiotherapy and
Chemotherapy is insensitive, is advanced renal cell cancer using VEGFR inhibitor Sorafenib and Sutent as the anti-tumor drugs targeting of representative
First-line treatment drug.Although up to ten kinds of drug for kidney treatment of FDA approval, these drugs are to transfer
The curative effect of property kidney is extremely limited, and is easy to produce drug resistance.Thus, it is found that and confirming the effect for the treatment of kidney specific drug newly
Target is a very urgent and significant task.
Hypoxia inducible factor-2 a (HIF-2a) is a kind of transcription factor of influence several genes expression.It is responsible for regulating cell
Reaction to anaerobic environment promotes survival and proliferation of the cell under anaerobic environment.The gene of HIF-2a regulation influences new old
The various physiological processes such as metabolism, angiogenesis, cell Proliferation, metastases, inflammation and escape antitumor immune reaction.It is recognized
To be related to the deterioration of kinds cancer, especially in clear cell renal cell carcinoma (Clear Cell Renal Cell
Carcinoma, ccRCC) in play the role of it is very important.Therefore, the target spot for developing HIF-2a inhibits drug to have important meaning
Justice.
Report at present about HIF-2a inhibitor is less, and only an inhibitor PT2385 is in 1 phase clinical stage.Cause
This, researches and develops new improved or more efficient HIF-2a inhibitor, for inhibiting the generation, transfer and recurrence of tumour to have very
Important clinical meaning.
Summary of the invention
The object of the present invention is to provide aryl phosphorus oxygen class and aryl phosphorus sulphur class compound and its preparation method and application, benefits
It uses aryl phosphorus oxygen class of the present invention and aryl phosphorus sulphur class compound as HIF-2a inhibitor, can be used for treating or/and pre-
Anti- mammal (including people) disease relevant to HIF-2 α or illness.
For achieving the above object, the present invention is achieved by the following scheme:
The first aspect of the present invention is the provision of aryl phosphorus oxygen class and aryl phosphorus sulphur class compound, is shown in formula (I)
Compound and its pharmaceutically acceptable salt,
Wherein: R1 is selected from aryl or heteroaryl；
R2 is selected from hydrogen, halogenated or alkyl；Or the carbon atom that two R2 are connected with them forms 3-8 member ring；
W is selected from oxygen or sulphur.
Further: the R1 is phenyl, bicyclic heteroaryl or bicyclic heteroaryl.
Further: the R1 is phenyl or pyridyl group.
It is further: to be replaced by least one substituent group for being selected from halogenated, C1-C4 alkyl alkoxy and cyano；R2 is fluorine
Generation, and n is 1,2 or 3.
The present invention also provides the compound, the compound is selected from:
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorobenzene
Formonitrile HCN；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1S) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -
5- fluorobenzonitrile；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1R) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -
5- fluorobenzonitrile；
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5 difluoro phenoxy group) -2,2- bis-] dimethyl phosphine；
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- ((5- chloropyridine -3- base) oxygen) -2,2- bis-] dimethyl oxygen
Change phosphine；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (dimethyl phosphine sulfide) -2,2- bis-] oxygroup -5- fluorobenzene first
Nitrile.
The second aspect of the present invention provides the method for preparation above compound, and preparation route is as follows:
The third aspect of the present invention provides a kind of pharmaceutical composition, and it includes formula described in first aspect present invention (I) changes
Close object or its pharmaceutically acceptable salt or solvate, and optional one or more pharmaceutically acceptable excipient.
The fourth aspect of the present invention provides compound of the present invention or its pharmaceutically acceptable salt and uses in preparation
Purposes in the drug treated and/or prevent mammal disease relevant to Hypoxia-inducible fa ctor 2α or illness.The food in one's mouth
Newborn animal includes the mankind.
Further, the disease relevant to Hypoxia-inducible fa ctor 2α or illness are selected from cancer, inflammation, metabolic disease
Disease.
Further, the cancer include cutaneum carcinoma, lung cancer, urological cancer, neoplastic hematologic disorder, breast cancer, glioma,
Digestive system tumor, genital system, lymthoma, nervous system neoplasm, brain tumor, head and neck cancer；The inflammation include pneumonia,
Enteritis, ephritis, arthritis, trauma infection contamination；The metabolic disease includes obesity, dyslipidemia, hyperlipidemia.
Compared with prior art, the compounds of this invention can effectively inhibit HIF-2a and HIF-1 β to form dimerization bluk recombination
Object；There is stronger external binding ability with HIF-2 α albumen；The expression of HIF-2a downstream target gene VEGF can effectively be inhibited.
Specific embodiment
Below by specific preparation embodiment and biological experiment, present invention be described in more detail, still, should manage
Solution, these embodiments and biological experiment, which are only used for illustrating, to be used, and should not be construed as with any shape
The formula limitation present invention.It will be apparent to those skilled in the art that hereinafter, if not specified, material used and operating method
It is well known in the art.Unless otherwise stated, in which: (1) temperature is indicated with degree Celsius (DEG C), and operation carries out at room temperature, institute
It states room temperature and refers generally to 15-35 DEG C, preferably 20-30 DEG C, more preferable 20-25 DEG C；(2) organic solvent is dry with anhydrous sodium sulfate, molten
The removal of agent is evaporated under reduced pressure using Rotary Evaporators, and bath temperature is not higher than 60 DEG C；(3) reaction process is tracked with thin-layer chromatography (TLC)；
(4) final product have satisfied hydrogen nuclear magnetic resonance spectrum (1) and mass spectrum (MS) data H-NMR.
Embodiment 1
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorobenzene
The structural formula of the synthesis of formonitrile HCN (compound 1), the compound 1 is as follows:
The preparation method of the compound 1 the following steps are included:
(1a): preparation 4- methoxyl group -1- indone
4- hydroxide radical-1-indenone (2.00g, 13.5mmol), potassium carbonate (7.5g, 54.0mmol) are added to acetone (40mL)
In, it is added iodomethane (3.8g, 27.0mmol), is warming up to 60 DEG C, stir 5h.TLC display reaction is completed, and is cooled to room temperature, will
Reaction mixture is poured into water, and ethyl acetate is added and extracts 2 times, and organic phase brine It is dried over anhydrous sodium sulfate, and
It is concentrated to dryness, obtains 4- methoxyl group -1- indone (2.18g, yield 99%).
