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CN115745983A - Angiotensin and endothelin receptor antagonist and application thereof - Google Patents

Angiotensin and endothelin receptor antagonist and application thereof Download PDF

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CN115745983A
CN115745983A CN202211470490.2A CN202211470490A CN115745983A CN 115745983 A CN115745983 A CN 115745983A CN 202211470490 A CN202211470490 A CN 202211470490A CN 115745983 A CN115745983 A CN 115745983A
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mixture
compound
pharmaceutically acceptable
methyl
enantiomer
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吴俊军
陆银锁
邢伟
胡浩
肖瑛
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Abstract

The invention belongs to the technical field of chemical medicines, and provides a compound which is an antagonist of both angiotensin and endothelin receptors, and a preparation method and medical application thereof.

Description

Angiotensin and endothelin receptor antagonist and application thereof
Technical Field
The invention belongs to the technical field of chemical medicines, and provides an angiotensin and endothelin receptor antagonist compound as well as a preparation method and medical application thereof.
Background
Sparsentan (CAS: 254740-64-2, structural formula below) is a dual angiotensin and endothelin receptor antagonist in clinical development for the treatment of renal diseases or disorders, some of which have no specific treatment or are associated with symptoms that cannot be completely controlled by other therapies.
Figure BDA0003958307910000011
Atrasentan (CAS: 173937-91-2, structural formula below) is a potent and selective angiotensin and endothelin receptor antagonist previously evaluated in clinical trials for the treatment of prostate cancer and now in clinical trials for the treatment of chronic kidney disease associated with type II diabetes. And has been shown to reduce albuminuria in diabetic nephropathy patients.
Figure BDA0003958307910000012
Currently, both products have not been approved for sale for a variety of reasons.
Disclosure of Invention
In view of the problems of the prior art, the present invention provides novel angiotensin and endothelin receptor antagonist compounds, methods for their preparation and their use in medicine.
In particular, the present invention provides compounds of general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
The invention is realized by the following technical scheme that the compound shown in the general formula (I), or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer, the mixture form or the pharmaceutically acceptable salt form thereof,
Figure BDA0003958307910000021
R 1 is selected from C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-8 Alkoxy or C 1-8 alkoxy-C 1-8 Alkyl radical, said R 1 The radicals may be substituted by one or moreA halogen substitution;
R 2 selected from hydrogen, halogen, C 1-8 Alkyl, (C) 3-8 Cycloalkyl) -C 1-8 Alkyl radical, C 1-8 alkoxy-C 1-8 Alkyl radical, C 1-8 Alkoxy, cyano, hydroxy or nitro radical, R 2 Groups may be substituted with one or more halogens or hydroxyl groups;
R 3 selected from oxazolyl, isoxazolyl or pyrazinyl, said R 3 The radicals may be substituted by one or more radicals selected from halogen, C 1-8 Alkyl radical, C 1-8 Alkoxy, nitro, cyano and trifluoromethyl;
ring A is selected from phenyl and C 5-6 Aromatic heterocyclic group, C 3-8 Cycloalkyl radical, C 3-8 A heterocycloalkyl group;
R 4 selected from hydrogen, halogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl and cyano, and n is 0, 1,2 or 3.
As a preferable embodiment of the present invention, C is 1-8 The alkyl group of (1) includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1, 2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1, 2-dimethylbutyl, 1-ethylbutyl.
As a preferable aspect of the present invention, said C 1-8 Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1, 2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1, 2-dimethylbutoxy, 1-ethylbutoxy.
As a preferred embodiment of the present invention, C 3-8 The cycloalkyl group includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclononane, and cycloquinane。
In a preferred embodiment of the present invention, the halogen includes fluorine, chlorine, bromine, and iodine.
As a preferred technical scheme of the invention, the aryl is selected from five-membered ring, six-membered ring, seven-membered ring, eight-membered ring, nine-membered ring and ten-membered ring, the aryl is monocyclic or bicyclic, preferably C 5-6 Aromatic ring groups (five-membered rings, six-membered rings); the heteroaryl refers to a heteroatom substituted for one or more carbon atoms in the aromatic ring.
As a preferable aspect of the present invention, said C 5-6 The aromatic heterocyclic group is selected from:
Figure BDA0003958307910000022
Figure BDA0003958307910000023
as a preferable embodiment of the present invention, C is 3-8 The cycloalkyl group of (a) includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclononane, and cycloquinane, and the heterocycloalkyl group means that one or more carbon atoms of the cycloalkane are substituted with a heteroatom.
In a preferred embodiment of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more.
As a preferable embodiment of the present invention, wherein:
R 1 selected from ethyl, propyl, n-butyl;
R 2 selected from methoxymethyl, ethoxymethyl, cyclopropyl-oxy-methyl, fluoro;
R 3 is selected from
Figure BDA0003958307910000031
Ring A is selected from benzene ring and cyclohexane, R 4 Selected from hydrogen, methyl, chlorine;
Figure BDA0003958307910000032
representing a connecting bond.
In a preferred embodiment of the present invention, the compound is selected from the following compounds:
Figure BDA0003958307910000033
Figure BDA0003958307910000041
Figure BDA0003958307910000051
as a preferable technical scheme of the invention, the compound shown in the general formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a non-natural proportion of atomic isotopes at the atoms selected from deuterium (d), (d) or (e) 2 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) And so on.
The invention further provides the use of a compound of the invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, particularly preferably for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with angiotensin and endothelin receptor antagonism.
Further, the diseases include the treatment of chronic kidney disease, igA, FSGS, hypertension, and the like.
The present invention further provides a pharmaceutical composition comprising the aforementioned compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base.
Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The atoms of the molecule of the compound are isotopes, and the compound can generally prolong half-life, reduce clearance rate, enhance metabolic stability, improve in-vivo activity and other effects through isotopic derivatization. Also, an embodiment is included wherein at least one atom is replaced with an atom having the same number of atoms (proton number) and different number of masses (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which each include 2 H、 3 H、 13 C、 14 C、 15 N、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 Cl. In particular, radioisotopes that emit radiation as they decay, such as 3H or 14C, may be used for topographic examination of pharmaceutical preparations or in vivo compounds. Stable isotopes do not decay or change with their amount, nor are they radioactive, and therefore they can be safely used. When the atoms constituting the molecule of the compound of the present invention are isotopes, the isotopes can be converted according to the general methods by substituting reagents used in the synthesis with reagents containing the corresponding isotopes.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioisotopes, such as deuterium (g) ((R)) 2 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Further, the compounds of the present invention are isotopically deuterated (C) on one or more hydrogen atoms 2 H) After being deuterated, the compound has the effects of prolonging half-life period, reducing clearance rate, enhancing metabolic stability, improving in-vivo activity and the like. The preparation method of the isotope derivative generally comprises: phase transfer catalysis processes. For example, a preferred method of deuteration employs a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu) 4 HSO 4 ). The exchange of methylene protons of diphenylmethane compounds using a phase transfer catalyst results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silanes) in the presence of an acid (e.g., methanesulfonic acid) or with lewis acids such as aluminum trichloride using sodium deuterated borate.
The term "pharmaceutically acceptable carrier" refers to any formulation vehicle or medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such bases include suspending agents, viscosity increasing agents, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on The vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed, lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "tautomeric" variant or "tautomeric" variant refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. Keto-enol tautomerism. Another example of tautomerism is phenol-ketone tautomerism. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to afford the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-III nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
MS was determined on an ISQ EC mass spectrometer (manufacturer: thermo, model: ISQ EC).
High Performance Liquid Chromatography (HPLC) analysis using Thermo U3000 HPLC DAD high performance liquid chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash Rf + LUMEN (TELEDYNE ISCO).
Cigarette platform silver dragon HSGF used for thin-layer chromatography silica gel plate 254 Or GF 254 The silica gel plate used in the Thin Layer Chromatography (TLC) adopts the specification of 0.17 mm-0.23 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 100-200 mesh silica gel from Nippon mammary gland as a carrier.
DMF N, N-dimethylformamide, chloromethyl ethyl carbonate, potassium iodide, cesium carbonate, DCM dichloromethane, N-hexane, ethyl acetate.
Example 1
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000081
The specific synthetic route is as follows:
step A: synthesis of methyl 4-bromo-3- (hydroxymethyl) benzoate
Figure BDA0003958307910000082
To a solution of methyl 4-bromo-3-formylbenzoate (1.0 g, 4.11 mmol) in methanol (10.0 ml) was added sodium borohydride (156 mg, 4.11 mmol) at 0 deg.c, and the reaction solution was stirred for 10 minutes.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/5) to obtain 1.0 g of methyl 4-bromo-3- (hydroxymethyl) benzoate as a colorless oily liquid (yield: 99%).
And B, step B: synthesis of methyl 4-bromo-3- (ethoxymethyl) benzoate
Figure BDA0003958307910000083
To N, N-dimethylformamide (10.0 ml) containing methyl 4-bromo-3- (hydroxymethyl) benzoate (1.0 g, 4.08 mmol) at 0 ℃, sodium hydride (195 mg, 4.89 mmol, 60%) was added under nitrogen, the reaction mixture was stirred for 10 minutes, subsequently iodoethane (764 mg, 4.89 mmol) was added, and the reaction warmed to room temperature and stirred for an additional 30 minutes.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 950 mg of methyl 4-bromo-3- (ethoxymethyl) benzoate as a colorless oily liquid (yield: 85%).
And C: synthesis of methyl 3- (ethoxymethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
Figure BDA0003958307910000091
Methyl 4-bromo-3- (ethoxymethyl) benzoate (950 mg, 3.48 mmol), pinan diborateAlcohol ester (1766 mg, 6.96 mmol), pd (dppf) Cl 2 (382 mg, 0.52 mmol) and potassium acetate (1024 mg, 10.43 mmol) were dissolved in1, 4-dioxane (15 ml) and the reaction was stirred at 100 ℃ for 2 hours under nitrogen.
After completion of the reaction, the mixture was filtered through celite, extracted with ethyl acetate (15 ml × 3 times), and the organic phases were combined, washed with saturated brine (15 ml × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 1.06 g of methyl 3- (ethoxymethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate as a white solid (yield: 95%).
Step D: synthesis of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) benzenesulfonamide
Figure BDA0003958307910000092
To a solution of 2-bromobenzenesulfonyl chloride (1.0 g, 8.91 mmol) and 4-dimethylaminopyridine (110 mg, 0.89 mmol) in pyridine (5.0 ml) was added 3-amino-4, 5-dimethylisoxazole (439 mg, 8.91 mmol) at 0 ℃ and the mixture was stirred for 30 minutes at 40 ℃.
After the reaction was complete, the mixture was diluted with methanol (30.0 ml) and sodium bicarbonate solution (50.0 ml, 3%) and then concentrated in vacuo. The pH of the mixture was adjusted to 1 with 1M hydrochloric acid at 0 ℃, extracted with ethyl acetate (10 ml. Times.3 times), the organic phases were combined, washed with saturated brine (10 ml. Times.2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/3) to give 840 mg of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) benzenesulfonamide (yield: 65%).
And E, step E: synthesis of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) benzenesulfonamide
Figure BDA0003958307910000093
To N, N-dimethylformamide (10.0 ml) containing 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) benzenesulfonamide (840 mg, 2.54 mmol) was added sodium hydride (112 mg, 2.79 mmol, 60%) under nitrogen at 0 deg.C, the reaction mixture was stirred for 10 minutes, followed by 2-methoxyethoxymethyl chloride (348 mg, 2.79 mmol), and the reaction was warmed to room temperature and stirred for 30 minutes.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/3) to give 681 mg of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) benzenesulfonamide (yield: 64%).
