CN112500293A - 1,1' -biphenyl-2, 6-diphenol compound and application thereof - Google Patents

1,1' -biphenyl-2, 6-diphenol compound and application thereof Download PDF

Info

Publication number
CN112500293A
CN112500293A CN202011451583.1A CN202011451583A CN112500293A CN 112500293 A CN112500293 A CN 112500293A CN 202011451583 A CN202011451583 A CN 202011451583A CN 112500293 A CN112500293 A CN 112500293A
Authority
CN
China
Prior art keywords
compound
biphenyl
esi
substituted
reduced pressure
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.)
Granted
Application number
CN202011451583.1A
Other languages
Chinese (zh)
Other versions
CN112500293B (en
Inventor
不公告发明人
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujian Sanan Sino Science Photobiotech Co Ltd
Original Assignee
Fujian Sanan Sino Science Photobiotech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujian Sanan Sino Science Photobiotech Co Ltd filed Critical Fujian Sanan Sino Science Photobiotech Co Ltd
Priority to CN202011451583.1A priority Critical patent/CN112500293B/en
Publication of CN112500293A publication Critical patent/CN112500293A/en
Priority to PCT/CN2021/107218 priority patent/WO2022121317A1/en
Application granted granted Critical
Publication of CN112500293B publication Critical patent/CN112500293B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/34—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a 1,1 '-biphenyl-2, 6-diphenol compound and application thereof, wherein the 1,1' -biphenyl-2, 6-diphenol compound is a novel compound and has good biological activity. The in vitro tumor cell activity experiment method finds that the compound has inhibitory activity on tumor cell proliferation and has the potential of developing antitumor drugs.