LCMS (ESI): m/z:163.1 [M+1].
(1b): the preparation iodo- 4- methoxyl group-indan-1-one of 7-
At 0 DEG C, into acetonitrile (150mL) solution of iodine (3.41g, 13.4mmol), 1- chloromethyl -4- fluoro- 1 is added,
Bicyclic [2.2.2] octane bis- (tetrafluoroborates) (3.97g, 11.2mmol) of 4- diammonium.Resulting solution is stirred at 0 DEG C
Then the 4- methoxyl group -1- indone (2.00g, 12.3mmol) is added in 10min.Reaction mixture is stirred at room temperature 5 hours
Afterwards, reaction mixture is evaporated and distributes residue between ethyl acetate and dilute sodium thiosulfate solution.By organic phase
It with saturated aqueous sodium thiosulfate, salt water washing, is dried over anhydrous sodium sulfate, and be concentrated to dryness, obtains the iodo- 4- methoxy of 7-
Base-indan-1-one (3.05g, yield 86%).
1H NMR (500MHz, DMSO-d6): 67.78 (d, J=8Hz, 1H), 7.03 (d, J=8Hz, 1H), 3.86 (s,
3H), 2.84 (m, 2H), 2.65 (m, 2H) .LCMS (ESI): m/z:289.1 [M+1].
(1c): the preparation iodo- indan-1-one of 4- hydroxyl -7-
At 0 DEG C, by trimethyl ammonium chloride (2.98g, 31.2mmol) add to aluminum trichloride (anhydrous) (8.31g,
62.5mmoL) in the suspension of DCM (20mL).After keeping temperature stirring 3h, the iodo- 4- methoxyl group-indane -1- of the 7- is added
DCM (100mL) solution of ketone (3.00g, 10.4mmol), reaction mixture become dark-brown.Reaction mixture is heated to 50
DEG C, and stir 12 hours.TLC display reaction is completed, and mixture is cooled to 0 DEG C, is added with stirring 1M HCL aqueous solution
(40mL).Sepia suspension is extracted with ethyl acetate 2 times.Organic phase is washed with brine, is dried over anhydrous sodium sulfate, and
It is concentrated to dryness, obtains the iodo- indan-1-one of 4- hydroxyl -7- (2.60g, yield 91%).
LCMS (ESI): m/z:273.1 [M-1].
(1d): preparation 7- iodine indane-Isosorbide-5-Nitrae-glycol
At 0 DEG C, sodium borohydride (0.70g, 18.5mmol) is added to the iodo- indan-1-one of the 4- hydroxyl -7-
In methanol (200mL) solution of (2.50g, 9.1mmol).Temperature is kept to stir 2h, reaction solution becomes clarification.Reaction mixture is dense
Contracting, residue distribute between ethyl acetate and 1M HCl.Ethyl acetate layer is washed with brine, is dried over anhydrous sodium sulfate,
And be concentrated to dryness, obtain 7- iodine indane-Isosorbide-5-Nitrae-glycol (2.40g, yield 95%).
LCMS (ESI): m/z:275.1 [M-1].
(1e): the preparation fluoro- 5- of 3- (the iodo- indane -4- base of 1- hydroxyl -7-) oxygroup-benzonitrile
By the 7- iodine indane-Isosorbide-5-Nitrae-glycol (2.00g, 7.2mmol), 3,5- difluorobenzonilyile (1.51g, 10.9mmol),
Potassium carbonate (3.00g, 21.7mmol) is added as in DMF (50mL), is heated to 110 DEG C and stirs 10h.TLC display has been reacted
At, it is cooled to room temperature, reaction mixture is poured into water, ethyl acetate is added and extracts 2 times, organic phase brine It, warp
Anhydrous sodium sulfate is dried and concentrated to doing, and by crude product, by column chromatography, (petroleum ether: ethyl acetate=10: 1) purifying obtains 3-
Fluoro- 5- (the iodo- indane -4- base of 1- hydroxyl -7-) oxygroup-benzonitrile (2.16g, yield 76%).
1H NMR (500MHz, DMSO-d6): δ 7.66 (d, J=8.3Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.28-
7.22 (m, 2H), 6.82-6.79 (m, 1H), 5.16 (d, J=7.3Hz, 1H), 4.92-4.87 (m, 1H) 2.90 (dt, J=
16.4,8.1Hz, 1H), 2.68 (dt, J=16.5,8.8Hz, 1H), 2.27-2.18 (m, 1H), 1.92-1.90 (m, 1H) .LCMS
(ESI): m/z:396.2 [M+1].
(1f): the preparation fluoro- 5- of 3- (the iodo- 1- oxo-indanes -4- base of 7-) oxygroup-benzonitrile
At room temperature, Dess-Martin oxidant (1.08g, 2.53mmol) is added to the fluoro- 5- of the 3- (1- hydroxyl -7-
Iodo- indane -4- base) oxygroup-benzonitrile (1.00g, 2.53mmol) methylene chloride (100mL) solution in.0.5h is stirred, TLC is aobvious
Show that reaction is completed.Reaction mixture is concentrated, residue is in ethyl acetate and dilute sodium thiosulfate solution and unsaturated carbonate
It is distributed between hydrogen sodium water solution.Ethyl acetate layer is washed with brine, is dried over anhydrous sodium sulfate, and is concentrated to dryness, 3- is obtained
Fluoro- 5- (the iodo- indane -4- base of 1- oxo -7-) oxygroup-benzonitrile (0.92g, yield 93%).
1H NMR (500MHz, DMSO-d6): δ 7.91 (d, J=4Hz, 1H), 7.65 (d, J=8Hz, 1H), 7.43 (m,
2H), 7.13 (d, J=8Hz, 1H), 2.83 (m, 2H), 2.50 (m, 2H) .LCMS (ESI): m/z:394.1 [M+1].