Step F: synthesis of methyl 2'- (N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) sulfamoyl) -2- (ethoxymethyl) - [1,1' -biphenyl ] -4-carboxylate
Figure BDA0003958307910000101
Methyl 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) benzenesulfonamide (680 mg, 1.62 mmol), methyl 3- (ethoxymethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (571 mg, 1.78 mmol), tetratriphenylphosphine palladium (375 mg, 0.32 mmol) and sodium carbonate (516 mg, 4.87 mmol) were dissolved in a mixed solvent of toluene (10 ml), ethanol (10 ml) and water (10 ml), and the reaction was stirred at 95 ℃ for 4 hours under nitrogen.
After completion of the reaction, the mixture was filtered through celite, extracted with ethyl acetate (15 ml × 3 times), and the organic phases were combined, washed with saturated brine (15 ml × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/4) to give 656 mg of methyl 2'- (N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) sulfamoyl) -2- (ethoxymethyl) - [1,1' -biphenyl ] -4-carboxylate (yield: 76%).
Step G: synthesis of N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -4' - (hydroxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000111
To a solution of methyl 2'- (N- (4, 5-dimethylisoxazol-3-yl) -N- ((2-methoxyethoxy) methyl) sulfamoyl) -2- (ethoxymethyl) - [1,1' -biphenyl ] -4-carboxylate (656 mg, 1.23 mmol) in tetrahydrofuran (8.0 mL) at 0 deg.C was added lithium aluminum hydride (93 mg, 2.46 mmol) under nitrogen and the reaction mixture was stirred for 10 minutes.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/1) to give 385 mg of N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -4' - (hydroxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide (yield: 62%).
Step H: synthesis of 4' - (bromomethyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000112
To a solution of N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -4' - (hydroxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide (385 mg, 0.76 mmol) in dichloromethane (10.0 mL) was added carbon tetrabromide (303 mg, 0.92 mmol) and triphenylphosphine (300 mg, 1.14 mmol) under nitrogen at 0 deg.C and the reaction mixture was stirred for 10min.
After the reaction, the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/3) to give 368 mg of 4' - (bromomethyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide (yield: 85%).
Step I: synthesis of butylthiourethane
Figure BDA0003958307910000113
Butyl magnesium chloride (2.0 mol/l, 13.2 ml) was added to tetrahydrofuran (30.0 ml) containing o-ethyl carbon thiocyanate (3.0 g, 22.00 mmol) at-78 deg.C, and the reaction was slowly warmed to room temperature after completion of the dropwise addition to react for 1.0 hour.
After the reaction is finished, water is added for quenching, the mixed solution is extracted by ethyl acetate (20 ml multiplied by 2 times), organic phases are combined, and the organic phases are washed by saturated ammonium chloride solution (20 ml multiplied by 2 times), then dried by anhydrous sodium sulfate and finally concentrated under reduced pressure. 1.80 g of butylthiourethane are obtained as a yellow oil. (yield: 43.2%). LCMS RT =2.04min, [ M-H ]] - ＝188.04。
Step J: synthesis of 5-butyl-2- (2-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000121
To ethanol (5.0 ml) containing butylthiourethane (0.7 g, 3.7 mmol), was added (2-chlorophenyl) hydrazine (0.6 g, 4.4 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction is completed, water is added for quenching, the mixed solution is extracted by ethyl acetate (10 ml multiplied by 2 times), organic phases are combined, and the organic phases are washed by saturated saline solution (12 ml multiplied by 2 times), dried by anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to giveTo 730.0 mg of 5-butyl-2- (2-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as a pale yellow oil (yield: 78.3%). LCMS RT =1.88min, [ M + H] + ＝252.11。
Step K: synthesis of 4' - (3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000122
To N, N-dimethylformamide (2.0 ml) containing 5-butyl-2- (2-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (30.0 mg, 0.12 mmol) was added sodium hydride (7.2 mg, 0.18 mmol) in a mass fraction of 60% at a time at room temperature, stirred under nitrogen for 10 minutes, and then 4' - (bromomethyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide (87.1 mg, 0.15 mmol) was added and reacted at room temperature for 1.0 hour.
After the reaction, the reaction was quenched by adding water, the mixture was extracted with ethyl acetate (5 ml × 3 times), and the organic phases were combined, washed with saturated brine (8 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol = 15/1) to give 45.6 mg of 4' - (3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl as a pale yellow oil]2-sulfonamide (yield: 51.4%). LCMS RT =2.27min, [ M + H] + ＝738.22。
Step L:4' - (3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000131
To ethanol (2.0 ml) containing 4' - (3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -N- ((2-methoxyethoxy) methyl) - [1,1' -biphenyl ] -2-sulfonamide (45.6 mg, 0.06 mmol) was added dropwise a 3N hydrochloric acid solution (0.1 ml) at room temperature, and reacted at 75 ℃ for 4.0 hours.
