An endothelin A (ETA) receptor antagonist compound, its preparation method and pharmaceutical uses

Abstract

This invention belongs to the field of chemical drug technology, and provides an endothelin A (ETA) receptor antagonist compound, its preparation method, and its pharmaceutical uses.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug technology, and provides an endothelin A (ETA) receptor antagonist compound, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Atrasentan (CAS: 173937-91-2) is a potent and selective endothelin A (ETA) receptor antagonist with the following structural formula: The drug used clinically is atrasentan hydrochloride (CAS: 195733-43-8), with the following structure: Previously evaluated in clinical trials for the treatment of prostate cancer, it is now being evaluated in clinical trials for the treatment of chronic kidney disease associated with type 2 diabetes. It has also been shown to reduce albuminuria in patients with diabetic nephropathy; however, there are currently no marketed products using it. Summary of the Invention

[0003] In view of the problems existing in the prior art, the present invention provides a novel endothelin A (ETA) receptor antagonist compound, its preparation method and its application in medicine.

[0004] Specifically, the present invention provides compounds of general formula (I), or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein all variables are as defined herein.

[0005] This invention is achieved through the following technical solution: a compound represented by general formula (I), or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0006] (I) Where: R1 is hydrogen or C 1-6 Alkyl group, where R2 is hydrogen or C 1-6 Alkyl groups, or C1 and R2 3-6 cycloalkyl; L is selected from substituted or unsubstituted C 1-6 -alkyl, C 3-6 cycloalkyl, C 1-6 The alkoxy, substituted or unsubstituted -(CH2)n-heterocycle, where n is a natural number from 0 to 3, selected from 0, 1, 2 and 3.

[0007] As a preferred technical solution of the present invention, C is replaced 1-6 - Alkyl substituents include hydroxyl, phosphate, amino, C 1-6-alkyl-substituted amino; substituted -(CH2)n-heterocyclic substituents include C 1-6 The alkyl, hydroxyl, and carbonyl groups, and the heterocycles are selected from C10. 3-6 A saturated or unsaturated heterocycle in which one or more C atoms are replaced by O, N or S.

[0008] In a preferred embodiment of the present invention, R1 and R2 are not both hydrogen.

[0009] As a preferred technical solution of the present invention, the C 1-6 The alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0010] As a preferred technical solution of the present invention, C 3-6 The cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0011] As a preferred technical solution of the present invention, the C 1-6 The alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; the substituted or unsubstituted heterocycle is selected from... , , , .

[0012] In a preferred embodiment of the present invention, R1 and R2 are individually selected from hydrogen and methyl, and R1 and R2 are not both hydrogen; L is selected from methyl, ethyl, isopropyl, ... Cyclopropyl , , , , , , , .

[0013] As a preferred embodiment of the present invention, the compounds are selected from the following:

[0014] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound refers to the compound, or its isomers, or its racemic mixtures, prepared with a pharmaceutically acceptable acid or base.

[0015] As a preferred embodiment of the present invention, the compound represented by general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, contains atomic isotopes in non-natural proportions, the isotopes being selected from deuterium (…). 2 H), Iodine-125 125 I) or C-14 14 C) etc.

[0016] The present invention further provides the use of the compounds described herein, or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, in the preparation of medicaments, particularly, preferably the use of the compounds or their pharmaceutically acceptable salts in the preparation of medicaments for the treatment and / or preendothelin A (ETA) receptor antagonism-related diseases.

[0017] Furthermore, the diseases mentioned include the treatment of chronic kidney disease, IgA, FSGS, and hypertension.

[0018] The present invention further provides a pharmaceutical composition comprising the aforementioned compound, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0019] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0020] The term "pharmaceutically acceptable salt" as used herein refers to derivatives of the compounds of this invention, wherein the parent compound is modified by forming a salt with an acid or a base.

[0021] The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0022] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0023] The atoms of the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, enhance metabolic stability, and improve in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 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, radioactive isotopes that emit radiation as they decay, such as 3H or 14C, can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the molecules of the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0024] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. Further, one or more hydrogen atoms in the compounds of the present invention are coated with the isotope deuterium (… 2The deuteration of the compounds of the present invention, by substitution with H), has the effects of prolonged half-life, reduced clearance rate, enhanced metabolic stability, and increased in vivo activity. The preparation method of the isotope derivative typically includes a phase-transfer catalytic method. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in the introduction of higher deuterium levels than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0025] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0026] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0027] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0028] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0029] The term "tautomer" or "tautomer form" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. Keto-enol tautomers are another example of tautomerism. Another example is phenol-keto tautomerism. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0030] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0031] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can 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 provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0032] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0033] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0034] The advantages of this invention over the prior art include: The present invention relates to an endothelin A (ETA) receptor antagonist compound, the prodrug of which can be completely converted into atrasentan in human liver microsomes, and pharmacokinetic studies show that it has technical effects comparable to atrasentan. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0036] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-III NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0037] MS measurements were performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0038] High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD high-performance liquid chromatograph.