(1g): preparation 3- [(7- (solutions of dimethyl phosphoryl base) -1- oxo-indanes -4- base) oxygroup] fluoro- benzonitrile of -5-
By the fluoro- 5- of the 3- (the iodo- 1- oxo-indanes -4- base of 7-) oxygroup-benzonitrile (800mg, 2.04mmol), diformazan
Base phosphine oxide (200mg, 2.55mmol), K3PO4(520mg, 2.55mmol), Xantphos (118mg, 0.20mmol) and palladium acetate
(46mg, 0.20mmol) is placed in DMF (15mL), and reaction mixture under nitrogen protection, is heated to 150 DEG C of stirring 10h.TLC
Display reaction is completed, and is cooled to room temperature, reaction mixture is poured into water, and is extracted with ethyl acetate (20mL × 3).It will merge
Organic phase washed with saturated brine, anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Crude product is chromatographed into (dichloro by column
Methane: methanol=50: 1,30: 1) purifying, it is fluoro- to obtain 3- [(7- (dimethyl phosphine oxide) -1- oxo-indanes -4- base) oxygroup] -5-
Benzonitrile (0.65g, yield 93%).
1H NMR (500MHz, DMSO-d6): δ 8.04 (m, 1H), 7.73 (dd, J=8Hz, 1H), 7.53 (m, 2H), 7.43
(d, J=8Hz, 1H), 3.03 (m, 2H), 2.74 (m, 2H), 1.76 (s, 3H), 1.73 (s, 3H) .LCMS (ESI): m/z:344.1
[M+1]。
(1h): preparation (E, Z) -3- [(7- (solutions of dimethyl phosphoryl base) -1- (3- methoxy-propyl imido grpup)-indane -4- base)
Oxygroup] the fluoro- benzonitrile of -5-
By the 3- [(7- (solutions of dimethyl phosphoryl base) -1- oxo-indanes -4- base) oxygroup] fluoro- benzonitrile of -5- (300mg,
0.87mmol), 3- METHOXY PROPYL AMINE (400mg, 4.49mmol), pivalic acid (18mg, 0.18mmol) are placed in toluene (20mL)
In the mixed solution of hexamethylene (10mL), 10h is heated at reflux with the Dean-Stark water segregator of connection.TLC display has been reacted
At, be cooled to room temperature, by reaction mixture be evaporated and by residue be directly used in next step react.
(1i): preparation 3- [(the fluoro- 1- oxo-indanes -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-) oxygroup] fluoro- benzene of -5-
Formonitrile HCN
By bicyclic [2.2.2] octane of the fluoro- Isosorbide-5-Nitrae-diammonium of 1- chloromethyl -4- bis- (tetrafluoroborates) (780mg,
2.20mmol), anhydrous sodium sulfate (250mg, 1.76mmol) is added into acetonitrile (10mL).Be heated to 70 DEG C, be added dropwise it is thick (E,
Z) -3- [(7- (solutions of dimethyl phosphoryl base) -1- (3- methoxy-propyl imido grpup)-indane -4- base) oxygroup] the fluoro- benzonitrile of -5-
Acetonitrile (10mL) solution of (360mg, 0.87mmol), continues to be stirred to react 2h.TLC display reaction is completed, and is cooled to room temperature, instead
It answers mixture 1M HCl (8mL, 8.0mmol) to handle, and 1h is stirred at room temperature.Reaction mixture is evaporated and makes residue
It is distributed between ethyl acetate and water.By organic phase saturated common salt water washing, it is dried over anhydrous sodium sulfate, and be concentrated to dryness,
By crude product, by column chromatography, (methylene chloride: methanol=50: 1) purifying obtains 3- [(7- (solutions of dimethyl phosphoryl base) -2,2- bis-
Fluoro- 1- oxo-indanes -4- base) oxygroup] the fluoro- benzonitrile of -5- (160mg, yield 48%).
1H NMR (500MHz, DMSO-d6): δ 8.11 (m, 1H), 7.78 (dd, J=8Hz, 1H), 7.59 (m, 2H), 7.51
(d, J=8Hz, 1H), 3.67 (t, J=12Hz, 2H), 1.78 (s, 3H), 1.74 (s, 3H) .LCMS (ESI): m/z:380.1 [M+
1]。
(1j): preparation 3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygen
Base -5- fluorobenzonitrile (compound 1)
At 0 DEG C, sodium borohydride (70mg, 18.4mmol) is added to the 3- [(7- (solutions of dimethyl phosphoryl base) -2,2- bis-
Fluoro- 1- oxo-indanes -4- base) oxygroup] the fluoro- benzonitrile of -5- (150mg, 0.40mmol) methanol (10mL) solution in, keep
Temperature stirs 3h, and TLC display reaction is completed.By reaction mixture be spin-dried for and by residue through column chromatography (methylene chloride: methanol=
40: 1) purifying, obtain 3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -
5- fluorobenzonitrile (136mg, 91%).
1H NMR (500MHz, DMSO-d6): δ 7.72 (m, 2H), 7.68 (d, J=4Hz, 1H), 7.45 (dd, J=12Hz,
1H), 7.10 (d, J=8Hz, 1H), 6.76 (d, J=8Hz, 1H), 5.44 (m, 1H), 3.40 (m, 2H), 1.77 (t, 6H) .LCMS
(ESI): m/z:382.1 [M+1].
Embodiment 2
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1S) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -
5- fluorobenzonitrile (compound 2)
At 0 DEG C, RuCl (p- isopropyl toluene) [(R, R)-Ts-DPEN] (16mg, 0.025mmol) is added to nitrogen and is rushed
Wash 3- [(the fluoro- 1- oxo-indanes -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-) oxygroup] fluoro- benzonitrile of -5- (150mg,
0.40mmol), the solution of formic acid (80mg, 1.58mmol) and triethylamine (0.15mL, 1.0mmol) in methylene chloride (20mL)
In.Reaction flask is sealed and is placed in 4 DEG C of refrigerator overnights.TLC display reaction is completed, and reaction mixture is spin-dried for and will be remaining
Through column chromatography, (methylene chloride: methanol=40: 1) purifying obtains 3- [the fluoro- 1- of (1S) -7- (solutions of dimethyl phosphoryl base) -2,2- bis- to object
Hydroxyl -2,3- dihydro -1H- indane -4- base] oxygroup -5- fluorobenzonitrile (120mg, 80%).