After the reaction is finished, water is added for quenching, the pH value is adjusted to 6 by using an aqueous solution of sodium bicarbonate (0.5 mol/L), a mixed solution is extracted by dichloromethane (5 ml multiplied by 2 times), organic phases are combined and then dried by anhydrous sodium sulfate, and a crude product is purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: agilent 5 Prep-C18 mm × 30mm 5 μ M; mobile phase: water (containing 0.1% ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted at 5.33 minutes from 38.6% acetonitrile; detection wavelength: 220nm. After purification, lyophilization at low temperature gave 10.3 mg of 4' - (3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl as a white solid]2-sulfonamide (yield: 25.4%). LCMS RT =2.20min, [ M + H] + ＝650.20； 1 H NMR(400MHz,DMSO-d 6 )δ10.50(s,1H),8.02(d,J＝8.1Hz,1H),7.66–7.45(m,6H),7.30(s,1H),7.14(d,J＝7.2Hz,1H),7.10(d,J＝7.8Hz,1H),6.95(d,J＝7.8Hz,1H),4.95(s,2H),4.03–3.93(m,2H),3.26–3.11(m,2H),2.52(t,J＝7.5Hz,2H),2.15(s,3H),1.62(s,3H),1.50(p,J＝7.5Hz,2H),1.28(h,J＝7.4Hz,2H),0.97(t,J＝7.0Hz,3H),0.79(t,J＝7.3Hz,3H)。
Example 2
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (methoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000132
The specific synthetic route is as follows:
step A: synthesis of methyl 4-bromo-3- (methoxymethyl) benzoate
Figure BDA0003958307910000141
To N, N-dimethylformamide (15.0 ml) containing methyl 4-bromo-3- (hydroxymethyl) benzoate (1.5 g, 6.12 mmol) at 0 ℃ under nitrogen was added sodium hydride (294 mg, 7.34 mmol, 60%) and the reaction mixture was stirred for 10 minutes, followed by methyl iodide (764 mg, 12.2 mmol) and the reaction warmed to room temperature and stirred overnight.
After completion of the reaction, the reaction mixture was carefully added to a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (30 ml × 3 times), the organic phases were combined, the organic phase was washed with a saturated saline solution (30 ml × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 1.23 g of methyl 4-bromo-3- (methoxymethyl) benzoate as a colorless oily liquid (yield: 78%).
From the above intermediate, analogously to example 1, steps C-L, 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (methoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.19min, [ M + H] + ＝636.25。 1 H NMR(400MHz,DMSO-d 6 )δ10.50(s,1H),8.05(dd,J＝8.2,1.3Hz,1H),7.70–7.49(m,6H),7.35(s,1H),7.18–7.10(m,2H),6.93(s,1H),4.96(t,J＝1.0Hz,2H),3.33(s,3H),3.30–3.16(m,2H),2.62(t,J＝8.1Hz,2H),2.16(s,3H),1.64(s,3H),1.55–1.44(m,2H),1.38–1.28(m,2H),0.81(t,J＝7.4Hz,3H).
Example 3
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - ((cyclopropyl) oxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000142
The specific synthetic route is as follows:
step A: synthesis of methyl 4-bromo-3- ((cyclopropyl) oxymethyl) benzoate
Figure BDA0003958307910000151
To anhydrous tetrahydrofuran (61 ml) containing methyl 4-bromo-3- (hydroxymethyl) benzoate (3.0 g, 12.2 mmol) was added potassium tert-butoxide (2.74 g, 24.4 mmol), 18-crown-6 (322 mg, 1.22 mmol) sequentially under nitrogen at room temperature, stirred at room temperature for 20 minutes, then cyclopropylbromide (2.95 g, 24.4 mmol) was added, the reaction was heated to 80 ℃ and stirred overnight.
After completion of the reaction, the reaction mixture was poured into a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (100 ml × 3 times), the organic phases were combined, the organic phase was washed with a saturated saline solution (100 ml × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 1.57 g of methyl 4-bromo-3- (ethoxymethyl) benzoate as a colorless oily liquid (yield: 45%). LCMS RT =2.18min, [ M + H] + ＝285.07,287.09。
From the above intermediate, similar operations were carried out with reference to steps C to L of example 1 to obtain 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - ((cyclopropyl) oxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.22min, [ M + H] + ＝662.30。
Example 4
Synthesis of 4' - ((3-propyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000152
The specific synthetic route is as follows:
step A: synthesis of propyl thiourethane
Figure BDA0003958307910000153
Propyl magnesium chloride (18.2 ml, 1.0 mol/l, 18.2 mmol) was added to tetrahydrofuran (20.0 ml) containing ethoxycarbonyl isothiocyanate (2.0 g, 15.2 mmol) at-78 ℃, and the reaction system was slowly warmed to room temperature for 1.0 hour after completion of dropwise addition.
After the reaction is finished, water is added for quenching, the mixed solution is extracted by ethyl acetate (50 ml multiplied by 2 times), organic phases are combined, and the organic phases are washed by saturated ammonium chloride solution (50 ml multiplied by 2 times), then dried by anhydrous sodium sulfate and finally concentrated under reduced pressure. 1.33 g of propylthiourethane were obtained as a pale yellow oil (yield: 50%). LCMS RT =2.02min, [ M-H ]] - ＝174.05。
From the above intermediate, analogously to example 1, steps J-L, 4' - ((3-propyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.18min, [ M + H] + ＝636.28； 1 H NMR(400MHz,DMSO-d 6 )δ10.81(s,1H),8.09(d,J＝8.4Hz,1H),7.70–7.42(m,6H),7.26(s,1H),7.16(d,J＝7.4Hz,1H),7.11(d,J＝7.5Hz,1H),6.93(d,J＝7.9Hz,1H),4.95(s,2H),4.05–3.97(m,2H),3.31–3.13(m,2H),2.56(t,J＝7.2Hz,2H),2.15(s,3H),1.70(s,3H),1.66–1.56(m,2H),1.00(t,J＝6.9Hz,3H),0.84(m,3H)。
Example 5
Synthesis of 4' - ((3-ethyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000161
The specific synthetic route is as follows:
step A: synthesis of Ethyl Thiocarbamate
Figure BDA0003958307910000162
Propyl magnesium chloride (9.1 ml, 2.0 mol/l, 18.2 mmol) was added to tetrahydrofuran (20.0 ml) containing ethoxycarbonyl isothiocyanate (2.0 g, 15.2 mmol) at-78 ℃, and the reaction system was slowly warmed to room temperature for 1.0 hour after completion of dropwise addition.