[0039] The CombiFlash rapid preparation system uses CombiFlash Rf+ LUMEN (TELEDYNE ISCO).

[0040] Thin-layer chromatography silica gel plates used are from Yantai Yinlong HSGF. 254 or GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.17mm to 0.23mm, while those used for TLC separation and purification of products have a size of 0.4mm to 0.5mm.

[0041] Silica gel column chromatography generally uses 100-200 mesh silica gel from Rushan Shangbang as the carrier.

[0042] DMF N,N-dimethylformamide, chloromethyl ethyl carbonate, potassium iodide, cesium carbonate, DCM dichloromethane, n-hexane, ethyl acetate.

[0043] Example 1 1-[(ethoxycarbonyl)oxy]methyl-(2R,3R,4S)-4-(benzo[d][1,3]dioxacyclopentan-5-yl)-1-[2-(dibutylamine)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0044] Step A: Synthesis of 1-[(ethoxycarbonyl)oxy]methyl(2R,3R,4S)-4-(benzo[d][1,3]dioxacyclopentan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0045] At room temperature, atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), chloromethyl ethyl carbonate (270 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 2 hours.

[0046] After the reaction was completed, the reaction solution was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 480 mg of colorless oily product [(ethoxycarbonyl)oxy]methyl(2R,3R,4S)-4-(benzo[d][1,3]dioxane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 79.9%).

[0047] LC-MS: RT = 2.20 min, [M+H] + =613.42.

[0048] 1 H NMR (400 MHz, DMSO) δ 7.23 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 1.2 Hz, 1H), 6.89 (d, J= 8.7 Hz, 2H), 6.84 – 6.76 (m, 2H), 5.98 (d, J = 4.6 Hz, 2H), 5.58 (q, J = 6.2 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.78 – 3.72 (m, 1H), 3.72 (s,3H), 3.49 (dd, J = 11.2, 5.3 Hz, 1H), 3.26 – 3.20 (m, 3H), 3.16 (s, 1H), 3.02 –2.90 (m, 3H), 2.86 – 2.80 (m, 1H), 2.71 (d, J = 13.8 Hz, 1H), 1.33 (dd, J = 14.6,7.0 Hz, 2H), 1.27 – 1.09 (m, 7H), 0.96 (dd, J = 14.7, 7.3 Hz, 2H), 0.81 (t, J =7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H). Example 2 1-[(ethoxycarbonyl)oxy]ethyl(2R,3R,4S)-4-(benzo[d][1,3]dioxacyclopentan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0049] Step A: Synthesis of 1-[(ethoxycarbonyl)oxy]ethyl(2R,3R,4S)-4-(benzo[d][1,3]dioxacyclopentan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0050] At room temperature, atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), 1-chloroethyl ethyl carbonate (298 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 2 hours.

[0051] After the reaction was completed, the reaction solution was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 442 mg of colorless oily product 1-[(ethoxycarbonyl)oxy]methyl(2R,3R,4S)-4-(benzo[d][1,3]dioxane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 66.5%).

[0052] LC-MS: RT = 2.21 min, [M+H] + =627.40. 1 H NMR (400 MHz, DMSO) δ 7.27 – 7.17(m, 2H), 7.09 – 6.98 (m, 1H), 6.92 – 6.85 (m, 2H), 6.85 – 6.74 (m, 2H), 6.60– 6.52 (m, 1H), 5.98 (d, J = 5.3 Hz, 2H), 4.11 (dq, J = 11.1, 7.1 Hz, 2H), 3.67-3.73 (m, 4H), 3.57 – 3.44 (m, 1H), 3.30 – 3.20 (m, 3H), 3.19 – 3.10 (m, 1H), 3.01 – 2.85 (m, 3H), 2.77 (ddd, J = 9.4, 6.9, 2.6 Hz, 1H), 2.70 (d, J = 13.9 Hz,1H), 1.39 – 1.22 (m, 6H), 1.21 – 1.04 (m, 6H), 1.01 – 0.89 (m, 2H), 0.81 (t,J = 7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H) Example 3 1-[(isopropoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0053] Step A: Synthesis of 1-[(isopropoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0054] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), 1-chloroethyl isopropyl carbonate (325 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 2 hours.

[0055] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 482 mg of the colorless oily product 1-[(isopropoxycarbonyl)oxy]ethyl-(2... R ,3 R 4 S )-4-(benzo[ d[1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 76.9%).

