Atrasentan derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, and discloses an atrasentan derivative as well as a preparation method and application thereof. The atrasentan derivative is a tetra-substituted pyrrole derivative designed by taking atrasentan as a pilot, and the synthesis difficulty and cost are remarkably reduced by reducing three chiral centers; the atrasentan derivative has relatively high safety to HK-2 cells, and the pathological state of fibrosis generated by TGF-beta induced HK-2 can be remarkably improved; the application has the potential of being applied to preparation of drugs for preventing and treating renal fibrosis related diseases, the synthesis bottleneck of atrasentan is broken through, and a brand new candidate drug is provided for renal fibrosis treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to an atrasentan derivative, a preparation method and application thereof. BACKGROUND

[0002] The prevalence of chronic kidney disease (CKD) shows a trend of increasing year by year, and renal fibrosis is the key pathological cause of CKD. Renal fibrosis is characterized by accumulation of a large amount of extracellular matrix, destruction of normal physiological structure and function of the kidney, mainly manifested as renal interstitial fibrosis and glomerular sclerosis. If the fibrosis is allowed to continue to develop, it will cause multiple organ dysfunction and eventually lead to multiple organ failure and death. Modern medicine has not found an effective treatment method, and at present only dialysis or kidney transplantation can be relied on to maintain life, therefore, the research and development of drugs for anti-renal fibrosis have great significance for the prevention and treatment of clinical renal fibrosis.

[0003] Endothelin-1 (ET-1) is an effective vasoactive peptide synthesized by almost all cell types in the kidney, and its production is stimulated by various vasoactive, inflammatory, fibrogenic and proliferative factors. ET-1 exists in two receptors: endothelin A receptor (ET A R) and endothelin B receptor (ET B R). Under normal circumstances, ET-1 causes vasoconstriction through ET A R, and causes vasodilation through ET B R stimulation of nitric oxide release. Under pathological conditions, activation of ET A R can induce immune cell migration, cytokine production, podocyte disappearance, extracellular matrix accumulation and fibrosis, and production of angiotensin II and aldosterone. Given the effects of ET-1 on the kidney, selective ET A R receptor antagonists have been developed as potential therapeutic agents.

[0004] Atrasentan is a selective endothelin A receptor antagonist that can block abnormal activation of the endothelin system and reduce the risk of renal fibrosis. On April 2, 2025, Novartis announced that the U.S. Food and Drug Administration has accelerated the approval of Vanrafia (Atrasentan) for reducing proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression.

[0005] However, atrasentan has three chiral centers, resulting in high synthesis cost, difficult process, and insufficient anti-fibrosis activity, so it is urgent to develop a compound that preserves / enhances pharmacological activity while simplifying the molecular skeleton and reducing synthesis difficulty. SUMMARY

[0006] The present application aims to solve at least one of the above technical problems in the prior art. To this end, one of the objects of the present application is to provide an atrasentan derivative;

[0007] A second object of the present application is to provide a method for preparing the atrasentan derivative;

[0008] A third object of the present application is to provide the use of the atrasentan derivative.

[0009] A fourth object of the present application is to provide an anti-renal fibrosis drug.

[0010] To achieve the above objects, the technical solution adopted by the present application is as follows:

[0011] The first aspect of the present application provides an atrasentan derivative, the structural formula of which is shown in formula (A) or formula (B):

[0012]

[0013] In formula (A) and formula (B),

[0014] R 1 are each independently selected from hydrogen, C 1-4 alkyl, benzoyl or derivatives thereof, -C-T, wherein T is selected from any one of carboxyl, ester, substituted or unsubstituted amide;

[0015] R 2 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl, methoxyl, halogen, amino or nitro;

[0016] R 3 are each independently selected from ester, carboxyl or substituted amide;

[0017] R 4 are each independently selected from hydrogen, hydroxyl, methoxyl, halogen, oxygen-containing heterocycle, amino, nitro or cyano.

[0018] In some embodiments of the present application, in formula (A) or formula (B), the R 1 are each independently selected from hydrogen, methyl, benzoyl, 4-methylbenzoyl, -C-COOR 5 or -C-CONR 6 R 7 , wherein R 5 is selected from hydrogen, linear or branched alkyl; R 6 and R 7 are each independently selected from hydrogen, C 2-8linear alkyl, -C2H4-heterocycle, or dimethylaminoalkyl.

[0019] In some preferred embodiments of the present application, in the formula (A) or (B), the R 1 are each independently selected from hydrogen, methyl, benzoyl, 4-methylbenzoyl, -C-COOR 5 or -C-CONR 6 R 7 wherein R 5 is selected from hydrogen or -CH3; R 6 and R 7 are each independently selected from hydrogen, C 2-8 linear alkyl, -C2H4-nitrogen five-membered heterocycle, -C2H4-nitrogen six-membered heterocycle, -C2H4-nitrogen oxygen six-membered heterocycle, or dimethylaminoalkyl.

[0020] In some embodiments of the present application, in the formula (A) or (B), the R 2 are each independently selected from hydrogen, hydroxyl, methyl, methoxy, or halogen.

[0021] In some embodiments of the present application, in the formula (A) or (B), the R 3 are each independently selected from -COOR 8 or -CONR 9 R 10 wherein R 8 is selected from hydrogen, linear or branched alkyl; R 9 and R 10 are each independently selected from hydrogen, propargyl, or C 1-4 linear alkyl.

[0022] In some embodiments of the present application, in the formula (A) or (B), the R 4 are each independently selected from hydrogen, hydroxyl, methoxy, halogen, or oxygen-containing heterocycle.

[0023] In some embodiments of the present application, the atrasentan derivative is as shown in formula 1 - formula 71 :

[0024]

[0025]

[0026]

[0027]

[0028] The second aspect of the present application provides a method for preparing the atrasentan derivative of the first aspect of the present application, when the atrasentan derivative is represented by formula (A), the method comprising the following steps:

[0029] A01, compound (a1) obtaining compound (a2) through esterification reaction under strong acid compound (a3) obtaining compound (a4) through nucleophilic substitution reaction in the presence of acyl halide

[0030] A02, compound (a5) with compound (a6) obtaining compound (a7) through nucleophilic substitution reaction

[0031] A03, ring-closing reaction of compound (a7) with compound (a2) to obtain compound (a8)

[0032] A04, nucleophilic substitution reaction of compound (a8) with compound (a4) to obtain compound (a9)

[0033] A05, ester hydrolysis reaction of compound (a9) to obtain the atrasentan derivative represented by formula (A);

[0034] when the atrasentan derivative is represented by formula (B), the method comprising the following steps:

[0035] B01, compound (b1) obtaining compound (b2) through bromination reaction with N-bromosuccinimide

[0036] B02, nucleophilic substitution reaction of compound (b2) with substituted benzoyl acetate to obtain compound (b3)

[0037] B03, ring-closing reaction of compound (b3) with glycine under the action of a catalyst to obtain compound (b4)

[0038] B04, amide condensation reaction of compound (b4) with amine compound to obtain compound (b5)

[0039] B05, ester hydrolysis reaction of compound (b5) to obtain the atrasentan derivative represented by formula (B);

[0040] wherein, the R1 R 2 R 4 R 6 R 7 R 8 The definition is as described in the first aspect of this invention.

[0041] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared. In step A01, the strong acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid; the acyl halide is selected from bromoacetyl bromide, ethyl bromoacetate or bromoacetic acid.

[0042] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and in step A01, the esterification reaction further includes the use of a solvent, the solvent including ethanol.

[0043] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and in step A01, the temperature of the esterification reaction is 0-120°C.

[0044] In some preferred embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and in step A01, the temperature of the esterification reaction is 0-90°C.

[0045] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared. In step A01, the nucleophilic substitution reaction further includes the use of a solvent selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, and N,N-dimethylformamide.

[0046] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and in step A01, the temperature of the nucleophilic substitution reaction is 0-120°C.

[0047] In some embodiments of the present invention, the atrasentan derivative shown in formula (A) is prepared, and in step A02, the molar ratio of compound (a5) to compound (a6) is (0.8-1.2):1.

[0048] In some preferred embodiments of the present invention, the atrasentan derivative shown in formula (A) is prepared, and in step A02, the molar ratio of compound (a5) to compound (a6) is (0.9-1.1):1.

[0049] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of an acid in step A02, wherein the acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.

[0050] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A02 further comprises using a solvent selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, toluene.

[0051] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A02, the temperature of the nucleophilic substitution reaction is 20-120°C.

[0052] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A03, the molar ratio of the compound (a7) to the compound (a2) is 1: (1-1.5).

[0053] In some preferred embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A03, the molar ratio of the compound (a7) to the compound (a2) is 1: (1-1.2).

[0054] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A03 further comprises using methyl iodide and a base selected from at least one of n-butyllithium, potassium tert-butoxide, lithium diisopropylamide, sodium amide, sodium hydroxide, sodium hydride.

[0055] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A03 further comprises using a solvent selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, toluene.

[0056] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A03, the temperature of the ring-closing reaction is 20-120°C.

[0057] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A04, the molar ratio of the compound (a8) to the compound (a4) is 1: (1.2-1.6).

[0058] In some preferred embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A04, the molar ratio of the compound (a8) to the compound (a4) is 1: (1.3-1.5).

[0059] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (A), step A04 further comprises using a base selected from at least one of n-butyllithium, potassium tert-butoxide, lithium diisopropylamide, sodium amide, sodium hydroxide, sodium hydride.

[0060] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (A), step A04 further comprises using a solvent selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide.

[0061] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (A), step A04, the temperature of the nucleophilic substitution reaction is 0-120°C.

[0062] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (A), step A05 further comprises using a base selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0063] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (A), step A05 further comprises using a solvent comprising ethanol.

[0064] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (A), step A05, the temperature of the ester hydrolysis reaction is 0-120°C.

[0065] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B01, the molar ratio of the compound (b1) to N-bromosuccinimide is (0.8-1.2):1.

[0066] In some preferred embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B01, the molar ratio of the compound (b1) to N-bromosuccinimide is (0.9-1.1):1.

[0067] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B01 further comprises using an acid selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.

[0068] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B01 further comprises using a solvent selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide.

[0069] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B01, the temperature of the bromination reaction is 0-120°C.

[0070] In some embodiments of the present application, for preparing the atrasentan derivative represented by formula (B), step B02, the molar ratio of the compound (b2) to substituted benzoyl acetate is (1-1.5):1.

[0071] In some preferred embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B02, the molar ratio of the compound (b2) to the substituted benzoyl acetate is (1-1.2): 1.

[0072] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B02, a base is further used, and the base is selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0073] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B02, a solvent is further used, and the solvent is selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, toluene.

[0074] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B02, the temperature of the nucleophilic substitution reaction is 0-120°C.

[0075] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B03, the molar ratio of the compound (b3) to glycine is 1:(4-5).

[0076] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B03, the molar ratio of the compound (b3) to glycine is 1:(4.5-4.7).

[0077] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B03, the catalyst is selected from sodium acetate, acetic acid, ammonium chloride or p-toluenesulfonamide.

[0078] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B03, a solvent is further used, and the solvent is selected from at least one of toluene, tetrahydrofuran, ethanol, acetic acid, N,N-dimethylformamide.