Description

1,1' -biphenyl-2, 6-diphenol compound and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to 1,1' -biphenyl-2, 6-diphenol compounds with broad-spectrum antitumor activity and application thereof.
Background
Cancer, also known as malignant tumor, is a malignant and common disease that seriously threatens human health, and has become the second leading killer after cardiovascular diseases. In 2019, data published by the national cancer center showed: malignant tumor death accounts for 23.91% of all the causes of death of residents, and the morbidity and mortality of the malignant tumor death are in a continuously rising state in recent ten years.
Despite the significant advances in the development of antineoplastic drugs, the standard treatment modalities available are surgical resection, chemotherapy, and radiation therapy. The traditional chemotherapy drugs have obvious curative effect clinically, but have poor selectivity and low targeting property, so that the traditional chemotherapy drugs have obvious toxic and side effects and are easy to have the phenomenon of multi-drug resistance, thereby reducing the life quality of patients. Therefore, the invention aims to develop the compound with high efficiency, low toxicity and broad-spectrum anti-tumor activity.
Disclosure of Invention
In view of the above, the invention obtains a series of 1,1' -biphenyl-2, 6-diphenol compounds through screening, designing and synthesizing, and the compounds have the activity of inhibiting tumor cell proliferation.
The invention adopts the specific technical scheme that:
one object of the present invention is to provide a 1,1' -biphenyl-2, 6-diol compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the chemical structural formula of the compound is shown as formula (I):
Figure BDA0002827193360000011
r1, R2, R3, R4 are each independently selected from:
hydrogen, halogen, nitro, cyano, amino or substituted amino, aldehyde group of C1-3, C1-6 alkyl or substituted alkyl, carboxyl or substituted carboxyl, hydroxyl or substituted hydroxyl, aryl or aryl substituted by 0-5 groups, heteroaryl or heteroaryl substituted by 0-5 groups;
the heteroaryl group is a 3-to 10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, O.
Wherein R1, R2, R3 and R4 are respectively preferably selected from:
Figure BDA0002827193360000021
the invention also provides a pharmaceutical composition which comprises the 1,1' -biphenyl-2, 6-diphenol compound shown in the formula (I).
The invention provides a 1,1 '-biphenyl-2, 6-diphenol compound shown in formula (I), pharmaceutically acceptable salts or stereoisomers thereof and application of a pharmaceutical composition containing the 1,1' -biphenyl-2, 6-diphenol compound in preparing an anti-tumor medicament.
Further, the specific use is for inhibiting tumor cell proliferation.
The invention has the beneficial effects that: the invention provides a novel compound which has good biological activity. The in vitro tumor cell activity experiment method finds that the compound has inhibitory activity on tumor cell proliferation and has the potential of developing antitumor drugs.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field.
Summary of the compound structures of the specific examples (table 1):
Table1
Figure BDA0002827193360000031
Table1(continued)
Figure BDA0002827193360000041
Table1(continued)
Figure BDA0002827193360000051
synthesis of the Experimental part
For the examples referred to below, the compounds of the invention are synthesized using the methods described herein or other methods well known in the art.
General purification and analytical methods:
thin layer chromatography was performed on silica gel GF254 pre-coated plates (merck). Column chromatography was carried out over silica gel (300-400 mesh, great) at medium pressure. The components are treated by UV light (254nm) and iodine vapor, alkaline KMnO4Solution (KMnO)4：K2CO3：NaOH：H2O ═ 1.5 g: 10 g: 0.125 g: 200ml) phosphomolybdic acid solution (10g phosphomolybdic acid +200ml ethanol). If necessary, the compound was purified by HPLC nano-chromatography (Chromcore 8-120C 18,8um,10X250 mm) column with acetonitrile/H as mobile phase2O (70% to 100%), flow rate: 10 ml/min.
1H-NMR spectra were recorded on a Bruker Avance 400 spectrometer (for 1H) operating at 400 MHz. Tetramethylsilane signal was used as reference. Chemical shifts are reported in parts per million (ppm) and coupling constants (J) are in Hz. The following abbreviations are used for peak splitting, s is mono; br.s. ═ wide signal; d is bis; t is three; m is multiple; dd is bis-bis.
Electrospray (ESI) mass spectra were obtained via Finnigan LCQ ion trap.
Reagent Purification is described in the paper of Purification of Laboratory Chemicals (Perrin, D.D., Armarego, W.L.F. and Perrin Eds, D.R.; Pergamon Press: Oxford, 1980). The petroleum ether is 60-90 deg.C fraction, and the ethyl acetate, methanol and dichloromethane are analytically pure.
The abbreviations below have the following meanings:
DCM: dichloromethane; hPLC: high performance liquid chromatography; TFA: trifluoroacetic acid; DIPEA: n, N-diisopropylethylamine; EDCI: 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride; HOBt: 1-hydroxybenzotriazole; rt: room temperature; EA is ethyl acetate; DMAP: 4-dimethylaminopyridine; DMP: 2, 2-dimethoxypropane; HATU: 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate; THF, tetrahydrofuran; boc2O: di-tert-butyl dicarbonate; DMF: n, N-dimethylformamide; DME: ethylene glycol dimethyl ether; PPTS: pyridinium p-toluenesulfonate; NIS: n-iodosuccinimide
Specific synthetic experiments
The embodiments of the present invention are described in detail below by way of specific examples, but they should not be construed as limiting the invention in any way.
Figure BDA0002827193360000071
1. The synthesis general formula of the compounds I-1 to I-6 is as follows:
Figure BDA0002827193360000072
preparation of compound 2: adding 5- (1, 1-dimethylheptyl) resorcinol (1.02g, 8.06mmol) and acetonitrile (16ml) into a 100ml single-neck bottle, placing the mixture into an ice water bath, adding NIS (1.86g, 8.06mmol) twice, then naturally heating to react for 2h, detecting the reaction by TLC, adding saturated NaHCO3, removing most of acetonitrile under reduced pressure, separating and extracting ether, combining organic phases, concentrating under reduced pressure, and separating and purifying by column chromatography (Hexanes/EA is 1:8) to obtain the iodo-compound of diphenol (1.88g, 93%).