[0056] LC-MS: RT = 2.29 min, [M+H] + =641.48. 1 H NMR (400 MHz, DMSO) δ 7.25 (t, J =9.0 Hz, 2H), 7.07–7.04 (m, 1H), 6.93–6.89 (m, 2H), 6.85–6.78 (m, 2H), 6.59–6.54 (m, 1H), 5.99 (d, J = 6.2 Hz, 2H), 4.79–4.69 (m, 1H), 3.76–3.70 (m, 4H), 3.55–3.44 (m, 1H), 3.33–3.23 (m, 4H), 3.21–3.13 (m, 1H), 3.02–2.90 (m, 3H),2.80–2.75 (m, 1H)2.71 (d, J = 13.9 Hz, 1H), 1.39–1.33 (m, 1H), 1.32 (d, J = 5.4Hz, 2H), 1.26 (d, J = 5.4 Hz, 2H), 1.22–1.14 (m, 9H), 1.00–0.94 (m, 2H), 0.82(t, J = 7.3 Hz, 3H), 0.72 (t, J = 7.3 Hz, 3H).

[0057] Example 4 1-[(methoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0058] Step A: Synthesis of 1-[(methoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S )-4-(benzo[d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0059] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), 1-chloroethyl methyl carbonate (270 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 2 hours.

[0060] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 428 mg of a colorless oily product, 1-[(methoxycarbonyl)oxy]ethyl-(2... R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 71.3%).

[0061] LC-MS: RT = 2.20 min, [M+H] + =613.42. 1 H NMR (400 MHz, DMSO) δ 7.25 (dd, J =10.3, 8.7 Hz, 2H), 7.08–7.04 (m, 1H), 6.91 (dd, J = 8.7, 2.9 Hz, 2H), 6.86–6.78(m, 2H), 6.60–6.55 (m, 1H), 5.99 (d, J= 5.1 Hz, 2H), 3.76–3.69 (m, 6H), 3.56–3.44 (m, 1H), 3.33–3.16 (m, 5H), 3.00–2.94 (m, 3H), 2.81–2.76 (m, 1H), 2.71(d, J = 13.7 Hz, 1H), 1.39–1.14 (m, 9H), 1.02– 0.93 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7.3 Hz, 3H).

[0062] Example 5 1-(((2-(methylamino)ethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0063] Step A: Synthesis of tert-butyl (2-(((1-chloroethoxy)carbonyl)oxy)ethyl)(methyl)carbamate

[0064] Under ice bath conditions, 2-(N-Boc-N-methylamino)ethanol (500 mg, 2.85 mmol) and pyridine (248 mg, 3.14 mmol) were added to 10 mL of dry dichloromethane. 1-Chloroethyl chloroformate (248 mg, 3.14 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 1 hour.

[0065] After the reaction was completed, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed twice with 1 M / L hydrochloric acid (20 mL), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to give 725 mg of colorless oily product (2-(((1-chloroethoxy)carbonyl)oxy)ethyl)(methyl)carbamate tert-butyl ester (yield: 90.6%).

[0066] Step B: Synthesis of 2,2,5-trimethyl-4,9-dioxo-3,8,10-trioxo-5-aza-11-ethyl-(2 R ,3 R 4 S )-4-(benzo[d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0067] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), (2-(((1-chloroethoxy)carbonyl)oxy)ethyl)(methyl)carbamate tert-butyl ester (550 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 4 hours.

[0068] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 625 mg of a colorless oily product, 2,2,5-trimethyl-4,9-dioxo-3,8,10-trioxo-5-aza-11-ethyl-(2-) R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 84.4%). LC-MS: RT = 2.34 min, [M+H] + =756.49.

[0069] Step C: Synthesis of 1-(((2-(methylamino)ethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0070] At room temperature, 2,2,5-trimethyl-4,9-dioxo-3,8,10-trioxo-5-aza-11-ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (300 mg, 0.39 mmol) was dissolved in 10 mL of ethyl acetate, and 2 mL of 4 M / L dioxane hydrochloride solution was added under ice bath. The reaction was carried out at room temperature for 2 hours.

[0071] After the reaction was completed, 260 mg of a yellow solid, 1-(((2-(methylamino)ethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 101.6%).

[0072] LC-MS: RT = 1.82 min, [M+H] + = 656.45. 1 H NMR (400 MHz, DMSO) δ 7.60 (m,2H), 7.21 (m, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 15.8 Hz, 2H), 6.50 (m,1H), 6.04 (s, 2H), 3.77 (s, 3H), 3.17 (d, J = 6.4 Hz, 3H), 3.08 – 2.90 (m, 4H), 2.52 (d, J = 5.6 Hz, 3H), 2.06 (d, J = 4.1 Hz, 3H), 1.90 (s, 6H), 1.33 (d, J = 34.4Hz, 4H), 1.23 – 1.10 (m, 7H), 0.83 (t, J = 7.0 Hz, 6H). Example 6 1-((((S)-2,3-dihydroxypropoxy)carbonyl)oxy)ethyl-(2 R ,3R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0073] Step A: 1-Chloroethyl(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)carbonate

[0074] Under ice bath conditions, (S)-(+)-1,2-isopropylglycerol (315 mg, 2.38 mmol) and pyridine (225 mg, 2.85 mmol) were added to 10 mL of dry dichloromethane. 1-Chloroethyl chloroformate (408 mg, 2.85 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours.