[0079] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B03, the temperature of the ring-closing reaction is 0-120°C.

[0080] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B04, the molar ratio of the compound (b4) to the amine compound is (0.8-1.2): 1.

[0081] In some preferred embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B04, the molar ratio of the compound (b4) to the amine compound is (0.9-1.1):1.

[0082] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B04, a base and a condensing agent are further used; the base is selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, imidazole or N-methylimidazole; and the condensing agent is selected from O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), chloro-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU) or O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU).

[0083] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B04, a solvent is further used, and the solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane and N,N-dimethylformamide.

[0084] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B04, the temperature of the amide condensation reaction is 20-25°C.

[0085] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B05, a base is further used, and the base is selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0086] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B05, a solvent is further used, and the solvent comprises ethanol.

[0087] In some embodiments of the present application, for preparing the atrasentan derivative shown in formula (B), in step B05, the temperature of the ester hydrolysis reaction is 0-120°C.

[0088] The third aspect of the present application provides use of the atrasentan derivative of the first aspect of the present application in the preparation of a drug for resisting renal fibrosis.

[0089] The fourth aspect of the present application provides a drug for resisting renal fibrosis, comprising the atrasentan derivative of the first aspect of the present application or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments of the present application, the drug for resisting renal fibrosis further comprises an excipient.

[0091] Compared with the prior art, the present application has the beneficial effects that:

[0092] 1) The atrasentan derivative provided by the present application has high safety for HK-2 cells, and can significantly improve the fibrosis pathological state induced by TGF-β in HK-2, and has the potential to be applied to the preparation of drugs for preventing and treating renal fibrosis related diseases;

[0093] 2) The preparation method of the atrasentan derivative provided by the present application provides two efficient general synthetic routes, obtains a tetra-substituted pyrrole derivative designed with atrasentan as a lead, significantly reduces the synthesis difficulty and cost by reducing three chiral centers, and the present application breaks through the synthesis bottleneck of atrasentan through the three-in-one strategy of "structure simplification-high efficiency synthesis-activity optimization", and provides a new candidate drug for the treatment of renal fibrosis. BRIEF DESCRIPTION OF DRAWINGS

[0094] Figure 1 Example 1

[0095] Figure 2 Example 1

[0096] Figure 3 Example 1

[0097] Figure 4 Example 1 DETAILED DESCRIPTION

[0098] The content of the present application will be further described in detail through specific examples. The raw materials, reagents or devices used in the examples can be obtained from conventional commercial channels, or can be obtained by the existing technical method, unless otherwise specified. Unless otherwise specified, the test or test method is the conventional method in the art.

[0099] Example 1

[0100] This embodiment prepares atrasentan derivative S8 S9 and S10 The steps are as follows:

[0101] A011、Into a 100 mL round bottom flask, 3,4-(Methylenedioxy)cinnamic acid (3.46 g, 18 mmol) and 30 mL of absolute ethanol were sequentially added, stirred until the solid was completely dissolved, and then methyl sulfonic acid (24 μL, 0.36 mmol) was slowly added under stirring. The reaction was heated to reflux at 90°C for 24 h. The reaction was quenched by adding water to the reaction solution in an ice bath. The reaction solution was concentrated until the ethanol was completely spun out. Then, 30 mL of ethyl acetate was added, the reaction was quenched with saturated NaHCO3solution (3 x 30 mL), and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3.68 g of yellow oil S2a at a yield of 93%.

[0102] A012、Into a 100 mL round bottom flask, 30 mL of dichloromethane was added under ice bath conditions, and then dibutylamine (1.53 mL, 9 mmol) and bromoacetyl bromide (1.57 mL, 18 mmol) were added under stirring. The reaction was quenched with saturated NaHCO3solution (3 x 30 mL) and washed with saturated NaCl solution. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2.19 g of yellow oil S4a at a yield of 97%.

[0103] A021、Into a 250 mL round bottom flask, 1H-benzotriazole-1-methanol (8.05 g, 54 mmol), 4-methoxythiobenzamide (9.02 g, 54 mmol), and 50 mL of toluene were sequentially added, stirred and dissolved, and then p-toluenesulfonic acid (51.30 mg, 0.27 mmol) was slowly added under stirring. A Dean-Stark trap device was installed, and the reaction was heated to reflux at 120°C for 10 h. The reaction solution was cooled to room temperature and placed in a refrigerator overnight. Filtration was performed to obtain 12.06 g of yellowish solid S7 at a yield of 75%.

[0104] A031、Into a 100 mL round bottom flask, compound S7 (1.49 g, 5 mmol), 30 mL of super dry tetrahydrofuran, iodomethane (343 μL, 5.5 mmol), and potassium tert-butoxide (616 mg, 5.5 mmol) were added under ice bath conditions. Stirring was performed for 2 h, and then compound S2a (1.21 g, 5.5 mmol) and potassium tert-butoxide (1.68 g, 15 mmol) were further added under ice bath conditions. The reaction was heated to reflux at 90°C for 2 h. The reaction solution was concentrated until the tetrahydrofuran was completely spun out. Then, 50 mL of dichloromethane was added, the reaction was quenched with saturated NaHCO3solution (3 x 50 mL), and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization was performed with a dichloromethane-methanol system, and filtration was performed to obtain 1.37 g of white solid S8 at a yield of 75%.

[0105] A041、Into a 50 mL round-bottom flask, compound S8 (365 mg, 1 mmol), compound S4a (350 mg, 1.4 mmol) and 10 mL of acetonitrile were added, stirred and dissolved, sodium hydride (60 mg, 1.5 mmol) was added slowly, and the reaction was carried out at room temperature for 6 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1, v / v) gave 518.1 mg of white solid S9 with a yield of 97%;

[0106] A051、Into a 50 mL round-bottom flask, compound S9 (152 mg, 0.28 mmol), 5 mL of ethanol and 1 mL of water were added, stirred, followed by the addition of lithium hydroxide hydrate (120 mg, 2.84 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, adjusted to pH to acidic with 1 mol / L hydrochloric acid, extracted with ethyl acetate (3 x 10 mL), washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v) gave 81.2 mg of white solid S10 with a yield of 57%.

[0107] wherein the structural formula of compound S2a is The structural formula of S4a is The structural formula of S7 is

[0108] The compounds S2a, S4a, S7, S8, S9 and S10 were subjected to 1 H NMR characterization, the results are:

[0109] S2a: 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (dd, J = 16.0, 2.5 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.81 (dd, J = 7.9, 2.4 Hz, 1H), 6.26 (dd, J = 16.0, 2.5 Hz, 1H), 6.00 (d, J = 2.4 Hz, 2H), 4.25 (qd, J = 7.2, 2.2 Hz, 2H), 1.33 (td, J = 7.1, 2.3 Hz, 3H).

[0110] S4a: 1 H NMR (400 MHz, Chloroform-d) δ 3.81 (d, J = 2.2 Hz, 2H), 3.39 - 3.17 (m, 4H), 1.67

[0111] - 1.42 (m, 4H), 1.31 (dq, J = 14.8, 7.8 Hz, 4H), 0.92 (dtd, J = 15.1, 7.4, 2.1 Hz, 6H).

[0112] S7: 1 H NMR (500 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.96 (dt, J = 8.4, 1.0 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.52 (ddd, J = 8.2, 7.0, 1.0 Hz, 1H), 7.37 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.85 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H).

[0113] S8: 1 H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.50 - 7.42 (m, 2H), 6.99 - 6.85 (m, 4H), 6.80 (dd, J = 8.0, 2.4 Hz, 1H), 6.71 (d, J = 2.9 Hz, 1H), 5.95 (d, J = 2.3 Hz, 2H), 4.08 (qd, J = 7.1, 2.1 Hz, 2H), 3.84 (d, J = 2.2 Hz, 3H), 1.05 (td, J = 7.2, 2.2 Hz, 3H).

[0114] S9: 1 H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 1.6 Hz, 1H), 6.93 (td, J = 5.9, 3.1 Hz, 3H), 6.78 (d, J = 7.9 Hz, 1H), 6.68 (s, 1H), 5.94 (s, 2H), 4.43 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.32 - 3.22 (m, 2H), 2.94 (t, J = 7.7 Hz, 2H), 1.51 - 1.41 (m, 2H), 1.32 - 1.19 (m, 5H), 1.11 (h, J = 7.3 Hz, 2H), 0.91 (td, J = 7.3, 1.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H).

[0115] S10: 1H NMR (400MHz, Chloroform-d) δ7.28 (s, 1H), 6.94 (dd, J = 17.9, 10.2Hz, 4H), 6.78

[0116] (d,J=7.9Hz,1H),6.69(s,1H),5.96(s,2H),4.43(s,2H),3.85(s,3H),3.29(t,J=7.6Hz,2H),2.94(t,J=7.7Hz,2H) ,1.48(t,J=7.7Hz,2H),1.27(h,J=7.7Hz,6H),1.13(h,J=7.4Hz,2H),0.94(t,J=7.4Hz,3H),0.85(t,J=7.3Hz,3H).

[0117] Example 2

[0118] This embodiment prepares atrasentan derivative A3. and A7 and A1 The steps are as follows:

[0119] A012. Under ice bath conditions, 10 mL of dichloromethane was added to a 50 mL round-bottom flask, and diethylamine (617 μL, 6 mmol) and bromoacetyl bromide (626 μL, 7.2 mmol) were added while stirring. The mixture was left at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution (3 × 30 mL), and the organic phase was washed. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 512 mg of yellow oily substance S4b, with a yield of 44%.

[0120] A041. Compounds S8 (365 mg, 1 mmol), S4b (272 mg, 1.4 mmol), and 10 mL of acetonitrile prepared in Example 1 were added to a 50 mL round-bottom flask and stirred to dissolve. Sodium hydride (60 mg, 1.5 mmol) was slowly added and the mixture was reacted at room temperature for 6 h. The reaction was quenched with water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 to 2:1, v / v) to give 429 mg of pale yellow solid A3, with a yield of 90%.

[0121] A051、Into a 50 mL round-bottom flask, compound A3 (240 mg, 0.5 mmol), 5 mL of ethanol and 1 mL of water were added with stirring, followed by lithium hydroxide hydrate (105 mg, 2.5 mmol), heated to reflux at 120 °C for 30 h, cooled to room temperature, 1 mol / L hydrochloric acid was added to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v), to obtain 51.1 mg of light yellow solid A7, yield 23%;

[0122] A051、Into a 50 mL round-bottom flask, compound A3 (240 mg, 0.5 mmol), 5 mL of ethanol and 1 mL of water were added with stirring, followed by lithium hydroxide hydrate (105 mg, 2.5 mmol), heated to reflux at 120 °C for 30 h, cooled to room temperature, 1 mol / L hydrochloric acid was added to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v), to obtain 51.1 mg of light yellow solid A7, yield 23%;

[0123] wherein the structural formula of compound S4b is

[0124] Compound S4b, A3, A7 and A1 were subjected to 1 H NMR characterization, the results are:

[0125] S4b: 1 H NMR (400 MHz, Chloroform-d) δ 3.77 (s, 2H), 3.39-3.21 (m, 4H), 1.11 (dt, J = 50.1, 3.6 Hz, 6H)

[0126] A3: 1 H NMR (500 MHz, Chloroform-d) δ 7.29 (s, 1H), 7.27 (s, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.95-6.90 (m, 3H), 6.78 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H), 5.94 (s, 2H), 4.44 (s, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.34 (q, J = 7.1 Hz, 2H), 3.04 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 6H).