A25 ml single-neck flask was charged with the above-mentioned diphenol iodide (0.5g,2mmol), acetone (10ml), K2CO3(0.83g, 6mmol), dimethyl sulfate (0.47ml,5mmol) and reacted at room temperature for 24h, after TLC detection. To the reaction system was added 10ml of water, and the mixture was stirred for 10min, then acetone was removed under reduced pressure, followed by liquid-separation extraction with ether, washing with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by column chromatography (Hexanes/EA: 1:20) to obtain compound 2(0.53g, 95%) as an oil.
A method for preparing compound 3: a25 ml reaction tube was taken, and Compound 2(0.22mmol), Compound 1(0.18mmol), Cs were added2CO3(0.36mmol)，Pd(PPh3)4(0.02mmol), 1, 4-dioxane (2ml) is used for replacing Ar gas, then the mixture is placed in an oil bath at the temperature of 80 ℃ for reaction for 12 hours, and the TLC detection reaction is finished. Filtering with diatomite, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound 3.
The preparation method of the compounds I-1 to I-6 comprises the following steps: a25 mL reaction tube was charged with Compound 3(0.18mmol), 2mL of DCM, placed in a bath of glacial ethanol (-15 ℃ C.), and 0.9mL of BBr was slowly added dropwise3(1.0M in DCM), naturally heating to react for 12h, and detecting by TLC to finish the reaction. The system was placed in an ice-water bath and quenched by the addition of 0.2ml MeOH. And adding water and dichloromethane, separating and extracting, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the compounds I-1 to I-6.
The synthesis of example compounds I-1 to I-6 is described in detail below:
example 1
Compound I-1:
Figure BDA0002827193360000081
compound 1 boronic acid preparation: a250 ml three-necked flask was charged with methyl 3-bromo-4-methylbenzoate (2.0 g, 8.77mmol), pinacoldiboron (4.46g, 17.54mmol), PdCl2(dppf), DCM (143 mg,0.175mmol), KOAc (3.44g,35.08mmol) were first replaced by Ar gas, 1, 4-dioxane (60 ml) was added, oxygen removed (septum pumping system, Ar gas replacement) and placed in an oil bath at 80 ℃ for 12h, and the reaction was checked by TLC. Filtering with diatomite, removing the solvent under reduced pressure, adding ether and water, separating and extracting, combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying by column chromatography (Hexanes/EA is 20:1) to obtain a purer borate compound, and removing the excessive boron reagent (Hexanes/EA) by recrystallization to obtain a white solid compound 1 borate (1.81g, 75%). Adding 20ml of methanol and 2.7ml of 12N concentrated sulfuric acid into the borate, heating and refluxing for 12h, performing TLC detection reaction, concentrating under reduced pressure, extracting with ethyl acetate, and adding anhydrous sulfurSodium salt was dried and concentrated under reduced pressure to give boronic acid compound 1(1.26 g, 95%).
Preparation of compound 3: a25 ml reaction tube was taken, and Compound 2(274mg,0.70mmol), Compound 1 boronic acid (150mg,0.77mmol), Cs were added2CO3(458mg,1.40mmol)，Pd(PPh3)4(0.07 mmol,81mg), 1, 4-dioxane (3 ml). After replacing Ar gas, placing the obtained product in an oil bath at the temperature of 80 ℃ for reaction for 12 hours, and detecting by TLC to finish the reaction. Filtration through celite, removal of the solvent under reduced pressure, and purification by column chromatography (Hexanes/EA ═ 8:1) gave intermediate 3(220mg, 76%).
Preparation of Compound I-1: a25 mL reaction tube was taken, added with the intermediate (100mg,0.24mmol) and 2.4mL of DCM, placed in a bath of glacial ethanol (-15 ℃ C.), and slowly added dropwise with 0.72mL of BBr3(1.0M in DCM), naturally heating to react for 3h, and detecting by TLC to finish the reaction. The mixture was placed in an ice-water bath, quenched with 0.2ml MeOH, quenched with saturated sodium bicarbonate and dichloromethane, extracted by liquid separation, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (Hexanes/EA ═ 1:3) to give compound I-1(23mg, 25%).1H NMR (400MHz,CDCl3)δ:8.04(dd,J＝8.0,1.7Hz,1H),7.99(s,1H),7.48(d,J＝8.0 Hz,1H),6.56(s,2H),4.51(s,2H),3.90(s,3H),2.24(s,3H),1.61–1.54(m,2H), 1.28(s,6H),1.26–1.19(m,6H),1.16–1.07(m,2H),0.86(t,J＝6.8Hz,3H). MS(ESI)m/z:385[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C24H33O4 + 385.2373；Found 385.2368.
Example 2
Compound I-2
Figure BDA0002827193360000101
Starting from Compound 2 and the corresponding boronic acid 1, I-2(72mg, 63%) was obtained according to the method for Compound I-1.1H NMR(400MHz,MeOD)δ:6.84(d,J＝1.7Hz,1H),6.81(d,J＝8.1 Hz,1H),6.71(dd,J＝8.1,1.8Hz,1H),6.41(s,2H),1.61–1.53(m,2H),1.32–1.19(m,6H),1.26(s,6H)1.17–1.05(m,2H),0.87(t,J＝6.2Hz,3H).
Example 3
Compound I-3
Figure BDA0002827193360000102
Starting from Compound 2 and the corresponding boronic acid 1, I-3(72 mg, 44%) was obtained according to the method for Compound I-1.1H NMR(400MHz,CDCl3)δ:7.33(t,J＝7.8Hz,1H),6.79–6.73 (m,2H),6.72–6.68(m,1H),6.56(s,2H),4.98(brs,2H),3.76(brs,2H),1.58– 1.55(m,2H),1.26(s,6H),1.25–1.17(m,6H),1.16–1.07(m,2H),0.86(t,J＝ 6.8Hz,3H).MS(ESI)m/z:328[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C21H30NO2 +328.2271；Found 328.2264.
Example 4
Compound I-4
Figure BDA0002827193360000111
Starting from Compound 2 and the corresponding boronic acid 1, I-4(100 mg, 70%) was obtained according to the method for Compound I-1.1H NMR(400MHz,CDCl3)δ7.46–7.38(m,2H),7.38–7.28(m, 2H),6.57(s,2H),4.82(s,2H),3.04–2.91(m,1H),1.63–1.55(m,2H),1.31(d,J ＝6.9Hz,6H),1.26(s,6H),1.25–1.19(m,6H),1.19–1.04(m,2H),0.86(t,J＝ 6.8Hz,3H).GC-MS(EI)m/z:[M]+354.24.
Example 5
Compound I-5
Figure BDA0002827193360000112
Starting from Compound 2 and the corresponding boronic acid 1, compound I-1 was prepared according to the procedure for preparation of Compound I-1, giving I-5(38 mg, 41%).1H NMR(400MHz,CDCl3)δ8.38–8.33(m,1H),8.25(ddd,J＝8.2, 2.3,1.1Hz,1H),7.84–7.77(m,1H),7.67(t,J＝7.9Hz,1H),6.53(s,2H),4.76(s, 2H),1.61–1.53(m,2H),1.27(s,6H),1.26–1.19(m,6H),1.15–1.04(m,2H), 0.86(t,J＝6.8Hz,3H).GC-MS(EI)m/z:[M]+357.19.
Example 6
Compound I-6
Figure BDA0002827193360000113
Starting from Compound 2 and the corresponding boronic acid 1, compound I-6(100 mg, 64%) was obtained according to the method for Compound I-1.1H NMR(400MHz,CDCl3)δ7.81–7.75(m,2H),7.67–7.61(m,2H), 7.54–7.46(m,4H),7.43–7.36(m,1H),6.59(s,2H),4.87(s,2H),1.63–1.56(m, 2H),1.29(s,6H),1.27–1.20(m,6H),1.17–1.09(m,2H),0.87(t,J＝6.8Hz, 3H).MS(ESI)m/z:389.2[M+H]+.