After the reaction is completed, water is added for quenching, the mixed solution is extracted by ethyl acetate (50 ml multiplied by 2 times), organic phases are combined, and the organic phases are washed by saturated ammonium chloride solution (50 ml multiplied by 2 times), then dried by anhydrous sodium sulfate and finally concentrated under reduced pressure. 1.16 g of propylthiourethane were obtained as a pale yellow oil (yield: 47%). LCMS RT =1.99min, [ M-H] - ＝160.06。
From the above intermediate, analogously to example 1, steps J-L, 4' - ((3-ethyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.18min, [ M + H] + ＝622.22。
Example 6
Synthesis of 4' - ((3-butyl-1-phenyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000171
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000172
Phenylhydrazine (890 mg, 8.24 mmol) was added to ethanol (10 ml) containing butylthiocarbamate (1.3 g, 6.87 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction is completed, water is added for quenching, the mixed solution is extracted by ethyl acetate (100 ml × 2 times), organic phases are combined, and the organic phases are washed by saturated saline solution (50 ml × 2 times), dried by anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to obtain 830 mg of 5-butyl-2-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one as pale yellow oil (yield: 55.6%). LCMS RT =1.85min, [ M + H] + ＝218.15。
From the above intermediate, analogously to example 1, steps K-L, 4' - ((3-butyl-1-phenyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl-e]-2-sulfonamides: LCMS RT =2.18min, [ M + H] + ＝616.30。
Example 7
Synthesis of 4' - ((3-propyl-1-phenyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000173
The specific synthetic route is as follows:
step A: synthesis of 5-propyl-2-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000181
Phenylhydrazine (829 mg, 7.67 mmol) was added to ethyl propylthiocarbamate (1.12 g, 6.39 mmol) in ethanol (10 ml) at room temperature, and the reaction was refluxed for 2.0 hours.
At the end of the reaction, addThe mixture was extracted with ethyl acetate (100 ml × 2 times), the organic phases were combined, washed with saturated brine (100 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (eluent: dichloromethane/methanol = 18/1), 66.5%). LCMS RT =1.74min, [ M + H] + ＝218.15。
From the above intermediate, analogously to example 1, steps K-L, 4' - ((3-propyl-1-phenyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl-e]-2-sulfonamides: LCMS RT =2.12min, [ M + H] + ＝602.30。
Example 8
Synthesis of 4' - ((3-butyl-1-phenyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (methoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000182
The title compound was obtained by performing similar operations from the intermediates of examples 2 and 6 with reference to the procedure of example 1: LCMS RT =2.11min, [ M + H] + ＝602.26； 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),8.01(dd,J＝8.2,1.2Hz,1H),7.82–7.72(m,3H),7.60–7.50(m,2H),7.45–7.37(m,2H),7.35(d,J＝8.4Hz,1H),7.30–7.19(m,3H),4.96(t,J＝1.0Hz,2H),3.39(s,3H),3.36–3.25(m,2H),2.71–2.60(m,2H),2.23(s,3H),1.64(s,3H),1.60–1.50(m,2H),1.39–1.27(m,2H),0.89(t,J＝7.4Hz,3H).
Example 9
Synthesis of 4' - ((3-butyl-1- (2-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000191
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2- (2-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000192
To ethyl alcohol (12 ml) containing butylthiourethane (1.5 g, 7.93 mmol) was added 2-methylphenylhydrazine hydrochloride (1.51 g, 9.51 mmol) and diisopropylethylamine (1.66 ml, 9.51 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to obtain 921 mg of 5-butyl-2- (2-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as a pale yellow oil (yield: 50.4%). LCMS RT =1.90min, [ M + H] + ＝231.17。
Similar operation was carried out with reference to example 1, steps K-L, to obtain 4' - ((3-butyl-1- (2-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.23min, [ M + H] + ＝630.33。
Example 10
Synthesis of 4' - ((3-propyl-1- (2-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000193
The title compound was obtained by performing similar operations from the intermediate of example 4 with reference to the procedure of example 9: LCMS RT =2.23min, [ M + H] + ＝616.29。
Example 11
Synthesis of 4' - ((3-butyl-1- (2-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (methoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000201
From the intermediates of examples 2 and 9, in analogy to the procedure of example 1, the title compound was obtained: LCMS RT =2.21min, [ M + H] + ＝616.30。
Example 12
Synthesis of 4' - ((3-butyl-1- (3-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000202
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2- (3-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000203
To ethyl alcohol (12 ml) containing butylthiourethane (1.5 g, 7.93 mmol) was added 3-chlorophenylhydrazine (1.36 g, 9.51 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to obtain 760 mg of 5-butyl-2- (3-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as pale yellow oil (yield: 38.2%). LCMS RT =1.89min, [ M + H] + ＝252.13。
Similar operation was conducted with reference to example 1, steps K-L to obtain 4' - ((3-butyl-1- (3-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.23min, [ M + H] + ＝650.26。
Example 13
Synthesis of 4' - ((3-butyl-1- (3-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000211
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2- (3-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000212
To ethyl alcohol (12 ml) containing butylthiourethane (1.35 g, 7.13 mmol) was added 3-methylphenylhydrazine (1.05 g, 8.56 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to obtain 913 mg of 5-butyl-2- (3-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as pale yellow oil (yield: 55.4%). LCMS RT =1.92min, [ M + H] + ＝232.20。
Similar operation was carried out with reference to example 1, steps K-L, to obtain 4' - ((3-butyl-1- (3-methylphenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.24min, [ M + H] + ＝630.33。
Example 14
Synthesis of 4' - ((3-butyl-1- (4-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000221
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2- (4-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000222
4-Chlorobenzhydrazide (1.72 g, 12.0 mmol) was added to ethanol (15 ml) containing butylthiourethane (1.9 g, 10.0 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1), to give 1.63 g of 5-butyl-2- (4-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as a pale yellow oil (yield: 64.9%). LCMS RT =1.88min, [ M + H] + ＝252.12。
By carrying out the similar operation with reference to example 1, steps K-L, 4' - ((3-butyl-1- (4-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl-4-yl ] methyl ] is obtained]-2-sulfonamides: LCMS RT =2.21min, [ M + H] + ＝650.30； 1 H NMR(400MHz,DMSO-d 6 )δ10.61(s,1H),8.05(dd,J＝8.4,1.4Hz,1H),7.83–7.73(m,3H),7.60–7.50(m,2H),7.42–7.28(m,5H),4.94(s,2H),4.05–3.95(m,2H),3.51–3.39(m,2H),2.61(t,J＝8.0Hz,2H),2.16(s,2H),1.64(s,3H),1.58–1.45(m,2H),1.33–1.25(m,3H),0.97(t,J＝7.0Hz,3H),0.82(t,J＝7.3Hz,3H)。
Example 15
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -5-fluoro- [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000223
The specific synthetic route is as follows:
step A: synthesis of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) -4-fluorobenzenesulfonamide
Figure BDA0003958307910000231
To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (1.5 g, 5.48 mmol) and 4-dimethylaminopyridine (67 mg, 0.55 mmol) in pyridine (10 ml) at 0 ℃ was added 3-amino-4, 5-dimethylisoxazole (614 mg, 5.48 mmol) and the mixture was stirred at 40 ℃ for 30 minutes.
