An atrasentan derivative, and a preparation method and application thereof

Abstract

This invention relates to the field of pharmaceutical technology, and discloses an atrasentan derivative, its preparation method, and its applications. The atrasentan derivative is a tetrasubstituted pyrrole derivative designed using atrasentan as a lead, significantly reducing the difficulty and cost of synthesis by decreasing three chiral centers. This atrasentan derivative exhibits high safety in HK-2 cells and can significantly improve the pathological state of fibrosis induced by TGF-β in HK-2 cells. It has the potential to be used in the preparation of drugs for the prevention and treatment of renal fibrosis-related diseases, breaking through the synthetic bottleneck of atrasentan and providing a novel candidate drug for the treatment of renal fibrosis.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an atrasentan derivative, its preparation method, and its application. Background Technology

[0002] The prevalence of chronic kidney disease (CKD) is showing an increasing trend year by year, and renal fibrosis is a key pathological cause of CKD. Renal fibrosis is characterized by the accumulation of large amounts of extracellular matrix and the destruction of the normal physiological structure and function of the kidneys. It mainly manifests as interstitial fibrosis and glomerular sclerosis. If fibrosis is allowed to continue to develop, it will cause multiple organ dysfunction, ultimately leading to multiple organ failure and death. Modern medicine has not yet found an effective treatment; currently, life can only be maintained through dialysis or kidney transplantation. Therefore, the research and development of anti-renal fibrosis drugs is of great significance for the prevention and treatment of clinical renal fibrosis.

[0003] Endothelin-1 (ET-1) is a potent vasoactive peptide synthesized by almost all cell types in the kidney. Its production is stimulated by various vasoactive, inflammatory, pro-fibrotic, and proliferative factors. ET-1 exists in two receptors: the endothelin A receptor (ET1). A R) and endothelin B receptor (ET) B R), Under normal circumstances, ET-1 passes through ET. A R causes vasoconstriction, while ET B R stimulates the release of nitric oxide, leading to vasodilation. Under pathological conditions, ET... A Activation of ET-1 can induce immune cell migration, cytokine production, podocyte disappearance, extracellular matrix accumulation and fibrosis, as well as the production of angiotensin II and aldosterone. Given the effects of ET-1 on the kidneys, selective ET... A R receptor antagonists have been developed as potential therapeutic agents.

[0004] Atrasentan is a selective endothelin A receptor antagonist that blocks abnormal activation of the endothelin system and reduces the risk of kidney fibrosis. On April 2, 2025, Novartis announced that the U.S. Food and Drug Administration (FDA) had granted accelerated approval to Vanrafia (Atrasentan) for the reduction of proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression.

[0005] However, atrasentan has three chiral centers, which leads to high synthesis costs, difficult processing, and insufficient anti-fibrotic activity. Therefore, there is an urgent need to develop a compound that can maintain / enhance pharmacological activity while simplifying the molecular skeleton and reducing the difficulty of synthesis. Summary of the Invention

[0006] The present invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, one objective of the present invention is to provide an atrasentan derivative;

[0007] A second objective of this invention is to provide a method for preparing this atrasentan derivative;

[0008] The third objective of this invention is to provide applications of this atrasentan derivative.

[0009] The fourth objective of this invention is to provide an anti-renal fibrosis drug.

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

[0011] A first aspect of the present invention provides an atrasentan derivative having the structural formula shown in formula (A) or formula (B):

[0012]

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

[0014] R 1 Selected independently from hydrogen and C 1-4 The alkyl group, benzoyl group or its derivative, and -CT are selected from the group consisting of the carboxyl group, ester group, substituted or unsubstituted amide group;

[0015] R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-4 Alkyl, methoxy, halogen, amino, or nitro;

[0016] R 3 Each group is independently selected from ester, carboxyl, or substituted amide groups;

[0017] R 4 Each group is independently selected from hydrogen, hydroxyl, methoxy, halogen, oxygen-containing heterocycle, amino, nitro, or cyano.

[0018] In some embodiments of the present invention, in formula (A) or formula (B), the R 1 Each is independently selected from hydrogen, methyl, benzoyl, 4-methylbenzoyl, -C-COOR 5 or -C-CONR 6 R 7 , where R 5 Selected from hydrogen, straight-chain or branched alkyl groups; R 6 and R 7 Selected independently from hydrogen and C 2-8Straight-chain alkyl, -C2H4- heterocyclic or dimethylaminoalkyl.

[0019] In some preferred embodiments of the present invention, in formula (A) or formula (B), the R 1 Each is independently selected from hydrogen, methyl, benzoyl, 4-methylbenzoyl, -C-COOR 5 OR-C-CONR 6 R 7 , where R 5 Selected from hydrogen or -CH3; R 6 and R 7 Selected independently from hydrogen and C 2-8 Straight-chain 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 invention, in formula (A) or formula (B), the R 2 Each is independently selected from hydrogen, hydroxyl, methyl, methoxy, or halogen.

[0021] In some embodiments of the present invention, in formula (A) or formula (B), the R 3 Selected independently from -COOR 8 or -CONR 9 R 10 , where R 8 Selected from hydrogen, straight-chain or branched alkyl groups; R 9 and R 10 Each is independently selected from hydrogen, propargyl, or C. 1-4 Straight-chain alkyl groups.

[0022] In some embodiments of the present invention, in formula (A) or formula (B), the R 4 Each is independently selected from hydrogen, hydroxyl, methoxy, halogen, or oxygen-containing heterocycles.

[0023] In some embodiments of the present invention, the atrasentan derivatives are shown in Formulas 1-71:

[0024]

[0025]

[0026]

[0027]

[0028] A second aspect of the present invention provides a method for preparing the atrasentan derivative described in the first aspect of the present invention, wherein when the atrasentan derivative is as shown in formula (A), the method for preparing it includes the following steps:

[0029] A01, Compound (a1) Compound (a2) was obtained by esterification under strong acid conditions. Compound (a3) A nucleophilic substitution reaction was carried out in the presence of an acyl halide to give compound (a4).

[0030] A02, Compound (a5) With compound (a6) A nucleophilic substitution reaction was carried out to give compound (a7).

[0031] A03. Compound (a7) undergoes a cyclization reaction with compound (a2) to obtain compound (a8).

[0032] A04. Compound (a8) undergoes a nucleophilic substitution reaction with compound (a4) to give compound (a9).

[0033] A05. The compound (a9) is subjected to ester hydrolysis to obtain the atrasentan derivative shown in formula (A);

[0034] When the atrasentan derivative is as shown in formula (B), its preparation method includes the following steps:

[0035] B01, Compound (b1) The compound (b2) was obtained by bromination with N-bromosuccinimide.

[0036] B02. Compound (b2) undergoes a nucleophilic substitution reaction with a substituted benzoyl acetate to give compound (b3).

[0037] B03. Compound (b3) undergoes a cyclization reaction with glycine under the action of a catalyst to obtain compound (b4).

[0038] B04. Compound (b4) undergoes an amide condensation reaction with an amine compound to yield compound (b5).

[0039] B05. The compound (b5) is subjected to ester hydrolysis to obtain the atrasentan derivative shown in 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 invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a solvent in step A02, wherein the solvent is selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, and toluene.

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

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

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

[0054] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes step A03 using iodomethane and a base, wherein the base is selected from at least one of n-butyllithium, potassium tert-butoxide, lithium diisopropylamino, sodium amino, sodium hydroxide, and sodium hydride.

[0055] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a solvent in step A03, wherein the solvent is selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, and toluene.

[0056] In some embodiments of the present invention, the atrasentan derivative shown in formula (A) is prepared, and in step A03, the cyclization reaction is carried out at a temperature of 20-120°C.

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

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

[0059] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a base in step A04, wherein the base is selected from at least one of n-butyllithium, potassium tert-butoxide, lithium diisopropylamino, sodium amino, sodium hydroxide, and sodium hydride.

[0060] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a solvent in step A04, wherein the solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, and N,N-dimethylformamide.

[0061] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and in step A04, the temperature of the nucleophilic substitution reaction is 0-120°C.

[0062] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a base in step A05, wherein the base is selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0063] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (A) further includes the use of a solvent, said solvent being ethanol, in step A05.

[0064] In some embodiments of the present invention, the atrasentan derivative of formula (A) is prepared, and the temperature of the ester hydrolysis reaction in step A05 is 0-120°C.

[0065] In some embodiments of the present invention, the atrasentan derivative of formula (B) is prepared, and in 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 invention, the atrasentan derivative of formula (B) is prepared, and in 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 invention, the preparation of the atrasentan derivative of formula (B) further includes the use of an acid in step B01, wherein the acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.

[0068] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a solvent in step B01, wherein the solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, and N,N-dimethylformamide.

[0069] In some embodiments of the present invention, the atrasentan derivative shown in formula (B) is prepared, and in step B01, the temperature of the bromination reaction is 0-120°C.

[0070] In some embodiments of the present invention, the atrasentan derivative of formula (B) is prepared, and in step B02, the molar ratio of the compound (b2) to the substituted benzoyl acetate is (1-1.5):1.

[0071] In some preferred embodiments of the present invention, the atrasentan derivative of formula (B) is prepared, and 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 invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a base in step B02, wherein the base is selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0073] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a solvent in step B02, wherein the solvent is selected from at least one of dioxane, tetrahydrofuran, acetonitrile, water, and toluene.

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

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

[0076] In some embodiments of the present invention, the atrasentan derivative shown in formula (B) is prepared, and 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 invention, the atrasentan derivative of formula (B) is prepared, and in step B03, the catalyst is selected from sodium acetate, acetic acid, ammonium chloride or p-toluenesulfonamide.

[0078] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a solvent in step B03, wherein the solvent is selected from at least one of toluene, tetrahydrofuran, ethanol, acetic acid, and N,N-dimethylformamide.

[0079] In some embodiments of the present invention, the atrasentan derivative shown in formula (B) is prepared, and in step B03, the cyclization reaction is carried out at a temperature of 0-120°C.

[0080] In some embodiments of the present invention, the atrasentan derivative shown in formula (B) is prepared, and 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 invention, the atrasentan derivative shown in formula (B) is prepared, and 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 invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a base and a condensing agent in step B04; the base is selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, imidazole or N-methylimidazole; the condensing agent is selected from O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (HATU), O-benzotriazol-N,N,N',N'-tetramethylurea (HBTU), chlorobenzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HCTU) or O-benzotriazol-N,N,N',N'-tetramethylurea (TBTU).

[0083] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a solvent in step B04, wherein 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 invention, the atrasentan derivative of formula (B) is prepared, and in step B04, the temperature of the amide condensation reaction is 20-25°C.

[0085] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a base in step B05, wherein the base is selected from sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide or lithium hydroxide.

[0086] In some embodiments of the present invention, the preparation of the atrasentan derivative of formula (B) further includes the use of a solvent, said solvent being ethanol, in step B05.

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

[0088] A third aspect of the present invention provides the use of the atrasentan derivative described in the first aspect of the present invention in the preparation of an anti-renal fibrosis drug.

[0089] A fourth aspect of the invention provides an anti-renal fibrosis drug comprising the atrasentan derivative or a pharmaceutically acceptable salt thereof described in the first aspect.

[0090] In some embodiments of the present invention, the anti-renal fibrosis drug further includes excipients.

[0091] Compared with the prior art, the beneficial effects of the present invention are:

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

[0093] 2) The atrasentan derivative preparation method provided by this invention provides two efficient and universal synthetic routes to obtain a tetrasubstituted pyrrole derivative designed with atrasentan as the lead. By reducing three chiral centers, the synthesis difficulty and cost are significantly reduced. This invention breaks through the synthesis bottleneck of atrasentan through the three-in-one strategy of "structural simplification-efficient synthesis-activity optimization" and provides a new candidate drug for the treatment of renal fibrosis. Attached Figure Description

[0094] Figure 1 This example is a 24-hour safety evaluation of atrasentan derivatives in HK-2 cells at a concentration of 10 μmol / L.

[0095] Figure 2 This example demonstrates the safety evaluation of atrasentan derivatives in HK-2 cells at a concentration of 20 μmol / L over 48 hours.

[0096] Figure 3 The example demonstrates the antifibrotic activity of atrasentan derivatives against TGF-β-induced HK-2 at a concentration of 10 μmol / L.

[0097] Figure 4 The antifibrotic activity of the compounds after initial screening against TGF-β-induced HK-2 at a concentration of 10 μmol / L was measured. Detailed Implementation

[0098] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments can be obtained from conventional commercial sources or by existing technical methods. Unless otherwise specified, the experimental or testing methods are conventional methods in the art.

[0099] Example 1

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

[0101] A011. 3,4-(methylenedioxy)cinnamic acid (3.46 g, 18 mmol) and 30 mL of anhydrous ethanol were added sequentially to a 100 mL round-bottom flask. The mixture was stirred until the solid was completely dissolved. Methanesulfonic acid (24 μL, 0.36 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, 30 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 3.68 g of yellow oily substance S2a, with a yield of 93%.

[0102] A012. Under ice bath conditions, 30 mL of dichloromethane was added to a 100 mL round-bottom flask, and dibutylamine (1.53 mL, 9 mmol) and bromoacetyl bromide (1.57 mL, 18 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 2.19 g of yellow oily substance S4a, with a yield of 97%.

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

[0104] A031. Under ice bath conditions, compound S7 (1.49 g, 5 mmol), 30 mL of ultra-dry tetrahydrofuran, iodomethane (343 μL, 5.5 mmol), and potassium tert-butoxide (616 mg, 5.5 mmol) were added to a 100 mL round-bottom flask and stirred for 2 h. Under ice bath conditions, compound S2a (1.21 g, 5.5 mmol) and potassium tert-butoxide (1.68 g, 15 mmol) were added. The mixture was heated to reflux at 90 °C for 2 h, then allowed to return to room temperature. The reaction solution was concentrated until the tetrahydrofuran was completely vortexed off. 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. Filtering yielded 1.37 g of white solid S8, with a yield of 75%.

[0105] A041. Compound S8 (365 mg, 1 mmol), compound S4a (350 mg, 1.4 mmol), and 10 mL of acetonitrile were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve the compounds. Sodium hydride (60 mg, 1.5 mmol) was slowly added. 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 = 5:1 to 3:1, v / v) to give 518.1 mg of white solid S9, with a yield of 97%.

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

[0107] The structural formula of compound S2a is as follows: The structural formula of S4a is: The structural formula of S7 is:

[0108] Compounds S2a, S4a, S7, S8, S9 and S10 were subjected to... 1 H NMR characterization, the results are as follows:

[0109] S2a: 1 H NMR(400MHz,Chloroform-d)δ7.59(dd,J=16.0,2.5Hz,1H),7.06–6.96(m,2H),6.81(dd,J=7.9,2.4Hz,1H),6 .26(dd,J=16.0,2.5Hz,1H), 6.00(d,J=2.4Hz,2H), 4.25(qd,J=7.2,2.2Hz,2H), 1.33(td,J=7.1,2.3Hz,3H).

[0110] S4a: 1 H NMR(400MHz,Chloroform-d)δ3.81(d,J=2.2Hz,2H),3.39–3.17(m,4H),1.67

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

[0112] S7: 1 H NMR(500MHz,Chloroform-d)δ8.89(s,1H),8.04(d,J=8.4Hz,1H),7.96(dt,J=8.4,1.0Hz,1H),7.88–7.83(m,2H),7.52(ddd,J=8.2,7.0,1.0Hz,1H),7.37(ddd,J=8.1,7.0,1.0Hz,1H),6.85(d,J=8.9Hz,2H),6.80(d,J=6.2Hz,2H),3.82(s,3H).

[0113] S8: 1 H NMR(400MHz,Chloroform-d)δ8.42(s,1H),7.50–7.42(m,2H),6.99–6.85(m,4H),6.80(dd,J=8.0,2.4Hz,1H),6.71(d,J=2.9Hz,1H),5.95(d,J=2.3Hz,2H),4.08(qd,J=7.1,2.1Hz,2H),3.84(d,J=2.2Hz,3H),1.05(td,J=7.2,2.2Hz,3H).

[0114] S9: 1 H NMR(500MHz,Chloroform-d)δ7.27(d,J=8.7Hz,2H),6.98(d,J=1.6Hz,1H),6.93(td,J=5.9,3.1Hz,3H),6.78(d,J=7.9Hz,1H),6.68(s,1H),5.94(s,2H),4.43(s,2H),3.96(q,J=7.1Hz,2H),3.83(s,3H),3.32–3.22(m,2H),2.94(t,J=7.7Hz,2H),1.51–1.41(m,2H),1.32–1.19(m,5H),1.11(h,J=7.3Hz,2H),0.91(td,J=7.3,1.6Hz,6H),0.83(t,J=7.3Hz,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. Compound A3 (240 mg, 0.5 mmol), 5 mL of ethanol and 1 mL of water were added to a 50 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (105 mg, 2.5 mmol) was added and the mixture was heated to reflux at 120 °C for 30 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v) to give 51.1 mg of pale yellow solid A7, with a yield of 23%.

[0122] A051. Compound A3 (45.2 mg, 0.09 mmol), 5 mL of ethanol, and 1 mL of water were added to a 50 mL round-bottom flask. The mixture was stirred, followed by the addition of lithium hydroxide hydrate (20 mg, 0.4 mmol). The mixture was heated to reflux at 120 °C for 48 h, cooled to room temperature, and the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), 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 = 2:1 to 1:1, v / v) to give 27 mg of pale yellow solid A1, with a yield of 63%.

[0123] The structural formula of compound S4b is as follows:

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

[0125] S4b: 1 H NMR(400MHz,Chloroform-d)δ3.77(s,2H),3.39–3.21(m,4H),1.11(dt,J=50.1,3.6Hz,6H)

[0126] A3: 1 H NMR(500MHz,Chloroform-d)δ7.29(s,1H),7.27(s,1H),6.98(d,J=1.6Hz,1H),6.95–6.90(m,3H),6.78(d,J=7.9Hz,1H),6.69(s,1H),5.94(s,2 H), 4.44 (s, 2H), 3.97 (q, J = 7.1Hz, 2H), 3.84 (s, 3H), 3.34 (q, J = 7.1Hz, 2H), 3.04 (q, J = 7.2Hz, 2H), 1.10 (t, J = 7.1Hz, 3H), 0.92 (t, J = 7.1Hz, 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. Compound A4 (183 mg, 0.36 mmol), 5 mL of ethanol, and 1 mL of water were added to a 50 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (73 mg, 1.74 mmol) was added, and the mixture was heated to reflux at 120 °C for 30 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1, v / v) to give 69.4 mg of pale yellow solid A8, with a yield of 40%.

[0135] The structural formula of compound S4c is as follows:

[0136] Compounds S4c, A4 and A8 were subjected to 1 H NMR characterization, the results are as follows:

[0137] S4c: 1 H NMR (400MHz, Chloroform-d) δ3.75 (s, 2H), 3.17 (q, J = 7.9Hz, 4H), 1.50 (dq, J = 32.2, 7.6Hz, 4H), 0.81 (dt, J = 20.0, 7.5Hz, 6H).

[0138] A4: 1 H NMR(500MHz,Chloroform-d)δ7.29(s,1H),7.27(s,1H),6.98(d,J=1.7Hz,1H),6.95–6. 89(m,3H),6.78(d,J=8.0Hz,1H),6.68(s,1H),5.94(s,2H),4.45(s,2H),3.97(q,J=7.1H z,2H),3.84(s,3H),3.28–3.19(m,2H),2.92(t,J=7.7Hz,2H),1.51(p,J=7.5Hz,2H),1. 33(h,J=7.4Hz,2H),0.92(t,J=7.1Hz,3H),0.86(t,J=7.4Hz,3H),0.75(t,J=7.4Hz,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. Compound A5 (320.8 mg, 0.54 mmol), 5 mL of ethanol, and 1 mL of water were added to a 50 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (114 mg, 2.72 mmol) was added, and the mixture was heated to reflux at 100 °C for 24 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and 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 1:1, v / v) to give 176.9 mg of white solid A9, with a yield of 58%.

[0147] The structural formula of compound S4d is as follows:

[0148] Compounds S4d, A5, and A9 were subjected to... 1 H NMR characterization, the results are as follows:

[0149] S4d: 1 H NMR (500MHz, Chloroform-d) δ3.82 (s, 2H), 3.28 (dt, J = 16.0, 7.7Hz, 4H), 1.59

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

[0151] A5: 1 H NMR(500MHz,Chloroform-d)δ7.27(d,J=8.5Hz,2H),6.98(d,J=1.7Hz,1H),6.92(dd,J= 7.9,5.6Hz,3H),6.77(d,J=8.0Hz,1H),6.68(s,1H),5.93(s,2H),4.43(s,2H),3.96(q,J =7.1Hz,2H),3.83(s,3H),3.26(t,J=7.6Hz,2H),2.93(t,J=7.8Hz,2H),1.47(p,J=7.3H z,2H),1.31–1.20(m,10H),1.20–1.12(m,2H),1.09(q,J=7.6Hz,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. Compound A6 (260 mg, 0.40 mmol), 5 mL of ethanol, and 1 mL of water were added to a 50 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (85 mg, 2.01 mmol) was added, and the mixture was heated to reflux at 100 °C for 24 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1, v / v) to give 126.1 mg of white solid A10, with a yield of 51%.

[0158] The structural formula of compound S4e is as follows:

[0159] Compounds S4e, A6 and A10 were subjected to 1 H NMR characterization, the results are as follows:

[0160] S4e: 1 H NMR (500MHz, Chloroform-d) δ3.83 (s, 2H), 3.28 (dt, J = 16.0, 7.8Hz, 4H), 1.60

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

[0162] A6: 1 H NMR(500MHz,Chloroform-d)δ7.27(d,J=8.6Hz,2H),6.98(d,J=1.7Hz,1H),6.94–6.8 9(m,3H),6.78(d,J=8.0Hz,1H),6.68(s,1H),5.94(s,2H),4.43(s,2H),3.96(q,J=7. 1Hz,2H),3.83(s,3H),3.26(t,J=7.6Hz,2H),2.93(t,J=7.8Hz,2H),1.47(p,J=7.4Hz ,2H),1.25(qq,J=20.2,13.7,10.2Hz,20H),1.09(q,J=7.6Hz,2H),0.95–0.84(m,9H).

[0163] A10: 1 H NMR(500MHz,Chloroform-d)δ7.25–7.21(m,2H),6.95(d,J=1.8Hz,1H),6.93

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

[0165] Example 6

[0166] This embodiment prepares atrasentan derivative A11 The steps are as follows:

[0167] A041. Compound S8 (365 mg, 1 mmol) prepared in Example 1, methyl iodide (22 μL, 0.36 mmol), and acetonitrile (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve, and sodium hydride (24 mg, 0.6 mmol) was slowly added. 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 = 7:1 to 5:1, v / v) to give 95.3 mg of white solid A11, yield 84%.

[0168] Compound A11 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.30(d,J=8.2Hz,2H),6.96(s,3H),6.91(d,J=7.4Hz,1H),6.80(d,J=7.9H z,1H),6.62(s,1H),5.95(s,2H),4.00(t,J=7.2Hz,2H),3.86(s,3H),3.43(s,3H),0.95(t,J=7.1Hz,3H).

[0169] Example 7

[0170] This embodiment prepares atrasentan derivative A12. The steps are as follows:

[0171] A041. Compound S8 (110 mg, 0.3 mmol) prepared in Example 1, p-methylbenzoyl chloride (48 μL, 0.36 mmol), and 3 mL of dichloromethane were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve, and N,N-diisopropylethylamine (105 μL, 0.6 mmol) was slowly added. The mixture was heated to reflux at 60 °C for 6 h, the reaction was quenched with water, and the mixture was extracted with dichloromethane (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 = 7:1 to 5:1, v / v) to give 113.8 mg of yellow oily substance A12, with a yield of 79%.

[0172] Compound A12 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=7.8Hz,2H),7.32(d,J=8.2Hz,2H),7.22(d,J=7.8Hz,2H),6.99(s,1H),6.96–6.89 (m,2H),6.82(dd,J=12.3,8.1Hz,3H),5.96(s,2H),4.08(q,J=7.1Hz,2H),3.79(s,3H),2.41(s,3H),1.01(t,J=7.1Hz,3H).

[0173] Example 8

[0174] This embodiment prepares atrasentan derivative A13. The steps are as follows:

[0175] A041. Compound S8 (110 mg, 0.3 mmol), benzoyl chloride (42 μL, 0.36 mmol), and 3 mL of dichloromethane prepared in Example 1 were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve, and N,N-diisopropylethylamine (105 μL, 0.6 mmol) was slowly added. The mixture was heated to reflux at 50 °C for 24 h, the reaction was quenched with water, and the mixture was extracted with dichloromethane (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 = 7:1 to 5:1, v / v) to give 129.1 mg of yellow oily substance A13, with a yield of 92%.

[0176] Compound A13 was subjected to 1 H NMR characterization, the results are as follows: 1H NMR(500MHz,Chloroform-d)δ7.73(d,J=8.0Hz,2H),7.58–7.51(m,1H),7.44–7.37(m,2H),7.34–7.28(m,2H),7.02(d,J=1.4Hz,1H),6 .97–6.89(m,2H),6.86–6.79(m,3H),5.96(d,J=1.3Hz,2H),4.08(q,J=7.1Hz,2H),3.78(d,J=1.3Hz,3H),1.01(td,J=7.2,1.3Hz,3H).

[0177] Example 9

[0178] This embodiment prepares atrasentan derivative A14. The steps are as follows:

[0179] A041. Compound S8 (219 mg, 0.6 mmol) prepared in Example 1, tert-butyl bromoacetate (120 μL, 0.84 mmol), and 5 mL of dichloromethane were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve, and sodium hydride (36 mg, 0.45 mmol) was slowly added. 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 = 10:1 to 7:1, v / v) to give 125.0 mg of colorless oil A14, with a yield of 87%.

[0180] Compound A14 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.28(s,2H),6.97(s,1H),6.96–6.90(m,3H),6.80(d,J=8.0Hz,1H),6.65( s,1H),5.95(s,2H),4.31(s,2H),3.98(q,J=7.1Hz,2H),3.85(s,3H),1.42(s,9H),0.93(t,J=7.1Hz,3H).

[0181] Example 10

[0182] This embodiment prepares atrasentan derivative A2. The steps are as follows:

[0183] A041. Compound A14 (27 mg, 0.056 mmol) prepared in Example 9 and 1 mL of dichloromethane were added to a 50 mL round-bottom flask. The mixture was stirred, and trifluoroacetic acid (0.5 mL, 2.95 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 2 h. The reaction was quenched with water and extracted with dichloromethane (3 × 3 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 (dichloromethane / methanol = 10:1, v / v) to give 9 mg of pale yellow solid A2, with a yield of 38%.

[0184] Compound A2 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz, Methanol-d4)δ7.27(d,J=8.1Hz,2H),6.97(d,J=7.6Hz,2H),6.94–6.85(m,2H),6.78(d ,J=7.3Hz,2H),5.93(s,2H),4.42(s,2H),3.92(q,J=7.2Hz,2H),3.84(s,3H),0.91(t,J=7.1Hz,4H).

[0185] Example 11

[0186] This embodiment prepares atrasentan derivative C1. The steps are as follows:

[0187] A011. 3,4-(methylenedioxy)cinnamic acid (384 mg, 2 mmol) and 10 mL of methanol were added sequentially to a 50 mL round-bottom flask. The mixture was stirred until the solid was completely dissolved. Methanesulfonic acid (3 μL, 0.04 mmol) was slowly added while stirring. The mixture was heated to reflux at 80 °C for 4 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 methanol was completely evaporated. Then, 10 mL of ethyl acetate was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 10 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 393.5 mg of yellow oily substance S2 g, with a yield of 96%.

[0188] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 30 mL of ultra-dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol), and potassium tert-butoxide (369 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 S2 g (679.8 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. 30 mL of dichloromethane was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 30 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. Filtering yielded 618 mg of white solid Cl, with a yield of 59%.

[0189] The structural formula of compound S2g is as follows:

[0190] Compounds S2g and C1 were subjected to 1 H NMR characterization, the results are as follows:

[0191] S2g: 1 H NMR(500MHz,Chloroform-d)δ7.57(d,J=15.9Hz,1H),7.03–6.95(m,2H),6.78

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

[0193] C1: 1 H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.46(d,J=8.7Hz,2H),6.97–6.91

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

[0195] Example 12

[0196] This embodiment prepares atrasentan derivative C2. The steps are as follows:

[0197] A011. 3,4-(methylenedioxy)cinnamic acid (1.15 mg, 6 mmol) and 30 mL isopropanol were added sequentially to a 100 mL round-bottom flask. The mixture was stirred until the solid was completely dissolved. Methanesulfonic acid (9 μL, 0.12 mmol) was slowly added while stirring. The mixture was heated to reflux at 120 °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 isopropanol was completely vortexed off. Then, 30 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 1.21 g of yellow oily substance S2h, with a yield of 86%.

[0198] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 30 mL of ultra-dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol), and potassium tert-butoxide (369 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 S2 (772.2 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 vortexed off. 30 mL of dichloromethane was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 30 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. 803.5 mg of a white to pale yellow solid C2 was obtained by suction filtration, with a yield of 71%.

[0199] The structural formula of compound S2h is as follows:

[0200] Compounds S2h and C2 were subjected to 1 H NMR characterization, the results are as follows:

[0201] S2h: 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J=15.9Hz,1H),6.99–6.89(m,2H),6.73

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

[0203] C2: 1H NMR(400MHz,Chloroform-d)δ8.29(s,1H),7.48(d,J=8.8Hz,2H),6.97–6.91

[0204] (m,3H),6.89(dd,J=8.0,1.7Hz,1H),6.80(d,J=8.0Hz,1H),6.72(d,J=2.5Hz ,1H),5.96(s,2H),5.01(p,J=6.2Hz,1H),3.84(s,3H),1.06(d,J=6.2Hz,6H).

[0205] Example 13

[0206] This embodiment prepares atrasentan derivative C3. The steps are as follows:

[0207] Compound S10 (47.6 mg, 0.094 mmol) prepared in Example 1, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (46.5 mg, 0.122 mmol), 2 mL of ultradry dichloromethane, dimethylacetamide (47 μL, 0.094 mmol), and N,N-diisopropylethylamine (33 μL, 0.188 mmol) were added to a 10 mL round-bottom flask. The mixture was stirred at room temperature for 15 min, the reaction was quenched with water, extracted with dichloromethane (3 × 3 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 ablation in a petroleum ether / ethyl acetate = 2:1 (v / v) system to give 22.1 mg of pale yellow solid C3, yield 44%.

[0208] Compound C3 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.32(d,J=8.8Hz,2H),6.97–6.92(m,2H),6.89(d,J=8. 8Hz,2H),6.81(s,1H),6.75(d,J=8.0Hz,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=7.4Hz,2H),0.94(t,J=7.3Hz,3H),0.84(t,J=7.3Hz,4H).

[0209] Example 14

[0210] This embodiment prepares atrasentan derivative C4. The steps are as follows:

[0211] Compound S10 (45.3 mg, 0.090 mmol) prepared in Example 1, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (44.2 mg, 0.116 mmol), 2 mL of ultradry dichloromethane, propargylamine (105 μL, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) were added to a 10 mL round-bottom flask. The mixture was stirred at room temperature for 15 min, the reaction was quenched with water, extracted with dichloromethane (3 × 3 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 plate preparation in a petroleum ether / ethyl acetate = 2:1 (v / v) system to give 13.8 mg of pale yellow solid C4, yield 30%.

[0212] Compound C4 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.33(d,J=8.2Hz,2H),7.00–6.90(m,4H),6.80(d,J=7.8H z,1H),6.70(s,1H),5.95(s,2H),4.45(s,2H),3.92(dd,J=5.7,2.5Hz,2H),3.82(s,3H) ,3.30(t,J=7.6Hz,2H),2.97(t,J=7.7Hz,2H),2.08–2.03(m,1H),1.49(t,J=7.6Hz,2H) ,1.31–1.27(m,4H),1.13(q,J=7.5Hz,2H),0.93(t,J=7.3Hz,3H),0.84(t,J=7.3Hz,4H).

[0213] Example 15

[0214] This embodiment prepares atrasentan derivative C5. The steps are as follows:

[0215] Compound C1 (140.4 mg, 0.4 mmol) prepared in Example 11, compound S4a (140 mg, 0.56 mmol) prepared in Example 1, and 4 mL of acetonitrile were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve the compounds, and sodium hydride (24 mg, 0.6 mmol) was slowly added. 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 = 5:1 to 4:1, v / v) to give 195 mg of white solid C5, with a yield of 94%.

[0216] Compound C5 was subjected to 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.27(d,J=8.6Hz,2H),6.96(d,J=1.7Hz,1H),6.95–6. 90(m,3H),6.78(d,J=7.9Hz,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=8.8,6.4Hz,2H),2.98–2.91(m,2H),1.51–1.43(m,2H),1. 31–1.21(m,5H),1.11(h,J=7.3Hz,2H),0.92(t,J=7.4Hz,3H),0.83(t,J=7.3Hz,3H).

[0217] Example 16

[0218] This embodiment prepares atrasentan derivative C6. The steps are as follows:

[0219] Compound C2 (151.6 mg, 0.4 mmol) prepared in Example 12, compound S4a (140 mg, 0.56 mmol) prepared in Example 1, and 4 mL of acetonitrile were added to a 50 mL round-bottom flask. The mixture was stirred to dissolve the compounds, and sodium hydride (24 mg, 0.6 mmol) was slowly added. 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, v / v) to give 214.8 mg of pale pink solid C6, with a yield of 98%.

[0220] Compound C6 was subjected to 1 H NMR characterization, the results are as follows: 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] The structural formula of compound S2b is as follows:

[0226] Compounds S2b and D1 were subjected to 1 H NMR characterization, the results are as follows:

[0227] S2b: 1 H NMR(500MHz,Chloroform-d)δ7.62(d,J=15.9Hz,1H),7.09(dd,J=8.3,2.0Hz,1H),7.04(d,J=2.0Hz,1H), 6.85(d,J=8.3Hz,1H),6.30(d,J=15.9Hz,1H),4.24(q,J=7.1Hz,2H),3.90(s,6H),1.32(t,J=7.1Hz,3H).

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

[0229] This embodiment prepares atrasentan derivative D2. The steps are as follows:

[0230] A011. 4-Methoxycinnamic acid (1.07 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, water was added to the reaction solution to quench the reaction 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 1.13 g of yellow oily substance S2c, with a yield of 91%.

[0231] 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 S2c (629 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. Filtering yielded 636 mg of pale yellow solid D2, with a yield of 60%.

[0232] The structural formula of compound S2c is as follows:

[0233] Compounds S2c and D2 were subjected to 1 H NMR characterization, the results are as follows:

[0234] S2c: 1 H NMR(500MHz,Chloroform-d)δ7.63(d,J=15.9Hz,1H),7.46(d,J=8.8Hz,2H),6.89(d,J=8.8 Hz, 2H), 6.30 (d, J = 15.9Hz, 1H), 4.24 (q, J = 7.1Hz, 2H), 3.82 (s, 3H), 1.32 (t, J = 7.1Hz, 3H).

[0235] D2: 1 H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.45(dd,J=8.7,1.2Hz,2H),7.36(d,J=8.6Hz,2H),6. 97–6.85(m,4H),6.68(d,J=2.1Hz,1H),4.06(q,J=7.1Hz,2H),3.83(s,6H),1.02(t,J=7.1Hz,3H).

[0236] Example 19

[0237] This embodiment prepares atrasentan derivative D3. The steps are as follows:

[0238] 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, ethyl cinnamate (558 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. 530 mg of pale yellow solid D3 was obtained by suction filtration, with a yield of 55%.

[0239] Perform on D3 1 H NMR characterization, the results are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.44(s,1H),7.45(dd,J=8.7,1.8Hz,2H),7.42–7.38(m,2H),7.32(t,J=7.6Hz,2H),7. 24(d,J=7.1Hz,1H),6.93–6.87(m,2H),6.71–6.66(m,1H),4.03(q,J=7.1Hz,2H),3.80(s,3H),0.97(t,J=7.1Hz,3H).

[0240] Example 20

[0241] This embodiment prepares atrasentan derivative D4. The steps are as follows:

[0242] A011. 4-Bromocinnamic acid (1.36 g, 6 mmol) and 10 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, water was added to the reaction solution to quench the reaction 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 × 10 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 1.40 g of colorless oily substance S2d, with a yield of 92%.

[0243] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of ultra-dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol), and potassium tert-butoxide (369 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 S2d (838 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. Filtration yielded 501 mg of pale yellow solid D4, with a yield of 47%.

[0244] The structural formula of compound S2d is as follows:

[0245] Compounds S2d and D4 were subjected to 1 H NMR characterization, the results are as follows:

[0246] S2d: 1 H NMR(500MHz,Chloroform-d)δ7.60(d,J=16.0Hz,1H),7.50(d,J=8.5Hz,2H),7.36(d ,J=8.5Hz,2H),6.41(d,J=16.0Hz,1H),4.25(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0247] D4: 1 H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.51–7.42(m,4H),7.30(d,J=8.1

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

[0249] Example 21

[0250] This embodiment prepares atrasentan derivative D5. The steps are as follows:

[0251] A011. 4-Chlorocinnamic acid (1.10 g, 6 mmol) and 10 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, water was added to the reaction solution to quench the reaction 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 × 10 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 1.16 g of colorless oily substance S2e, with a yield of 92%.

[0252] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of ultra-dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol), and potassium tert-butoxide (369 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 S2e (693 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. 458 mg of pale yellow solid D5 was obtained by suction filtration, with a yield of 43%.

[0253] The structural formula of compound S2e is as follows:

[0254] Compounds S2e and D5 were subjected to 1 H NMR characterization, the results are as follows:

[0255] S2e: 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=16.0Hz,1H),7.43(d,J=8.2Hz,2H),7.33(d ,J=8.2Hz,2H),6.39(d,J=16.0Hz,1H),4.25(q,J=7.1Hz,2H),1.32(t,J=7.2Hz,3H).

[0256] D5: 1H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.47(d,J=8.3Hz,2H),7.36(d,J=8.2Hz,2H),7.31(d,J=8.2Hz,2 H), 6.93 (d, J = 8.3Hz, 2H), 6.72 (d, J = 2.4Hz, 1H), 4.06 (q, J = 7.1Hz, 2H), 3.84 (s, 3H), 1.02 (t, J = 7.1Hz, 3H).

[0257] Example 22

[0258] This embodiment prepares atrasentan derivative D6. The steps are as follows:

[0259] A011. 4-Fluorocinic acid (2.99 g, 18 mmol) and 10 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 (24 μL, 0.36 mmol) was slowly added while stirring. The mixture was heated to reflux at 90 °C for 24 h. After cooling to room temperature, water was added to the reaction solution to quench the reaction under ice bath conditions. The reaction solution was concentrated until the ethanol was completely evaporated. Then, 15 mL of ethyl acetate was added, and the reaction was quenched with saturated NaHCO3 solution (3 × 15 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 3.13 g of colorless oily substance S2f, with a yield of 90%.

[0260] A031. Under ice bath conditions, compound S7 (894 mg, 3 mmol) prepared in Example 1, 18 mL of ultra-dry tetrahydrofuran, iodomethane (205 μL, 3.3 mmol), and potassium tert-butoxide (369 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 S2f (729 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. Filtering yielded 315.3 mg of pale yellow solid D6, with a yield of 31%.

[0261] The structural formula of compound S2f is as follows:

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

[0263] S2f: 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=16.0Hz,1H),7.50(dd,J=8.7,5.5Hz,2H),7.07 (t,J=8.6Hz,2H),6.35(d,J=16.0Hz,1H),4.26(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0264] D6: 1 H NMR(500MHz,Chloroform-d)δ8.77–8.42(m,1H),7.50–7.40(m,2H),7.37(t,J=7.1Hz,2H),7.08–6.99(m,2H),6 .95–6.88(m,2H),6.64(d,J=2.7Hz,1H),4.10–3.99(m,2H),3.82(d,J=1.9Hz,3H),1.00(td,J=7.1,2.1Hz,3H).

[0265] Example 23

[0266] This embodiment prepares atrasentan derivative D10. and D16 The steps are as follows:

[0267] Compound D4 (61.4 mg, 0.15 mmol) prepared in Example 20, compound S4a (45 mg, 0.18 mmol) prepared in Example 1, and 3 mL of acetonitrile were added to a 10 mL round-bottom flask. The mixture was stirred to dissolve the compounds, and potassium tert-butoxide (20 mg, 0.18 mmol) was slowly added. The mixture was reacted at room temperature for 6 h, 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 = 7:1 to 5:1, v / v) to give 69.0 mg of colorless oil D10, with a yield of 81%.

[0268] Compound D10 (124 mg, 0.22 mmol), 5 mL of ethanol, and 1 mL of water were added to a 25 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (46 mg, 1.1 mmol) was added, and the mixture was heated to reflux at 100 °C for 24 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and 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 = 7:1 to 3:1, v / v) to give 70.7 mg of white solid D16, with a yield of 60%.

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

[0270] D10: 1 H NMR (500MHz, Chloroform-d) δ7.43 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8. 0Hz,2H),6.93(d,J=8.2Hz,2H),6.72(s,1H),4.44(s,2H),3.95(q,J=7.2Hz,2H),3.84(s ,3H),3.27(t,J=7.6Hz,2H),2.95(t,J=7.6Hz,2H),1.47(t,J=7.7Hz,2H),1.26(p,J=10. 4,9.0Hz,4H),1.11(q,J=7.5Hz,2H),0.91(dt,J=12.3,7.3Hz,6H),0.84(t,J=7.3Hz,3H).

[0271] D16: 1 H NMR(500MHz,Chloroform-d)δ7.42(dd,J=8.3,1.8Hz,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 = 1.5Hz, 1H), 4.42(s, 2H), 3.84(d, J = 1.4Hz, 3H), 3.26(t, J = 7.6Hz, 2H), 2.93(t, J = 7.7Hz, 2H), 1.50–1.42(m, 2H), 1.25(dq, J = 17.0, 8.9, 8.3Hz, 5H), 1.11(q, J = 7.5Hz, 2H), 0.91(t, J = 7.4Hz, 3H), 0.83(t, J = 7.3Hz, 3H). Example 24

[0273] This embodiment prepares atrasentan derivative D11 and D17 The steps are as follows:

[0274] Compound D5 (150 mg, 0.42 mmol) prepared in Example 21, compound S4a (129 mg, 0.51 mmol) prepared in Example 1, and 3 mL of acetonitrile were added to a 10 mL round-bottom flask. The mixture was stirred to dissolve the compounds, and potassium tert-butoxide (57 mg, 0.51 mmol) was slowly added. 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 = 7:1 to 5:1, v / v) to give 69.0 mg of colorless oil D11, with a yield of 89%.

[0275] Compound D11 (104.8 mg, 0.2 mmol), 2 mL of ethanol, and 0.4 mL of water were added to a 10 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (42 mg, 1 mmol) was added, and the mixture was heated to reflux at 100 °C for 24 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and 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 = 7:1 to 3:1, v / v) to give 56.8 mg of white solid D17, with a yield of 57%.

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

[0277] D11: 1 H NMR(400MHz,Chloroform-d)δ7.42–7.38(m,2H),7.27(dd,J=8.6,4.2Hz,4H),6.95 –6.90(m,2H),6.72(s,1H),4.44(s,2H),3.95(q,J=7.1Hz,2H),3.83(s,3H),3.32–3 .23(m,2H),2.99–2.90(m,2H),1.46(ddt,J=9.2,7.6,3.5Hz,2H),1.32–1.20(m,4H ), 1.11 (dq, J=14.5, 7.2Hz, 2H), 0.90 (dt, J=9.2, 7.2Hz, 6H), 0.83 (t, J=7.2Hz, 3H).

[0278] D17:1 H NMR(500MHz,Chloroform-d)δ7.38(d,J=8.0Hz,2H),7.24(dd,J=13.1,8.3Hz,4H),6.89(d,J=8.2Hz,2H),6.69(s,1H),4.40(s,2H),3.83(s,3H),3.26 (t,J=7.6Hz,2H),2.91(t,J=7.7Hz,2H),1.46(p,J=7.5Hz,2H),1.29–1.22( m,5H),1.10(p,J=7.4Hz,2H),0.91(t,J=7.3Hz,3H),0.82(t,J=7.2Hz,3H).

[0279] Example 25

[0280] This embodiment prepares atrasentan derivative D12 and D18 The steps are as follows:

[0281] Compound D6 (150 mg, 0.45 mmol) prepared in Example 22, compound S4a (135 mg, 0.54 mmol) prepared in Example 1, and 3 mL of acetonitrile were added to a 10 mL round-bottom flask. The mixture was stirred to dissolve the compounds, and potassium tert-butoxide (60 mg, 0.54 mmol) was slowly added. The mixture was reacted at room temperature for 6 h, 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 = 7:1 to 5:1, v / v) to give 208.0 mg of colorless oil D12, with a yield of 91%.

[0282] Compound D12 (101.6 mg, 0.2 mmol), 2 mL of ethanol, and 0.4 mL of water were added to a 10 mL round-bottom flask and stirred. Then, lithium hydroxide hydrate (42 mg, 1 mmol) was added, and the mixture was heated to reflux at 100 °C for 24 h. After cooling to room temperature, the pH was adjusted to acidic by adding 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and 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 = 7:1 to 3:1, v / v) to give 44.1 mg of white solid D18, with a yield of 46%.

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

[0284] D12: 1H NMR (400MHz, Chloroform-d) δ7.42 (dd, J=8.8, 5.5Hz, 2H), 7.27 (d, J=8.8Hz, 2H), 7. 00(t,J=8.8Hz,2H),6.92(d,J=8.7Hz,2H),6.70(s,1H),4.44(s,2H),3.94(q,J=7.1H z,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=13.1,7.2Hz,7H),0.83(t,J=7.2Hz,3H).

[0285] D18: 1 H NMR(500MHz,Chloroform-d)δ7.40(dd,J=8.3,5.5Hz,2H),7.23(d,J=8.2Hz,2H), 6.97(t,J=8.6Hz,2H),6.89(d,J=8.2Hz,2H),6.67(s,1H),4.40(s,2H),3.83(s,3H ),3.26(t,J=7.6Hz,2H),2.92(t,J=7.7Hz,2H),1.46(t,J=7.7Hz,2H),1.25(dd,J= 14.5, 6.5Hz, 4H), 1.15–1.06 (m, 2H), 0.91 (t, J = 7.4Hz, 3H), 0.82 (t, J = 7.3Hz, 3H).

[0286] Example 26

[0287] This embodiment prepares atrasentan derivative S14 S15 and S16 The steps are as follows:

[0288] B011. 3,4-Methylenedioxyacetophenone (1.48 g, 9 mmol), p-toluenesulfonic acid hydrate (171 mg, 0.9 mmol), and 12 mL of acetonitrile were added sequentially to a 50 mL round-bottom flask. The mixture was stirred, followed by the addition of N-bromosuccinimide (1.60 g, 9 mmol). The reaction was carried out 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 = 5:1 to 3:1, v / v) to give 1.79 g of pale yellow solid S12, yield 82%.

[0289] B021. Add S12 (765 mg, 3.15 mmol), ethyl 3-(4-methoxyphenyl)-3-oxopropionate (366 μL, 2.88 mmol), and 4 mL of acetonitrile to a 50 mL round-bottom flask, stir, then add potassium carbonate (432 mg, 3.15 mmol), react at room temperature for 3 h, quench the reaction with water, extract with ethyl acetate (3 × 10 mL), wash the combined organic phases with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1, v / v) to give 3.32 g of pale yellow oil S13, yield 96%;

[0290] B031. Add S13 (336.9 mg, 0.88 mmol), glycine (150 mg, 4.0 mmol), and 8 mL of acetic acid to a 50 mL round-bottom flask. Reflux overnight at 120 °C. Allow the reaction to return to room temperature. Adjust the pH to neutral with 5 mol / L sodium hydroxide solution. Extract with ethyl acetate (3 × 10 mL). Wash the combined organic phases with saturated NaCl solution. Dry the mixture in anhydrous Na2SO4. Filter and concentrate under reduced pressure. Purify by silica gel column chromatography (dichloromethane / methanol = 20:1 to 10:1, v / v) to give 176.1 g of black oily substance S14, yield 47%.

[0291] B041. Add S14 (46.1 mg, 0.11 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (53.2 mg, 0.14 mmol), 5 mL of ultra-dry dichloromethane, di-n-butylamine (13 μL, 0.11 mmol), and N,N-diisopropylethylamine (38 μL, 0.22 mmol) to a 25 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 petroleum ether / ethyl acetate = 4:1 (v / v) system to obtain 38.2 mg of white oily substance S15, yield 65%.

[0292] B051. Add S15 (29.8 mg, 0.056 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (11.7 mg, 0.27 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 in a petroleum ether / ethyl acetate = 1:1 (v / v) system to obtain 18.6 mg of black oily substance S16, yield 66%.

[0293] The structural formula of compound S12 is as follows: The structural formula of S13 is:

[0294] Compounds S12, S13, S14, S15, and S16 were subjected to... 1 H NMR characterization, the results are as follows:

[0295] S12: 1 H NMR (500MHz, Chloroform-d) δ7.58(dd,J=8.2,1.4Hz,1H),7.43(s,1H),6.86(d,J=8.0Hz,1H),6.06(s,2H),4.36(s,2H).

[0296] S13: 1 H NMR(500MHz,Chloroform-d)δ8.07(d,J=8.4Hz,2H),7.62(dd,J=8.1,1.7Hz,1H),7.43(d,J=1.8Hz,1H),6.96(d,J=8.5Hz,2H),6.84 (d,J=8.1Hz,1H),6.03(s,2H),5.05(t,J=6.8Hz,1H),4.15(q,J=7.1Hz,2H),3.87(s,3H),3.72–3.59(m,2H),1.17(t,J=7.1Hz,3H).

[0297] S14: 1 H NMR(500MHz,Methanol-d4)δ7.31(d,J=8.7Hz,2H),6.98–6.90(m,4H),6.82

[0298] (d,J=7.9Hz,1H),6.55(s,1H),5.95(s,2H),4.23(s,2H),4.04(q,J=7.1Hz,2H),3.82(s,3H),1.08(t,J=7.1Hz,3H).

[0299] S15: 1 H NMR(500MHz,Chloroform-d)δ7.33(d,J=8.7Hz,2H),6.94(d,J=1.7Hz,1H),6.93–6.88(m,3H),6.80(d,J=7. 9Hz,1H),6.66(s,1H),5.97(s,2H),4.34(s,2H),4.11(q,J=7.1Hz,2H),3.82(s,3H),3.26(t,J=7.4Hz,2H), 2.85(t,J=7.4Hz,2H),1.67(s,1H),1.48–1.39(m,2H),1.24(h,J=7.3Hz,2H),1.13(t,J=7.1Hz,3H),1.08(d dd,J=10.9,7.4,5.0Hz,2H),1.01(ddd,J=9.5,7.2,4.5Hz,2H),0.92(t,J=7.3Hz,3H),0.76(t,J=7.2Hz,3H).

[0300] S16: 1 H NMR(500MHz,Chloroform-d)δ7.32(d,J=8.3Hz,2H),6.96–6.86(m,4H),6.79

[0301] (d,J=7.9Hz,1H),6.68(s,1H),5.96(s,2H),4.31(s,2H),3.82(s,3H),3.26(t,J=7.4Hz,2H),2.84(t,J=7.4Hz,2H),1.43(p,J =7.5Hz,2H),1.25(d,J=7.8Hz,3H),1.07(q,J=7.9Hz,2H),1.00(q,J=7.4Hz,2H),0.92(t,J=7.3Hz,3H),0.76(t,J=7.1Hz,3H).

[0302] Example 27

[0303] This embodiment prepares atrasentan derivative E1. and E2 The steps are as follows:

[0304] 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)pyrrolidine (18 μL, 0.14 mmol), and N,N-diisopropylethylamine (49 μL, 0.28 mmol) to a 25 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 48.8 mg of white oily substance E1, yield 67%.

[0305] B051. Add E1 (29.4 mg, 0.057 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (11.9 mg, 0.283 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 22.9 mg of white solid E2, yield 82%.

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

[0307] E1: 1 H NMR(500MHz,Chloroform-d)δ7.28(s,1H),6.93(d,J=8.7Hz,2H),6.84(dd,J=9.6,2.0Hz,3H),6.70(s,1H),6.13(s,1H),5.99(s,2H), 4.39(s,2H),4.13(dd,J=10.6,3.6Hz,2H),3.83(s,3H),3.21(d,J=5.7Hz,2H),2.49(s,6H),1.77(d,J=1.6Hz,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(500MHz,Chloroform-d)δ7.25(d,J=8.5Hz,2H),6.92(d,J=8.7Hz,2H),6.82(d,J=4.7Hz,3H),6.73(s,1H),6.16(s,1H),5.98(s,2H),4.39(s, 2H),4.11(q,J=7.1Hz,2H),3.82(s,3H),3.17(q,J=5.5Hz,2H),2.31(t,J =5.9Hz,6H),1.57–1.47(m,4H),1.44–1.34(m,2H),1.14(t,J=7.1Hz,3H).

[0315] E4: 1 H NMR(500MHz,Chloroform-d)δ8.26(s,1H),7.40(s,2H),6.99(d,J=6.6Hz,2H),6.80(dd,J=8.5,6.2Hz,3 H),6.65(s,1H),5.96(s,2H),4.37(s,2H),3.81(s,3H),3.38(s,2H),2.45(t,J=4.8Hz,6H),1.32(s,6H).

[0316] Example 29

[0317] This embodiment prepares atrasentan derivative E5. and E6 The steps are as follows:

[0318] 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, N-(2-aminoethyl)morpholine (18 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 44.7 mg of pale yellow oil E5, yield 60%.

[0319] B051. Add E5 (25.1 mg, 0.047 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (9.59 mg, 0.235 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 20.7 mg of white solid E6, yield 87%.

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

[0321] E5: 1 H NMR(500MHz,Chloroform-d)δ7.24(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,2H),6.82(dd,J=6.1,0.9Hz,3H),6.73(s,1H),5.98(s,2H),5.90(s,1 H),4.40(s,2H),4.13(q,J=7.1Hz,2H),3.82(s,3H),3.63(t,J=4.6Hz,4H),3.20(q,J=5.6Hz,2H),2.44–2.30(m,6H),1.15(t,J=7.1Hz,3H).

[0322] E6: 1 H NMR(500MHz,Chloroform-d)δ7.40(s,1H),7.30(d,J=8.6Hz,2H),6.93(d,J=8.0Hz,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=5.0Hz,2H),2.43(s,6H).

[0323] Example 30

[0324] This embodiment prepares atrasentan derivative E7. and E8 The steps are as follows:

[0325] B041. Add S14 (60.2 mg, 0.14 mmol) prepared in Example 26, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (72.2 mg, 0.19 mmol), 2 mL of ultra-dry dichloromethane, n-butylamine (14 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 × 3 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 44.4 mg of pale yellow solid E7, yield 66%.

[0326] B051. Add E7 (24.3 mg, 0.051 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (10.7 mg, 0.25 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 = 20:1 (v / v) system to give 20.2 mg of white solid E8, yield 97%.

[0327] Compounds E7 and E8 were characterized by 1H NMR, and the results are as follows:

[0328] E7: 1 H NMR(500MHz,Chloroform-d)δ7.24(d,J=8.7Hz,2H),6.92(d,J=8.7Hz,2H),6.86–6.81(m,3H),6.71(d,J=2.0Hz,1H),5.98(s,2H),5.24(s,1H),4.38(s,2 H),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=7.3,6.5,2.4Hz,2H), 1.14(t,J=7.1Hz,3H), 0.87(t,J=7.3Hz,3H).

[0329] E8: 1H NMR(500MHz,Methanol-d4)δ7.29(d,J=8.6Hz,2H),6.98–6.88(m,4H),6.85(d,J=7.8Hz,1H),6.59(s,1H),5.98(s,2H) ,4.30(s,2H),3.83(s,3H),3.06(t,J=6.9Hz,2H),1.34(d,J=6.9Hz,2H),1.20(q,J=7.4Hz,2H),0.90(d,J=7.3Hz,3H).

[0330] Example 31

[0331] This embodiment prepares atrasentan derivative E9. and E10 The steps are as follows:

[0332] B041. Add S14 (60.2 mg, 0.14 mmol) prepared in Example 26, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea (72.2 mg, 0.19 mmol), 2 mL of ultra-dry dichloromethane, N1,N1-dimethylethane-1,2-diamine (13 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 × 3 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 = 10:1 (v / v) system to obtain 39.5 mg of pale yellow solid E9, yield 53%.

[0333] B051. Add E9 (37.6 mg, 0.074 mmol), 2.5 mL ethanol and 0.5 mL water to a 10 mL round-bottom flask, stir, then add lithium hydroxide hydrate (15.6 mg, 0.37 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 in a dichloromethane / methanol = 20:1 (v / v) system to give 12.1 mg of white solid E10, yield 34%.

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

[0335] E9: 1H NMR(500MHz,Chloroform-d)δ7.28(d,J=8.7Hz,2H),6.93(d,J=8.7Hz,2H),6.89–6.84(m,2H),6.82(d,J=7.9Hz,1H),6.70(s,1H),6.12(t,J=5.1Hz, 1H),5.98(s,2H),4.37(s,2H),4.12(q,J=7.1Hz,2H),3.83(s,3H),3.21(q ,J=5.6Hz,2H),2.33(t,J=5.9Hz,2H),2.21(s,6H),1.14(t,J=7.1Hz,3H).

[0336] E10: 1 H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.26(d,J=7.8Hz,2H),7.01–6.90

[0337] (m,2H),6.80(dd,J=8.2,4.3Hz,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 the atrasentan derivatives prepared in Examples 1-31 on HK-2 cells:

[0339] 1) Preparation of test samples: Dissolve the atrasentan derivatives prepared in Examples 1-31 in dimethyl sulfoxide to prepare 10 mmol / L stock solutions;

[0340] 2) HK-2 cells in the logarithmic growth phase were seeded in 96-well plates and cultured at 37°C in a 5% CO2 incubator for 24 h. A blank control group was set up, with 3 replicates per group. The drug treatment group was replaced with complete medium containing 10 μmol / L (or 20 μmol / L) atrasentan derivative and cultured for another 24 h (or 48 h). Then, high-content imaging was performed, and the number of cells in each group under different compound treatment conditions was analyzed and counted. The cell viability under different derivative treatment conditions was then calculated using the formula: Cell viability = Number of cells in the drug treatment group / Number of cells in the control group * 100%.

[0341] TGF-β (transforming growth factor-β) is a triggering factor for fibrosis and a key factor in the development of fibrosis after acute injury. It can induce excessive accumulation of extracellular matrix (ECM) such as fibronectin (FN), collagen, vimentin, and alpha-smooth muscle actin (α-SMA) in human renal tubular epithelial cells (HK-2), leading to the differentiation of fibroblasts into myofibroblasts, increased secretion of inflammatory mediators, and ultimately irreversible organ fibrosis. Therefore, recombinant TGF-β 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 This example demonstrates the 24-hour safety evaluation of atrasentan derivatives in HK-2 cells at a concentration of 10 μmol / L. Figure 2 For the safety evaluation of atrasentan derivatives in HK-2 cells at a concentration of 20 μmol / L for 48 hours in the examples, 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 derivative provided in the examples has low toxicity to HK-2 cells.

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

[0343] HK-2 cells in logarithmic growth phase were seeded in 96-well plates and cultured at 37°C in a 5% CO2 incubator for 24 h. A blank control group and a positive control group were set up, with three replicates in each group. The culture medium in all wells was replaced with serum-free medium, and the cells were cultured for another 24 h. The blank control group was then replaced with complete culture medium, the positive control group with complete culture medium containing 5 ng / mL TGF-β, and the drug-treated group with complete culture medium containing 10 μmol / L atrasentan derivative and 5 ng / mL TGF-β, and the cells were cultured for another 48 h. After fixation, permeabilization, blocking, incubation with primary antibody, incubation with secondary antibody, and incubation with DAPI, high-content imaging was used to analyze and statistically determine the average level of fibronectin (nor. Fn) under different compound treatment conditions.

[0344] Figure 3 To demonstrate the antifibrotic activity of atrasentan derivatives against TGF-β-induced HK-2 at a concentration of 10 μmol / L in the examples, [the following data was obtained]. Figure 3It was found that after TGF-β-induced HK-2, Fibronectin expression was significantly higher than normal; after atrasentan treatment, Fibronectin protein levels decreased to some extent; and after treatment with the synthesized atrasentan derivatives, Fibronectin protein levels were mostly reduced, and the levels of S15 and E8 were significantly lower than those of atrasentan. This indicates that most of the atrasentan derivatives synthesized in this invention have anti-fibrotic effects, and more than half of the derivatives have better anti-fibrotic effects than atrasentan.

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

[0346] HK-2 cells in logarithmic growth phase were seeded in 6-well plates and cultured at 37°C in a 5% CO2 incubator for 24 h. A blank control group and a positive control group were set up, with 3 replicates in each group. The culture medium in all wells was replaced with serum-free medium, and the cells were cultured for another 24 h. The blank control group was replaced with complete culture medium, the positive control group was replaced with complete culture medium containing 5 ng / mL TGF-β, and the drug-treated group was replaced with complete culture medium containing 10 μmol / L atrasentan derivative and 5 ng / mL TGF-β. The cells were cultured for another 48 h. Then, proteins were extracted from different samples and the expression levels of Fibronectin (Fn) and Vimentin (Vim) were detected by SDS-PAGE gel electrophoresis.

[0347] Figure 4 The compounds selected in the initial screening exhibited antifibrotic activity against TGF-β-induced HK-2 at a concentration of 10 μmol / L. Figure 4 (a) shows the antifibrotic activity of compounds S10, A8, D13, D14, D15, A5, A6, A2, and E8 against TGF-β-induced HK-2 at a concentration of 10 μmol / L. Figure 4 (b) shows the antifibrotic activity of compounds C3, C4, S9, A4, D3, D8, D11, D12, and D13 against TGF-β-induced HK-2 at a concentration of 10 μmol / L. Figure 4 It was found that after TGF-β-induced HK-2, Fibronectin expression and Vimentin expression were significantly higher than normal levels. After atrasentan treatment, the protein levels of Fibronectin and Vimentin were somewhat reduced. Compounds A8, A5, A6, C4, S9, D3, and D11 showed significantly lower levels of Fibronectin and Vimentin compared to atrasentan. This indicates that the synthesized atrasentan derivatives have a better anti-fibrotic effect than atrasentan itself.

Claims

1. An atrasentan derivative, characterized in that, Its structural formula is selected from any of the following: 、 、 、 、 Formula 2 Formula 3 Formula 4 Formula 5 、 、 、 、 Formula 6, Formula 7, Formula 8, Formula 9 、 、 、 、 Formula 10, Formula 11, Formula 12, Formula 13 、 、 、 、 Formula 14, Formula 15, Formula 16, Formula 17 、 、 、 、 Formula 36, ​​Formula 37, Formula 38, Formula 39 、 、 、 Formula 40, Formula 41, Formula 45 、 、 、 、 Formula 46, Formula 47, Formula 48, Formula 49 、 、 、 、 Formula 50, Formula 51, Formula 52, Formula 53 、 、 、 、 Formula 54, Formula 56, Formula 57, Formula 58 、 、 、 、 Formula 59, Formula 60, Formula 61, Formula 62 、 、 、 、 Formula 64, Formula 66, Formula 67, Formula 68 、 、 、 Formula 69, Formula 70, Formula 71, Formula 72.

2. The use of the atrasentan derivative according to claim 1 in the preparation of an anti-renal fibrosis drug.

3. An anti-renal fibrosis drug, characterized in that, Includes the atrasentan derivative of claim 1 or a pharmaceutically acceptable salt thereof.

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