2. The synthetic route of the compound I-7 is as follows:
Figure BDA0002827193360000121
example 7
Compound I-7
Figure BDA0002827193360000122
Preparation of compound 4: a25 ml single-neck bottle was taken, and compound 3(125mg,0.30mmol), methanol 1.5ml and THF 1.5ml were added in an oil bath at 50 ℃ and reacted for 12h, and the reaction was checked by TLC. Removing the solvent under reduced pressure, adding water, and adding 1N HCl to adjust the pH value to 3-5. Extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (Hexanes: EA: AcOH ═ 4:1:0.05) to give intermediate 4(110mg, 91%).
A25 mL reaction tube was charged with Compound 4(50mg,0.13mmol), 1.2mL of DCM, placed in a bath of glacial ethanol (-15 ℃ C.), and 0.6mL of BBr was slowly added dropwise3(1.0M in DCM), naturally heating to react for 12h, detecting by TLC after the reaction is finished, placing the mixture in an ice-water bath, adding 0.2ml of MeOH for quenching, dichloromethane, separating and extracting, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to prepare, separate and purify (Hexanes/Acetone ═ 1:1) to obtain the compound I-7(10mg, 20%).1H NMR(400MHz,Acetone)δ7.94–7.83(m, 2H),7.72(s,2H),7.37(d,J＝7.9Hz,1H),6.54(s,2H),2.23(s,3H),1.63–1.55 (m,2H),1.26(s,6H),1.25–1.21(m,6H),1.14(d,J＝4.6Hz,2H),0.85(t,J＝6.8 Hz,3H).MS(ESI)m/z:371[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C23H31O4 +371.2217；Found 371.2216.
3. Compounds I-8 and I-9 were synthesized as follows:
Figure BDA0002827193360000131
example 8
Compound I-8
Figure BDA0002827193360000132
A25 ml reaction tube was charged with Compound 4(30mg, 0.075mmol), DMAP (1mg,0.01 mmol), EDCI (17.2mg,0.09mmol), Et3N (26ul,0.19mmol) is stirred for 30min at room temperature, then 1-naphthylhydrazine hydrochloride (0.15mmol) is added for reaction for 12h, and the TLC detection reaction is finished. Adding saturated NaHCO3Extracting with dichloromethane, mixing organic phases, washing with saturated NaCl, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain amide intermediate 5.
A25 mL reaction tube was taken, added with substrate amide 5(0.038mmol) and 1mL DCM, placed in a bath of ice and ethanol (-15 deg.C), and slowly dropped with 0.2mL BBr3(1.0M in DCM), naturally heating to react for 12h, and detecting by TLC to finish the reaction. Placing in ice water bath, adding 0.1ml MeOH for quenching, adding 2ml saturated sodium bicarbonate and dichloromethane, separating, extracting, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying to obtain compound I-8(23mg, 57%).1H NMR(400MHz,Acetone)δ:9.84(d,J＝3.7 Hz,1H),8.31–8.22(m,1H),7.90(dd,J＝7.9,1.9Hz,1H),7.87–7.83(m,2H), 7.77–7.71(m,3H),7.52–7.47(m,2H),7.43–7.35(m,2H),7.34–7.29(m,1H), 7.04(d,J＝7.4Hz,1H),6.55(s,2H),2.24(s,3H),1.63–1.56(m,3H),1.31– 1.21(m,6H),1.27(s,6H),1.19–1.12(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI) m/z:511[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C33H39N2O3 +511.2955； Found 511.2959.
Example 9
Compound I-9
Figure BDA0002827193360000141
Using compound 4 and n-butylamine as starting materials, compound I-8 was referenced to give I-9(14mg, 46%).1H NMR(400MHz,CDCl3)δ:7.81(dd,J＝7.9,1.8Hz,1H),7.61(d,J＝ 1.7Hz,1H),7.46(d,J＝8.0Hz,1H),6.57(s,2H),6.09(s,1H),4.68(s,2H),3.43 (dd,J＝13.0,7.0Hz,2H),2.22(s,3H),1.63–1.52(m,4H),1.40(dd,J＝15.1,7.4 Hz,2H),1.28(s,6H),1.24(d,J＝10.8Hz,6H),1.12(s,2H),0.95(t,J＝7.3Hz, 3H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:426[M+H]+.HRMS(ESI)m/z: [M+H]+Calcd for C27H40NO3 +426.3003；Found 426.3000。
4. The compounds I-10 to I-14 and I-21 have the following synthesis general formulas:
Figure BDA0002827193360000151
example 10
Compound I-10
Figure BDA0002827193360000152
A25 ml reaction tube was taken, and compound I-7(30mg, 0.08mmol), s-configured proline methyl ester hydrochloride (20mg, 0.12mmol), HATU (46.2mg,0.12mmol), DIPEA (35ul,0.19 mmol) were added and stirred at room temperature for 12h, and TLC detection was performed to complete the reaction. Adding saturated NaHCO3Extraction with dichloromethane, combination of the organic phases, washing with saturated NaCl, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography gave compound I-10(29mg, 75%).1H NMR(400MHz,CDCl3)δ7.61(d,J＝ 7.8Hz,1H),7.53(s,1H),7.45(d,J＝7.9Hz,1H),6.56(s,2H),4.65(dd,J＝8.4, 4.7Hz,1H),3.76(s,3H),3.74–3.65(m,1H),3.64–3.52(m,1H),2.80(s,2H), 2.37–2.24(m,1H),2.20(s,3H),2.10–1.84(m,3H),1.59–1.50(m,2H),1.26(s, 6H),1.25–1.17(m,6H),1.16–1.05(m,2H),0.85(t,J＝6.7Hz,3H).
MS(ESI)m/z:482[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C29H40NO5 + 482.2901；Found 482.2894.
Example 11
Compound I-11
Figure BDA0002827193360000161
Compound I-11(26mg, 47%) was obtained by the method described for compound I-10, starting from tyrosine methyl ester of the compound I-7, S configuration.1H NMR(400MHz,CDCl3)δ7.65–7.53(m,2H), 7.36(d,J＝7.9Hz,1H),7.00–6.90(m,2H),6.82(d,J＝7.8Hz,1H),6.72–6.61 (m,2H),6.60–6.51(m,2H),5.75(s,1H),5.08–4.95(m,2H),4.83(s,1H),3.71 (s,3H),3.19(dd,J＝14.0,5.7Hz,1H),3.05(dd,J＝14.0,6.4Hz,1H),2.19(s, 3H),1.61–1.51(m,2H),1.26(s,6H),1.25–1.18(m,6H),1.17–1.05(m,2H), 0.85(t,J＝6.7Hz,3H).MS(ESI)m/z:548[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C33H42NO6 +548.3007；Found 548.3004.
Example 12
Compound I-12
Figure BDA0002827193360000162
Starting from histidine methyl ester dihydrochloride, compound I-7, S configuration, compound I-12(25mg, 60%) was obtained according to the procedure for compound I-10.1H NMR(400MHz,CDCl3)δ7.83(d,J ＝7.4Hz,1H),7.64(s,1H),7.60(d,J＝8.4Hz,1H),7.35(s,1H),7.27(s,1H), 6.69(s,1H),6.54(d,J＝4.6Hz,2H),4.93–4.82(m,1H),3.67(s,3H),3.15– 3.01(m,2H),2.18(s,3H),1.61–1.48(m,2H),1.24(s,6H),1.21(s,6H),1.14– 1.06(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:522[M+H]+.HRMS(ESI) m/z:[M+H]+Calcd for C30H40N3O5 +522.2962；Found 522.2960.
Example 13
Compound I-13
Figure BDA0002827193360000171
Compound I-13(14mg, 32%) was obtained according to the method for Compound I-10, starting from Compound I-7, p-bromophenylhydrazine.1H NMR(400MHz,Acetone)δ9.75–9.66(m,1H),7.83(dd, J＝8.0,1.9Hz,1H),7.77(d,J＝1.8Hz,1H),7.69(s,2H),7.37(d,J＝8.0Hz,1H), 7.35–7.28(m,2H),6.94–6.88(m,2H),6.54(s,2H),2.81(s,2H),2.22(s,3H), 1.65–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.18–1.12(m,2H),0.85(t, J＝6.8Hz,3H).MS(ESI)m/z:539[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C29H36BrN2O3 +539.1904；Found 539.1898.
