CN109776607B - Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof - Google Patents
Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof Download PDFInfo
- Publication number
- CN109776607B CN109776607B CN201910135589.9A CN201910135589A CN109776607B CN 109776607 B CN109776607 B CN 109776607B CN 201910135589 A CN201910135589 A CN 201910135589A CN 109776607 B CN109776607 B CN 109776607B
- Authority
- CN
- China
- Prior art keywords
- indan
- dihydro
- oxy
- difluoro
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The aryl phosphorus oxygen compound and the aryl phosphorus sulfur compound can be used as an HIF-2 alpha inhibitor and used for preparing medicaments for treating and/or preventing diseases or symptoms related to hypoxia inducible factor 2 alpha of mammals. The structural formulas of the aryl phosphorus oxygen compound and the aryl phosphorus sulfur compound are as follows:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel aryl phosphorus oxygen and aryl phosphorus sulfur compounds with antitumor activity, and a preparation method and application thereof.
Background
Renal cancer is a malignant tumor originating in the epithelial system of the urinary tubule of the renal parenchyma, and is known as renal cell carcinoma in academic terms, which is also called renal adenocarcinoma, and is referred to as renal cancer for short. The kidney cancer accounts for about 2-3% of adult malignant tumor and 80-90% of adult malignant tumor. The rising rate of renal cancer has ranked first among malignant tumors in recent years. Clinical treatment shows that kidney cancer is insensitive to radiotherapy and chemotherapy, and targeted antitumor drugs represented by VEGFR inhibitors sorafenib and sunitinib are first-line treatment drugs of late-stage kidney cancer. Although there are up to ten FDA-approved drugs for the treatment of renal cancer, these drugs have a very limited therapeutic effect on metastatic renal cancer and are susceptible to drug resistance. Therefore, finding and confirming a new target for the action of a specific drug for treating kidney cancer is a very urgent and significant task.
Hypoxia inducible factor 2a (HIF-2a) is a transcription factor that affects the expression of a variety of genes. It is responsible for regulating and controlling the reaction of cells to the anoxic environment and promoting the survival and proliferation of cells in the anoxic environment. HIF-2a regulated genes affect a variety of physiological processes including metabolism, angiogenesis, cell proliferation, tumor metastasis, inflammation, and escape from anti-cancer immune responses. It is thought to be associated with the exacerbation of a variety of cancers, and plays a very important role, particularly in Clear Cell Renal Cell Carcinoma (ccRCC). Therefore, the development of HIF-2a target inhibition drugs is of great significance.
There are currently few reports of HIF-2a inhibitors, with only one inhibitor PT2385 being in phase 1 clinical stage. Therefore, the development of new improved or more potent HIF-2a inhibitors is of great clinical significance for inhibiting the occurrence, metastasis and recurrence of tumors.
Disclosure of Invention
The aryl phosphorus oxygen compound and the aryl phosphorus sulfur compound are used as HIF-2a inhibitors and can be used for treating or/and preventing HIF-2 alpha-related diseases or symptoms of mammals (including human beings).
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the first aspect of the invention provides aryl phosphorus oxygen compounds and aryl phosphorus sulfur compounds, which are compounds shown in a formula (I) and pharmaceutically acceptable salts thereof,
wherein: r1 is selected from aryl or heteroaryl;
r2 is selected from hydrogen, halo or alkyl; or two R2 and the carbon atoms to which they are attached form a 3-8 membered ring;
w is selected from oxygen or sulfur.
Further: and R1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl.
Further: the R1 is phenyl or pyridyl.
Further: substituted with at least one substituent selected from halo, C1-C4 alkylalkoxy and cyano; r2 is fluoro and n is 1, 2 or 3.
The present invention also provides said compound selected from the group consisting of:
3- [7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile;
3- [ (1S) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile;
3- [ (1R) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile;
[7- (3,5 difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide;
[7- ((5-chloropyridin-3-yl) oxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide;
3- [7- (dimethylphosphinothioyl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile.
In a second aspect, the present invention provides a process for the preparation of the above compound, the preparation route being as follows:
a third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable excipients.
In a fourth aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition in a mammal associated with hypoxia inducible factor 2 α. The mammal includes a human.
Further, the disease or disorder related to hypoxia inducible factor 2 alpha is selected from cancer, inflammation and metabolic diseases.
Further, the cancer comprises skin cancer, lung cancer, urinary tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck cancer; the inflammation comprises pneumonia, enteritis, nephritis, arthritis and trauma infection; the metabolic diseases comprise obesity, dyslipidemia and hyperlipidemia.
Compared with the prior art, the compound can effectively inhibit HIF-2a and HIF-1 beta from forming a dimer complex; has stronger in vitro binding capacity with HIF-2 alpha protein; can effectively inhibit expression of a downstream target gene VEGF of HIF-2 a.