[0127] A7: 1 H NMR(500MHz,Chloroform-d)δ7.26–7.23(m,2H),6.96(d,J=1.7Hz,1H),6.94

[0128] –6.87(m,3H),6.76(d,J=8.0Hz,1H),6.67(s,1H),5.94(s,2H),4.40(s,2H),3.83(s,3H), 3.33(q,J=7.1Hz,2H), 3.01(q,J=7.1Hz,2H), 1.09(t,J=7.1Hz,3H), 0.90(t,J=7.1Hz,3H).

[0129] A1: 1 H NMR (500MHz, Methanol-d4) δ7.28–7.21(m,2H),6.99–6.87(m,4H),6.80–6.73(m,2H),5.92(s,2H),4.49(s,2H),3.84(s,3H).

[0130] Example 3

[0131] This embodiment prepares atrasentan derivative A4. and A8 The steps are as follows:

[0132] A012. Under ice bath conditions, 10 mL of dichloromethane was added to a 50 mL round-bottom flask, and dipropylamine (821 μL, 6 mmol) and bromoacetyl bromide (626 μL, 7.2 mmol) were added while stirring. The mixture was left at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution (3 × 30 mL), and the organic phase was washed. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 742 mg of colorless oil S4c, with a yield of 56%.

[0133] A041. Compounds S8 (365 mg, 1 mmol), S4c (350 mg, 1.4 mmol), and 10 mL of acetonitrile prepared in Example 1 were added to a 50 mL round-bottom flask and stirred to dissolve. Sodium hydride (60 mg, 1.5 mmol) was slowly added and the mixture was reacted at room temperature for 6 h. The reaction was quenched with water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 to 2:1, v / v) to give 499 mg of pale yellow solid A4, with a yield of 90%.

[0134] A051、Into a 50 mL round-bottom flask was added compound A4 (183 mg, 0.36 mmol), 5 mL of ethanol and 1 mL of water, stirred, then added lithium hydroxide hydrate (73 mg, 1.74 mmol), heated to reflux at 120 °C for 30 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v) to obtain 69.4 mg of light yellow solid A8, yield 40%.

[0135] wherein the structural formula of compound S4c is

[0136] The compounds S4c, A4 and A8 were subjected to 1 H NMR characterization, the results are:

[0137] S4c: 1 H NMR (400 MHz, Chloroform-d) δ 3.75 (s, 2H), 3.17 (q, J = 7.9 Hz, 4H), 1.50 (dq, J = 32.2, 7.6 Hz, 4H), 0.81 (dt, J = 20.0, 7.5 Hz, 6H).

[0138] A4: 1 H NMR (500 MHz, Chloroform-d) δ 7.29 (s, 1H), 7.27 (s, 1H), 6.98 (d, J = 1.7 Hz, 1H), 6.95 - 6.89 (m, 3H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.94 (s, 2H), 4.45 (s, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.28 - 3.19 (m, 2H), 2.92 (t, J = 7.7 Hz, 2H), 1.51 (p, J = 7.5 Hz, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H).

[0139] A8: 1H NMR(500MHz,Chloroform-d)δ7.25(d,J=8.6Hz,2H),6.95(d,J=1.7Hz,1H),6. 91(td,J=6.8,1.9Hz,3H),6.76(d,J=8.0Hz,1H),6.66(s,1H),5.94(s,2H),4. 41(s,2H),3.83(s,3H),3.27–3.18(m,2H),2.90(t,J=7.7Hz,2H),1.51(h,J=7 .5Hz,2H),1.31(h,J=7.5Hz,2H),0.85(t,J=7.4Hz,3H),0.74(t,J=7.4Hz,3H).

[0140] Example 4

[0141] This embodiment prepares atrasentan derivative A5. and A9 The steps are as follows:

[0142] A012. Under ice bath conditions, 10 mL of dichloromethane was added to a 50 mL round-bottom flask, and dihexylamine (465 μL, 2 mmol) and bromoacetyl bromide (209 μL, 2.4 mmol) were added while stirring. The mixture was left at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution (3 × 30 mL), and the organic phase was washed. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 534.4 mg of a pale yellow oily substance S4d, with a yield of 87%.

[0143] A041. Add compounds S8 (347 mg, 0.95 mmol), S4d (408 mg, 1.33 mmol), and 15 mL of acetonitrile prepared in Example 1 to a 50 mL round-bottom flask, stir to dissolve, and slowly add sodium hydride (75 mg,

[0144] 1.43 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 × 10 mL).

[0145] The combined organic phases were washed with NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 2:1, v / v) to give 523.2 mg of white solid A5, yield 93%.

[0146] A051、Into a 50 mL round-bottom flask was added compound A5 (320.8 mg, 0.54 mmol), 5 mL of ethanol and 1 mL of water, stirred, then added lithium hydroxide hydrate (114 mg, 2.72 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1, v / v) to obtain 176.9 mg of white solid A9, yield 58%.

[0147] wherein the structural formula of compound S4d is

[0148] Compound S4d, A5 and A9 were subjected to 1 H NMR characterization, the results are:

[0149] S4d: 1 H NMR (500 MHz, Chloroform-d) δ 3.82 (s, 2H), 3.28 (dt, J = 16.0, 7.7 Hz, 4H), 1.59

[0150] (q, J = 7.4 Hz, 2H), 1.51 (q, J = 7.3 Hz, 2H), 1.29 (d, J = 11.9 Hz, 12H), 0.87 (dd, J = 11.8, 6.6 Hz, 6H).

[0151] A5: 1 H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 1.7 Hz, 1H), 6.92 (dd, J = 7.9, 5.6 Hz, 3H), 6.77 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.93 (s, 2H), 4.43 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.26 (t, J = 7.6 Hz, 2H), 2.93 (t, J = 7.8 Hz, 2H), 1.47 (p, J = 7.3 Hz, 2H), 1.31 - 1.20 (m, 10H), 1.20 - 1.12 (m, 2H), 1.09 (q, J = 7.6 Hz, 2H), 0.94 - 0.83 (m, 9H).

[0152] A9: 1H NMR(500MHz,Chloroform-d)δ7.25(d,J=8.3Hz,2H),6.96(d,J=1.6Hz,1H),6.90(d d,J=10.6,8.2Hz,3H),6.76(d,J=7.9Hz,1H),6.66(s,1H),5.94(s,2H),4.40(s,2H ),3.83(s,3H),3.25(t,J=7.6Hz,2H),2.91(t,J=7.8Hz,2H),1.47(p,J=7.6Hz,2H) ,1.26(tt,J=14.6,6.6Hz,13H),1.08(q,J=7.9Hz,2H),0.88(dd,J=7.0,4.7Hz,6H).

[0153] Example 5

[0154] This embodiment prepares atrasentan derivative A6. and A10 The steps are as follows:

[0155] A012. Under ice bath conditions, 10 mL of dichloromethane was added to a 50 mL round-bottom flask, and diheptylamine (612 μL, 2 mmol) and bromoacetyl bromide (209 μL, 2.4 mmol) were added while stirring. The mixture was left at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution (3 × 30 mL), and the organic phase was washed. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 668.4 mg of a pale yellow oil, S4e, with a yield of 92%.

[0156] A041. Compound S8 (365 mg, 1 mmol), S4e (507 mg, 1.4 mmol), and 10 mL of acetonitrile prepared in Example 1 were added to a 50 mL round-bottom flask and stirred to dissolve. Sodium hydride (60 mg, 1.5 mmol) was slowly added and the mixture was reacted at room temperature for 6 h. The reaction was quenched with water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 2:1, v / v) to give 595.2 mg of white solid A6, yield 92%.

[0157] A051、Into a 50 mL round-bottom flask was added compound A6 (260 mg, 0.40 mmol), 5 mL of ethanol and 1 mL of water, stirred, then added lithium hydroxide hydrate (85 mg, 2.01 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1, v / v) to obtain 126.1 mg of white solid A10, yield 51%.

[0158] wherein the structural formula of compound S4e is

[0159] The compounds S4e, A6 and A10 were subjected to 1 H NMR characterization, the results are:

[0160] S4e: 1 H NMR (500 MHz, Chloroform-d) δ 3.83 (s, 2H), 3.28 (dt, J = 16.0, 7.8 Hz, 4H), 1.60

[0161] (p, J = 7.3 Hz, 2H), 1.52 (p, J = 7.1 Hz, 2H), 1.28 (dq, J = 13.0, 6.2, 5.6 Hz, 21H), 0.87 (q, J = 6.7 Hz, 7H).

[0162] A6: 1 H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 1.7 Hz, 1H), 6.94 - 6.89 (m, 3H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.94 (s, 2H), 4.43 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.26 (t, J = 7.6 Hz, 2H), 2.93 (t, J = 7.8 Hz, 2H), 1.47 (p, J = 7.4 Hz, 2H), 1.25 (qq, J = 20.2, 13.7, 10.2 Hz, 20H), 1.09 (q, J = 7.6 Hz, 2H), 0.95 - 0.84 (m, 9H).

[0163] A10: 1 H NMR (500 MHz, Chloroform-d) δ 7.25 - 7.21 (m, 2H), 6.95 (d, J = 1.8 Hz, 1H), 6.93

[0164] - 6.86 (m, 3H), 6.75 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 5.94 (s, 2H), 4.39 (s, 2H), 3.82 (s, 3H), 3.25 (t, J = 7.6 Hz, 2H), 2.90 (t, J = 7.7 Hz, 2H), 1.47 (p, J = 7.4 Hz, 2H), 1.34 - 1.17 (m, 20H), 1.08 (q, J = 7.5, 7.0 Hz, 2H), 0.94 - 0.84 (m, 6H).

[0165] Example 6

[0166] This example prepares amlodipine derivative A11 The procedure is as follows:

[0167] A041、Into a 50 mL round-bottom flask was added compound S8 prepared in Example 1 (365 mg, 1 mmol), iodomethane (22 μL, 0.36 mmol) and 2 mL of acetonitrile, stirred to dissolve, slowly added sodium hydride (24 mg, 0.6 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to obtain 95.3 mg of white solid A11, yield 84%.

[0168] Compound A11 was subjected to 1 H NMR characterization, the results are: 1 H NMR (500 MHz, Chloroform-d) δ 7.30 (d, J = 8.2 Hz, 2H), 6.96 (s, 3H), 6.91 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.62 (s, 1H), 5.95 (s, 2H), 4.00 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.43 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H).

[0169] Example 7

[0170] This example prepares amlodipine derivative A12 The procedure is as follows:

[0171] A041、Into a 50 mL round-bottom flask was placed compound S8 prepared in Example 1 (110 mg, 0.3 mmol), p-tolyl benzoyl chloride (48 μL, 0.36 mmol) and 3 mL of dichloromethane, stirred to dissolve, slowly added N,N-diisopropylethylamine (105 μL, 0.6 mmol), heated to reflux at 60 °C for 6 h, quenched the reaction with water, and extracted with dichloromethane (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to give 113.8 mg of yellow oil A12, yield 79%.