After the reaction was complete, the mixture was diluted with methanol (30.0 ml) and sodium bicarbonate solution (50.0 ml, 3%) and then concentrated in vacuo. The pH of the mixture was adjusted to 1 with 1M hydrochloric acid at 0 ℃, extracted with ethyl acetate (100 ml. Times.3 times), the organic phases were combined, washed with saturated brine (100 ml. Times.2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/N-hexane = 1/3) to obtain 1.41 g of 2-bromo-N- (4, 5-dimethylisoxazol-3-yl) -4-fluoro-benzenesulfonamide (yield: 73.7%). LCMS RT =1.91min, [ M-H ]] - ＝346.99,349.01。
The above intermediate was similarly conducted with reference to steps E to L of example 1 to obtain 4' - ((3-butyl-1- (4-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) -5-fluoro- [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.23min,[M+H] + ＝668.31。
Example 16
Synthesis of 4' - ((3-butyl-1-cyclohexyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000232
The specific synthetic route is as follows:
step A: synthesis of 5-butyl-2-cyclohexyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Figure BDA0003958307910000233
Cyclohexylhydrazine (1.09 g, 9.51 mmol) was added to ethanol (12 ml) containing butylthiocarbamate (1.5 g, 7.93 mmol) at room temperature, and the reaction was refluxed for 2.0 hours.
After the reaction, water was added to quench, the mixture was extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 18/1) to obtain 630 mg of 5-butyl-2- (4-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one as pale yellow oil (yield: 35.6%). LCMS RT =1.92min, [ M + H] + ＝224.23。
Similar operation was conducted with reference to example 1, steps K-L to obtain 4' - ((3-butyl-1-cyclohexyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' - (ethoxymethyl) - [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.25min, [ M + H] + ＝621.35。
Example 17
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' -methyl- [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000241
The specific synthetic route is as follows:
step A: synthesis of methyl 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
Figure BDA0003958307910000242
Methyl 4-bromo-3-methylbenzoate (2.0 g, 8.73 mmol), pinacol diboron (4.43 g, 17.5 mmol), pd (dppf) Cl 2 (319 mg, 0.44 mmol) and potassium acetate (1.72 g, 17.5 mmol) were dissolved in1, 4-dioxane (35 ml) and the reaction was stirred at 100 ℃ for 2h under nitrogen.
After completion of the reaction, the mixture was filtered through celite, extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 1.53 g of methyl 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate as a white solid (yield: 75.9%). LCMS RT =2.25min, no associated ion flux.
From the above intermediate, similar operations were carried out with reference to steps F to L of example 1 to obtain 4' - ((3-butyl-1-cyclohexyl-5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' -methyl- [1,1' -biphenyl]-2-sulfonamides: LCMS RT =2.15min, [ M + H] + ＝606.30。
Example 18
Synthesis of 4' - ((3-butyl-1- (2-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methyl) -N- (4, 5-dimethylisoxazol-3-yl) -2' -fluoro- [1,1' -biphenyl ] -2-sulfonamide
Figure BDA0003958307910000251
The specific synthetic route is as follows:
step A: synthesis of methyl 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
Figure BDA0003958307910000252
Methyl 4-bromo-3-fluorobenzoate (2.0 g, 8.58 mmol), pinacol diborate (4.36 g, 17.2 mmol), pd (dppf) Cl 2 (314 mg, 0.43 mmol) and potassium acetate (1.69 g, 17.2 mmol) were dissolved in1, 4-dioxane (35 ml) and the reaction was stirred at 100 ℃ for 2 hours under nitrogen.
After completion of the reaction, the mixture was filtered through celite, extracted with ethyl acetate (100 ml × 2 times), and the organic phases were combined, washed with saturated brine (100 ml × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/10) to obtain 1.15 g of methyl 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate as a white solid (yield: 47.9%).