1H NMR (500MHz, DMSO-d6): δ 7.72 (m, 2H), 7.68 (d, J=4Hz, 1H), 7.45 (dd, J=12Hz,
1H), 7.10 (d, J=8Hz, 1H), 6.76 (d, J=8Hz, 1H), 5.45 (m, 1H), 3.40 (m, 2H), 1.77 (t, 6H) .LCMS
(ESI): m/z:382.1 [M+1].
Embodiment 3
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1R) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -
5- fluorobenzonitrile (compound 3)
At 0 DEG C, RuCl (p- isopropyl toluene) [(S, S)-Ts-DPEN] (16mg, 0.025mmol) is added to nitrogen and is rushed
Wash 3- [(the fluoro- 1- oxo-indanes -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-) oxygroup] fluoro- benzonitrile of -5- (150mg,
0.40mmol), the solution of formic acid (80mg, 1.58mmol) and triethylamine (0.15mL, 1.0mmol) in methylene chloride (20mL)
In.Reaction flask is sealed and is placed in 4 DEG C of refrigerator overnights.TLC display reaction is completed, and reaction mixture is spin-dried for and will be remaining
Through column chromatography, (methylene chloride: methanol=40: 1) purifying obtains 3- [the fluoro- 1- of (1R) -7- (solutions of dimethyl phosphoryl base) -2,2- bis- to object
Hydroxyl -2,3- dihydro -1H- indane -4- base] oxygroup -5- fluorobenzonitrile (122mg, 81%).
1H NMR (500MHz, DMSO-d6): δ 7.71 (m, 2H), 7.68 (d, J=4Hz, 1H), 7.45 (dd, J=12Hz,
1H), 7.10 (d, J=8Hz, 1H), 6.76 (d, J=8Hz, 1H), 5.44 (m, 1H), 3.40 (m, 2H), 1.77 (t, 6H) .LCMS
(ESI): m/z:382.1 [M+1].
Embodiment 4
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5- difluoro phenoxy group) -2,2- bis-] dimethyl
The structural formula of phosphine (compound 4), the compound 4 is as follows:
The preparation method of the compound 4 the following steps are included:
(4a): preparation iodo- 2, the 3- dihydro -1H- indane -1- alcohol of 4- (3,5- difluoro phenoxy group) -7-
By 7- iodine indane-Isosorbide-5-Nitrae-glycol (1.50g, 5.4mmol), 1,3,5- trifluoro-benzenes (1.08g, 8.1mmol), cesium carbonate
(3.50g, 10.8mmol) is added as in DMF (40mL), is heated to 100 DEG C and is stirred overnight.TLC display reaction is completed, cold
But to room temperature, reaction mixture is poured into water, ethyl acetate is added and extracts 2 times, organic phase brine It, through anhydrous sulphur
Sour sodium is dried and concentrated to doing, and by crude product, by column chromatography, (petroleum ether: ethyl acetate=10: 1) purifying obtains 4- (3,5-
Difluoro phenoxy group) iodo- 2, the 3- dihydro -1H- indane -1- alcohol of -7- (1.26g, yield 60%).
1H NMR (500MHz, DMSO-d6): δ 7.56 (d, J=8.3Hz, 1H), 6.85-6.75 (m, 3H), 6.25 (m,
1H), 5.12 (s, 1H), 4.90-4.86 (m, 1H) 2.89 (d, J=8.1Hz, 1H), 2.68 (d, J=8.8Hz, 1H), 2.27-
2.18 (m, 1H), 1.92-1.90 (m, 1H) .LCMS (ESI): m/z:389.2 [M+1].
(4b): preparation iodo- 2, the 3- dihydro -1H- indan-1-one of 4- (3,5- difluoro phenoxy group) -7-
At room temperature, Dess-Martin oxidant (1.09g, 2.58mmol) is added to the 4- (3,5- difluorobenzene oxygen
Base) iodo- 2, the 3- dihydro -1H- indane -1- alcohol (1.00g, 2.58mmol) of -7- methylene chloride (50mL) solution in.Stirring
0.5h, TLC display reaction are completed.Reaction mixture is concentrated, residue ethyl acetate and dilute sodium thiosulfate solution with
And it is distributed between saturated sodium bicarbonate aqueous solution.Ethyl acetate layer is washed with brine, is dried over anhydrous sodium sulfate, and is concentrated into
It is dry, obtain 4- iodo- 2, the 3- dihydro -1H- indan-1-one of (3,5- difluoro phenoxy group) -7- (0.90g, yield 91%).
1H NMR (500MHz, DMSO-d6): δ 7.65 (d, 1H), 7.03-7.08 (m, 3H), 6.35 (m, 1H), 2.80 (m,
2H), 2.50 (m, 2H) .LCMS (ESI): m/z:387.1 [M+1].
(4c): preparation 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl base) -2,3- dihydro -1H- indan-1-one
By iodo- 2, the 3- dihydro -1H- indan-1-one (600mg, 1.55mmol) of the 4- (3,5- difluoro phenoxy group) -7-,
Dimethyl phosphine oxide (151mg, 1.94mmol), K3PO4(412mg, 1.94mmol), Xantphos (90mg, 0.16mmol) and acetic acid
Palladium (35mg, 0.16mmol) is placed in DMF (15mL), and reaction mixture under nitrogen protection, is heated to 150 DEG C of stirring 10h.
TLC display reaction is completed, and is cooled to room temperature, reaction mixture is poured into water, and extracted with ethyl acetate (20mL × 3).It will
Combined organic phase is washed with saturated brine, and anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Crude product is chromatographed by column
(methylene chloride: methanol=50: 1,30: 1) purifying, obtain 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl base) -2,3- bis-
- 1 ketone of hydrogen -1H- indane (0.39g, yield 76%).