[0172] Compound A12 was subjected to 1 H NMR characterization, the results were: 1 H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6.99 (s, 1H), 6.96 - 6.89 (m, 2H), 6.82 (dd, J = 12.3, 8.1 Hz, 3H), 5.96 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.41 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H).

[0173] Example 8

[0174] This example prepared atrasentan derivative A13 The steps are as follows:

[0175] A041、Into a 50 mL round-bottom flask was placed compound S8 prepared in Example 1 (110 mg, 0.3 mmol), p-tolyl benzoyl chloride (48 μL, 0.36 mmol) and 3 mL of dichloromethane, stirred to dissolve, slowly added N,N-diisopropylethylamine (105 μL, 0.6 mmol), heated to reflux at 60 °C for 6 h, quenched the reaction with water, and extracted with dichloromethane (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to give 113.8 mg of yellow oil A12, yield 79%.

[0176] Compound A13 was subjected to 1 H NMR characterization, the results were: 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 8.0 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.44 - 7.37 (m, 2H), 7.34 - 7.28 (m, 2H), 7.02 (d, J = 1.4 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.86 - 6.79 (m, 3H), 5.96 (d, J = 1.3 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.78 (d, J = 1.3 Hz, 3H), 1.01 (td, J = 7.2, 1.3 Hz, 3H).

[0177] Example 9

[0178] This example prepared atrasentan derivative A14 The procedure was as follows:

[0179] A041、Into a 50 mL round-bottom flask was added compound S8 prepared in Example 1 (219 mg, 0.6 mmol), tert-butyl bromoacetate (120 μL, 0.84 mmol) and 5 mL of dichloromethane, stirred to dissolve, slowly added sodium hydride (36 mg, 0.45 mmol), reacted at room temperature for 6 h, quenched the reaction with water, and extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 7:1, v / v) to obtain 125.0 mg of colorless oil A14, yield 87%.

[0180] Compound A14 was subjected to 1 H NMR characterization, the results were: 1 H NMR (500 MHz, Chloroform-d) δ 7.28 (s, 2H), 6.97 (s, 1H), 6.96 - 6.90 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 5.95 (s, 2H), 4.31 (s, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.42 (s, 9H), 0.93 (t, J = 7.1 Hz, 3H).

[0181] Example 10

[0182] This example prepared atrasentan derivative A2 The procedure was as follows:

[0183] A041、Into a 50 mL round-bottom flask was added compound A14 prepared in Example 9 (27 mg, 0.056 mmol) and 1 mL of dichloromethane, stirred, slowly added trifluoroacetic acid (0.5 mL, 2.95 mmol), reacted at room temperature for 2 h, quenched the reaction with water, and extracted with dichloromethane (3 x 3 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (dichloromethane / methanol = 10:1, v / v) to obtain 9 mg of light yellow solid A2, with a yield of 38%.

[0184] Compound A2 was subjected to 1 H NMR characterization, the results were: 1 H NMR (500 MHz, Methanol-d4) δ 7.27 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 7.6 Hz, 2H), 6.94 - 6.85 (m, 2H), 6.78 (d, J = 7.3 Hz, 2H), 5.93 (s, 2H), 4.42 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 0.91 (t, J = 7.1 Hz, 4H).

[0185] Example 11

[0186] This example prepared atrasentan derivative C1 The steps are as follows:

[0187] A011、Into a 50 mL round-bottom flask was added compound A14 prepared in Example 9 (27 mg, 0.056 mmol) and 1 mL of dichloromethane, stirred, slowly added trifluoroacetic acid (0.5 mL, 2.95 mmol), reacted at room temperature for 2 h, quenched the reaction with water, and extracted with dichloromethane (3 x 3 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (dichloromethane / methanol = 10:1, v / v) to obtain 9 mg of light yellow solid A2, with a yield of 38%.

[0188] A031、Into a 100 mL round bottom flask, under ice bath condition, was added compound S7 (894 mg, 3 mmol) prepared in Example 1, 30 mL of super dry tetrahydrofuran, methyl iodide (205 μL, 3.3 mmol) and potassium tert-butoxide (369 mg, 3.3 mmol), stirred for 2 h, under ice bath condition, compound S2g (679.8 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were added, heated to reflux at 90 °C for 2 h, cooled to room temperature, the reaction was concentrated to complete removal of tetrahydrofuran, 30 mL of dichloromethane was added, quenched with saturated NaHCO3solution (3 x 30 mL) and washed the organic phase, the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, recrystallized with dichloromethane-methanol system, and filtered to give 618 mg of white solid C1, with a yield of 59%.

[0189] wherein the compound S2g has the structural formula

[0190] The compound S2g and C1 were subjected to 1 H NMR characterization, the results were:

[0191] S2g: 1 H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 15.9 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.78

[0192] (d, J = 8.0 Hz, 1H), 6.24 (d, J = 15.9 Hz, 1H), 5.98 (s, 2H), 3.77 (s, 3H).

[0193] C1: 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 6.97 - 6.91

[0194] (m, 3H), 6.89 (dd, J = 7.9, 1.7 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 5.97 (s, 2H), 3.85 (s, 3H), 3.60 (s, 3H).

[0195] Example 12

[0196] This example prepared atrasentan derivative C2 The steps are as follows:

[0197] A011、Into a 100 mL round bottom flask, 3,4-(Methylenedioxy)cinnamic acid (1.15 mg, 6 mmol)) and 30 mL of isopropyl alcohol were sequentially added, stirred until the solid was completely dissolved, and then methyl sulfonic acid (9 μL, 0.12 mmol) was slowly added under stirring, and heated to reflux at 120°C for 24 h. The reaction was cooled to room temperature, and then water was added to quench the reaction in an ice bath. The reaction liquid was concentrated until the isopropyl alcohol was completely spun out, and then 30 mL of ethyl acetate was added. The reaction was quenched with saturated NaHCO3 solution (3 x 30 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.21 g of yellow oil S2h with a yield of 86%;

[0198] A031、Into a 100 mL round bottom flask, 3,4-(Methylenedioxy)cinnamic acid (1.15 mg, 6 mmol)) and 30 mL of isopropyl alcohol were sequentially added, stirred until the solid was completely dissolved, and then methyl sulfonic acid (9 μL, 0.12 mmol) was slowly added under stirring, and heated to reflux at 120°C for 24 h. The reaction was cooled to room temperature, and then water was added to quench the reaction in an ice bath. The reaction liquid was concentrated until the isopropyl alcohol was completely spun out, and then 30 mL of ethyl acetate was added. The reaction was quenched with saturated NaHCO3 solution (3 x 30 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.21 g of yellow oil S2h with a yield of 86%;

[0199] wherein the compound S2h has the structural formula

[0200] The compound S2h and C2 were subjected to 1 H NMR characterization, and the results were:

[0201] S2h: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 15.9 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.73

[0202] (d, J = 8.0 Hz, 1H), 6.18 (d, J = 15.9 Hz, 1H), 5.92 (s, 2H), 5.08 (p, J = 6.3 Hz, 1H), 1.26 (d, J = 6.3 Hz, 6H).

[0203] C2: 1H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.97 - 6.91 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.92 (s, 2H), 4.52 (s, 2H), 3.81 (s, 3H), 3.38 - 3.30 (m, 2H), 3.08 - 3.00 (m, 2H), 2.86 (s, 3H), 2.59 (s, 3H), 1.57 - 1.48 (m, 2H), 1.38 - 1.27 (m, 4H), 1.16 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz, 4H).

[0204] H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.97 - 6.91 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.92 (s, 2H), 4.52 (s, 2H), 3.81 (s, 3H), 3.38 - 3.30 (m, 2H), 3.08 - 3.00 (m, 2H), 2.86 (s, 3H), 2.59 (s, 3H), 1.57 - 1.48 (m, 2H), 1.38 - 1.27 (m, 4H), 1.16 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz, 4H).

[0205] Example 13

[0206] This example prepared atrasentan derivative C3 The procedure was as follows:

[0207] To a 10 mL round-bottom flask was added compound S10 prepared in Example 1 (47.6 mg, 0.094 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46.5 mg, 0.122 mmol), 2 mL of super dry dichloromethane, dimethylacetamide (47 μL, 0.094 mmol) and N,N-diisopropylethylamine (33 μL, 0.188 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 3 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in petroleum ether / ethyl acetate = 2: 1 (v / v) system to obtain 22.1 mg of light yellow solid C3, yield 44%.

[0208] Compound C3 was subjected to 1 H NMR characterization, the results were: 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.97 - 6.91 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.92 (s, 2H), 4.52 (s, 2H), 3.81 (s, 3H), 3.38 - 3.30 (m, 2H), 3.08 - 3.00 (m, 2H), 2.86 (s, 3H), 2.59 (s, 3H), 1.57 - 1.48 (m, 2H), 1.38 - 1.27 (m, 4H), 1.16 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz, 4H).

[0209] Example 14

[0210] This example prepared a compound C4 The procedure was as follows:

[0211] To a 10 mL round-bottom flask was added compound S10 prepared in Example 1 (45.3 mg, 0.090 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (44.2 mg, 0.116 mmol), 2 mL of super dry dichloromethane, propargylamine (105 μL, 0.090 mmol) and N,N-diisopropylethylamine (31 μL, 0.18 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 3 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in petroleum ether / ethyl acetate = 2:1 (v / v) system to give 13.8 mg of light yellow solid C4, yield 30%.

[0212] Compound C4 was subjected to 1 H NMR characterization, the results were: 1 H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 8.2 Hz, 2H), 7.00 - 6.90 (m, 4H), 6.80 (d, J = 7.8 Hz, 1H), 6.70 (s, 1H), 5.95 (s, 2H), 4.45 (s, 2H), 3.92 (dd, J = 5.7, 2.5 Hz, 2H), 3.82 (s, 3H), 3.30 (t, J = 7.6 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.08 - 2.03 (m, 1H), 1.49 (t, J = 7.6 Hz, 2H), 1.31 - 1.27 (m, 4H), 1.13 (q, J = 7.5 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz, 4H).

[0213] Example 15

[0214] This example prepared a compound C5 The procedure was as follows:

[0215] To a 50 mL round-bottom flask was added compound C1 prepared in Example 11 (140.4 mg, 0.4 mmol), compound S4a prepared in Example 1 (140 mg, 0.56 mmol) and 4 mL of acetonitrile, stirred to dissolve, slowly added sodium hydride (24 mg, 0.6 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 4:1, v / v), to obtain 195 mg of white solid C5, yield 94%.

[0216] Compound C5 was subjected to 1 H NMR characterization, the results were: 1 H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 1.7 Hz, 1H), 6.95 - 6.90 (m, 3H), 6.78 (d, J = 7.9 Hz, 1H), 6.68 (s, 1H), 5.95 (s, 2H), 4.43 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H), 3.27 (dd, J = 8.8, 6.4 Hz, 2H), 2.98 - 2.91 (m, 2H), 1.51 - 1.43 (m, 2H), 1.31 - 1.21 (m, 5H), 1.11 (h, J = 7.3 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).