From the above intermediates, in analogy to example 1, steps F-L, the title compound was obtained: LCMS RT =2.11min, [ M + H] + ＝610.19； 1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),8.10(dd,J＝8.2,1.3Hz,1H),7.75–7.65(m,2H),7.63–7.52(m,2H),7.48–7.34(m,3H),7.29–7.24(m,1H),7.22–7.16(m,1H),7.15–7.11(m,1H),4.28(s,2H),2.66(t,J＝8.1Hz,2H),2.15(s,3H),1.65(s,3H),1.55–1.45(m,2H),1.36–1.27(m,2H),0.78(t,J＝7.4Hz,3H)。
Example 19 Activity assay for Endothelin Type A Receptor (ETAR) inhibitors
This experiment utilizes the FLIPR calcium flux detection method to determine the inhibitory effect of the test compound on the endothelin A type receptor ETA
The experimental method comprises the following steps: flpIN-CHO-ETA stable pool cell line in whole medium at 37 ℃ with 5% CO 2 Culturing, digesting at 70-90% fusion degree, resuspending and then adding 6,500 cells/well were seeded in 384-well cell culture plates (Corning, 3764) and cultured overnight. 20 xCoomponent A was thawed to room temperature and diluted with assay buffer (1X HBSS +20mM HEPES) to 2X working concentration (liquid 1) containing 5mM Probenecid and left at room temperature until ready for use. The cell culture plates were allowed to stand at room temperature for 10 minutes, FBS was diluted to 0.03% using Apricot and assay buffer, and 20. Mu.L of the final solution was added to the plates, followed by addition of 20. Mu.L of liquid 1 to each assay well, centrifugation at 200g for 3-5 minutes at room temperature, and incubation at 37 ℃ for 2 hours.
Preparing a positive control compound and a working solution (6 x) of a compound to be detected, and placing the working solutions at room temperature for later use (liquid 2); endothelin1 was diluted to 30nM (6X) with assay buffer, and 50. Mu.L 384 well plates (Corning, 3657) were transferred and left at room temperature until use (liquid 3).
Standing the cell culture plate for 10 minutes at room temperature; add 10. Mu.L of liquid 2 to 384 well cell culture plate corresponding experimental wells and incubate for 30min at room temperature. Data were collected by adding 10 μ L of liquid 3 to each experimental well using FLIPR Tetra.
Example 20 determination of angiotensin I type receptor (AT 1R) inhibitor Activity
The inhibition of the test compound on angiotensin I receptor (AT 1R) was determined using FLIPR calcium flow assay.
The experimental scheme is as follows: flpIN-CHO-AT1 stable pool cell line in whole medium AT 37 ℃ with 5% CO 2 Culture was performed overnight in 384-well cell culture plates (Corning, 3764) with 6,500 cells/well after digestion treatment at 70% -90% confluence and resuspension. 20 xCoomponent A was thawed to room temperature, diluted with assay buffer (1X HBSS +20mM HEPES) to 2X working concentration (liquid 1) containing 5mM Probenecid, and left at room temperature until use. The cell culture plates were allowed to stand at room temperature for 10 minutes, FBS was diluted to 0.03% using Apricot and assay buffer, and 20. Mu.L of the final solution was added to the plates, followed by addition of 20. Mu.L of liquid 1 to each assay well, centrifugation at 200g for 3-5 minutes at room temperature, and incubation at 37 ℃ for 2 hours.
Preparing a positive control compound and a working solution (6 x) of a compound to be tested, and placing the working solutions at room temperature for later use (liquid 2); angiotensin II was diluted to 0.375nM (6X) with assay buffer, 50. Mu.L was transferred to 384 well plates (Corning, 3657) and left at room temperature until use (liquid 3).
Standing the cell culture plate for 10 minutes at room temperature; add 10. Mu.L of liquid 2 to 384 well cell culture plate corresponding experimental wells and incubate for 30min at room temperature. 10 μ L of liquid 3 was added to each experimental well using FLIPR Tetra and data collected.
The test results for examples 19 and 20 are shown in table 1 below:
TABLE 1
Figure BDA0003958307910000261
Figure BDA0003958307910000271
Example 21
Compound liver microsome stability study
(1) Experimental materials
Human liver microsomes were purchased from reed liver disease research (shanghai) ltd.
Reagent: DMSO (dimethyl sulfoxide), acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
The instrument comprises the following steps: sammerfel LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
(2) Experimental method
Precisely weighing a certain amount of compound, dissolving in DMSO to obtain 10mM stock solution, and adding diluent (ACN: H) 2 O = 1) stock solution was diluted to 100 μ M working solution, and then diluted with 0.1M potassium phosphate buffer solution to 3 μ M dosing solution for use. Adding 75 μ L liver microsome into 925 μ L0.1M potassium phosphate buffer solution, mixing to obtain 1.5mg/mL liver microsome suspension, and pre-incubating at 37 deg.C for 10min. Preparation of point 0: and adding 6mM NADPH solution into 15 mu L of the liver microsome suspension, immediately adding 150 mu L of propranolol acetonitrile solution for precipitation, adding 15 mu L of the administration solution, and uniformly mixing for later use. 20min and 60min sample preparation: mu.L of the dosing solution was added with 15. Mu.L of the liver microsome suspension and 15. Mu.L of 6mM NAThe DPH solution was mixed well and incubated at 37 ℃ for 20min and 60min, respectively. The sample preparation was a double-well parallel operation. When the samples are incubated to the relevant time point, 150 mu L of propranolol acetonitrile solution is added to stop the reaction. All the samples were centrifuged at 4000rpm for 5min, 100. Mu.L of supernatant was added to 100. Mu.L of ultrapure water and mixed well for LC-MS/MS analysis. The LC-MS/MS detection conditions were as follows:
a chromatographic column: waters acuitytm PREMIER HSS T3, 50 x 2.1mm,1.8 μm.