Detailed Description
The present invention is further illustrated in detail by specific preparation examples and biological experiments, but it should be understood that these examples and biological experiments are for illustrative purposes only and are not to be construed as limiting the present invention in any way. It will be clear to those skilled in the art that, in the following, the materials used and the methods of operation are well known in the art, if not specifically stated. Unless otherwise stated, wherein: (1) temperatures are expressed in degrees Celsius (. degree. C.) and the operation is carried out at room temperature, which is generally 15-35℃, preferably 20-30℃, more preferably 20-25℃; (2) drying the organic solvent with anhydrous sodium sulfate, and removing the solvent with ethyl acetatePerforming reduced pressure evaporation by using an evaporator, wherein the bath temperature is not higher than 60 ℃; (3) the reaction process was followed by Thin Layer Chromatography (TLC); (4) the final product has satisfactory hydrogen nuclear magnetic resonance spectrum (1H-NMR), and Mass Spectrometry (MS) data.
Example 1
Synthesis of 3- [7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (compound 1), the structural formula of said compound 1 is as follows:
the preparation method of the compound 1 comprises the following steps:
(1a) the method comprises the following steps Preparation of 4-methoxy-1-indanone
4-hydroxy-1-indanone (2.00g, 13.5mmol) and potassium carbonate (7.5g, 54.0mmol) were added to acetone (40mL), iodomethane (3.8g, 27.0mmol) was added, the temperature was raised to 60 ℃ and stirred for 5 h. TLC showed the reaction was complete, cooled to room temperature, poured the reaction mixture into water, extracted 2 times with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 4-methoxy-1-indanone (2.18g, 99% yield).
LCMS(ESI)：m/z：163.1[M+1]。
(1b) The method comprises the following steps Preparation of 7-iodo-4-methoxy-indan-1-one
To a solution of iodine (3.41g, 13.4mmol) in acetonitrile (150mL) at 0 deg.C was added 1-chloromethyl-4-fluoro-1, 4-diammonium bicyclo [2.2.2] octane bis (tetrafluoroborate) (3.97g, 11.2 mmol). The resulting solution was stirred at 0 deg.C for 10min, then the 4-methoxy-1-indanone (2.00g, 12.3mmol) was added. After the reaction mixture was stirred at room temperature for 5 hours, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and dilute aqueous sodium thiosulphate solution. The organic phase was washed with saturated aqueous sodium thiosulfate, brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 7-iodo-4-methoxy-indan-1-one (3.05g, 86% yield).
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 method comprises the following steps Preparation of 4-hydroxy-7-iodo-indan-1-one
Trimethylammonium chloride (2.98g, 31.2mmoL) was added to a suspension of anhydrous aluminum trichloride (8.31g, 62.5mmoL) in DCM (20mL) at 0 deg.C. After stirring for 3h while maintaining temperature, a solution of the 7-iodo-4-methoxy-indan-1-one (3.00g, 10.4mmol) in DCM (100mL) was added and the reaction mixture turned dark brown. The reaction mixture was heated to 50 ℃ and stirred for 12 hours. TLC showed the reaction was complete and the mixture was cooled to 0 ℃ and 1M aqueous HCl (40mL) was added with stirring. The tan suspension was extracted 2 times with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 4-hydroxy-7-iodo-indan-1-one (2.60g, 91% yield).
LCMS(ESI)：m/z：273.1[M-1]。
(1d) The method comprises the following steps Preparation of 7-iodoindan-1, 4-diol
Sodium borohydride (0.70g, 18.5mmol) was added to a solution of the 4-hydroxy-7-iodo-indan-1-one (2.50g, 9.1mmol) in methanol (200mL) at 0 deg.C. The temperature was maintained and stirring was continued for 2h, whereupon the reaction solution became clear. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and 1M HCl. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 7-iodoindan-1, 4-diol (2.40g, 95% yield).
LCMS(ESI)：m/z：275.1[M-1]。
(1e) The method comprises the following steps Preparation of 3-fluoro-5- (1-hydroxy-7-iodo-indan-4-yl) oxy-benzonitrile
The 7-iodoindan-1, 4-diol (2.00g, 7.2mmol), 3, 5-difluorobenzonitrile (1.51g, 10.9mmol), potassium carbonate (3.00g, 21.7mmol) were added to DMF (50mL), heated to 110 ℃ and stirred for 10 h. TLC showed the reaction was complete, cooled to room temperature, poured the reaction mixture into water, extracted 2 times with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to give 3-fluoro-5- (1-hydroxy-7-iodo-indan-4-yl) oxy-benzonitrile (2.16g, 76% yield).