Examples 14 and 15
Compound I-14 and Compound I-21
Figure BDA0002827193360000172
Compounds I-14(3mg, 8%) and I-21(4mg, 10%) were obtained by the method described for compound I-10, starting from compound I-7, 3-aminophenol. Compound I-14:1H NMR(400MHz,Acetone) δ9.47(s,1H),8.30(brs,1H),7.86(dd,J＝7.9,2.0Hz,1H),7.77(d,J＝1.9Hz, 1H),7.68(brs,2H),7.57(t,J＝2.1Hz,1H),7.37(d,J＝8.0Hz,1H),7.29–7.20 (m,1H),7.11(t,J＝8.1Hz,1H),6.59–6.53(m,3H),2.21(s,3H),1.60(dd,J＝ 9.8,6.4Hz,2H),1.27(s,6H),1.26–1.21(m,6H),1.19–1.13(m,2H),0.86(t,J ＝6.8Hz,3H).MS(ESI)m/z:462[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C29H36NO4 +462.2639, respectively; found 462.2636, Compound I-21:1H NMR(400MHz, Acetone)δ8.00–7.95(m,2H),7.86–7.77(m,2H),7.50–7.42(m,1H),7.08(t, J＝8.0Hz,1H),6.61–6.52(m,4H),6.48–6.42(m,1H),4.82(brs,2H),2.79(s, 2H),2.26(s,3H),1.63–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.18–
1.10(m,2H),0.85(t,J＝6.7Hz,3H).MS(ESI)m/z:462[M+H]+.HRMS(ESI) m/z:[M+H]+Calcd for C29H36NO4 +462.2639；Found 462.2635.
5. the synthetic route of the compound I-15 is as follows:
Figure BDA0002827193360000181
example 16
Compound I-15
Figure BDA0002827193360000182
A25 ml reaction tube was taken, added with I-2(70mg,0.19mmol), toluene 2ml, 2-DMP (35. mu.l, 0.29mmol) and PPTS (2.4mg,0.01mmol), heated under reflux, followed by TLC, and after 6 hours the reaction was substantially complete. Heating was stopped, cooling was performed to room temperature, saturated sodium bicarbonate was added, DCM was added for liquid-separation extraction, the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (Hexanes/EA ═ 10:1) to give compound I-15(34mg, 47%).1H NMR(400MHz, CDCl3)δ:6.89(d,J＝7.8Hz,1H),6.82(dd,J＝7.9,1.6Hz,1H),6.77(d,J＝1.6 Hz,1H),6.55(s,2H),4.88(s,2H),1.73(s,6H),1.60–1.52(m,2H),1.26(s,6H), 1.25–1.16(m,6H),1.15–1.06(m,2H),0.86(t,J＝6.8Hz,3H).GC-MS(EI) m/z：384.24[M]+。
6. The synthetic route of the compound I-16 is as follows:
Figure BDA0002827193360000191
example 17
Compound I-16
Figure BDA0002827193360000192
A25 ml reaction tube was charged with I-3(23mg,0.07mmol), THF 1ml, Boc2O (20ul, 0.084mmol) was heated under reflux for 12h and the reaction was essentially complete by TLC. Cooling to room temperature, adding saturated sodium bicarbonate, removing the solvent under reduced pressure, performing liquid-separation extraction with DCM, combining organic phases, washing with saturated salt water, and drying with anhydrous sodium sulfate. Concentrated under reduced pressure and purified by column chromatography (Hexanes/EA: 3:1) to give compound I-16(24 mg, 80%).1H NMR(400MHz,CDCl3)δ:7.54–7.38(m,3H),7.09(d,J＝7.2 Hz,1H),6.55(brs,3H),4.86(s,2H),1.59–1.54(m,2H),1.53(s,9H),1.31–1.17 (m,6H),1.26(s,6H),1.15–1.06(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z: 428[M+H]+HRMS(ESI)m/z:[M+H]+Calcd for C26H38NO4 +428.2795；Found 428.2789.
6. The synthetic route of the compound I-17 is as follows:
Figure BDA0002827193360000201
example 18
Compound I-17
Figure BDA0002827193360000202
A25 ml reaction tube was charged with Compound I-3(30mg,0.09mmol), HoBt (15mg,0.11 mmol), EDCI (21.2mg,0.11mmol) and 1ml of DCM, stirred at room temperature for 30min, then added with 4-phenylbutyric acid (18mg, 0.11mmol), reacted for 12h, and the reaction was complete by TLC. Adding saturated NaHCO3Extraction with dichloromethane, combination of the organic phases, washing with saturated NaCl, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography gave compound I-17(34mg, 78%).1H NMR(400MHz, CDCl3)δ:7.65–7.56(m,1H),7.52–7.44(m,2H),7.33–7.26(m,3H),7.23– 7.12(m,5H),6.55(s,2H),4.93(brs,1H),2.71(t,J＝7.5Hz,2H),2.35(t,J＝7.6 Hz,2H),2.11–2.02(m,2H),1.61–1.52(m,2H),1.26(s,6H),1.24–1.19(m, 6H),1.15–1.05(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:474[M+H]+. HRMS(ESI)m/z:[M+H]+Calcd for C31H40NO3 +474.3003；Found 474.2996
7. Compounds I-18 to I-20, I-22 were synthesized as follows:
Figure BDA0002827193360000211
example 19
Compound I-18
Figure BDA0002827193360000212
Preparation of compound 6: compound 6(88mg, 50%) was obtained by the method described for Compound 3, starting from Compound 2 and 3-aminoboronic acid.
Preparation of compound 7: a25 ml reaction tube was taken, and compound 6(25mg,0.07mmol), DMAP (1.3mg,0.01mmol), EDCI (20mg,0.10mmol) and DIPEA (36ul,0.21mmol) were added thereto, and the mixture was stirred at room temperature for 30min, followed by addition of N-acetyl-L-isoleucine (0.08mmol), reaction for 12h, and completion of TLC detection. Adding saturated NaHCO3Extracting with dichloromethane, mixing organic phases, washing with saturated NaCl, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain amide intermediate 7.
Preparation of Compound I-18: a25 mL reaction tube was charged with amide intermediate 7(0.038mmol) and 1mL DCM, placed in a bath of glacial ethanol (-15 deg.C), and 0.2mL BBr was slowly added dropwise3(1.0M in DCM), naturally heating to react for 12h, and detecting by TLC to finish the reaction. Placing in ice water bath, adding 0.1ml MeOH to quench, adding 2ml saturated sodium bicarbonate and dichloromethane, separating, extracting, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying to obtain compound I-18(10mg, 30%). MS (ESI) M/z 483[ M + H ]]+. HRMS(ESI)m/z:[M+H]+Calcd for C29H43N2O4 +483.3217；Found 483.3213.
Example 20
Compound I-19
Figure BDA0002827193360000221
Compound I-19(19mg, 30%) was obtained according to the synthetic method for compound I-18 starting from compound 6, N-acetylglycine.1H NMR(400MHz,Acetone)δ9.15(s,1H), 7.68–7.55(m,4H),7.44(brs,1H),7.29(t,J＝7.9Hz,1H),7.13–7.08(m,1H), 6.50(s,2H),3.98(d,J＝5.7Hz,2H),1.97(s,3H),1.63–1.52(m,2H),1.33– 1.18(m,12H),1.17–1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:427 [M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C25H35N2O4 +427.2591；Found 427.2587.
Example 21
Compound I-20
Figure BDA0002827193360000222
Compound I-20(12mg, 35%) was obtained according to the synthetic method for compound I-18 starting from compound 6, N-acetylglycine.1H NMR(400MHz,Acetone)δ9.73(s,1H), 8.14(d,J＝8.0Hz,1H),7.81–7.71(m,2H),7.62(d,J＝8.0Hz,1H),7.38(t,J＝ 8.0Hz,1H),7.21(d,J＝7.7Hz,1H),6.52(s,2H),2.91(s,2H),1.66–1.52(m, 2H),1.33–1.19(m,12H),1.16–1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI) m/z:501[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C27H31Cl2N2O3 +501.1706； Found 501.1702.
Example 22
Compound I-22
Figure BDA0002827193360000231