[0217] Example 16

[0218] This example prepared atrasentan derivative C6 The steps are as follows:

[0219] To a 50 mL round-bottom flask was added compound C2 prepared in Example 12 (151.6 mg, 0.4 mmol), compound S4a prepared in Example 1 (140 mg, 0.56 mmol) and 4 mL of acetonitrile, stirred to dissolve, slowly added sodium hydride (24 mg, 0.6 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v), to obtain 214.8 mg of light pink solid C6, yield 98%.

[0220] Compound C6 was subjected to 1 H NMR characterization, the results were: 1H NMR(500MHz,Chloroform-d)δ7.26(d,J=8.6Hz,2H),6.98(d,J=1.7Hz,1H),6.95–6.89(m,3H ),6.77(d,J=8.0Hz,1H),6.67(s,1H),5.94(s,2H),4.88(p,J=6.2Hz,1H),4.42(s,2H),3.83( s,3H),3.26(t,J=7.6Hz,2H),2.94(t,J=7.7Hz,2H),1.46(ddt,J=12.6,7.8,3.9Hz,2H),1.25 (tq,J=15.2,7.7Hz,4H),1.11(h,J=7.3Hz,2H),0.92(d,J=6.1Hz,9H),0.83(t,J=7.3Hz,3H).

[0221] Example 17

[0222] This embodiment prepares atrasentan derivative D1. The steps are as follows:

[0223] A011. 3,4-Dimethoxycinnamic acid (1.25 g, 6 mmol) and 30 mL of anhydrous ethanol were added sequentially to a 50 mL round-bottom flask. The mixture was stirred until the solid was completely dissolved. Methanesulfonic acid (8 μL, 0.12 mmol) was slowly added while stirring. The mixture was heated to reflux at 90 °C for 24 h. After cooling to room temperature, the reaction was quenched by adding water to the reaction solution under ice bath conditions. The reaction solution was concentrated until the ethanol was completely evaporated. Then, 10 mL of ethyl acetate was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 30 mL). The organic phase was washed, and the combined organic phases were washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.26 g of pale yellow solid S2b, with a yield of 89%.

[0224] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of ultra-dry tetrahydrofuran, iodomethane (206 μL, 3.3 mmol), and potassium tert-butoxide (370 mg, 3.3 mmol) were added to a 100 mL round-bottom flask. The mixture was stirred for 2 h. Under ice bath conditions, compound S2b (779 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were added. The mixture was heated to reflux at 90 °C for 2 h. After returning to room temperature, the reaction solution was concentrated until the tetrahydrofuran was completely evaporated. 50 mL of dichloromethane was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 50 mL). The organic phase was washed, and the combined organic phase was washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and recrystallized from a dichloromethane-methanol system. 777 mg of white solid D1 was obtained by suction filtration, with a yield of 68%.

[0225] wherein the compound S2b has the structural formula

[0226] The compound S2b and D1 were subjected to 1 H NMR characterization, the results are:

[0227] S2b: 1 H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 15.9 Hz, 1H), 7.09 (dd, J = 8.3, 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.90 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H).

[0228] D1: 1 H NMR (500 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.46 (dd, J = 8.7, 1.8 Hz, 2H), 7.01 - 6.95 (m, 2H), 6.92 (dd, J = 8.6, 1.8 Hz, 2H), 6.87 (d, J = 8.1 Hz, 1H), 6.72 (q, J = 2.1, 1.6 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.91 - 3.86 (m, 6H), 3.83 (d, J = 1.3 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). Example 18

[0229] This example prepares a atrasentan derivative D2 The steps are as follows:

[0230] A011、Into a 50 mL round-bottom flask, 4-methoxycinnamic acid (1.07 g, 6 mmol) and 30 mL of anhydrous ethanol were sequentially added, stirred until the solid was completely dissolved, and then 8 μL of methanesulfonic acid (0.12 mmol) was slowly added under stirring. The reaction was heated to reflux at 90°C for 24 h. The reaction was cooled to room temperature, and then water was added to quench the reaction in an ice bath. The reaction liquid was concentrated until the ethanol was completely spun out, followed by the addition of 10 mL of ethyl acetate. The reaction was quenched with saturated NaHCO3 solution (3 x 30 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.13 g of yellow oil S2c with a yield of 91 %;

[0231] A031、Into a 100 mL round bottom flask, under ice bath condition, was added compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of super dry tetrahydrofuran, methyl iodide (206 μL, 3.3 mmol) and potassium tert-butoxide (370 mg, 3.3 mmol), stirred for 2 h, under ice bath condition, compound S2c (629 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were added, heated to reflux at 90 °C for 2 h, cooled to room temperature, the reaction was concentrated to tetrahydrofuran was completely spun out, 50 mL of dichloromethane was added, the reaction was quenched with saturated NaHCO3solution (3 x 50 mL) and washed with organic phase, the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, recrystallized with dichloromethane-methanol system, and filtered to give 636 mg of light yellow solid D2, with a yield of 60%.

[0232] wherein the compound S2c has the structural formula

[0233] The compound S2c and D2 were subjected to 1 H NMR characterization, the results are:

[0234] S2c: 1 H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J = 15.9 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.30 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0235] D2: 1 H NMR (500 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.45 (dd, J = 8.7, 1.2 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.97 - 6.85 (m, 4H), 6.68 (d, J = 2.1 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.83 (s, 6H), 1.02 (t, J = 7.1 Hz, 3H).

[0236] Example 19

[0237] This example prepares amlodipine derivative D3 The steps are as follows:

[0238] A031、Into a 100 mL round bottom flask, was added compound S7 prepared in Example 1 (894 mg, 3 mmol), 18 mL of super dry tetrahydrofuran, iodomethane (206 μL, 3.3 mmol) and potassium tert-butoxide (370 mg, 3.3 mmol) under ice bath condition, stirred for 2 h, continued to add ethyl cinnamate (558 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) under ice bath condition, heated to reflux at 90 °C for 2 h, returned to room temperature, concentrated the reaction solution to complete spin out of tetrahydrofuran, added 50 mL of dichloromethane, quenched the reaction with saturated NaHC03solution (3 x 50 mL) and washed the organic phase, washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, recrystallized with dichloromethane-methanol system, and filtered under suction to give 530 mg of light yellow solid D3 with a yield of 55%.

[0239] D3 was subjected to 1 H NMR characterization, the results are: 1 H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 1H), 7.45 (dd, J = 8.7, 1.8 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 7.1 Hz, 1H), 6.93 - 6.87 (m, 2H), 6.71 - 6.66 (m, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H).

[0240] Example 20

[0241] This example prepares amlodipine derivative D4 The steps are as follows:

[0242] A011、Into a 100 mL round bottom flask, was added compound S7 prepared in Example 1 (894 mg, 3 mmol), 18 mL of super dry tetrahydrofuran, iodomethane (206 μL, 3.3 mmol) and potassium tert-butoxide (370 mg, 3.3 mmol) under ice bath condition, stirred for 2 h, continued to add ethyl cinnamate (558 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) under ice bath condition, heated to reflux at 90 °C for 2 h, returned to room temperature, concentrated the reaction solution to complete spin out of tetrahydrofuran, added 50 mL of dichloromethane, quenched the reaction with saturated NaHC03solution (3 x 50 mL) and washed the organic phase, washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, recrystallized with dichloromethane-methanol system, and filtered under suction to give 530 mg of light yellow solid D3 with a yield of 55%.

[0243] A031、Into a 100 mL round bottom flask, was added compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of super dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol) and potassium tert-butoxide (369 mg, 3.3 mmol) under ice bath condition, stirred for 2 h, under ice bath condition, compound S2d (838 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were added, heated to reflux at 90 °C for 2 h, cooled to room temperature, the reaction was concentrated to tetrahydrofuran was completely spun out, 50 mL of dichloromethane was added, quenched with saturated NaHCO3solution (3 x 50 mL) and washed the organic phase, the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, recrystallized with dichloromethane-methanol system, and filtered under suction to give 501 mg of light yellow solid D4, yield 47%.

[0244] wherein the compound S2d has the structural formula

[0245] The compound S2d and D4 were subjected to 1 H NMR characterization, the results are:

[0246] S2d: 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 16.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0247] D4: 1 H NMR (500 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.51 - 7.42 (m, 4H), 7.30 (d, J = 8.1

[0248] Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 2.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H).

[0249] Example 21

[0250] This example prepares amlodipine derivative D5 The steps are as follows:

[0251] A011、Into a 50 mL round bottom flask, 4-chlorocinnamic acid (1.10 g, 6 mmol) and 10 mL of anhydrous ethanol were sequentially added, stirred until the solid was completely dissolved, and then 10 mL of anhydrous ethanol was added. Methanesulfonic acid (8 μL, 0.12 mmol) was slowly added under stirring, and the reaction was heated to reflux at 90°C for 24 h. The reaction was cooled to room temperature, and then water was added to quench the reaction in an ice bath. The reaction was concentrated until the ethanol was completely spun out, followed by the addition of 10 mL of ethyl acetate. The reaction was quenched with saturated NaHCO3solution (3 x 10 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.16 g of colorless oil S2e with a yield of 92%.

[0252] A031、Into a 100 mL round bottom flask, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of super dry tetrahydrofuran, methyl iodide (205 μL, 3.3 mmol), and potassium tert-butoxide (369 mg, 3.3 mmol) were sequentially added under ice bath conditions. After stirring for 2 h, compound S2e (693 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were sequentially added under ice bath conditions. The reaction was heated to reflux at 90°C for 2 h, and then the reaction was concentrated until the tetrahydrofuran was completely spun out. 50 mL of dichloromethane was added, and then the reaction was quenched with saturated NaHCO3solution (3 x 50 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization was performed with a dichloromethane-methanol system, and then filtration was performed to obtain 458 mg of light yellow solid D5 with a yield of 43%.

[0253] wherein the structural formula of compound S2e is

[0254] Compound S2e and D5 were subjected to 1 H NMR characterization showed the following results:

[0255] S2e: 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 16.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[0256] D5: 1H NMR (500 MHz, Chloroform-d) d 8.46 (s, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 2.4 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H).

[0257] Example 22

[0258] This example prepares a compound D6 The steps are as follows:

[0259] A011, Into a 50 mL round bottom flask, 4-fluorocinnamic acid (2.99 g, 18 mmol) and 10 mL of anhydrous ethanol were sequentially added, and stirred until the solid was completely dissolved. Methyl sulfonic acid (24 μL, 0.36 mmol) was slowly added under stirring, and heated to reflux at 90 °C for 24 h. The reaction was quenched by adding water to the reaction solution under ice bath, and the reaction solution was concentrated until the ethanol was completely spun out. Then 15 mL of ethyl acetate was added, and the reaction was quenched by saturated NaHCO3solution (3 x 15 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3.13 g of colorless oil S2f with a yield of 90%;

[0260] A031, Into a 100 mL round bottom flask, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of super dry tetrahydrofuran, methyl iodide (205 μL, 3.3 mmol), and potassium tert-butoxide (369 mg, 3.3 mmol) were sequentially added under ice bath condition, and stirred for 2 h. Compound S2f (729 mg, 3.3 mmol) and potassium tert-butoxide (1.0 g, 9 mmol) were continuously added under ice bath condition, and heated to reflux at 90 °C for 2 h. The reaction solution was concentrated until the tetrahydrofuran was completely spun out, 50 mL of dichloromethane was added, and the reaction was quenched by saturated NaHCO3solution (3 x 50 mL) and the organic phase was washed. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization was performed with dichloromethane-methanol system, and suction filtration was performed to obtain 315.3 mg of light yellow solid D6 with a yield of 31%.