[0075] After the reaction was complete, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to dryness, and the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give 250 mg of colorless oily product 1-chloroethyl(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl) carbonate (yield: 44.2%).

[0076] Step B: Synthesis of 1-(((((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[d][1,3]dioxacyclopentan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0077] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d[1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (100 mg, 0.20 mmol), 1-chloroethyl(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl) carbonate (72 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol), and potassium iodide (66.4 mg, 0.4 mmol) were added to 5 mL of dry DMF, and the mixture was heated to 65°C and reacted for 4 hours.

[0078] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 85 mg of a colorless oily product 1-(((((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 59.9%). LC-MS: RT = 2.21 min, [M+H] + =713.46.

[0079] Step C: Synthesis of 1-((((S)-2,3-dihydroxypropoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0080] At room temperature, 1-(((((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (80 mg, 0.11 mmol) was dissolved in 10 mL of dichloromethane solvent, and 2 mL of trifluoroacetic acid solution was added. The reaction was carried out at room temperature for 0.5 h.

[0081] After the reaction was complete, the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to give 56 mg of a yellow solid 1-((((S)-2,3-dihydroxypropoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 74.1%).

[0082] LC-MS: RT = 2.06 min, [M+H] + = 673.39. 1 H NMR (400 MHz, DMSO) δ 7.32 –7.17 (m, 2H), 7.12 – 7.04 (m, 1H), 6.93 (s, 2H), 6.84 (s, 2H), 6.55 (s, 1H),6.00 (d, J = 5.2 Hz, 2H), 4.18 – 4.06 (m, 2H), 3.90 (s, 1H), 3.73 (s, 3H), 3.64(s, 2H), 3.55 – 3.42 (m, 2H), 3.18 – 3.07 (m, 3H), 3.00 (s, 4H), 2.66 (s,1H), 2.44 – 2.35 (m, 2H), 2.32 (s, 1H), 1.31 (s, 3H), 1.18 (s, 3H), 0.99 (s,3H), 0.81 (t, J = 7.4 Hz, 3H), 0.74 (s, 3H). Example 7 1-[(cyclopropoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0083] Step A: Synthesis of 1-[(cyclopropoxycarbonyl)oxy]ethyl-(2 R ,3 R 4 S)-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0084] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (500 mg, 0.98 mmol), 1-chloroethylcyclopropyl carbonate (240 mg, 1.96 mmol), cesium carbonate (640 mg, 1.96 mmol), and potassium iodide (325 mg, 1.96 mmol) were added to 10 mL of dry DMF, and the mixture was heated to 65°C and reacted for 2 hours.

[0085] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (100 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to give 412 mg of a colorless oily product, 1-[(cyclopropoxycarbonyl)oxy]ethyl-(2... R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 65.8%). LC-MS: RT = 2.29 min, [M+H] + =639.40. 1 H NMR (400 MHz, DMSO) δ 7.25 (s, 2H), 7.06 (d, J = 10.4 Hz,1H), 6.90 (m, 2H), 6.83 (m, 2H), 6.57 (m, 1H), 5.98 (s, 2H), 4.09 (s, 2H),3.73 (m, 4H), 3.53 – 3.42 (m, 2H), 2.95 (m, 5H), 2.71 (d, J= 13.2 Hz, 3H), 1.98 (s, 1H), 1.38 – 1.02 (m, 9H), 0.99 – 0.87 (m, 2H), 0.81 (s, 2H), 0.71(d, J = 7.0 Hz, 6H). Example 8 1-(((2-hydroxyethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0086] Step A: Synthesis of 2-((tert-butyldimethylsilyl)oxy)ethyl(1-chloroethyl) carbonate

[0087] Under ice bath conditions, 1000 mg of 2-tert-butyldimethylsilyloxyethanol (5.67 mmol) and pyridine (739 mg, 9.36 mmol) were added to 10 mL of dry dichloromethane. 1-Chloroethyl chloroformate (900 mg, 6.24 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature and react for 1 hour.

[0088] After the reaction was complete, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to dryness, and the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give 245 mg of colorless oily product 2-((tert-butyldimethylsilyl)oxo)ethyl(1-chloroethyl) carbonate (yield: 15.4%).

[0089] Step B: Synthesis of 2,2,3,3-tetramethyl-8-oxo-4,7,9-trioxa-3-silaz-10-ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0090] At room temperature, atrasentan (2 R ,3R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (100 mg, 0.20 mmol), 2-((tert-butyldimethylsilyl)oxy)ethyl(1-chloroethyl) carbonate (85 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol), and potassium iodide (66.4 mg, 0.4 mmol) were added to 5 mL of dry DMF, and the mixture was heated to 65°C and reacted for 4 hours.