1H NMR(500MHz，DMSO-d6)：δ7.66(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 method comprises the following steps Preparation of 3-fluoro-5- (7-iodo-1-oxo-indan-4-yl) oxy-benzonitrile
Dess-Martin oxidant (1.08g, 2.53mmol) was added to the solution of 3-fluoro-5- (1-hydroxy-7-iodo-indan-4-yl) oxy-benzonitrile (1.00g, 2.53mmol) in dichloromethane (100mL) at room temperature. Stir for 0.5h and TLC showed the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and dilute aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 3-fluoro-5- (1-oxo-7-iodo-indan-4-yl) oxy-benzonitrile (0.92g, 93% yield).
1H NMR(500MHz，DMSO-d6)：δ7.91(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) The method comprises the following steps Preparation of 3- [ (7- (dimethylphosphoryl) -1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile
Reacting the 3-fluoro-5- (7-iodo-1-oxo-indan-4-yl) oxy-benzonitrile (800mg, 2.04mmol), dimethylphosphineoxide (200mg, 2.55mmol), K3PO4(520mg, 2.55mmol), Xantphos (118mg, 0.20mmol) and palladium acetate (46mg, 0.20mmol) were taken up in DMF (15mL) and the reaction mixture was heated to 150 ℃ under nitrogen and stirred for 10 h. TLC showed the reaction was complete, cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 50: 1, 30: 1) to give 3- [ (7- (dimethylphosphino) -1-oxo-indan-4-yl) oxy]-5-fluoro-benzonitrile (0.65g, 93% yield).
1H NMR(500MHz，DMSO-d6)：δ8.04(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) The method comprises the following steps Preparation of (E, Z) -3- [ (7- (dimethylphosphoryl) -1- (3-methoxypropylimino) -indan-4-yl) oxy ] -5-fluoro-benzonitrile
The 3- [ (7- (dimethylphosphoryl) -1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile (300mg, 0.87mmol), 3-methoxypropylamine (400mg, 4.49mmol), pivalic acid (18mg, 0.18mmol) were placed in a mixed solution of toluene (20mL) and cyclohexane (10mL) and heated at reflux with a Dean-Stark trap attached for 10 h. TLC showed the reaction was complete, cooled to room temperature, the reaction mixture was evaporated to dryness and the residue was used directly for the next reaction.
(1i) The method comprises the following steps Preparation of 3- [ (7- (dimethylphosphoryl) -2, 2-difluoro-1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile
1-chloromethyl-4-fluoro-1, 4-diammonium bicyclo [2.2.2] octane bis (tetrafluoroborate) (780mg, 2.20mmol), anhydrous sodium sulfate (250mg, 1.76mmol) was added to acetonitrile (10 mL). Heated to 70 ℃ and a solution of crude (E, Z) -3- [ (7- (dimethylphosphoryl) -1- (3-methoxypropylimino) -indan-4-yl) oxy ] -5-fluoro-benzonitrile (360mg, 0.87mmol) in acetonitrile (10mL) was added dropwise and the reaction was stirred for 2 h. TLC showed the reaction was complete, cooled to room temperature, and the reaction mixture was treated with 1M HCl (8mL, 8.0mmol) and stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 50: 1) to give 3- [ (7- (dimethylphosphoryl) -2, 2-difluoro-1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile (160mg, 48% yield).
1H NMR(500MHz，DMSO-d6)：δ8.11(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) The method comprises the following steps Preparation of 3- [7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (Compound 1)
Sodium borohydride (70mg, 18.4mmol) was added to the solution of 3- [ (7- (dimethylphosphoryl) -2, 2-difluoro-1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile (150mg, 0.40mmol) in methanol (10mL) at 0 deg.C, the temperature was maintained and stirring was continued for 3h, TLC showed the reaction was complete. The reaction mixture was spun dry and the residue was purified by column chromatography (dichloromethane: methanol 40: 1) to give 3- [7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (136mg, 91%).
1H NMR(500MHz，DMSO-d6)：δ7.72(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]。
Example 2
3- [ (1S) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (Compound 2)
RuCl (p-isopropyltoluene) [ (R, R) -Ts-DPEN ] (16mg, 0.025mmol) was added to a nitrogen flushed solution of 3- [ (7- (dimethylphosphoryl) -2, 2-difluoro-1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile (150mg, 0.40mmol), formic acid (80mg, 1.58mmol) and triethylamine (0.15mL, 1.0mmol) in dichloromethane (20mL) at 0 ℃. The reaction vial was sealed and placed in a 4 ℃ freezer overnight. TLC showed the reaction was complete, the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol ═ 40: 1) to give 3- [ (1S) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (120mg, 80%).