1H NMR (500MHz, DMSO-d6): δ 7.76 (d, 2H), 7.21 (m, 2H), 7.03 (s, 1H), 3.01 (m, 2H),
2.71 (m, 2H), 1.75 (s, 3H), 1.73 (s, 3H) .LCMS (ESI): m/z:337.1 [M+1].(4d): preparation (E, Z)-[(7-
(3,5- difluoro phenoxy group) -3- (3- methoxy-propyl imido grpup) -2,3- dihydro -1H- indane -4- base)] dimethyl phosphine
By the 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl base) -2,3- dihydro -1H- indan-1-one
(260mg, 0.77mmol), 3- METHOXY PROPYL AMINE (413mg, 4.64mmol), pivalic acid (16mg, 0.16mmol) are placed in toluene
In the mixed solution of (20mL) and hexamethylene (10mL), 10h is heated at reflux with the Dean-Stark water segregator of connection.TLC is shown
Reaction is completed, and is cooled to room temperature, and reaction mixture is evaporated and is directly used in residue and is reacted in next step.
(4e): preparation fluoro- 2, the 3- dihydro -1H- indenes of 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-
Full -1 ketone
By bicyclic [2.2.2] octane of the fluoro- Isosorbide-5-Nitrae-diammonium of 1- chloromethyl -4- bis- (tetrafluoroborates) (682mg,
2.20mmol), anhydrous sodium sulfate (220mg, 1.76mmol) is added into acetonitrile (10mL).70 DEG C are heated to, system is walked in dropwise addition
(E, Z)-[(7- (3,5- difluoro the phenoxy group) -3- (3- methoxy-propyl imido grpup) -2,3- dihydro -1H- indane -4- base)] obtained
Acetonitrile (10mL) solution of dimethyl phosphine, continues to be stirred to react 2h.TLC display reaction is completed, and is cooled to room temperature, reaction is mixed
It closes object to be handled with 1M HCl (8mL, 8.0mmol), and 1h is stirred at room temperature.Reaction mixture is evaporated and makes residue in second
It is distributed between acetoacetic ester and water.By organic phase saturated common salt water washing, it is dried over anhydrous sodium sulfate, and be concentrated to dryness, it will be thick
By column chromatography, (methylene chloride: methanol=50: 1) purifying obtains 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl to product
Base) bis- fluoro- -1 ketone of 2,3- dihydro -1H- indane (120mg, yield 58%) of -2,2-.
1H NMR (500MHz, DMSO-d6): δ 7.81 (d, 2H), 7.27 (m, 2H), 7.05 (s, 1H), 3.58 (m, 2H),
1.76 (s, 3H), 1.73 (s, 3H) .LCMS (ESI): m/z:373.1 [M+1].
(4f): preparation [fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5- difluoro phenoxy group) -2,2- bis-] two
Methyl oxidation phosphine (compound 4)
At 0 DEG C, sodium borohydride (41mg, 10.8mmo1) is added to 4- (3,5- difluoro phenoxy group) -7- (solutions of dimethyl phosphoryl
Base) -2,2- bis- fluoro- -1 ketone (100mg, 0.27mmol) of 2,3- dihydro -1H- indane methanol (10mL) solution in, keep temperature
3h is stirred, TLC display reaction is completed.By reaction mixture be spin-dried for and by residue through column chromatography (methylene chloride: methanol=40:
1) it purifies, obtains [fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5- difluoro phenoxy group) -2,2- bis-] dimethyl oxygen
Change phosphine (91mg, 90%).
1H NMR (500MHz, DMSO-d6): δ 7.56 (m, 2H), 7.18 (d, 1H), 7.09 (d, 1H), 6.76 (m, 2H),
5.41 (m, 1H), 3.38 (m, 2H), 1.75 (t, 6H) .LCMS (ESI): m/z:375.1 [M+1].
Embodiment 5
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- ((5- chloropyridine -3- base) oxygroup) -2,2- bis-] dimethyl
The structural formula of phosphine oxide (compound 5), the compound 5 is as follows:
The preparation method of the compound 5 the following steps are included:
(5a): preparation 4- [(5- chloropyridine -3- base) oxygroup] iodo- 2,3- dihydro -1H- indane -1- alcohol of -7-
By 7- iodine indane-Isosorbide-5-Nitrae-glycol (1.50g, 5.4mmol), 3,5- dichloropyridine (1.20g, 8.1mmol), cesium carbonate
(3.50g, 10.8mmol) is added as in DMF (40mL), is heated to 100 DEG C and is stirred overnight.TLC display reaction is completed, cold
But to room temperature, reaction mixture is poured into water, ethyl acetate is added and extracts 2 times, organic phase brine It, through anhydrous sulphur
Sour sodium is dried and concentrated to doing, and by crude product, by column chromatography, (petroleum ether: ethyl acetate=5: 1) purifying obtains 4- [(5- chlorine
Pyridin-3-yl) oxygroup] iodo- 2, the 3- dihydro -1H- indane -1- alcohol of -7- (1.02g, yield 48%).
1H NMR (500MHz, DMSO-d6): δ 8.66 (d, 1H), 8.50 (d, 1H), 7.46 (m, 2H), 6.81 (m, 1H),
5.16 (s, 1H), 5.01 (m, 1H), 3.21 (m, 2H), 2.37-2.25 (m, 2H) .LCMS (ESI): m/z:388.2 [M+1].
(5b): preparation 4- [(5- chloropyridine -3- base) oxygroup] iodo- 2,3- dihydro -1H- indan-1-one of -7-
At room temperature, Dess-Martin oxidant (657mg, 1.55mmol) is added to 4- [(5- chloropyridine -3- base) oxygen
Base] iodo- 2, the 3- dihydro -1H- indane -1- alcohol (600mg, 1.55mmol) of -7- methylene chloride (30mL) solution in.Stirring
0.5h, TLC display reaction are completed.Reaction mixture is concentrated, residue ethyl acetate and dilute sodium thiosulfate solution with
And it is distributed between saturated sodium bicarbonate aqueous solution.Ethyl acetate layer is washed with brine, is dried over anhydrous sodium sulfate, and is concentrated into
It is dry, obtain 4- [(5- chloropyridine -3- base) oxygroup] iodo- 2,3- dihydro -1H- indan-1-one of -7- (561mg, yield 93%).
1H NMR (500MHz, DMSO-d6): δ 8.71 (d, 1H), 8.56 (d, 1H), 7.63 (m, 2H), 7.21 (d, 1H),
3.03 (m, 2H), 2.67 (m, 2H) .LCMS (ESI): m/z:386.1 [M+1].