[0261] wherein the compound S2f has a structural formula of

[0262] The compound S2f and D6 were subjected to 1 H NMR characterization, and the results were as follows:

[0263] S2f: 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 16.0 Hz, 1H), 7.50 (dd, J = 8.7, 5.5 Hz, 2H), 7.07 (t, J = 8.6 Hz, 2H), 6.35 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0264] D6: 1 H NMR (500 MHz, Chloroform-d) δ 8.77 - 8.42 (m, 1H), 7.50 - 7.40 (m, 2H), 7.37 (t, J = 7.1 Hz, 2H), 7.08 - 6.99 (m, 2H), 6.95 - 6.88 (m, 2H), 6.64 (d, J = 2.7 Hz, 1H), 4.10 - 3.99 (m, 2H), 3.82 (d, J = 1.9 Hz, 3H), 1.00 (td, J = 7.1, 2.1 Hz, 3H).

[0265] Example 23

[0266] This example prepared atrasentan derivative D10 and D16 The procedure was as follows:

[0267] To a 10 mL round-bottom flask was added compound D4 prepared in Example 20 (61.4 mg, 0.15 mmol), compound S4a prepared in Example 1 (45 mg, 0.18 mmol) and 3 mL of acetonitrile, stirred to dissolve, slowly added potassium tert-butoxide (20 mg, 0.18 mmol), reacted at room temperature for 6 h, quenched the reaction with water, and extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7: 1 to 5: 1, v / v) to obtain 69.0 mg of colorless oil D10, yield 81 %;

[0268] To a 25 mL round-bottom flask was added compound D10 (124 mg, 0.22 mmol), 5 mL of ethanol and 1 mL of water, stirred, followed by lithium hydroxide hydrate (46 mg, 1.1 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, 1 mol / L hydrochloric acid was added to adjust the pH to acidic, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 3:1, v / v) to give 70.7 mg of white solid D16, yield 60%.

[0269] Compound D10 and D16 were subjected to 1 H NMR characterization, the results are:

[0270] D10: 1 H NMR (500 MHz, Chloroform-d) δ 7.43 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.72 (s, 1H), 4.44 (s, 2H), 3.95 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.27 (t, J = 7.6 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.47 (t, J = 7.7 Hz, 2H), 1.26 (p, J = 10.4, 9.0 Hz, 4H), 1.11 (q, J = 7.5 Hz, 2H), 0.91 (dt, J = 12.3, 7.3 Hz, 6H), 0.84 (t, J = 7.3 Hz, 3H).

[0271] D16: 1 H NMR (500 MHz, Chloroform-d) δ 7.42 (dd, J = 8.3, 1.8 Hz, 2H), 7.34 (dd, J = 8.3, 1.7

[0272] Hz, 2H), 7.26–7.22 (m, 2H), 6.95–6.87 (m, 2H), 6.71 (d, J = 1.5 Hz, 1H), 4.42 (s, 2H), 3.84 (d, J = 1.4 Hz, 3H), 3.26 (t, J = 7.6 Hz, 2H), 2.93 (t, J = 7.7 Hz, 2H), 1.50–1.42 (m, 2H), 1.25 (dq, J = 17.0, 8.9, 8.3 Hz, 5H), 1.11 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).

[0273] Example 1 Preparation of atrasentan derivative D11 and D17 The procedure is as follows:

[0274] To a 10 mL round-bottom flask was added compound D5 prepared in Example 21 (150 mg, 0.42 mmol), compound S4a prepared in Example 1 (129 mg, 0.51 mmol) and 3 mL of acetonitrile, stirred to dissolve, slowly added potassium tert-butoxide (57 mg, 0.51 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to obtain 69.0 mg of colorless oil D11, yield 89%;

[0275] To a 10 mL round-bottom flask was added compound D11 (104.8 mg, 0.2 mmol), 2 mL of ethanol and 0.4 mL of water, stirred, then added lithium hydroxide hydrate (42 mg, 1 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, adjusted pH to acidic with 1 mol / L hydrochloric acid, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 3:1, v / v) to obtain 56.8 mg of white solid D17, yield 57%.

[0276] Compound D11 and D17 were subjected to 1 H NMR characterization, the results are:

[0277] D11: 1 H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.38 (m, 2H), 7.27 (dd, J = 8.6, 4.2 Hz, 4H), 6.95 - 6.90 (m, 2H), 6.72 (s, 1H), 4.44 (s, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.32 - 3.23 (m, 2H), 2.99 - 2.90 (m, 2H), 1.46 (ddt, J = 9.2, 7.6, 3.5 Hz, 2H), 1.32 - 1.20 (m, 4H), 1.11 (dq, J = 14.5, 7.2 Hz, 2H), 0.90 (dt, J = 9.2, 7.2 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H).

[0278] D17:1 H NMR (500 MHz, Chloroform-d) d 7.38 (d, J = 8.0 Hz, 2H), 7.24 (dd, J = 13.1, 8.3 Hz, 4H), 6.89 (d, J = 8.2 Hz, 2H), 6.69 (s, 1H), 4.40 (s, 2H), 3.83 (s, 3H), 3.26 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.7 Hz, 2H), 1.46 (p, J = 7.5 Hz, 2H), 1.29 - 1.22 (m, 5H), 1.10 (p, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H).

[0279] Example 25

[0280] Example 25 and D18 The procedure is as follows:

[0281] To a 10 mL round-bottom flask was added compound D6 prepared in Example 22 (150 mg, 0.45 mmol), compound S4a prepared in Example 1 (135 mg, 0.54 mmol) and 3 mL of acetonitrile, stirred to dissolve, slowly added potassium tert-butoxide (60 mg, 0.54 mmol), reacted at room temperature for 6 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to obtain 208.0 mg of colorless oil D12, yield 91 %;

[0282] To a 10 mL round-bottom flask was added compound D12 (101.6 mg, 0.2 mmol), 2 mL of ethanol and 0.4 mL of water, stirred, then added lithium hydroxide hydrate (42 mg, 1 mmol), heated to reflux at 100 °C for 24 h, cooled to room temperature, adjusted pH to acidic with 1 mol / L hydrochloric acid, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 3:1, v / v) to obtain 44.1 mg of white solid D18, yield 46 %.

[0283] Compound D12 and D18 were subjected to 1 H NMR characterization, the results are:

[0284] D12: 1H NMR (400 MHz, Chloroform-d) δ 7.42 (dd, J = 8.8, 5.5 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 8.8 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 4.44 (s, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.30 - 3.23 (m, 2H), 2.99 - 2.90 (m, 2H), 1.51 - 1.42 (m, 2H), 1.31 - 1.20 (m, 4H), 1.17 - 1.06 (m, 2H), 0.90 (dt, J = 13.1, 7.2 Hz, 7H), 0.83 (t, J = 7.2 Hz, 3H).

[0285] D18: 1 H NMR (500 MHz, Chloroform-d) δ 7.40 (dd, J = 8.3, 5.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.97 (t, J = 8.6 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.67 (s, 1H), 4.40 (s, 2H), 3.83 (s, 3H), 3.26 (t, J = 7.6 Hz, 2H), 2.92 (t, J = 7.7 Hz, 2H), 1.46 (t, J = 7.7 Hz, 2H), 1.25 (dd, J = 14.5, 6.5 Hz, 4H), 1.15 - 1.06 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H).

[0286] Example 26

[0287] This example prepared atrasentan derivative S14 S15 and S16 The procedure was as follows:

[0288] B011、Into a 50 mL round-bottom flask was added 3,4-methylenedioxyacetophenone (1.48 g, 9 mmol), p-toluenesulfonic acid hydrate (171 mg, 0.9 mmol) and 12 mL of acetonitrile in sequence, stirred, then added N-bromosuccinimide (1.60 g, 9 mmol), reacted at room temperature for 6 h, quenched the reaction with water, and extracted with ethyl acetate (3 x 10 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2S04, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1, v / v) to obtain 1.79 g of light yellow solid S12, yield 82%;

[0289] B021, Into a 50 mL round-bottom flask was placed S12 (765 mg, 3.15 mmol), 3-(4- methoxyphenyl)-3-oxopropanoic acid ethyl ester (366 μL, 2.88 mmol) and 4 mL of acetonitrile, stirred, then added potassium carbonate (432 mg, 3.15 mmol), reacted at room temperature for 3 h, quenched with water, and extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to obtain 3.32 g of light yellow oil S13, yield 96%;

[0290] B031, Into a 50 mL round-bottom flask was placed S13 (336.9 mg, 0.88 mmol), glycine (150 mg, 4.0 mmol) and 8 mL of acetic acid, refluxed at 120 °C overnight, the reaction was returned to room temperature, 5 mol / L sodium hydroxide solution was added to adjust the pH to neutral, extracted with ethyl acetate (3 x 10 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel column chromatography (dichloromethane / methanol = 20:1 to 10:1, v / v) to obtain 176.1 g of black oil S14, yield 47%;

[0291] B041, Into a 25 mL round-bottom flask was placed S14 (46.1 mg, 0.11 mmol), O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53.2 mg, 0.14 mmol), 5 mL of super dry dichloromethane, di-n-butylamine (13 μL, 0.11 mmol) and N,N- diisopropylethylamine (38 μL, 0.22 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 5 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified by silica gel preparative plate in petroleum ether / ethyl acetate = 4:1 (v / v) system to obtain 38.2 mg of white oil S15, yield 65%;

[0292] B051、Into a 10 mL round-bottom flask was added S15 (29.8 mg, 0.056 mmol), 2.5 mL of ethanol and 0.5 mL of water, stirred, then added lithium hydroxide hydrate (11.7 mg, 0.27 mmol), heated to reflux at 100 °C for 6 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 5 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in petroleum ether / ethyl acetate = 1:1 (v / v) system to obtain 18.6 mg of black oil S16, yield 66%.

[0293] wherein the structural formula of compound S12 is The structural formula of S13 is

[0294] The compounds S12, S13, S14, S15 and S16 were subjected to 1 H NMR characterization, the results are:

[0295] S12: 1 H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 8.2, 1.4 Hz, 1H), 7.43 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H), 4.36 (s, 2H).

[0296] S13: 1 H NMR (500 MHz, Chloroform-d) δ 8.07 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 8.1, 1.7 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.03 (s, 2H), 5.05 (t, J = 6.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.72 - 3.59 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0297] S14: 1 H NMR (500 MHz, Methanol-d4) δ 7.31 (d, J = 8.7 Hz, 2H), 6.98 - 6.90 (m, 4H), 6.82

[0298] H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 1.7 Hz, 1H), 6.93 - 6.88 (m, 3H), 6.80 (d, J = 7.9 Hz, 1H), 6.66 (s, 1H), 5.97 (s, 2H), 4.34 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.26 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 1.67 (s, 1H), 1.48 - 1.39 (m, 2H), 1.24 (h, J = 7.3 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H), 1.08 (ddd, J = 10.9, 7.4, 5.0 Hz, 2H), 1.01 (ddd, J = 9.5, 7.2, 4.5 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H).