1H NMR(500MHz，DMSO-d6)：δ7.72(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]。
Example 3
3- [ (1R) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (Compound 3)
RuCl (p-isopropyltoluene) [ (S, S) -Ts-DPEN ] (16mg, 0.025mmol) was added to a nitrogen flushed solution of 3- [ (7- (dimethylphosphoryl) -2, 2-difluoro-1-oxo-indan-4-yl) oxy ] -5-fluoro-benzonitrile (150mg, 0.40mmol), formic acid (80mg, 1.58mmol) and triethylamine (0.15mL, 1.0mmol) in dichloromethane (20mL) at 0 ℃. The reaction vial was sealed and placed in a 4 ℃ freezer overnight. TLC showed the reaction was complete and the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol 40: 1) to give 3- [ (1R) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (122mg, 81%).
1H NMR(500MHz，DMSO-d6)：δ7.71(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]。
Example 4
[7- (3, 5-Difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (Compound 4), said Compound 4 having the formula:
the preparation method of the compound 4 comprises the following steps:
(4a) the method comprises the following steps Preparation of 4- (3, 5-Difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-ol
7-iodoindan-1, 4-diol (1.50g, 5.4mmol), 1, 3, 5-trifluorobenzene (1.08g, 8.1mmol), cesium carbonate (3.50g, 10.8mmol) were added to DMF (40mL), heated to 100 ℃ and stirred overnight. TLC showed the reaction was complete, cooled to room temperature, poured the reaction mixture into water, extracted 2 times with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to give 4- (3, 5-difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-ol (1.26g, 60% yield).
1H NMR(500MHz，DMSO-d6)：δ7.56(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) The method comprises the following steps Preparation of 4- (3, 5-difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-one
Dess-Martin oxidant (1.09g, 2.58mmol) was added to the solution of 4- (3, 5-difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-ol (1.00g, 2.58mmol) in dichloromethane (50mL) at room temperature. Stir for 0.5h and TLC showed the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and dilute aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 4- (3, 5-difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-one (0.90g, 91% yield).
1H NMR(500MHz，DMSO-d6)：δ7.65(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) The method comprises the following steps Preparation of 4- (3, 5-Difluorophenoxy) -7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1-one
Mixing the 4- (3, 5-difluorophenoxy) -7-iodo-2, 3-dihydro-1H-indan-1-one (600mg, 1.55mmol), dimethylphosphineoxide (151mg, 1.94mmol), K3PO4(412mg, 1.94mmol), Xantphos (90mg, 0.16mmol) and palladium acetate (35mg, 0.16mmol) were placed in DMF (15mL) and the reaction mixture was heated to 150 ℃ under nitrogen and stirred for 10 h. TLC showed the reaction was complete, cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 50: 1, 30: 1) to give 4- (3, 5-difluorophenoxy) -7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1-one (0.39g, 76% yield).
1H NMR(500MHz，DMSO-d6)：δ7.76(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) The method comprises the following steps Preparation of (E, Z) - [ (7- (3, 5-difluorophenoxy) -3- (3-methoxypropylimino) -2, 3-dihydro-1H-indan-4-yl)]Dimethyl phosphine oxide
The 4- (3, 5-difluorophenoxy) -7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1-one (260mg, 0.77mmol), 3-methoxypropylamine (413mg, 4.64mmol), pivalic acid (16mg, 0.16mmol) were placed in a mixed solution of toluene (20mL) and cyclohexane (10mL) and heated at reflux with a Dean-Stark trap attached for 10H. TLC showed the reaction was complete, cooled to room temperature, the reaction mixture was evaporated to dryness and the residue was used directly for the next reaction.
(4e) The method comprises the following steps Preparation of 4- (3, 5-Difluorophenoxy) -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1-one
1-chloromethyl-4-fluoro-1, 4-diammonium bicyclo [2.2.2] octane bis (tetrafluoroborate) (682mg, 2.20mmol), anhydrous sodium sulfate (220mg, 1.76mmol) was added to acetonitrile (10 mL). Heating to 70 ℃, dropwise adding the acetonitrile (10mL) solution of the (E, Z) - [ (7- (3, 5-difluorophenoxy) -3- (3-methoxypropylimino) -2, 3-dihydro-1H-indan-4-yl) ] dimethyl phosphine oxide prepared in the previous step, and continuously stirring for reaction for 2H. TLC showed the reaction was complete, cooled to room temperature, and the reaction mixture was treated with 1M HCl (8mL, 8.0mmol) and stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 50: 1) to give 4- (3, 5-difluorophenoxy) -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1 one (120mg, 58% yield).
1H NMR(500MHz，DMSO-d6)：δ7.81(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) The method comprises the following steps Preparation of [7- (3, 5-Difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (Compound 4)
Sodium borohydride (41mg, 10.8mmol 1) was added to a solution of 4- (3, 5-difluorophenoxy) -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1-one (100mg, 0.27mmol) in methanol (10mL) at 0 deg.C, the temperature was maintained and stirring was continued for 3H, TLC indicated completion of the reaction. The reaction mixture was spun dry and the residue was purified by column chromatography (dichloromethane: methanol 40: 1) to give [7- (3, 5-difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (91mg, 90%).