A25 ml reaction tube was taken, added with compound I-3(10mg,0.03mmol), HATU (14mg,0.036 mmol), DIPEA (16ul,0.09mmol), 1-adamantane acid (7mg, 0.036mmol), reacted for 12h, and TLC detection was done. Adding saturated NaHCO3Extraction with dichloromethane, combination of the organic phases, washing with saturated NaCl, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography gave compound I-22(1.5 mg, 10%). MS (ESI) M/z 490[ M + H ]]+.HRMS(ESI)m/z:[M+H]+Calcd for C32H44NO3 +490.3316；Found 490.3306.
8. The synthetic routes of the compounds I-23 and I-24 are as follows:
Figure BDA0002827193360000241
examples 23 and 24
Compound I-23 and compound I-24
Figure BDA0002827193360000242
Taking a 25ml reaction tube, adding the compound 6(25mg,0.07mmol), DMF 1ml, TBAI (2.6 mg, 0.007mmol), K2CO3(19.3mg, 0.14mmol), benzyl bromide (10ul,0.084mmol), mixing uniformly, placing in an oil bath at 80 ℃, reacting for 12h, detecting the reaction completion by TLC, cooling to room temperature, adding water and diethyl ether for liquid separation extraction, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain a mono-benzyl product 8(12mg, 38%) and a di-benzyl product 9(25mg, 60%). (Hexanes: EA ═ 20:1)
Adding the benzyl product and 1ml of DCM into two 10ml reaction tubes respectively, placing into the glacial ethanol, and slowly adding 5.0eq of BBr3(1.0M in DCM), naturally heating to react for 5h, adding methanol and saturated sodium bicarbonate to quench, separating DCM, concentrating under reduced pressure, and performing column chromatography to obtain compound I-23(8mg, 27%)1H NMR(400MHz,CDCl3)δ7.40–7.28(m,6H),6.75–6.68(m,2H),6.67– 6.62(m,1H),6.56(s,2H),4.99(s,2H),4.35(s,2H),4.26(brs,1H),1.59–1.53 (m,2H),1.26(s,6H),1.23–1.17(m,6H),1.16–1.07(m,2H),0.85(t,J＝6.8Hz, 3H).MS(ESI)m/z:418[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C28H36NO2 +418.2741Found 418.2731 Compound I-24(16mg, 45%)1H NMR(400 MHz,CDCl3)δ7.40–7.31(m,5H),7.30–7.20(m,6H),6.85–6.78(m,1H), 6.75–6.67(m,2H),6.51(s,2H),4.96(s,2H),4.69(s,4H),1.58–1.49(m,2H), 1.29–1.15(m,12H),1.14–1.05(m,2H),0.84(t,J＝6.8Hz,3H).MS(ESI)m/z: 508[M+H]+.HRMS(ESI)m/z:[M+H]+Calcd for C35H42NO2 +508.3210；Found 508.3200.
Antitumor Activity test section
The specific test method is as follows:
1. seed cell
Culturing human liver cancer cells HepG2 and human lung cancer cells A549 in a culture dish by using a DMEM complete culture solution (containing 10% fetal calf serum and 1X penicillin-streptomycin double-antibody solution), taking cells in a logarithmic growth phase, when the cells grow to 70% -80% fusion, after the cells are digested by pancreatin, re-suspending the cells by using the culture solution and counting the cells to prepare a cell suspension with the density of about 7X 104 cells/mL, inoculating the cells into a 96-well plate by using 100 mu L of cell suspension per well, and culturing in an incubator at 37 ℃ until the cells adhere to the wall.
2. Dosing
Test compounds with concentration of 20mg/mL are prepared by taking DMSO as a solvent, and the test compounds are diluted to the required working concentration by using culture solution during the experiment. After the culture solution is discarded from the 96-well plate, 100 muL of compound solutions with different working concentrations are respectively added into the experimental group, 100 muL of the culture solution is added into the blank control group, 100 muL of the anti-tumor drugs cisplatin and gemcitabine solutions with different concentrations are added into the positive control group, and the 96-well plate is continuously placed in an incubator for culture.
3. CCK8 assay
After 48h incubation, 10. mu.L of CCK8 reagent was added to each well, the plates were gently tapped to aid mixing, incubated at 37 ℃ for 1-2 hours in an incubator, and absorbance at 450nm was measured using a microplate reader. The experiment was repeated 3 times and the mean value was taken. The above compounds were tested at concentrations of 2.5. mu.g/mL, 5. mu.g/mL, 10. mu.g/mL, 20. mu.g/mL, 40. mu.g/mL, and the results are shown in Table 2 below.
TABLE 2 inhibitory Activity of Compounds on liver cancer (HepG2) and lung cancer (A549) cells
Compound numbering HepG2 IC50(μM) A549 IC50(μM)
I-1 23.43 51.54
I-2 21.94 62.91
I-3 52.04 55.74
I-4 2.58 16.44
I-5 14.74 20.39
I-6 9.40 74.25
I-7 >161 >161
I-8 24.38 45.04
I-9 26.32 28.71
I-10 18.36 46.65
I-11 29.71 18.07
I-12 52.39 38.47
I-13 10.64 14.01
I-14 18.38 24.00
I-15 29.25 26.91
I-16 20.36 21.66
I-17 22.19 22.95
I-18 6.40 32.59
I-19 ＞140 ＞140
I-20 6.03 14.51
I-21 8.64 15.51
I-22 17.15 6.65
I-23 14.26 17.37
I-24 >118 >118
Cis-platinum 37.53 6.01
Gemcitabine 2.93 0.00054
Experimental results and discussion:
except the compounds I-3, I-7, I-12, I-19 and I-24, the inhibition effect of the other compounds on HepG2 cells is better than that of the positive drug cisplatin, wherein the inhibition effect of the compound I-4 on HepG2 cells is equivalent to that of the positive drug gemcitabine; the compound also has an inhibiting effect on lung cancer A549 cells, but the inhibiting activity is slightly inferior to that of positive medicaments of cisplatin and gemcitabine.
The experimental results show that the 1,1' -biphenyl-2, 6-diphenol compound with biological activity provided by the invention has the activity of inhibiting tumor cell proliferation, has great drug development potential, and can be used as a lead compound for developing anticancer drugs.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the phrases "comprising … …" or "comprising … …" does not exclude the presence of additional elements in a process, method, article, or terminal that comprises the element. Further, herein, "greater than," "less than," "more than," and the like are understood to exclude the present numbers; the terms "above", "below", "within" and the like are to be understood as including the number.
Although the embodiments have been described, once the basic inventive concept is known, other variations and modifications can be made to the embodiments by those skilled in the art, so that the above embodiments are only examples of the present invention, and not intended to limit the scope of the present invention, and all equivalent structures or equivalent processes that can be used in the present specification or directly or indirectly applied to other related fields are encompassed by the present invention.