Mobile phase: water (0.1% formic acid) -acetonitrile were subjected to gradient elution according to the following table
Time (min) Water (with 0.1% formic acid) Acetonitrile (ACN)
0 85％ 15％
0.6 85％ 15％
1 20％ 80％
2.3 20％ 80％
2.31 85％ 15％
3 85％ 15％
(3) Data analysis
The test substance/Internal Standard (IS) peak area ratio IS converted into the remaining percentage (remaining percentage%), and the formula IS as follows:
remaining rate% = subject-to-IS peak area ratio at each time point/subject-to-IS peak area ratio when t =0 × 100
The slope was calculated based on the remaining rate at each time point, and the half-life of each test substance in liver microsomes was calculated. The results are shown in Table 2 below.
TABLE 2 stability data for liver microsomes
Figure BDA0003958307910000281
The results show that the example compounds are all stable in human liver microsomes, with half-lives longer than Sparsentan, suggesting that metabolism may be slower than Sparsentan in humans.
EXAMPLE 22 rat pharmacokinetic Studies with Compounds
(1) Experimental materials
SD rat: male, 180-250g, purchased from Experimental animals technology, inc. of Viton, beijing.
Reagent: DMSO (dimethylsulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
The instrument comprises: sammerfel LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
(2) Experimental method
Weighing the compound, dissolving the compound in a DMSO-PEG-400-normal saline (5, 35 v/v/v), collecting 200 mu L venous blood in an EDTA-K2 anticoagulation EP tube at 15min, 30min, 1h, 2h, 5h, 7h and 24h (iv group is collected for 5 min) after intravenous or intragastric administration of rats, centrifuging at 12000rpm for 2min, and collecting plasma at-80 ℃ for cryopreservation to be tested. Precisely weighing a certain amount of test sample, dissolving the test sample in DMSO to 2mg/mL to obtain stock solution. Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with plasma concentrations of 1,3, 5, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. And (3) taking 30 mu L of plasma (diluted by 10 times in 5min, 15min and 30min of intravenous administration), adding 200 mu L of acetonitrile solution of internal standard propranolol (50 ng/mL), uniformly mixing by vortex, adding 100 mu L of purified water, uniformly mixing by vortex again, centrifuging at 4000rpm for 5min, and taking supernatant for LC-MS (liquid chromatography-mass spectrometry) for analysis. The LC-MS detection conditions were as follows:
a chromatographic column: saimerfil HYPERSIL GOLD C-18 UPLC column, 100 × 2.1mm,1.7 μm.
Mobile phase: water (0.1% formic acid) -acetonitrile were subjected to gradient elution according to the following table.
Time (min) Water (with 0.1% formic acid) Acetonitrile (ACN)
0 90％ 10％
0.6 90％ 10％
1 10％ 90％
2.6 10％ 90％
2.61 90％ 10％
4 90％ 10％
3. Data processing
After LC-MS detection of blood concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and non-compartmental modeling, and the results are shown in Table 3.
TABLE 3 rat PK data
Figure BDA0003958307910000291
The results show that: the oral absorption of the rats in examples 2,4 and 14 is better than that of Sparsentan, and the oral exposure of example 2 is higher than that of Sparsentan under the same dosage.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.

Claims (13)

1. A compound of the general formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure FDA0003958307900000011
R 1 is selected from C 1-8 Alkyl radical, C 3-8 Cycloalkyl, C 1-8 Alkoxy or C 1-8 alkoxy-C 1-8 Alkyl, or said R 1 A group is substituted with one or more halogens;
R 2 selected from hydrogen, halogen, C 1-8 Alkyl, (C) 3-8 Cycloalkyl) -C 1-8 Alkyl radical, C 1-8 alkoxy-C 1-8 Alkyl radical, C 1-8 Alkoxy, cyano, hydroxy or nitro, or said R 2 The radicals being substituted by one or more halogens or hydroxyl groups;
R 3 selected from oxazolyl, isoxazolyl or pyrazinyl, or said R 3 The radicals being substituted by one or more radicals selected from halogen, C 1-8 Alkyl radical, C 1-8 Alkoxy, nitro, cyano and trifluoromethyl;
ring A is selected from phenyl and C 5-6 Aromatic heterocyclic group, C 3-8 Cycloalkyl, C 3-8 A heterocycloalkyl group;
R 4 selected from hydrogen, halogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl and cyano, and n is 0, 1,2 or 3.
2. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein C is 1-8 The alkyl group of (1) includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1, 2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1, 2-dimethylbutylA group, 1-ethylbutyl.
3. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein C is 1-8 Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1, 2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1, 2-dimethylbutoxy, 1-ethylbutoxy.
4. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein C is 3-8 The cycloalkyl group of (b) includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclononane, and cycloquinane.
5. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the halogen comprises fluorine, chlorine, bromine, iodine.
6. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein C is 5-6 The aromatic heterocyclic group is selected from:
Figure FDA0003958307900000021
Figure FDA0003958307900000022
7. the compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein heterocycloalkyl means that one or more carbon atoms of a cycloalkane are replaced with a heteroatom selected from nitrogen, oxygen, and sulfur.
8. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
R 1 selected from ethyl, propyl, n-butyl;
R 2 selected from methoxymethyl, ethoxymethyl, cyclopropyl-oxy-methyl, fluoro;
R 3 is selected from
Figure FDA0003958307900000023
Ring A is selected from benzene ring and cyclohexane, R 4 Selected from hydrogen, methyl, chlorine;
Figure FDA0003958307900000024
representing a connecting bond.
9. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure FDA0003958307900000025
Figure FDA0003958307900000031
Figure FDA0003958307900000041
10. the compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that one or more of the atoms constituting the compound contains unnatural proportions of atomic isotopes selected from deuterium (I), (II), and (III) 2 H) Iodine-125 (I) 125 I) Or C-14 ( 14 C)。
11. Use of a compound according to any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with angiotensin and endothelin receptor antagonism.
12. Use according to claim 11, wherein the diseases include diseases of chronic kidney disease, igA, FSGS and hypertension.
13. A pharmaceutical composition comprising a compound according to any one of the preceding claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
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