1H NMR(500MHz，DMSO-d6)：δ7.56(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]。
Example 5
[7- ((5-chloropyridin-3-yl) oxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (Compound 5), the compound 5 having the formula:
the preparation method of the compound 5 comprises the following steps:
(5a) the method comprises the following steps Preparation of 4- [ (5-Chloropyridin-3-yl) oxy ] -7-iodo-2, 3-dihydro-1H-indan-1-ol
7-Iodoindan-1, 4-diol (1.50g, 5.4mmol), 3, 5-dichloropyridine (1.20g, 8.1mmol), cesium carbonate (3.50g, 10.8mmol) were added to DMF (40mL), heated to 100 ℃ and stirred overnight. TLC showed the reaction was complete, cooled to room temperature, poured the reaction mixture into water, extracted 2 times with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate 5: 1) to give 4- [ (5-chloropyridin-3-yl) oxy ] -7-iodo-2, 3-dihydro-1H-indan-1-ol (1.02g, 48% yield).
1H NMR(500MHz，DMSO-d6)：δ8.66(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) The method comprises the following steps Preparation of 4- [ (5-chloropyridin-3-yl) oxy ] -7-iodo-2, 3-dihydro-1H-indan-1-one
Dess-Martin oxidant (657mg, 1.55mmol) was added to a solution of 4- [ (5-chloropyridin-3-yl) oxy ] -7-iodo-2, 3-dihydro-1H-indan-1-ol (600mg, 1.55mmol) in dichloromethane (30mL) at room temperature. Stir for 0.5h and TLC showed the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and dilute aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 4- [ (5-chloropyridin-3-yl) oxy ] -7-iodo-2, 3-dihydro-1H-indan-1-one (561mg, 93% yield).
1H NMR(500MHz，DMSO-d6)：δ8.71(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) The method comprises the following steps Preparation of 4- [ (5-chloropyridin-3-yl) oxy ] -7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1-one
Reacting 4- [ (5-chloropyridin-3-yl) oxy]-7-iodo-2, 3-dihydro-1H-indan-1-one (500mg, 1.30mmol), dimethylphosphineoxide (127mg, 1.62mmol), K3PO4(344mg, 1.94mmol), Xantphos (73mg, 0.13mmol) and palladium acetate (29mg, 0.13mmol) were taken up in DMF (20mL) and the reaction mixture was heated to 150 ℃ under nitrogen and stirred for 10 h. TLC showed the reaction was complete, cooled to room temperature, poured into water and extracted with ethyl acetate (50mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol ═ 30: 1) to give 4- [ (5-chloropyridine)-3-yl) oxy]-7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1 one (0.36g, 82% yield).
1H NMR(500MHz，DMSO-d6)：δ8.76(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) The method comprises the following steps Preparation of (E, Z) - [ (5-chloropyridin-3-yl) oxy) -3- (3-methoxypropylimino) -2, 3-dihydro-1H-indan-4-yl) ] dimethylphosphine oxide
4- [ (5-Chloropyridin-3-yl) oxy ] -7- (dimethylphosphoryl) -2, 3-dihydro-1H-indan-1 one (260mg, 0.77mmol), 3-methoxypropylamine (413mg, 4.64mmol), pivalic acid (16mg, 0.16mmol) were placed in a mixed solution of toluene (20mL) and cyclohexane (10mL) and heated at reflux with a Dean-Stark trap attached for 10H. TLC showed the reaction was complete, cooled to room temperature, the reaction mixture was evaporated to dryness and the residue was used directly for the next reaction.
(5e) The method comprises the following steps Preparation of 4- [ (5-chloropyridin-3-yl) oxy) ] -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1-one
1-chloromethyl-4-fluoro-1, 4-diammonium bicyclo [2.2.2] octane bis (tetrafluoroborate) (682mg, 2.20mmol), anhydrous sodium sulfate (250mg, 1.76mmol) was added to acetonitrile (10 mL). Heating to 70 ℃, dropwise adding the acetonitrile (10mL) solution of the (E, Z) - [ (5-chloropyridin-3-yl) oxy) -3- (3-methoxypropylimino) -2, 3-dihydro-1H-indan-4-yl) ] dimethyl phosphine oxide prepared in the previous step, and continuously stirring for reaction for 2H. TLC showed the reaction was complete, cooled to room temperature, and the reaction mixture was treated with 1M HCl (8mL, 8.0mmol) and stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 50: 1) to give 4- [ (5-chloropyridin-3-yl) oxy) ] -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1 one (116mg, 56% yield).