Claims (5)

1,1' -biphenyl-2, 6-diol compounds, pharmaceutically acceptable salts thereof or stereoisomers thereof, characterized in that the chemical structural formula thereof is as shown in formula (I):
Figure FDA0002827193350000011
wherein:
r1, R2, R3, R4 are each independently selected from:
hydrogen, halogen, nitro, cyano, amino or substituted amino, aldehyde group of C1-3, C1-6 alkyl or substituted alkyl, carboxyl or substituted carboxyl, hydroxyl or substituted hydroxyl, aryl or aryl substituted by 0-5 groups, heteroaryl or heteroaryl substituted by 0-5 groups;
the heteroaryl group is a 3-to 10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, O.
2. The 1,1' -biphenyl-2, 6-diol compound according to claim 1, wherein R1, R2, R3, R4 are each selected from the group consisting of:
Figure FDA0002827193350000012
3. a pharmaceutical composition is characterized by comprising 1,1' -biphenyl-2, 6-diphenol compounds shown in formula (I).
4. 1,1 '-biphenyl-2, 6-diphenol compound shown in formula (I), pharmaceutically acceptable salt or stereoisomer thereof and application of pharmaceutical composition containing 1,1' -biphenyl-2, 6-diphenol compound in preparing antitumor drugs.
5. Use according to claim 4, for inhibiting tumor cell proliferation.
CN202011451583.1A 2020-12-10 2020-12-10 1,1' -biphenyl-2, 6-diphenol compound and application thereof Active CN112500293B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202011451583.1A CN112500293B (en) 2020-12-10 2020-12-10 1,1' -biphenyl-2, 6-diphenol compound and application thereof
PCT/CN2021/107218 WO2022121317A1 (en) 2020-12-10 2021-07-20 1,1'-biphenyl-2,6-diphenolic compound and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011451583.1A CN112500293B (en) 2020-12-10 2020-12-10 1,1' -biphenyl-2, 6-diphenol compound and application thereof