[0299] S15: 1 H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 1.7 Hz, 1H), 6.93 - 6.88 (m, 3H), 6.80 (d, J = 7.9 Hz, 1H), 6.66 (s, 1H), 5.97 (s, 2H), 4.34 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.26 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 1.67 (s, 1H), 1.48 - 1.39 (m, 2H), 1.24 (h, J = 7.3 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H), 1.08 (ddd, J = 10.9, 7.4, 5.0 Hz, 2H), 1.01 (ddd, J = 9.5, 7.2, 4.5 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H).

[0300] S16: 1 H NMR (500 MHz, Chloroform-d) δ 7.32 (d, J = 8.3 Hz, 2H), 6.96 - 6.86 (m, 4H), 6.79

[0301] H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 1.7 Hz, 1H), 6.93 - 6.88 (m, 3H), 6.80 (d, J = 7.9 Hz, 1H), 6.66 (s, 1H), 5.97 (s, 2H), 4.34 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.26 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 1.67 (s, 1H), 1.48 - 1.39 (m, 2H), 1.24 (h, J = 7.3 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H), 1.08 (ddd, J = 10.9, 7.4, 5.0 Hz, 2H), 1.01 (ddd, J = 9.5, 7.2, 4.5 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H).

[0302] Example 27

[0303] Example 27 and E2 The procedure is as follows:

[0304] B041、Into a 25 mL round bottom flask was added S14 prepared in Example 26 (58.7 mg, 0.14 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68.4 mg, 0.18 mmol), 2 mL of super dry dichloromethane, 1-(2-aminoethyl)pyrrolidine (18 μL, 0.14 mmol), and N,N-diisopropylethylamine (49 μL, 0.28 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 5 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 20:1 (v / v) system to give 48.8 mg of E1 as white oil, yield 67%.

[0305] B051、Into a 10 mL round bottom flask was added E1 (29.4 mg, 0.057 mmol), 2.5 mL of ethanol and 0.5 mL of water, stirred, then added lithium hydroxide hydrate (11.9 mg, 0.283 mmol), heated to reflux at 100 °C for 6 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 5 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 15:1 (v / v) system to give 22.9 mg of E2 as white solid, yield 82%.

[0306] Compound E1 and E2 were subjected to 1 H NMR characterization, the results are:

[0307] E1: 1 H NMR (500 MHz, Chloroform-d) δ 7.28 (s, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.84 (dd, J = 9.6, 2.0 Hz, 3H), 6.70 (s, 1H), 6.13 (s, 1H), 5.99 (s, 2H), 4.39 (s, 2H), 4.13 (dd, J = 10.6, 3.6 Hz, 2H), 3.83 (s, 3H), 3.21 (d, J = 5.7 Hz, 2H), 2.49 (s, 6H), 1.77 (d, J = 1.6 Hz, 4H), 1.19 - 1.11 (m, 3H).

[0308] E2: 1H NMR(500MHz,Chloroform-d)δ8.32(s,1H),7.34(d,J=8.2Hz,2H),6.97(d,J=10.4Hz,2H),6.80(dd,J=8.3 ,2.9Hz,3H),6.61(s,1H),5.97(s,2H),4.36(s,2H),3.82(s,3H),3.38(s,2H),2.62(s,6H),1.62(s,4H).

[0309] Example 28

[0310] This embodiment prepares atrasentan derivative E3. and E4 The steps are as follows:

[0311] B041. Add S14 (58.7 mg, 0.14 mmol) prepared in Example 26, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (68.4 mg, 0.18 mmol), 2 mL of ultra-dry dichloromethane, 1-(2-aminoethyl)piperidine (22 μL, 0.14 mmol), and N,N-diisopropylethylamine (49 μL, 0.28 mmol) to a 10 mL round-bottom flask. Stir at room temperature for 15 min, quench the reaction with water, extract with dichloromethane (3 × 5 mL), wash the combined organic phases with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify with silica gel plates in a dichloromethane / methanol = 20:1 (v / v) system to obtain 49.9 mg of pale yellow oil E3, yield 67%.

[0312] B051. Add E3 (24.1 mg, 0.045 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (9.5 mg, 0.22 mmol), heat to reflux at 100 °C for 6 h, cool to room temperature, add 1 mol / L hydrochloric acid to adjust the pH to acidic, extract with ethyl acetate (3 × 5 mL), wash the combined organic phases with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify with silica gel plate preparation in a dichloromethane / methanol = 15:1 (v / v) system to give 22.3 mg of white solid E4, yield 98%.

[0313] Compounds E3 and E4 were subjected to 1 H NMR characterization, the results are as follows:

[0314] E3: 1H NMR (500 MHz, Chloroform-d) δ 7.25 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 4.7 Hz, 3H), 6.73 (s, 1H), 6.16 (s, 1H), 5.98 (s, 2H), 4.39 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.17 (q, J = 5.5 Hz, 2H), 2.31 (t, J = 5.9 Hz, 6H), 1.57 - 1.47 (m, 4H), 1.44 - 1.34 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0315] E4: 1 H NMR (500 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.40 (s, 2H), 6.99 (d, J = 6.6 Hz, 2H), 6.80 (dd, J = 8.5, 6.2 Hz, 3H), 6.65 (s, 1H), 5.96 (s, 2H), 4.37 (s, 2H), 3.81 (s, 3H), 3.38 (s, 2H), 2.45 (t, J = 4.8 Hz, 6H), 1.32 (s, 6H).

[0316] Example 29

[0317] This example prepared atrasentan derivative E5 and E6 The procedure was as follows:

[0318] B041、Into a 10 mL round-bottom flask was placed S14 prepared in Example 26 (58.7 mg, 0.14 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68.4 mg, 0.18 mmol), 2 mL of super dry dichloromethane, N-(2-aminoethyl)morpholine (18 μL, 0.14 mmol) and N,N-diisopropylethylamine (49 μL, 0.28 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 5 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 20:1 (v / v) system to obtain 44.7 mg of light yellow oil E5, yield 60%.

[0319] B051、Into a 10 mL round-bottom flask was placed E5 (25.1 mg, 0.047 mmol), 2.5 mL of ethanol and 0.5 mL of water, stirred, then lithium hydroxide hydrate (9.59 mg, 0.235 mmol) was added, heated to reflux at 100 °C for 6 h, cooled to room temperature, 1 mol / L hydrochloric acid was added to adjust the pH to acidic, extracted with ethyl acetate (3 x 5 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 15:1 (v / v) system to obtain 20.7 mg of white solid E6, yield 87%.

[0320] Compounds E5 and E6 were subjected to 1 H NMR characterization, the results were:

[0321] E5: 1 H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.82 (dd, J = 6.1, 0.9 Hz, 3H), 6.73 (s, 1H), 5.98 (s, 2H), 5.90 (s, 1H), 4.40 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.63 (t, J = 4.6 Hz, 4H), 3.20 (q, J = 5.6 Hz, 2H), 2.44 - 2.30 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H).

[0322] E6: 1 H NMR (500 MHz, Chloroform-d) δ 7.40 (s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.83 (dd, J = 13.5, 8.1 Hz, 3H), 6.67 (s, 1H), 5.98 (s, 2H), 4.38 (s, 2H), 3.82 (s, 3H), 3.47 (s, 4H), 3.33 (d, J = 5.0 Hz, 2H), 2.43 (s, 6H).

[0323] Example 30

[0324] This example prepared atrasentan derivatives E7 and E8 The steps are as follows:

[0325] B041、Into a 10 mL round bottom flask was added S14 prepared in Example 26 (60.2 mg, 0.14 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (72.2 mg, 0.19 mmol), 2 mL of super dry dichloromethane, n-butylamine (14 μL, 0.14 mmol) and N,N-diisopropylethylamine (49 μL, 0.28 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 3 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 20:1 (v / v) system to give 44.4 mg of E7 as a light yellow solid with a yield of 66%.

[0326] B051、Into a 10 mL round bottom flask was added E7 (24.3 mg, 0.051 mmol), 2.5 mL of ethanol and 0.5 mL of water, stirred, then added lithium hydroxide hydrate (10.7 mg, 0.25 mmol), heated to reflux at 100 °C for 6 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 5 mL), washed the combined organic phase with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 20:1 (v / v) system to give 20.2 mg of E8 as a white solid with a yield of 97%.

[0327] Compounds E7 and E8 were characterized by1H NMR with the following results:

[0328] E7: 1 H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.86 - 6.81 (m, 3H), 6.71 (d, J = 2.0 Hz, 1H), 5.98 (s, 2H), 5.24 (s, 1H), 4.38 (s, 2H), 4.15 - 4.08 (m, 2H), 3.82 (s, 3H), 3.15 - 3.07 (m, 2H), 1.35 - 1.30 (m, 2H), 1.19 (qd, J = 7.3, 6.5, 2.4 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0329] E8: 1H NMR (500 MHz, Methanol-d4) δ 7.29 (d, J = 8.6 Hz, 2H), 6.98 - 6.88 (m, 4H), 6.85 (d, J = 7.8 Hz, 1H), 6.59 (s, 1H), 5.98 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H), 3.06 (t, J = 6.9 Hz, 2H), 1.34 (d, J = 6.9 Hz, 2H), 1.20 (q, J = 7.4 Hz, 2H), 0.90 (d, J = 7.3 Hz, 3H).

[0330] Example 31

[0331] Example 31 and E10 The procedure is as follows:

[0332] B041、Into a 10 mL round-bottom flask was placed S14 prepared in Example 26 (60.2 mg, 0.14 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (72.2 mg, 0.19 mmol), 2 mL of super dry dichloromethane, N1,N1-dimethylethane-1,2-diamine (13 μL, 0.14 mmol) and N,N-diisopropylethylamine (49 μL, 0.28 mmol), stirred at room temperature for 15 min, quenched with water, extracted with dichloromethane (3 x 3 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 10:1 (v / v) system to obtain 39.5 mg of light yellow solid E9 with a yield of 53%.

[0333] B051、Into a 10 mL round-bottom flask was placed E9 (37.6 mg, 0.074 mmol), 2.5 mL of ethanol and 0.5 mL of water, stirred, then added lithium hydroxide hydrate (15.6 mg, 0.37 mmol), heated to reflux at 100 °C for 6 h, cooled to room temperature, added 1 mol / L hydrochloric acid to adjust the pH to acidic, extracted with ethyl acetate (3 x 5 mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure after filtration, purified with silica gel preparative plate in dichloromethane / methanol = 20:1 (v / v) system to obtain 12.1 mg of white solid E10 with a yield of 34%.

[0334] The compounds E9 and E10 were characterized by 1H NMR, and the results were as follows:

[0335] E9: 1H NMR (500 MHz, Chloroform-d) δ 7.28 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.89 - 6.84 (m, 2H), 6.82 (d, J = 7.9 Hz, 1H), 6.70 (s, 1H), 6.12 (t, J = 5.1 Hz, 1H), 5.98 (s, 2H), 4.37 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.21 (q, J = 5.6 Hz, 2H), 2.33 (t, J = 5.9 Hz, 2H), 2.21 (s, 6H), 1.14 (t, J = 7.1 Hz, 3H).