[0091] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 62 mg of a colorless oily product, 2,2,3,3-tetramethyl-8-oxo-4,7,9-trioxa-3-silaz-10-ethyl-(2-ethylhexane)-2-ethylhexane. R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 41.0%). LC-MS: RT = 2.75 min, [M+H] + =757.50.

[0092] Step C: Synthesis of 1-(((2-hydroxyethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0093] At room temperature, 2,2,3,3-tetramethyl-8-oxo-4,7,9-trioxa-3-silaz-10-ethyl-(2 R ,3 R 4 S S)-4-(benzo[ d[1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (62 mg, 0.08 mmol) was dissolved in 10 mL of dichloromethane solvent, and 2 mL of 4 M / L dioxane hydrochloride solution was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours.

[0094] After the reaction was complete, the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to give 40 mg of a yellow solid 1-(((2-hydroxyethoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 77.9%).

[0095] LC-MS: RT = 2.07 min, [M+H] + = 643.44. 1 H NMR (400 MHz, DMSO) δ 7.71 –7.38 (m, 2H), 7.19 (d, J = 12.2 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.93 – 6.79(m, 2H), 6.48 (s, 1H), 6.03 (s, 2H), 4.02 (d, J = 7.1 Hz, 3H), 3.76 (m, 4H), 3.57 – 3.48 (m, 3H), 3.20 – 3.09 (m, 1H), 3.08 – 2.90 (m, 3H), 1.45 – 1.02(m, 14H), 0.91 – 0.68 (m, 8H). Example 9 1-(((((R)-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0096] Step A: ((R 1,4-Dioxane-2-yl)methyl(1-chloroethyl) carbonate

[0097] Under the ice bath, ( R 1,4-Dioxane-2-yl)methanol (280 mg, 2.38 mmol) and pyridine (225 mg, 2.85 mmol) were added to 10 mL of dry dichloromethane, and 1-chloroethyl chloroformate (408 mg, 2.85 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours.

[0098] After the reaction was complete, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give 212 mg of a colorless oily product. R )-1,4-dioxane-2-yl)methyl(1-chloroethyl) carbonate (yield: 39.8%).

[0099] Step B: Synthesize 1-((((() R )-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0100] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (100 mg, 0.20 mmol), (( R 1,4-Dioxane-2-yl)methyl(1-chloroethyl) carbonate (67.2 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol), and potassium iodide (66.4 mg, 0.4 mmol) were added to 5 mL of dry DMF and the mixture was heated to 65°C and reacted for 4 hours.

[0101] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 80 mg of a colorless oily product 1-((((( R )-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 59.9%).

[0102] LC-MS: RT = 2.16 min, [M+H] + =699.42. 1 H NMR (400 MHz, DMSO) δ 7.24 (dd, J =11.6, 8.6 Hz, 2H), 7.06 (d, J = 11.4 Hz, 1H), 6.91 (dd, J = 8.6, 2.7 Hz, 2H), 6.85–6.75 (m, 2H), 6.59–6.53 (m, 1H), 5.99 (d, J = 6.0 Hz, 2H), 4.06 (dd, J =9.5, 4.7 Hz, 2H), 3.75–3.56 (m, 8H), 3.53 (d, J = 9.9 Hz, 1H), 3.50–3.41 (m,2H), 3.29–3.21 (m, 5H), 2.95 (dd, J = 18.3, 10.6 Hz, 3H), 2.79–2.73 (m, 1H), 2.69 (d, J = 14.1 Hz, 1H), 1.33 (t, J = 8.5 Hz, 3H), 1.29–1.21 (m, 3H), 1.17 (dd, J = 14.8, 7.4 Hz, 3H), 0.96 (d, J = 4.7 Hz, 2H), 0.81 (t, J= 7.3 Hz, 3H), 0.71(t, J = 7.3 Hz, 3H). Example 10 1-((((oxecyclobutane-3-yl)oxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0103] Step A: 1-Chloroethyloxetane-3-yl carbonate

[0104] Under ice bath conditions, oxetane-3-ol (176 mg, 2.38 mmol) and pyridine (225 mg, 2.85 mmol) were added to 10 mL of dry dichloromethane. 1-Chloroethyl chloroformate (408 mg, 2.85 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours.

[0105] After the reaction was complete, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to dryness, and the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give 200 mg of colorless oily product 1-chloroethyloxetane-3-yl carbonate (yield: 46.7%).

[0106] Step B: Synthesis of 1-((((oxecyclobutane-3-yl)oxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0107] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d[1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (100 mg, 0.2 mmol), 1-chloroethyloxetane-3-yl carbonate (54 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol), and potassium iodide (66.4 mg, 0.4 mmol) were added to 5 mL of dry DMF, and the mixture was heated to 65°C and reacted for 4 hours.