1H NMR(500MHz，DMSO-d6)：δ8.78(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) The method comprises the following steps Preparation of [7- ((5-Chloropyridin-3-yl) oxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (Compound 5)
Sodium borohydride (40mg, 1.07mmol) was added to a solution of 4- [ (5-chloropyridin-3-yl) oxy) ] -7- (dimethylphosphoryl) -2, 2-difluoro-2, 3-dihydro-1H-indan-1 one (80mg, 0.21mmol) in methanol (10mL) at 0 ℃ and the temperature was maintained stirring for 3H and TLC indicated completion of the reaction. The reaction mixture was spun dry and the residue was purified by column chromatography (dichloromethane: methanol ═ 30: 1) to give [7- (3, 5-difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl ] dimethylphosphine oxide (75mg, 94%).
1H NMR(500MHz，DMSO-d6)：δ8.71(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]。
Example 6
3- [7- (dimethylphosphinothioyl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (compound 6), said compound 6 having the formula:
3- [7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (25mg, 0.065mmol), Lawson's reagent (14mg, 0.033mmol) was added to toluene (10 mL). Heated to 100 ℃ and stirred for 5H, the reaction mixture was dried by spinning and the residue was purified by column chromatography (dichloromethane: methanol ═ 50: 1) to give 3- [7- (dimethylthiophosphine) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl ] oxy-5-fluorobenzonitrile (15mg, 58%).
1H NMR(500MHz，DMSO-d6)：δ7.70(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]。
Example 7: biological experiments
1.VEGF ELISA measurement
786-0 cells in logarithmic growth phase were seeded in 96-well plates (Fisher Scientific) at 7500 cells per well (180. mu.L/well), and after 4h of culture, 20. mu.L of different concentrations of compound stock was added to each well to give final concentrations as follows (μ M): 0.01, 0.05, 0.25, 1.25, 6.25, 30. After about 20h, the medium was removed by aspiration and 180 μ L of growth medium was provided to each well. Add 20 μ L of a fresh stock of 6 test compound to each well. Hypoxic (1% oxygen + 5% carbon dioxide) culture for 24h, the cell culture medium was removed. Then, in a manner conforming to the manufacturer's recommendations, the following R is adopted&VEGF concentrations were determined by ELISA kits purchased from D Systems. The reaction was stopped by adding 50. mu.L of Celltiter Glo reagent to each well, and the plate was gently shaken to sufficiently progress the stop reaction. The cell-seeded plates were subjected to CellTiter-Glo luminescent cell viability assay (Promega) and the light absorbance of each well was immediately measured at a wavelength of 450nm using a microplate reader. EC was calculated by analyzing data using a dose-response-inhibition (four parameter) equation by GraphPadPrism50The results are shown in Table 1.
EC for selected Compounds in the determination of Table 1, VEGF ELISA50
| Compound (I) | 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 drug: PT-2385.
As shown in the experimental results in Table 1: compounds 1-6 all had activity in inhibiting VEGF expression, with compounds 2 and 4 having better activity than the positive control PT-2385.
2. Dual luciferase reporter gene assay
1) Experimental reagent: dulbecco 'Modified Eagle's Medium, Total Bovine Serum, Trypsin-EDTA (0.25%), penicillin, streptomycin, Lipofectamine2000, 786-O cells, Dual-
Reporter Assay System, 96-well white plate, HRE-Luc plasmid, PRL-SV-40 plasmid, TOP10 strain, plasmid petite kit
2) The instrument model is as follows: thermo Scientific LuminoskanTM MAscent
3) The experimental process comprises the following steps:
amplification and extraction of HRE-Luc and PRL-SV-40 plasmids
Plasmid transformation into TOP10 competent cells: 50 mu L of escherichia coli competent cells (TOP10) are taken, 1 mu L of plasmid is added, ice bath is carried out for 30min, heat shock is carried out for 90s at 42 ℃, the mixture is immediately put back on ice, and ice bath is carried out for 2 min; adding 400 μ L LB culture medium, and culturing at 37 deg.C with shaking table for 45-60 min; 50-100. mu.L of the culture broth was applied to LB solid medium containing ampicillin (100. mu.g/mL) and cultured overnight at 37 ℃ in an inverted state.