Publications (2)

Publication Number Publication Date
CN112500293A true CN112500293A (en) 2021-03-16
CN112500293B CN112500293B (en) 2022-10-18

Family

ID=74972022

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011451583.1A Active CN112500293B (en) 2020-12-10 2020-12-10 1,1' -biphenyl-2, 6-diphenol compound and application thereof

Country Status (2)

Country Link
CN (1) CN112500293B (en)
WO (1) WO2022121317A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114605236A (en) * 2022-03-16 2022-06-10 福建省中科生物股份有限公司 Biaryl phenol compound and pharmaceutical composition, preparation method and application thereof
WO2022121317A1 (en) * 2020-12-10 2022-06-16 福建省中科生物股份有限公司 1,1'-biphenyl-2,6-diphenolic compound and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671639A (en) * 2002-08-23 2005-09-21 康涅狄格大学 Novel biphenyl and biphenyl-like cannabinoids
WO2008013963A2 (en) * 2006-07-28 2008-01-31 University Of Connecticut Fatty acid amide hydrolase inhibitors
WO2009052319A1 (en) * 2007-10-16 2009-04-23 Northeastern University Monoacylglycerol lipase inhibitors for modulation of cannabinoid activity
CN101668425A (en) * 2007-03-02 2010-03-10 田纳西州立大学研究基金会 Tri-aryl/heteroaroaromatic cannabinoids and use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9580400B2 (en) * 2013-02-26 2017-02-28 Northeastern University Cannabinergic nitrate esters and related analogs
CN112500293B (en) * 2020-12-10 2022-10-18 福建省中科生物股份有限公司 1,1' -biphenyl-2, 6-diphenol compound and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671639A (en) * 2002-08-23 2005-09-21 康涅狄格大学 Novel biphenyl and biphenyl-like cannabinoids
WO2008013963A2 (en) * 2006-07-28 2008-01-31 University Of Connecticut Fatty acid amide hydrolase inhibitors
CN101668425A (en) * 2007-03-02 2010-03-10 田纳西州立大学研究基金会 Tri-aryl/heteroaroaromatic cannabinoids and use thereof
WO2009052319A1 (en) * 2007-10-16 2009-04-23 Northeastern University Monoacylglycerol lipase inhibitors for modulation of cannabinoid activity
WO2009052320A1 (en) * 2007-10-16 2009-04-23 Northeastern University Methods and compounds for modulating cannabinoid activity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAS: "RN1349762-92-0等", 《REGISTRY》 *
F. MINUTOLO等: "Metabolically Labile Cannabinoid Esters A Soft Drug Approach for the Development of Cannabinoid-Based Therapeutic Drugs", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
YVES GAREAU等: "Structure Activity Relationships of Tetrahydrocanabinol Analogs on Human Cannabinoid Receptors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022121317A1 (en) * 2020-12-10 2022-06-16 福建省中科生物股份有限公司 1,1'-biphenyl-2,6-diphenolic compound and use thereof
CN114605236A (en) * 2022-03-16 2022-06-10 福建省中科生物股份有限公司 Biaryl phenol compound and pharmaceutical composition, preparation method and application thereof
CN114605236B (en) * 2022-03-16 2023-12-29 福建省中科生物股份有限公司 Biaryl phenol compound and pharmaceutical composition, preparation method and application thereof

Also Published As

Publication number Publication date
CN112500293B (en) 2022-10-18
WO2022121317A1 (en) 2022-06-16

Similar Documents

Publication Publication Date Title
CN106661000A (en) Egfr inhibitor, and preparation and application thereof
CN110028475B (en) Novel CDK9 inhibitor based on benzopyran structure, preparation method and application thereof
CN110156787B (en) Triazole pyrimidine derivative compound, pharmaceutical composition containing triazole pyrimidine derivative compound and application of triazole pyrimidine derivative compound
FR3037958A1 (en)
CN110698461B (en) Preparation method of third-generation EGFR inhibitor
CN112500293B (en) 1,1' -biphenyl-2, 6-diphenol compound and application thereof
CN109867676B (en) Pyrrolopyrimidine derivative compound, pharmaceutical composition and application thereof
JP6781806B2 (en) Inhibition of CREB-binding protein (CBP)
CN111961034A (en) Compounds useful as RET kinase inhibitors and uses thereof
CN110372703A (en) Five-ring heterocycles miazines compound and application thereof
CN113149993A (en) Pyrrolopyrimidine derivative compound, pharmaceutical composition and application thereof
CN112110897B (en) Preparation method of deuterated crizotinib and derivative thereof
CN115175902A (en) Compound used as kinase inhibitor and application thereof
CN109879888B (en) Forrestrex carbazole base A compound and preparation method and application thereof
CN110054627B (en) Novel IDO inhibitor, preparation method, pharmaceutical composition and application thereof
CN111372936B (en) Mcl-1 selective inhibitors, their preparation and use
AU618536B2 (en) Novel 3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives
KR20200097771A (en) Salt forms and crystal forms thereof as Akt inhibitors
CN111606888B (en) Pyrrole derivative and preparation method and application thereof
CN107235969B (en) Key intermediate for synthesizing hexahydropyridine-2, 3-indole-2-ketone framework compound and preparation method and application thereof
CN108341774B (en) Substituted quinolinone inhibitors
CN114605236B (en) Biaryl phenol compound and pharmaceutical composition, preparation method and application thereof
CN111943959A (en) Synthetic method of JAK inhibitor
CN116217611B (en) Cyclobutanone derivative, preparation method and application
CN111560013B (en) Autophagy inhibitor and application thereof

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