[0108] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 76 mg of a colorless oily product 1-((((oxecyclobutane-3-yl)oxy)carbonyl)oxy)ethyl-(2- ... 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl)oxy)oxy)oxy)oxy)oxy)oxy)oxy) 1-(2-yl) R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 58.0%).

[0109] LC-MS: RT = 2.18 min, [M+H] + =655.39. 1 H NMR (400 MHz, DMSO) δ 7.24 (t, J =8.4 Hz, 2H), 7.05 (d, J = 12.1 Hz, 1H), 6.94–6.86 (m, 2H), 6.85–6.71 (m, 2H), 6.61–6.50 (m, 1H), 5.99 (d, J = 5.7 Hz, 2H), 5.41–5.26 (m, 1H), 4.82–4.63 (m,2H), 4.53–4.32 (m, 2H), 3.80–3.60 (m, 4H), 3.57–3.41 (m, 1H), 3.27–3.11 (m,4H), 2.98 (dd, J = 14.1, 6.6 Hz, 3H), 2.82 – 2.74 (m, 1H), 2.68 (s, 1H), 1.32(t, J = 7.1 Hz, 3H), 1.26 (dd, J= 18.2, 7.3 Hz, 3H), 1.17 (dd, J = 14.8, 7.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H). Example 11 1-((((( S )-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0110] Step A: (( S 1,4-Dioxane-2-yl)methyl(1-chloroethyl) carbonate

[0111] Under the ice bath, ( S 1,4-Dioxane-2-yl)methanol (280 mg, 2.38 mmol) and pyridine (225 mg, 2.85 mmol) were added to 10 mL of dry dichloromethane, and 1-chloroethyl chloroformate (408 mg, 2.85 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours.

[0112] After the reaction was complete, the product was poured into 40 mL of ice-water solution, extracted with dichloromethane (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give 219 mg of a colorless oily product. S )-1,4-dioxane-2-yl)methyl(1-chloroethyl) carbonate (yield: 41.0%).

[0113] Step B: Synthesize 1-((((() S )-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d[1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester

[0114] At room temperature, atrasentan (2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (100 mg, 0.20 mmol), ((S)-1,4-dioxane-2-yl)methyl(1-chloroethyl) carbonate (44.8 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol), and potassium iodide (66.4 mg, 0.4 mmol) were added to 5 mL of dry DMF, and the mixture was heated to 65°C and reacted for 4 hours.

[0115] After the reaction was complete, the mixture was cooled to room temperature and poured into 40 mL of ice-water solution. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude compound was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 92 mg of a colorless oily product 1-((((( S )-1,4-dioxane-2-yl)methoxy)carbonyl)oxy)ethyl-(2 R ,3 R 4 S )-4-(benzo[ d [1,3]dioxacyclopentane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid ester (yield: 65.8%).

[0116] LC-MS: RT = 2.14 min, [M+H] + =699.43. 1 H NMR (400 MHz, DMSO) δ 7.24 (dd, J =11.6, 8.7 Hz, 2H), 7.06 (d, J = 10.7 Hz, 1H), 6.91 (dd, J = 8.6, 2.7 Hz, 2H), 6.85–6.70 (m, 2H), 6.59–6.53 (m, 1H), 5.99 (d, J= 6.2 Hz, 2H), 4.09–3.97 (m,2H), 3.75–3.65 (m, 6H), 3.56 (dd, J = 22.9, 9.5 Hz, 3H), 3.47–3.38 (m, 2H), 3.23 (dd, J = 31.0, 20.1 Hz, 5H), 2.96 (dt, J = 16.3, 8.0 Hz, 3H), 2.84–2.62 (m,2H), 1.33 (t, J = 8.2 Hz, 3H), 1.29–1.20 (m, 3H), 1.19–1.07 (m, 3H), 0.96 (d, J =7.4 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H). Example 12 Compound microparticle research (1) Experimental materials Human liver microsomes were all purchased from Red Liver Disease Research (Shanghai) Co., Ltd.

[0117] Reagents: DMSO (dimethyl sulfoxide), acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0118] Instruments: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0119] (2) Experimental methods Accurately weigh a certain amount of the compound and dissolve it in DMSO to prepare a 10 mM stock solution. Dilute the stock solution to 100 μM working solution with a diluent (ACN:H2O=1:1), and then dilute it with 0.1 M potassium phosphate buffer to prepare a 3 μM dosing solution. Add 75 μL of liver microsomes to 925 μL of 0.1 M potassium phosphate buffer solution and mix well to obtain a 1.5 mg / mL liver microsome suspension. Pre-incubate at 37 °C for 10 min. Preparation at 0 min: Add 15 μL of the above liver microsome suspension to 6 mM NADPH solution, immediately add 150 μL of propranolol acetonitrile solution to precipitate, and then add 15 μL of the above dosing solution and mix well. Sample preparation at 20 min and 60 min: Add 15 μL of the dosing solution to 15 μL of liver microsome suspension and 15 μL of 6 mM NADPH solution, mix well, and incubate at 37 °C for 20 min and 60 min respectively. All sample preparations were performed in duplicate in parallel. At the relevant time points, 150 μL of propranolol acetonitrile solution was added to terminate the reaction. All samples were centrifuged at 4000 rpm for 5 min, and 100 μL of the supernatant was added to 100 μL of ultrapure water and mixed thoroughly before LC-MS / MS analysis. The LC-MS / MS detection conditions are as follows: Chromatographic column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1mm, 1.8μm.

[0120] Mobile phase: Water (0.1% formic acid) - acetonitrile, gradient elution performed according to the table below. Table 1

[0121] (3) Data processing Using the initial 0 point as 100%, the relative remaining content of the drug at each time point was calculated. Using each time point of atrasentan as 100%, the relative amount of the compound in the example converted to atrasentan was calculated. The results are shown in Tables 2 and 3. Table 2. Prototype changes of each drug in microsomes

[0122] Table 3. Amounts of compounds from the examples converted to atrasentan in microsomes.

[0123] The results showed that the compound in Example 3 could be rapidly metabolized in human microsomes and completely converted into atrazotan.

[0124] Example 13 Pharmacokinetics of Compounds in Rats (1) Experimental materials SD rats: male, 200-300g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0125] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0126] Instruments: Thermo Fisher LC-MS / MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0127] (2) Experimental methods The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After oral administration to rats, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h post-administration into heparinized EP tubes containing sodium fluoride. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 20 μL of each of the above standard solutions was accurately pipetted and added to 180 μL of blank plasma. The mixture was vortexed to prepare plasma samples equivalent to concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Take 30 μL of plasma, add 200 μL of acetonitrile solution containing propranolol (50 ng / mL) as internal standard, vortex to mix, then add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and collect the supernatant for LC-MS / MS analysis. The LC-MS / MS detection conditions are as follows: Chromatographic column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1mm, 1.8μm.

[0128] Mobile phase: Water (0.1% formic acid) - acetonitrile, gradient elution performed according to the table below.

[0129] (3) Data processing After LC-MS / MS determination of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and a non-compartmental model method. The results are shown in Table 4. Table 4. Pharmacokinetic parameters of atracentan after gavage administration in SD rats of Examples 3 and 4.

[0130] Note: Dosage is converted to atracentan dosage. The compounds in Examples 3 and 4 showed higher exposure levels in rats than the same dose of atrasentan, and their absorption after gavage administration was superior to that of atrasentan.

[0131] Example 14 Pharmacokinetics of Compounds in Rats (1) Experimental materials SD rats: male, 200-300g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0132] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0133] Instruments: Thermo Fisher LC-MS / MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0134] (2) Experimental methods The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After oral administration to rats, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h post-administration into heparinized EP tubes containing sodium fluoride. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 20 μL of each of the above standard solutions was accurately pipetted and added to 180 μL of blank plasma. The mixture was vortexed to prepare plasma samples equivalent to concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Take 30 μL of plasma, add 200 μL of acetonitrile solution containing propranolol (50 ng / mL) as internal standard, vortex to mix, then add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and collect the supernatant for LC-MS / MS analysis. The LC-MS / MS detection conditions are as follows: Chromatographic column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1mm, 1.8μm.

[0135] Mobile phase: Water (0.1% formic acid) - acetonitrile, gradient elution performed according to the table below.

[0136] (3) Data processing After LC-MS / MS determination of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and a non-compartmental model method. The results are shown in Table 5. Table 5. Pharmacokinetic parameters of atracentan after gavage administration in SD rats (Example 7)

[0137] The compound in Example 7 showed significantly lower exposure in rats than the same dose of atrasentan, and its absorption after gavage administration was inferior to that of atrasentan.

[0138] In summary, Examples 12, 13, and 14 show that the compound of Example 3 can be rapidly converted to atrasentan both in vivo and in vitro, and the exposure at oral equimolar doses is higher than that of atrasentan.

[0139] Example 15: Antihypertensive effect and renal function evaluation of the test compound in a Dahl / SS rat model of hypertension. 1. Laboratory animals and experimental groups Male Dahl / SS rats were used in the experiment and were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. After the acclimatization period, the animals were randomly divided into 5 groups based on their baseline blood pressure and body weight. Specific grouping and drug administration regimens are shown in Table 6 below: Table 6. Laboratory Animals and Experimental Groups

[0140] 2. Experimental methods and results All animals were fed a 0.3% salt-concentrated diet and acclimatized to a non-invasive blood pressure monitor for one week. Based on blood pressure and body weight, the animals were randomly divided into a normal control group, a model group, and three treatment groups. The normal control group continued to be fed a 0.3% salt-concentrated diet, while the model group and the three treatment groups were switched to an 8% salt-concentrated diet, and this feeding was continued for 6 weeks. Drug administration was performed simultaneously with model establishment, via oral gavage daily for 6 consecutive weeks. Blood pressure was measured at 1, 3, 7, and 24 hours after drug administration, and the area under the curve (AUC) was calculated. Serum creatinine was measured once before grouping and once at the experimental endpoint. Kidney samples were collected from rats at the experimental endpoint for histopathological examination.

[0141] Measurement indicators are expressed as mean ± standard deviation. Data from groups with a sample size of less than 3 were not included in the statistical comparison. Data were entered and statistically analyzed using Excel 2010, GraphPad Prism 7, SPSS 22.0, and Stata 15.0 software. The quantitative indicators were first tested using the LEVENE test for homogeneity of variance. When the variances were homogeneous (P > 0.05), the results of the ANOVA were directly used to determine whether the overall difference was statistically significant. When the overall difference was statistically significant (P ≤ 0.05), the Dunnett-t test was used to compare the differences between groups. When the overall difference was not statistically significant (P > 0.05), the statistical analysis ended. When the LEVENE test for homogeneity of variance showed that the variances were not homogeneous (P ≤ 0.05), a nonparametric test (Kruskal-Wallis H test) was used. When the Kruskal-Wallis H test showed that the overall difference was statistically significant (P ≤ 0.05), the Mann-Whitney U test was used to compare the differences between groups. When the Kruskal-Wallis H test showed that the overall difference was not statistically significant (P > 0.05), the statistical analysis ended.

[0142] Table 7 Summary of statistical analysis results of the area under the systolic blood pressure curve (Mean±SD)

[0143] Note: *P≤0.05 indicates a statistically significant difference compared to the normal control group. & P≤0.05 indicates that the difference is statistically significant compared with the model control group.

[0144] Table 8. Statistical analysis results of serum creatinine (Mean ± SD)

[0145] Note: *P≤0.05 indicates a statistically significant difference compared to the normal control group. & P≤0.05 indicates that the difference is statistically significant compared with the model control group.

[0146] Table 9. Summary of statistical analysis results of glomerular sclerosis scores in animal kidneys (Mean±SD)

[0147] Note: *P≤0.05 indicates a statistically significant difference compared to the normal control group. & P≤0.05 indicates that the difference is statistically significant compared with the model control group.

[0148] Based on the above results, under the experimental conditions, when the dosage was 10 mg / kg to 40 mg / kg, the intervention of the compound of Example 3 administered once daily during modeling had a significant antihypertensive effect.

[0149] Meanwhile, under the conditions of this experiment, the filtration and excretion functions of the kidneys of Dahl salt-sensitive rats were severely damaged after 2 weeks of high-salt diet feeding. The intervention of compound 10-40 mg / kg per day in Example 3 significantly improved the damage to the kidney filtration and excretion functions. In addition, compound 3 had a significant effect on improving the pathological changes in kidney tissue.

[0150] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that, (I) Wherein: R1 and R2 are individually selected from hydrogen and methyl, and R1 and R2 are not both hydrogen; L is selected from C. 1-6 Alkyl groups.

2. The compound or its pharmaceutically usable salt according to claim 1, characterized in that, R1 is selected from hydrogen and R2 is selected from methyl.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, The C 1-6 The alkyl group is selected from ethyl, propyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, L is not selected from methyl or isopropyl.

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 。 6. The compound or its pharmaceutically acceptable salt according to claim 1 or 5, characterized in that, The pharmaceutically acceptable salt of the compound refers to the compound prepared with a pharmaceutically acceptable acid or base.

7. Use of the compound or a pharmaceutically usable salt thereof according to any one of claims 1-6 in the preparation of a medicament for treating and / or preventing diseases related to endothelin A receptor antagonism, said diseases being selected from chronic kidney disease, IgA, FSGS, and hypertension.

8. A pharmaceutical composition comprising a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

9. Use of the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing endothelin A receptor antagonism-related diseases, said diseases being selected from chronic kidney disease, IgA, FSGS, and hypertension.

10. The use according to claim 7, characterized in that, The disease is selected from chronic kidney disease, and the compound or its pharmaceutically usable salt is selected from the following compounds. Or its medicinal salts.

11. The use according to claim 7, characterized in that, The disease is selected from IgA, and the compound or its pharmaceutically acceptable salt is selected from the following compounds. Or its medicinal salts.

12. The use according to claim 7, characterized in that, The disease is selected from FSGS, and the compound or its pharmaceutically acceptable salt is selected from the following compounds. Or its medicinal salts.

13. The use according to claim 7, characterized in that, The disease is selected from hypertension, and the compound or its pharmaceutically usable salt is selected from the following compounds. Or its medicinal salts.

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