Amplification, plasmid extraction: plasmid extraction was performed according to the instructions of the Tiangen plasmid miniprep kit.
b. Transfection
Log phase growth of 786-O cells was seeded into 48 well plates at 200 μ L per well, approximately 200000 cells. After overnight culture, the old medium was discarded, and 200. mu.L of serum-free and double-antibody-free DMEM medium was added thereto and starved for 6 hours. Taking 1.5mL ep tube, taking 1 mu L Lopo2000 liposome from the tube A, adding the liposome into 50 mu L serum-free and double-antibody-free DMEM medium, uniformly mixing, and standing at room temperature for 5 min; 0.4mg (HRE-Luc: PRL-SV-40 ═ 20: 1) of the plasmid is taken from the tube B, added into 50 μ L serum-free and double-resistant DMEM medium and mixed evenly; mix tube A in tube B, and react at room temperature for 20 min. Old media in 48-well plates was discarded, A, B mixed media was gently added, and the cells were cultured under reduced oxygen (1% oxygen and 5% carbon dioxide) for 6 h.
c. Administration of drugs
Concentration gradients were set at 0.01, 0.05, 0.25, 1.25, 6.25, 30uM, and blank. The test compound (stock solution concentration 10mM) was diluted to the above concentration with 10% serum-containing DMEM medium. Old culture medium in 48-well plate is discarded, washed by PBS, and added with prepared drug-containing culture medium. Culturing under low oxygen for 24 h.
d. Detection of
The 48-well plate was removed, the old medium was discarded, PBS was washed twice, and Dual-
The Reporter Assay System performs the detection. Add 100. mu.L of 1 × Lysis to each well and lyse in ice bath for 1 h. Adding 30 mu L of the cracking solution in an 48-hole plate into a 96-hole white plate, adding 30 mu L of firefly fluorescein substrate into each hole, and immediately detecting; add 30. mu.L of 1 × stop per well&Glo substrate, detected immediately.
4) Results of the experiment
EC calculation Using Dotmatics software50The results are shown in table 2:
TABLE 2 EC for selected compounds in Dual luciferase assay50
| Compound (I) | 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 drug: PT-2385.
As shown in the experimental results in Table 2: the compounds 1-6 all have certain in vitro activity, wherein the activity of the compound 2 and the compound 4 is superior to that of a positive control PT-2385.
3. Testing compound interactions with HIF-2 alpha protein using the SPRi System
1) Principle of experiment
The biomolecule interaction system is a Surface Plasma Resonance Imaging (SPRi) system based on microarray technology, thousands of sampling points on a chip are shot by adopting two-dimensional CCD technology, the interaction among various biomolecules is analyzed in real time, and no mark is needed. Therefore, the specificity of molecular combination is known, the kinetic data of molecular combination is accurately calculated, and the combination process of biological molecules is known. The method is widely used for the determination of various biological systems, including the interaction among various small molecular compounds, polypeptides, proteins, oligonucleotides and saccharides. Kinetic data such as binding curves, binding, dissociation, equilibrium dissociation constants, etc. can be obtained by data Analysis and fitting with PLEXERA SPR Date Analysis Module (DAM) Analysis software.
2) Experimental methods
The compound is placed on the surface of a biochip Graft-to-PCL by means of SpotBot3microarray control software in an Arrayit, SpotBot3 needle point platform, and the compound is crosslinked on the surface of the biochip by ultraviolet light for 15 min. Diluting the initial concentration of protein at 0.1-1 μ M with PBS buffer solution according to a certain proportion, and injecting prepared compounds with different concentrations for detection. The data obtained were analyzed and fitted according to the PLEXERA SPR Date Analysis Module (DAM) Analysis software to obtain binding kinetics constants, the results of which are shown in Table 3.
Buffer (buffer): 1 XPBS
A regeneration liquid: Gly-Hcl (PH 2)
The sample introduction flow rate is 1 mul/s, and the sample introduction time is 180 s; the dissociation flow rate is 1 mul/s, and the sample introduction time is 200 s;
the regeneration flow rate is 2 mul/s, and the regeneration time is 200s
3) Results of the experiment
The binding constant (ka), dissociation constant (KD), and equilibrium dissociation constant (KD) for example compounds to HIF-2 α protein are shown in table 3.
TABLE 3 binding kinetics constants of Compounds to HIF-2. alpha. protein
| Compound (I) | 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 shown in the experimental results in Table 3: the test compounds were determined to bind to HIF-2. alpha. protein, with Compound 1 and Compound 4 having greater binding capacity to HIF-2. alpha.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing examples, it will be apparent to those skilled in the art that various changes in the embodiments and modifications can be made, and equivalents can be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (6)
1. Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, which are characterized in that the compounds are compounds shown as a formula (I) and pharmaceutically acceptable salts thereof,
（Ⅰ）
wherein: r1 is selected from phenyl or pyridyl substituted with at least one of halo, cyano, C1-C4 alkyl and C1-C4 alkoxy;
said R2 is fluoro, and n is 1, 2 or 3;
w is selected from oxygen or sulfur.