[0336] E10: 1 H NMR (500 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.01 - 6.90

[0337] (m, 2H), 6.80 (dd, J = 8.2, 4.3 Hz, 3H), 6.61 (s, 1H), 5.97 (s, 2H), 4.34 (s, 2H), 3.81 (s, 3H), 3.35 (s, 2H), 2.44 (s, 2H), 2.18 (s, 6H).

[0338] 1. Safety evaluation of atrasentan derivatives prepared in Examples 1-31 on HK-2 cells:

[0339] 1) Preparation of samples to be tested: atrasentan derivatives prepared in Examples 1-31 were dissolved in dimethyl sulfoxide to prepare 10 mmol / L stock solutions;

[0340] 2) HK-2 cells in the logarithmic growth phase were inoculated in a 96-well plate and cultured in a 37°C, 5% CO2 incubator for 24 h; a blank control group was set up, three replicate wells were set up in each group, and the drug group was replaced with complete culture medium containing 10 μmol / L (or 20 μmol / L) atrasentan derivatives, and cultured for 24 h (or 48 h), then high content was taken, and the number of cells in each group under the action of different compounds was analyzed and counted, and the cell survival rate under the action of different derivatives was calculated, the formula was: cell survival rate = drug group cell number / control group cell number*100%.

[0341] TGF-β (transforming growth factor-β) is a trigger of fibrosis and a key factor for the development of fibrosis after acute injury, which can induce human renal tubular epithelial cells (HK-2) to initiate excessive accumulation of extracellular matrix (ECM) such as fibronectin (FN), collagen, vimentin, alpha-smooth muscle actin (α-SMA), etc., leading to differentiation of fibroblasts into myofibroblasts, increased secretion of inflammatory mediators, and ultimately irreversible organ fibrosis. Therefore, TGF-β recombinant protein is often used to induce human renal tubular epithelial cells (HK-2) in vitro to construct a renal interstitial fibrosis cell model. Figure 1 To evaluate the 24h safety of the atrasentan derivatives in the examples at a concentration of 10 μmol / L on HK-2 cells, Figure 2 To evaluate the 48h safety of the atrasentan derivatives in the examples at a concentration of 20 μmol / L on HK-2 cells, by Figure 1 and Figure 2 It can be seen that the survival rate of HK-2 cells is generally greater than 80% under different concentrations and treatment times, indicating that the atrasentan derivatives provided in the examples have less toxicity to HK-2 cells.

[0342] 2. Preliminary evaluation of the anti-fibrosis activity of the atrasentan derivatives prepared in Examples 1-31 in vitro:

[0343] HK-2 cells in the logarithmic growth phase were inoculated in a 96-well plate and cultured in a 37°C, 5% CO2 incubator for 24h; a blank control group and a positive control group were set up, with 3 replicate wells in each group, and the culture medium in all wells was replaced with serum-free culture medium and continued to be cultured for 24h; the blank control group was replaced with complete culture medium, the positive control group was replaced with complete culture medium containing 5ng / mL TGF-β, and the drug administration group was replaced with complete culture medium containing 10 μmol / L atrasentan derivatives and 5ng / mL TGF-β, and continued to be cultured for 48h; then, after fixation, permeabilization, blocking, incubation of the first antibody, incubation of the second antibody, incubation of DAPI, high-content imaging was used, and the average level of fibronectin (nor.Fn) under the action of different compounds was analyzed and statistically analyzed.

[0344] Figure 3 To evaluate the anti-fibrosis activity of the atrasentan derivatives in the examples at a concentration of 10 μmol / L on TGF-β induced HK-2, by Figure 3It can be known that after TGF-β induces HK-2, the expression of Fibronectin is obviously higher than the normal level; after the action of atrasentan, the protein level of Fibronectin has a certain degree of reduction; and after the action of the synthesized atrasentan derivatives, the protein level of Fibronectin is mostly reduced, and the protein level of Fibronectin of S15, E8 and the like is significantly reduced compared with atrasentan. Therefore, it is shown that the synthesized atrasentan derivatives mostly have the anti-fibrosis effect, and more than half of the derivatives have the anti-fibrosis effect better than atrasentan.

[0345] 3. Secondary evaluation of in-vitro anti-fibrosis activity of the atrasentan derivatives prepared in Examples 1-31:

[0346] HK-2 cells in the logarithmic growth phase are inoculated in a 6-well plate and cultured in a 37℃, 5% CO2 incubator for 24h; a blank control group and a positive control group are set, each group is set with three duplicate wells, the culture medium in all the wells is replaced with serum-free culture medium, and the culture is continued for 24h; the blank control group is replaced with complete culture medium, the positive control group is replaced with complete culture medium containing 5ng / mL TGF-β, and the drug administration group is replaced with complete culture medium containing 10μmol / L atrasentan derivatives and 5ng / mL TGF-β, and the culture is continued for 48h; then, the proteins in different samples are extracted, subjected to SDS-PAGE gel electrophoresis, and the expression levels of Fibronectin (Fn) and Vimentin (Vim) proteins are developed.

[0347] Figure 4 For the anti-fibrosis activity of the compounds after the initial screening at a concentration of 10μmol / L on TGF-β-induced HK-2, wherein, Figure 4 (a) in the above (a) is the anti-fibrosis activity of compounds S10, A8, D13, D14, D15, A5, A6, A2, E8 at a concentration of 10μmol / L on TGF-β-induced HK-2, Figure 4 (b) in the above (b) is the anti-fibrosis activity of compounds C3, C4, S9, A4, D3, D8, D11, D12, D13 at a concentration of 10μmol / L on TGF-β-induced HK-2, and Figure 4 It can be known that after TGF-β induces HK-2, the expression of Fibronectin is obviously higher than the normal level, and the expression of Vimentin is higher than the normal level; after the action of atrasentan, the protein levels of Fibronectin and Vimentin have a certain degree of reduction; and the protein levels of Fibronectin and Vimentin of compounds A8, A5, A6, C4, S9, D3 and D11 are significantly reduced compared with atrasentan. Therefore, it is shown that the anti-fibrosis effect of the synthesized atrasentan derivatives is better than that of atrasentan.

Claims

1. An atrasentan derivative, characterized by, The structural formula is shown as formula (A) or formula (B): In formula (A) and formula (B), R 1 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, benzoyl or derivatives thereof, -C-T, wherein T is selected from the group consisting of carboxyl, ester, substituted or unsubstituted amide; R 2 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl, methoxy, halogen, amino or nitro; R 3 are independently selected from an ester group, a carboxyl group or a substituted amide group; R 4 are each independently selected from hydrogen, hydroxyl, methoxy, halogen, oxygen-containing heterocycle, amino, nitro, or cyano.

2. The atrasentan derivative according to claim 1, characterized in that, In the formula (A) or (B), the R 1 are each independently selected from the group consisting of hydrogen, methyl, benzoyl, 4-methylbenzoyl, -C-COOR 5 or -C-CONR 6 R 7 wherein R 5 is selected from the group consisting of hydrogen, linear or branched alkyl; R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 2-8 linear alkyl, -C2H4-heterocycle or dimethylaminoalkyl; and / or, said R 2 are each independently selected from hydrogen, hydroxyl, methyl, methoxy or halogen; and / or, said R 3 are each independently selected from -COOR 8 or -CONR 9 R 10 wherein R 8 is selected from hydrogen, linear or branched alkyl; R 9 and R 10 are each independently selected from hydrogen, propargyl or C 1-4 linear alkyl; and / or, the R 4 are each independently selected from hydrogen, hydroxyl, methoxy, halogen or an oxygen-containing heterocycle.

3. The atrasentan derivative according to claim 1, characterized in that, The atrasentan derivative is shown as formula 1 to formula 72:

4. The method of preparing an atrasentan derivative according to claim 2 or 3, characterized in that, When the atrasentan derivative is shown as formula (A), the preparation method comprises the following steps: A01. Compound (a1) Compound (a2) is obtained by esterification reaction under strong acid Compound (a3) Compound (a4) is obtained by nucleophilic substitution reaction in the presence of acyl halide A02、compound (a5) with compound (a6) a nucleophilic substitution reaction to give compound (a7) A03. said compound (a7) is subjected to a ring closure reaction with compound (a2) to give compound (a8) A04. The compound (a8) is subjected to a nucleophilic substitution reaction with the compound (a4) to obtain a compound (a9) A05, the compound (a9) is subjected to ester hydrolysis reaction to obtain the atrasentan derivative shown as formula (A); When the atrasentan derivative is shown as formula (B), the preparation method comprises the following steps: B01, compound (b1) Bromination with N-bromosuccinimide to give compound (b2) B02, the compound (b2) is subjected to a nucleophilic substitution reaction with a substituted benzoyl acetate to obtain a compound (b3) B03, the compound (b3) is subjected to a cyclization reaction with glycine in the presence of a catalyst to obtain a compound (b4) B04, the compound (b4) is subjected to an amide condensation reaction with an amine compound to obtain a compound (b5) B05, the compound (b5) is subjected to ester hydrolysis reaction to obtain the atrasentan derivative shown as formula (B); wherein R 1 , R 2 , R 4 , R 6 , R 7 , R 8 are as defined in claim 2 or 3.

5. The production method according to claim 4, characterized by, The atrasentan derivative shown as formula (A) is prepared, and the molar ratio of the compound (a5) to the compound (a6) is (0.8-1.2):1; And / or, the molar ratio of the compound (a7) to the compound (a2) is 1:(1-1.5); And / or, the molar ratio of the compound (a8) to the compound (a4) is 1:(1.2-1.6).

6. The preparation method according to claim 4, characterized in that, In the preparation of the atrasentan derivative shown as formula (A), in step A01, the strong acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid; and the acyl halide is selected from bromoacetyl bromide, ethyl bromoacetate or bromoacetic acid. And / or, in step A03, iodomethane and a base are further used, and the base is selected from at least one of n-butyllithium, potassium tert-butoxide, lithium diisopropylamide, sodium amide, sodium hydroxide and sodium hydride.

7. The preparation method according to claim 4, characterized in that, In the preparation of the atrasentan derivative shown as formula (B), the molar ratio of the compound (b1) to N-bromosuccinimide is (0.8-1.2):1; And / or, the molar ratio of the compound (b2) to the substituted benzoyl acetate is (1-1.5):1; And / or, the molar ratio of the compound (b3) to glycine is 1:(4-5); And / or, the molar ratio of the compound (b4) to the amine compound is (0.8-1.2):

1.

8. The preparation method according to claim 4, characterized in that, In the preparation of the atrasentan derivative shown as formula (B), in step B04, a base and a condensing agent are further used; the base is selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, imidazole or N-methylimidazole; and the condensing agent is selected from O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate, chlorobenzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate or O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate.

9. Use of the atrasentan derivative of any one of claims 1-3 in the preparation of a drug for resisting renal fibrosis.

10. An anti-renal fibrosis drug, characterized by, The atrasentan derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-3 is included.

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