(5c): preparation 4- [(5- chloropyridine -3- base) oxygroup] -7- (solutions of dimethyl phosphoryl base) -2,3- dihydro -1H- indane -1
Ketone
By 4- [(5- chloropyridine -3- base) oxygroup] iodo- 2,3- dihydro -1H- indan-1-one (500mg, 1.30mmol) of -7-,
Dimethyl phosphine oxide (127mg, 1.62mmol), K3PO4(344mg, 1.94mmol), Xantphos (73mg, 0.13mmol) and acetic acid
Palladium (29mg, 0.13mmol) is placed in DMF (20mL), and reaction mixture under nitrogen protection, is heated to 150 DEG C of stirring 10h.
TLC display reaction is completed, and is cooled to room temperature, reaction mixture is poured into water, and extracted with ethyl acetate (50mL × 3).It will
Combined organic phase is washed with saturated brine, and anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Crude product is chromatographed by column
It (methylene chloride: methanol=30: 1) purifies, obtains 4- [(5- chloropyridine -3- base) oxygroup] -7- (solutions of dimethyl phosphoryl base) -2,3- bis-
- 1 ketone of hydrogen -1H- indane (0.36g, yield 82%).
1H NMR (500MHz, DMSO-d6): δ 8.76 (d, 1H), 8.58 (d, 1H), 7.73 (s, 1H), 7.13 (m, 2H),
3.08 (m, 2H), 2.76 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H) .LCMS (ESI): m/z:336.3 [M+1].
(5d): preparation (E, Z)-[(5- chloropyridine -3- base) oxygroup) -3- (3- methoxy-propyl imido grpup) -2,3- dihydro -
1H- indane -4- base)] dimethyl phosphine
By 4- [(5- chloropyridine -3- base) oxygroup] -7- (solutions of dimethyl phosphoryl base)--1 ketone of 2,3- dihydro -1H- indane
(260mg, 0.77mmol), 3- METHOXY PROPYL AMINE (413mg, 4.64mmol), pivalic acid (16mg, 0.16mmol) are placed in toluene
In the mixed solution of (20mL) and hexamethylene (10mL), 10h is heated at reflux with the Dean-Stark water segregator of connection.TLC is shown
Reaction is completed, and is cooled to room temperature, and reaction mixture is evaporated and is directly used in residue and is reacted in next step.
(5e): fluoro- 2, the 3- dihydro-of preparation 4- [(5- chloropyridine -3- base) oxygroup)] -7- (solutions of dimethyl phosphoryl base) -2,2- bis-
- 1 ketone of 1H- indane
By bicyclic [2.2.2] octane of the fluoro- Isosorbide-5-Nitrae-diammonium of 1- chloromethyl -4- bis- (tetrafluoroborates) (682mg,
2.20mmol), anhydrous sodium sulfate (250mg, 1.76mmol) is added into acetonitrile (10mL).70 DEG C are heated to, system is walked in dropwise addition
(E, Z)-[(5- chloropyridine -3- base) oxygroup) -3- (3- methoxy-propyl imido grpup) -2,3- dihydro -1H- indane -4-
Base)] acetonitrile (10mL) solution of dimethyl phosphine, continues to be stirred to react 2h.TLC display reaction is completed, and is cooled to room temperature, instead
It answers mixture 1M HCl (8mL, 8.0mmol) to handle, and 1h is stirred at room temperature.Reaction mixture is evaporated and makes residue
It is distributed between ethyl acetate and water.By organic phase saturated common salt water washing, it is dried over anhydrous sodium sulfate, and be concentrated to dryness,
By crude product, by column chromatography, (methylene chloride: methanol=50: 1) being purified, and obtains 4- [(5- chloropyridine -3- base) oxygroup)] -7-
Fluoro- -1 ketone of 2,3- dihydro -1H- indane (116mg, yield 56%) of (solutions of dimethyl phosphoryl base) -2,2- bis-.
1H NMR (500MHz, DMSO-d6): δ 8.78 (d, 1H), 8.59 (d, 1H), 7.75 (s, 1H), 7.13 (m, 2H),
3.68 (m, 2H), 1.78 (s, 3H), 1.76 (s, 3H) .LCMS (ESI): m/z:372.5 [M+1].
(5f): preparation [fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- of 7- ((5- chloropyridine -3- base) oxygroup) -2,2- bis-
Base] dimethyl phosphine (compound 5)
At 0 DEG C, sodium borohydride (40mg, 1.07mmol) is added to 4- [(5- chloropyridine -3- base) oxygroup)] -7- (diformazan
Base phosphoryl) -2,2- bis- fluoro- -1 ketone (80mg, 0.21mmol) of 2,3- dihydro -1H- indane methanol (10mL) solution in, keep
Temperature stirs 3h, and TLC display reaction is completed.By reaction mixture be spin-dried for and by residue through column chromatography (methylene chloride: methanol=
30: 1) purifying, obtain [fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5- difluoro phenoxy group) -2,2- bis-] diformazan
Base phosphine oxide (75mg, 94%).
1H NMR (500MHz, DMSO-d6): δ 8.71 (d, 1H), 8.56 (d, 1H), 7.65 (s, 1H), 7.10 (d, 2H),
6.46 (s, 1H), 5.56 (m, 1H), 3.60 (m, 2H), 1.78 (t, 6H) .LCMS (ESI): m/z:374.5 [M+1].
Embodiment 6
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (dimethyl phosphine sulfide) -2,2- bis-] oxygroup -5- fluorobenzene first
The structural formula of nitrile (compound 6), the compound 6 is as follows:
By 3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorine
Benzonitrile (25mg, 0.065mmol), lawesson reagent (14mg, 0.033mmol) are added into toluene (10mL).It is heated to 100 DEG C
5h is stirred, reaction mixture is spin-dried for and (methylene chloride: methanol=50: 1) purifying obtains 3- [7- through column chromatography by residue
Fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (dimethyl phosphine sulfide) -2,2- bis-] oxygroup -5- fluorobenzonitrile (15mg,
58%).
1H NMR (500MHz, DMSO-d6): δ 7.70 (m, 2H), 7.65 (d, 1H), 7.45 (d, 1H), 7.08 (d, 1H),
6.76 (d, 1H), 5.40 (m, 1H), 3.36 (m, 2H), 0.78 (t, 6H) .LCMS (ESI): m/z:398.2 [M+1].
Embodiment 7: biological experiment
1, VEGF ELISA is measured
By the 786-0 cell inoculation in logarithmic growth phase in 96 orifice plates (Fisher Scientific), every hole 7500
20 μ L various concentration compound stock solutions after cultivating 4h, are added to each hole so that final dense by a cell (180 hole μ L/)
It spends following (μM): 0.01,0.05,0.25,1.25,6.25,30.After about 20h, mention by suction removal culture medium and to each hole
For the growth medium of 180 μ L.The 6x untested compound stock solution that 20 μ L are newly prepared is added to each hole.Hypoxemia (1% oxygen
+ 5% carbon dioxide) it cultivates for 24 hours, cell culture medium is removed.Then, the method to suggest in accordance with manufacturer, using from R&D
The ELISA kit of Systems purchase determines VEGF concentration.Celltiter Glo by adding from 50 μ L to each hole is tried
Agent terminates reaction, and shaking gently ELISA Plate carries out termination reaction sufficiently.CellTiter-Glo is carried out to the plate of inoculating cell
Luminescent cell vitality test (Promega) uses microplate reader in the absorbance value in each hole of 450nm wavelength measurement immediately after.Make
Data are analyzed by GraphPadPrism with dosage-response-inhibition (four parameters) equation, calculate EC50, the results are shown in Table 1.
The EC of compound is selected in table 1.VEGF ELISA measurement50
| Compound | EC50(μM) |
| 1 | 0.51 |
| 2 | 0.035 |
| 3 | 0.121 |
| 4 | 0.029 |
| 5 | 0.075 |
| 6 | 0.92 |
| Positive control | 0.067 |
Note: positive control medicine: PT-2385.
As known to 1 experimental result of table: compound 1-6 all has the activity for inhibiting vegf expression, wherein compound 2 and chemical combination
4 activity of object is better than positive control PT-2385.
2, luciferase reporter gene is tested
1) experiment reagent: Dulbecco ' Modified Eagle ' s Medium, Fetal Bovine Serum,
Trypsin-EDTA (0.25%), penicillin, streptomysin, Lipofectamine2000,786-O cell, Dual-Reporter Assay System, 96 hole blanks, HRE-Luc plasmid, PRL-SV-40 plasmid, TOP10 bacterial strain,
The small extraction reagent kit of plasmid
2) instrument model: Thermo Scientific LuminoskanTM MAscent
3) experimentation:
The amplification and extraction of a.HRE-Luc and PRL-SV-40 plasmid
Plasmid conversion enters in TOP10 competent cell: taking 50 μ L competent escherichia coli cells (TOP10), 1 μ L is added
Plasmid, after ice bath 30min, 42 DEG C of heat shock 90s are put back on ice, ice bath 2min at once；Add 400 μ L LB culture mediums, is shaken in 37 DEG C
Bed shakes shaken cultivation 45-60min slowly；50-100 μ L is taken to be coated in the LB solid medium containing ampicillin (100 μ g/mL)
On, 37 DEG C of inversion overnight incubations.
Amplification, plasmid extract: plasmid is extracted to be extracted according to the small extraction reagent kit specification of Tiangeng plasmid.
B. it transfects
By the 786-O cell inoculation of logarithmic phase growth into 48 orifice plates, every 200 μ L of hole, about 200000 cells.It cultivated
Night discards old culture medium, and 200 μ L serum-frees DMEM culture medium without double antibody is added, 6 hours hungry.1.5mL ep is taken to manage, in A pipe
1 μ L Lopo2000 liposome is taken, the static 5min of room temperature after 50 μ L serum-frees DMEM culture medium without double antibody mixes is added to；In B pipe
It takes 0.4mg (HRE-Luc: PRL-SV-40=20: 1) plasmid to be added to 50 μ L serum-free DMEM culture mediums without double antibody, mixes；By B
A pipe mixes in pipe, reacts at room temperature 20min.Old culture medium in 48 orifice plates is discarded, A, B mixed culture medium, hypoxemia (1% is gently added
Oxygen and 5% carbon dioxide) culture 6h.
C. it is administered
Concentration gradient 0.01,0.05,0.25,1.25,6.25,30uM and blank control are set.By untested compound
(mother liquid concentration 10mM) is diluted to concentrations above with the DMEM culture medium containing 10% serum.Culture medium old in 48 orifice plates is discarded,
PBS cleaning, is added configured pastille culture medium.Hypoxemia culture is for 24 hours.
D. it detects
48 orifice plates are taken out, old culture medium is discarded, PBS is cleaned twice, uses Dual-Reporter
Assay System is detected.100 μ L, 1 x Lysis is added into every hole, ice bath cracks 1h.It takes in 30 μ L48 orifice plates and splits
Solution liquid is added in 96 hole blanks, and 30 μ L of firefly luciferin substrate is added in every hole, is detected immediately；30 μ L, 1 x is added in every hole
Stop&Glo substrate, is detected immediately.
4) experimental result
EC is calculated using Dotmatics software50, the results are shown in Table 2:
The EC of compound is selected in the experiment of 2. Dual-Luciferase of table50
| Compound | EC50(μM) |
| 1 | 0.053 |
| 2 | 0.011 |
| 3 | 0.78 |
| 4 | 0.024 |
| 5 | 0.061 |
| 6 | 0.12 |
| Positive control | 0.023 |
Note: positive control medicine: PT-2385.
As known to 2 experimental result of table: compound 1-6 all has certain external activity, and wherein compound 2 and compound 4 are living
Property be better than positive control PT-2385.
3, the interaction of SPRi system testing compound and HIF-2 α albumen is utilized
1) experimental principle
Bio-molecular interaction system is a kind of surface plasma resonance image-forming (SPRi) based on microarray technology
System shoots the thousands of sampling points on chip using two-dimensional CCD technology, the phase between real-time analysis of various biomolecules
Interaction, without label.To understand the specificity of molecule combination, the dynamics data of molecule combination is accurately calculated, understands life
The cohesive process of object molecule.Be widely used in the measurement of various biosystems, including all kinds of small molecule compounds, polypeptide, protein,
Oligonucleotides, the interaction between carbohydrate.By PLEXERA SPR Date Analysis Module (DAM) analyze software into
The analysis of row data and fitting, available binding curve, in conjunction with, dissociation, the dynamics datas such as equilibrium dissociation constant.
2) experimental method
By Arrayit, the SpotBot3Microarrayer in SpotBot3 pin mark platform controls software for compound
As for the surface biochip Graft-to-PCL, ultraviolet light cross-linking 15min is by compound crosslink in chip surface.Albumen it is initial
Concentration is 0.1-1 μM with PBS buffer solution, is diluted according to a certain percentage, the compound sample introduction of configured various concentration
Detection.Obtained data analyze software according to PLEXERA SPR Date Analysis Module (DAM) and carry out data analysis
With fitting, binding kinetics constant is obtained, the results are shown in Table 3.
Buffer (buffer): 1 × PBS
It lives again liquid: Gly-Hcl (PH=2)
Sample introduction flow velocity 1 μ l/s, sample injection time 180s；Dissociate 1 μ l/s of flow velocity, sample injection time 200s；
Live again 2 μ l/s of flow velocity, and live again time 200s
3) experimental result
Binding constant (ka), dissociation constant (kd) and the equilibrium dissociation constant (KD) of embodiment compound and HIF-2 α albumen
As shown in table 3.
3. compound of table and HIF-2 α protein binding kinetic constant
| Compound | Ka(1/Ms) | Kd(1/s) | KD(M) |
| 1 | 5.92e2 | 3.73e-3 | 6.31e-6 |
| 4 | 2.05e3 | 1.94e-3 | 9.47e-7 |
| 5 | 3.05e2 | 9.8e-3 | 9.55e-5 |
| 6 | 7.41e2 | 1.03e-2 | 1.38e-5 |
| PT2385 | 4.77e2 | 2.55e-3 | 5.34e-6 |
As known to 3 experimental result of table: determining that test compound can be combined with HIF-2 α albumen, wherein compound 1 and change
Closing object 4 and HIF-2 α has stronger binding ability.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than is limited；Although referring to aforementioned reality
Invention is explained in detail for example, to those skilled in the art, still can be to previous embodiment institute
The technical solution of record is modified or equivalent replacement of some of the technical features；And these modifications or substitutions, and
The essence of corresponding technical solution is not set to be detached from the spirit and scope of claimed technical solution of the invention.
Claims (10)
1. aryl phosphorus oxygen class and aryl phosphorus sulphur class compound, it is characterised in that it is compound shown in formula (I) and its pharmaceutically may be used
The salt of receiving,
Wherein: R1 is selected from aryl or heteroaryl；
R2 is selected from hydrogen, halogenated or alkyl；
W is selected from oxygen or sulphur.
2. compound according to claim 1, it is characterised in that: the R1 is phenyl, bicyclic heteroaryl or bicyclic heteroaryl
Base.
3. compound according to claim 1, it is characterised in that: the R1 is phenyl or pyridyl group.
4. compound according to claim 3, it is characterised in that: the phenyl or pyridyl group are selected from halogen by least one
The substituent group substitution in generation, cyano, C1-C4 alkyl and C1-C4 alkoxy.
5. compound according to claim 1, it is characterised in that: the R2 is fluoro, and n is 1,2 or 3.
6. any one of -5 compound according to claim 1, it is characterised in that: the compound is selected from:
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorobenzene first
Nitrile；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1S) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorine
Benzonitrile；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of (1R) -7- (solutions of dimethyl phosphoryl base) -2,2- bis-] oxygroup -5- fluorine
Benzonitrile；
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (3,5 difluoro phenoxy group) -2,2- bis-] dimethyl phosphine；
[fluoro- 3- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- ((5- chloropyridine -3- base) oxygen) -2,2- bis-] dimethyl
Phosphine；
3- [fluoro- 1- hydroxyl -2, the 3- dihydro -1H- indane -4- base of 7- (dimethyl phosphine sulfide) -2,2- bis-] oxygroup -5- fluorobenzonitrile.
7. the preparation method of compound described in claim 1, it is characterised in that the preparation method is as follows:
8. a kind of pharmaceutical composition, it includes compound described in any one of claims 1-6 or its pharmaceutically acceptable salt,
And optional one or more pharmaceutically acceptable excipient.
9. compound described in any one of claims 1-6 or its pharmaceutically acceptable salt are in preparation for treating and/or pre-
Purposes in the drug of anti-mammal disease relevant to Hypoxia-inducible fa ctor 2α or illness.
10. purposes according to claim 9, it is characterised in that: the disease relevant to Hypoxia-inducible fa ctor 2α or
Illness is selected from cancer, inflammation, metabolic disease；
The cancer include cutaneum carcinoma, lung cancer, urological cancer, neoplastic hematologic disorder, breast cancer, glioma, digestive system tumor,
Genital system, lymthoma, nervous system neoplasm, brain tumor, head and neck cancer；The inflammation includes pneumonia, enteritis, ephritis, pass
Section inflammation, trauma infection contamination；The metabolic disease includes obesity, dyslipidemia, hyperlipidemia.
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| WO2021093724A1 (en) * | 2019-11-15 | 2021-05-20 | 武汉光谷亚太医药研究院有限公司 | Novel 2,3-hydrindene derivative compound, preparation method and application |
| CN112812136B (en) * | 2019-11-15 | 2022-04-12 | 武汉光谷亚太医药研究院有限公司 | Novel 2, 3-indane derivative compound, preparation method and application |
| US11407712B2 (en) | 2020-03-19 | 2022-08-09 | Arcus Biosciences, Inc. | Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2α |
| US11787762B2 (en) | 2020-03-19 | 2023-10-17 | Arcus Biosciences, Inc. | Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha |
| EP4074317A1 (en) | 2021-04-14 | 2022-10-19 | Bayer AG | Phosphorus derivatives as novel sos1 inhibitors |
| WO2022219035A1 (en) | 2021-04-14 | 2022-10-20 | Bayer Aktiengesellschaft | Phosphorus derivatives as novel sos1 inhibitors |
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