2. The compound of claim 1, wherein: the compound is selected from:
3- [7- (dimethyl)Phosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl]Oxy-5-fluorobenzonitrile;
3- [ (1S) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl]Oxy-5-fluorobenzonitrile;
3- [ (1R) -7- (dimethylphosphoryl) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl]Oxy-5-fluorobenzonitrile;
[7- (3, 5-Difluorophenoxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1-ylH-indan-4-yl]Dimethyl phosphine oxide;
[7- ((5-Chloropyridin-3-yl) oxy) -2, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-indan-4-yl]Dimethyl phosphine oxide;
3- [7- (dimethylthiophosphine) -2, 2-difluoro-1-hydroxy-2, 3-dihydro-1-olH-indan-4-yl]Oxy-5-fluorobenzonitrile.
3. A process for the preparation of a compound according to claim 1, characterized in that it is as follows:
4. a pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
5. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with hypoxia inducible factor 2 alpha in a mammal.
6. Use according to claim 5, characterized in that: the disease or condition related to hypoxia inducible factor 2 alpha is selected from cancer, inflammation and metabolic diseases;
the cancer is selected from skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, menstrual system tumor, brain tumor, and head and neck cancer; the inflammation is selected from pneumonia, enteritis, nephritis, arthritis, and traumatic infection; the metabolic disease is selected from obesity, dyslipidemia and hyperlipidemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910135589.9A CN109776607B (en) | 2019-02-21 | 2019-02-21 | Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910135589.9A CN109776607B (en) | 2019-02-21 | 2019-02-21 | Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109776607A CN109776607A (en) | 2019-05-21 |
| CN109776607B true CN109776607B (en) | 2021-06-04 |
Family
ID=66486985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910135589.9A Active CN109776607B (en) | 2019-02-21 | 2019-02-21 | Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776607B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| AU2021240068A1 (en) | 2020-03-19 | 2022-09-08 | 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105530923A (en) * | 2013-09-09 | 2016-04-27 | 佩洛通治疗公司 | Aryl ethers and uses thereof |
| CN106928275A (en) * | 2015-12-29 | 2017-07-07 | 齐鲁制药有限公司 | The Preparation Method And Their Intermediate and crystal formation of volution amine aryl phosphoric-oxygenic compound |
-
2019
- 2019-02-21 CN CN201910135589.9A patent/CN109776607B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105530923A (en) * | 2013-09-09 | 2016-04-27 | 佩洛通治疗公司 | Aryl ethers and uses thereof |
| CN106928275A (en) * | 2015-12-29 | 2017-07-07 | 齐鲁制药有限公司 | The Preparation Method And Their Intermediate and crystal formation of volution amine aryl phosphoric-oxygenic compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109776607A (en) | 2019-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230286981A1 (en) | Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer | |
| CN107074827B (en) | Pladienolide pyridine compounds and methods of use | |
| CN109776607B (en) | Aryl phosphorus oxygen and aryl phosphorus sulfur compounds, and preparation method and application thereof | |
| US20180318287A1 (en) | Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer | |
| US11339142B2 (en) | Di-substituted pyrazole compounds for the treatment of diseases | |
| US20230119547A1 (en) | Di-substituted pyrazole compounds for the treatment of diseases | |
| KR102382039B1 (en) | Tyrosine kinase inhibitor and application thereof | |
| JP2021533186A (en) | Iminosulfone compounds as bromodomain protein inhibitors, pharmaceutical compositions and their pharmaceutical uses | |
| WO2019206069A1 (en) | Diaryl macrocyclic compound and pharmaceutical composition, and use thereof | |
| US20210347775A1 (en) | Deuterated Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer | |
| CN109369620B (en) | Pyridine compound, preparation method thereof and application thereof in resisting gastric cancer | |
| WO2019024876A1 (en) | Formylpyridine derivative having fgfr4 inhibitory activity, preparation method therefor and use thereof | |
| US11203565B2 (en) | Ester compound and PIN1 inhibitor, inflammatory disease therapeutic, and colon cancer therapeutic in which said ester compound is used | |
| CN111247137A (en) | Pyrimidine compound, preparation method and medical application thereof | |
| CN111303053B (en) | Cyclopenta [ d ] pyrimidine compound and pharmaceutically acceptable salt, solvate or prodrug thereof and application | |
| JP2023536634A (en) | Small molecules for the treatment of autoimmune diseases and cancer | |
| CN105384738A (en) | Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof | |
| CN111606884A (en) | Rimonabant derivative and preparation method and application thereof | |
| CN112759564A (en) | Diaryl urea compound and its preparation method and medicinal use | |
| CN111269240B (en) | Compound and preparation method and application thereof | |
| CN115368277B (en) | Biphenyl compound containing hydroxamic acid structure and application thereof | |
| JP7349572B2 (en) | Crosslinked ring-fused formylpyridine derivatives and their applications | |
| CN114560813A (en) | Benzimidazole MK2 allosteric inhibitor and preparation method and application thereof | |
| CN115745892A (en) | EP4 antagonist compound and salt, polymorphism and application thereof | |
| Zhu et al. | Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |