Aromatic alkylamine ferroptosis inhibitor based on butylphthalide structure as well as preparation method and application of aromatic alkylamine ferroptosis inhibitor

Abstract

The invention discloses an aromatic alkylamine ferroptosis inhibitor based on a butylphthalide structure and a preparation method and application thereof. The chemical structural formula of the ferroptosis inhibitor is shown as a formula 1 or a formula 2. The ferroptosis inhibitor can inhibit ferroptosis caused by a ferroptosis inducer and can reduce the level of active oxygen in cells. Nerve injury caused by cerebral ischemia reperfusion can be relieved, and symptoms of neurological diseases such as Alzheimer's disease and Parkinson's disease can be relieved; compared with a ferroptosis inhibitor Ferrostatin-1, the aryl alkyl amine compound disclosed by the invention has better metabolic stability and is suitable for in-vivo drug effect evaluation. Therefore, the novel aryl alkyl amine compound provided by the invention has a very good application value in treatment of neurological diseases related to ferroptosis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an aromatic alkylamine ferroptosis inhibitor based on butylphthalide structure, its preparation method, and its application. Background Technology

[0002] Cell death can be broadly classified into two categories: uncontrolled cell death caused by excessive cellular damage and regulated cell death dependent on tightly controlled molecular pathways. Apoptosis is the most typical form of regulated cell death, initiating cell death through the activation of caspases. Ferroptosis, a novel cell death mechanism discovered in recent years, is an oxidative cell death induced by various factors, exhibiting iron ion dependence. Its occurrence stems from an imbalance between the generation and degradation of intracellular lipid reactive oxygen species (ROS). In the early years after its discovery, the mechanisms controlling ferroptosis primarily revolved around cysteine ​​and glutathione metabolism, and the phospholipid peroxidase GPX4's prevention of lipid peroxidation accumulation. Ferroptosis inducers act directly or indirectly on glutathione peroxidases (GPXs) through different pathways, leading to decreased cellular antioxidant capacity, ROS accumulation, and ultimately oxidative cell death. The complex interactions between lipid, iron, and cysteine ​​metabolism have become important regulators of this cell death pathway. Recently, the regulation of ferroptosis has become an attractive strategy for intervening in human diseases, including cancer, neurodegenerative diseases, and ischemic diseases.

[0003] Ferroplasmosis can be inhibited by iron chelators, lipophilic antioxidants, and / or ferrostatin-1 (fer-1). Fer-1 is an aryl alkylamine with antioxidant properties and was one of the first feroplasmosis inhibitors identified. As a lipid peroxidation agent, Fer-1 intercepts and scavenges lipid free radicals through hydrogen atom transfer or direct reduction. The specific structural formula of Fer-1 is as follows:

[0004]

[0005] Butylphthalide (NBP) is a racemic compound containing levo- and dextro-butylphthalide, initially isolated from celery seeds. Extensive experimental and clinical studies have confirmed that NBP possesses anti-inflammatory, antioxidant, blood-brain barrier protective, cerebral microcirculation-improving, angiogenesis-promoting, and neuroprotective activities. Furthermore, based on its complex pharmacological mechanism, NBP's clinical applications are increasingly evident. Studies have found significant therapeutic effects on some neurodegenerative diseases such as Alzheimer's disease, vascular dementia, and Parkinson's disease. The specific structure of NBP is as follows:

[0006] Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide an aromatic alkylamine ferroptosis inhibitor based on a butylphthalide structure, its preparation method, and its applications. The aromatic alkylamine compound exhibits strong anti-ferroptosis activity and can be used to prepare drugs for treating ferroptosis-related diseases; it also overcomes the poor metabolic stability of Fer-1 and can be used for subsequent pharmacological and biological evaluations related to ferroptosis; this type of inhibitor can also be used to treat existing symptoms of NBP, providing novel structural molecules for the treatment of neurological diseases and ferroptosis-related diseases.

[0008] To achieve the above-mentioned objectives, the present invention employs the following technical solution:

[0009] An aromatic alkylamine ferroptosis inhibitor based on a butylphthalide structure, wherein the structural formula of the aromatic alkylamine ferroptosis inhibitor is shown in Formula 1 or Formula 2:

[0010]

[0011] In the formula R 1 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, amino, phenyl, benzyl, naphthyl, C5-C 10 Aromatic heterocyclic groups or C3-C7 saturated heterocyclic groups;

[0012] R 2 Selected from C0-C8 alkyl, C3-C 12 Cycloalkyl, adamantyl, or polyacetylenic;

[0013] R 3 Selected from hydrogen, alkyl, aryl, C1-C6 alkyl-aryl, C1-C6 alkyl-phenolic or C3-C4 10 cycloalkyl;

[0014] R 4 Selected from alkyl or haloalkyl, aryl, and heteroaryl groups of RC1-C10;

[0015] R 5 Selected from C0 to C6 alkyl-C3 to C6 cycloalkyl-C0 to C6 alkyl or C0 to C6 alkyl-C3 to C6 cycloalkyl-C0 to C6 alkyl, C0 to C6 alkyl-Z-C0 to C6 alkyl or C0 to C6 alkyl-Z-C0 to C6 alkyl containing 1-3 independent substituents; wherein Z is selected from N, NR a , -SO2-, OC, OC=O, CO or C=OO;

[0016] Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, phenyl, benzyl, naphthyl, C5-C 10 Aromatic heterocyclic groups, C3-C7 saturated heterocyclic groups, C3-C 12 Cycloalkyl, polyynyl, aryl, C1-C6 alkyl-aryl, C1-C6 alkyl-phenolic or C3-C 10 Cycloalkyl groups can be substituted by one or more atoms or groups;

[0017] R a The group is selected from H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl or optionally substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocyclic alkyl, heteroaryl, C1-C6 alkoxy, NH (C1-C4 alkyl) and N (C1-C4 alkyl)2, wherein the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acrylate.

[0018] Furthermore, the inhibitor is compounds I-1 to I-14, II-1 to II-12, and III-1 to III-3, whose structural formulas are as follows:

[0019]

[0020]

[0021] This invention also provides a method for preparing an aromatic alkylamine ferroptosis inhibitor based on a butylphthalide structure, the method comprising the following steps:

[0022] The synthesis of compounds I-1 to I-14 is as follows: 5-bromophthalide was used as a starting material, and under the catalysis of AIBN, a free radical substitution reaction was carried out via NBS to obtain compound 2, which was then hydrolyzed to obtain compound 3; compound 3 reacted with the corresponding Grignard reagent to obtain compound 4; compound 4 reacted with potassium nitrate under concentrated sulfuric acid conditions to generate compound 5; compound 5 and cyclohexylamine underwent a substitution reaction in a mixed solution of DMF / tetrahydrofuran to obtain compound 6; compound 7 was obtained by reducing the nitro group of compound 6 with zinc powder, and then subjected to a reductive amination reaction with the corresponding aldehydes and ketones to obtain compounds I-1 to I-14.

[0023]

[0024] Reagents and reaction conditions: (a) NBS, AIBN, chloroform, reflux; (b) water, 110℃; (c) butyl magnesium bromide, tetrahydrofuran; (d) concentrated sulfuric acid, potassium nitrate; (e) cyclohexylamine, triethylamine, DMF, tetrahydrofuran; (f) zinc powder, hydrochloric acid, methanol; (g) the corresponding amine, acetic acid, sodium triacetoxyborohydride, dichloromethane.

[0025] The synthesis of compounds III-1 to III-3 is as follows: compound 10 is synthesized as described above, and then hydrolyzed under alkaline conditions to obtain compound 11, which is further reacted with acyl chloride to obtain the corresponding ester 12. Compound 13 is formed by the condensation of 12 and the corresponding alcohol in the presence of HDTU and DIEPA. The target compounds III-1 to III are obtained by reduction reaction.

[0026]

[0027] Reagents and reaction conditions: (a) NBS, AIBN, chloroform, reflux; (b) water, 110°C; (c) butyl magnesium bromide, tetrahydrofuran; (d) concentrated sulfuric acid, potassium nitrate; (e) cyclohexylamine, triethylamine, DMF, tetrahydrofuran; (h) sodium hydroxide, methanol, water, 50°C; (i) acetyl chloride, triethylamine, dichloromethane, -10°C; (j) HATU, DMAP, dichloromethane, room temperature -50°C; (f) zinc powder, hydrochloric acid, methanol; (g) the corresponding amine, acetic acid, sodium triacetoxyborohydride, dichloromethane.

[0028] This invention also provides the use of the described inhibitor in the preparation of ferroptosis inhibitors and butylphthalide (NBP)-related structural drugs.

[0029] The present invention also provides the use of the inhibitor in the preparation of medicaments for treating ferroptosis-related diseases.

[0030] Furthermore, the iron death-related diseases include neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, Alzheimer's disease, Parkinson's syndrome and other neurodegenerative diseases, cardiovascular diseases, liver and kidney failure, inflammation, and diabetic complications.

[0031] Furthermore, the drug also contains pharmaceutically acceptable salts, carriers, or adjuvants.

[0032] Furthermore, the use of the aromatic alkylamine compounds to treat ferroptosis is because these compounds can act as free radical scavengers to reduce intracellular reactive oxygen species and lipid peroxides, thereby rescuing ferroptosis caused by reactive oxygen species.

[0033] Furthermore, the use of the aromatic alkylamine compounds to treat ferroptosis is because these compounds can act as free radical scavengers to rescue ferroptosis caused by ferroptosis inducers; wherein ferroptosis inducers include, but are not limited to, RSL3 and its derivatives, Erastin and its derivatives, ML162 and its derivatives.

[0034] Furthermore, the aromatic alkylamine compounds can be used to treat NBP-related diseases, resist brain damage caused by ischemia, improve neurodegenerative diseases, improve cerebral microcirculation, inhibit platelet aggregation, protect mitochondria, regulate energy metabolism, and reduce oxidative stress damage.

[0035] Compared with existing technologies, the advantages and beneficial effects of this invention are as follows: This invention, through rational drug design and various synthetic methods, obtains a class of arylalkylamine compounds capable of acting on ferroptosis, enriching the structure of ferroptosis inhibitors. Experimental verification shows that the arylalkylamine compounds can inhibit ferroptosis induced by ferroptosis inducers and reduce the level of intracellular reactive oxygen species. Experimental verification also shows that the metabolic stability of the arylalkylamine compounds is significantly improved compared to compound Fer-1. Therefore, the arylalkylamines provided by this invention have significant application value in the treatment of ferroptosis and NBP-related diseases. Detailed Implementation

[0036] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0037] Example 1

[0038] 1. 3,5-Dibromoisobenzofuran-1(3H)-one (Compound 2)

[0039] 5-Bromoisobenzofuran-1(3H)-one (1.0 g, 4.69 mmol), NBS (1.0 g, 5.63 mmol), and AIBN (0.45 g, 0.47 mmol) were added to a round-bottom flask containing 40 mL of chloroform and reacted at 70 °C for 5 h. The reaction was monitored by TLC until completion. The reaction mixture was poured into 50 mL of water, and the aqueous layer was extracted with DCM (50 mL × 3). The organic phases were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 20:1) to give a yellow solid compound 2 (1.2 g, 92%). 1 H NMR (400MHz, Chloroform-d) δ7.96 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 2.2, 0.7 Hz, 1H), 7.54 (dd, J = 8.5, 2.3 Hz, 1H), 6.86 (s, 1H).

[0040] 2. 5-Bromo-3-hydroxyisobenzofuran-1(3H)-one (Compound 3)

[0041] 3,5-Dibromoisobenzofuran-1(3H)-one (1 g, 3.46 mmol) was added to a reaction flask, and 20 mL of water was used as a solvent. The reaction was carried out at 110 °C for 1 h. After the reaction was completed, the white solid compound 3 (1 g, 94%) was obtained by filtration. 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=8.0Hz,1H),7.90–7.88(m,1H),7.82(dd,J=8.1,1.7Hz,1H),7.73(d,J=8.1Hz,1H),6.61(s,1H).

[0042] 3. 5-Bromo-3-butylisobenzofuran-1(3H)-one (Compound 4)

[0043] 5-Bromo-3-hydroxyisobenzofuran-1(3H)-one (1 g, 4.38 mmol) was added to a reaction flask, with 15 mL of tetrahydrofuran as the solvent. The mixture was substituted three times with N2 and protected with N2. Butylmagnesium bromide (1.4 g, 8.76 mmol) was slowly added dropwise to the reaction flask under ice bath conditions. The reaction was carried out at room temperature for 5 h. After the reaction was complete, dilute hydrochloric acid was added dropwise under ice bath conditions to adjust the pH to 2. The mixture was stirred for another 1 h at room temperature. The reaction solution was then poured into 50 mL of water, and the aqueous layer was extracted with DCM (50 mL × 3). The organic phases were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 20:1) to give a yellow solid compound 4 (0.2 g, 28%). 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.5Hz,1H),7.61(d,J=2.1Hz,1H),7.56(dd,J=8 .5,2.3Hz,1H),5.48–5.42(m,1H),2.02(tdd,J=9.1,4.9,1.4Hz,2H),1.43–1.31(m,4H).

[0044] 4. 5-Bromo-3-butyl-6-nitroisobenzofuran-1(3H)-one (Compound 5)

[0045] 5-Bromo-3-butylisobenzofuran-1(3H)-one (0.2 g, 0.75 mmol) was added to a reaction flask containing 1 mL of concentrated H₂SO₄. KNO₃ (0.37 g, 3.66 mmol) was slowly added to the flask under ice bath conditions, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, ice water was slowly added to quench the reaction, and the reaction mixture was then poured into 20 mL of water. The aqueous layer was extracted with DCM (50 mL × 3), and the organic phases were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 15:1) to give a white solid compound 5 (0.18 g, 91%). 1H NMR (400MHz, Chloroform-d) δ8.56 (s, 1H), 7.94 (d, J = 0.6Hz, 1H), 5.47 (dd, J = 5.2, 4.4Hz, 1H), 2.02 (tdd, J = 9.0, 4.9, 1.7Hz, 2H), 1.45–1.31 (m, 4H).

[0046] 5. 3-Butyl-5-(cyclohexylamino)-6-nitroisobenzofuran-1(3H)-one (Compound 6)

[0047] 5-Bromo-3-butyl-6-nitroisobenzofuran-1(3H)-one (0.05 g, 0.16 mmol), cyclohexylamine (0.047 g, 0.48 mmol), and triethylamine (0.03 g, 0.32 mmol) were added to a reaction flask. 0.5 mL of DMF and 1.5 mL of tetrahydrofuran were used as solvents. The reaction was carried out at 70 °C for 5 h. After the reaction was complete, the reaction solution was poured into 30 mL of water, and the aqueous layer was extracted with DCM (30 mL × 3). The organic phases were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 10:1) to give a yellow solid compound 6 (0.04 g, 83%). 1 HNMR(400MHz,Chloroform-d)δ8.55(s,1H),7.60–7.53(m,2H),5.47(dd,J=5.2,4.4Hz,1H),3.49(dt,J=7.3,4.8Hz,1H),2.01(tdd,J=9.1,4.9,2.8Hz ,2H),1.89–1.78(m,2H),1.67–1.43(m,5H),1.47–1.40(m,3H),1.40(dd,J =3.2,1.3Hz,1H),1.41–1.37(m,1H),1.39–1.33(m,2H),1.36–1.31(m,1H).

[0048] 6. 6-Amino-3-butyl-5-(cyclohexylamino)isobenzofuran-1(3H)-one (Compound 7)

[0049] Compound 6 (0.04 g, 0.12 mmol) was added to a reaction flask, 5 mL of CH3OH was used as solvent, 1 mL of dilute hydrochloric acid and excess zinc powder were added, and the mixture was reacted at room temperature for 10 minutes. The zinc powder was removed by filtration, and the mixture was separated by column chromatography (PE:EA = 2:1) to obtain black solid compound 7 (0.04 g, 83%). 1H NMR (400MHz, Methanol-d4) δ7.04(d,J=2.9Hz,1H),6.56(d,J=2.4Hz,1H),5.35(dt,J=6.6,3.0Hz, 1H),3.44(ddt,J=10.8,7.2,3.2Hz,1H),2.15–1.94(m,5H),1.88–1.63(m,7H),1.55–1.41(m,6H).

[0050] 7. 5-(cyclohexylamino)-6-((2,6-dichlorobenzyl)amino)-3-pentylisobenzofuran-1(3H)-one (Compound I-1)

[0051] Compound 7 (0.03 g, 0.099 mmol), cyclohexanone (0.014 g, 0.011 mmol), and NaBH(OAc)3 were added to a reaction flask containing 4 mL of DCE. One drop of acetic acid was added, and the reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into 30 mL of water, and the aqueous layer was extracted with DCM (30 mL × 3). The organic phases were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 4:1) to give a black solid compound I-1 (0.015 g, 64%). 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J=7.9Hz,2H),7.25–7.18(m,2H),6.44(s,1H),5.31(dd,J=8.0,3.8Hz,1H),4.42(s,2H),3. 33(tt,J=10.1,3.8Hz,1H),2.02(dtd,J=35.1,9.9,8.9,3.9Hz,3H),1.85–1.61(m,5H),1.51–1.32(m,8H),0.91(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.34,140.49,139.81,137.02,124.99,112.39,109.94,80.10,52 .75,52.70,33.93,33.45,33.41,33.38,27.77,26.18,26.16,25.31,25.29,25.26,22.81,14.09.

[0052]

[0053] 8. 3-Butyl-5-(cyclohexylamino)-6-((4-nitrobenzyl)amino)isobenzofuran-1(3H)-one (Compound I-2)

[0054] The synthesis method is the same as I-1, yielding a yellow solid with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J=8.4Hz,2H),7.60–7.54(m,2H),7.14(s,1H),7.09(s,1H),5.91(t,J=5.3Hz,1H),5.82(d,J=7.8Hz,1H),5.52–5.3 5(m,1H),4.44(dt,J=5.3,1.0Hz,2H),3.55–3.36(m,1H),2.02(tdd,J=9.0,4 .9,1.7Hz,2H),1.90–1.76(m,2H),1.67–1.24(m,13H),0.87(t,J=7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.34,146.84,144.22,140.70,139.59,135.78,128.65,125.31, 123.53,111.39,109.73,80.10,52.70,48.27,33.93,33.38,27.77,26.16,25.26,22.81,14.09.

[0055] 9. 3-Butyl-5-(cyclohexylamino)-6-((pyridin-4-ylmethyl)amino)isobenzofuran-1(3H)-one (Compound I-3)

[0056] The synthesis method is the same as I-1, yielding a yellow solid with a yield of 59%. 1 H NMR(400MHz,Chloroform-d)δ8.17–8.10(m,2H),7.50(dd,J=8.8,2.0Hz,2H),6.94(d,J=1.2Hz,1H),6.48(s,1H),5.26(dd,J=8.0,3.8Hz,1H),4.41( s,2H),3.35(tt,J=10.1,3.7Hz,1H),2.12–2.03(m,2H),2.01–1.91(m,2H) ,1.80(dp,J=12.4,4.3,3.8Hz,3H),1.73–1.65(m,2H),1.44–1.24(m,10H). 13C NMR(101MHz,Chloroform-d)δ171.37,156.04,152.54,150.70,148.23,142.55,136.03,122.28,112 .99,112.48,100.87,80.81,51.21,34.69,32.78,32.72,26.95,25.68,24.76,24.68,22.53,13.98.

[0057] 10. 3-Butyl-5-(cyclohexylamino)-6-((4-methylbenzyl)amino)isobenzofuran-1(3H)-one (Compound I-4)

[0058] The synthesis method is the same as I-1, resulting in a black solid with a yield of 54%. 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J=8.0Hz,2H),7.17(d,J=7.7Hz,2H),7.13(s,1H), 6.46(s,1H),5.29(dd,J=7.9,3.8Hz,1H),4.22(s,2H),3.41–3.24(m,1H),2.35(s,3H),2. 10–2.01(m,2H),2.01–1.92(m,1H),1.79(dq,J=12.9,3.8Hz,2H),1.68(ddd,J=14.4,5.8 ,3.5Hz,2H),1.47–1.35(m,6H),1.24(ddd,J=6.8,5.2,2.1Hz,3H),0.90(t,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.34,140.70,139.59,137.30,136.45,135.78,129.64,127.84,125 .31,111.39,109.73,80.10,52.70,48.27,33.93,33.38,27.77,26.16,25.26,22.81,21.04,14.09.

[0059] 11. 3-Butyl-5-(cyclohexylamino)-6-(cyclopentylamino)isobenzofuran-1(3H)-one (Compound I-5)

[0060] The synthesis method is the same as I-1, resulting in a black solid with a yield of 64%. 1H NMR(400MHz,Chloroform-d)δ7.11(s,1H),6.44(s,1H),5.29(dd,J=8.0,3.8Hz,1H),3.77(ddd,J=12.1, 6.8,5.2Hz,1H),3.31(td,J=10.0,5.0Hz,1H),2.12–1.93(m,5H),1.84–1.61(m,8H),1.54–1.22(m,14H). 13 C NMR(101MHz,Chloroform-d)δ168.34,140.49,139.81,136.65,124.99,112.39,109.94 ,80.10,55.47,52.70,33.93,33.38,33.05,27.77,26.16,25.26,23.51,22.81,14.09.

[0061] 12. 3-Butyl-5-(cyclohexylamino)-6-((naphth-1-ylmethyl)amino)isobenzofuran-1(3H)-one (Compound I-6)

[0062] The synthesis method is the same as I-1, resulting in a black solid with a yield of 64%. 1 H NMR(400MHz,Chloroform-d)δ8.11–8.06(m,1H),7.93–7.83(m,2H),7.55–7.46(m,4H),7.29(s,1H),6.49(s,1H),5.33(dd,J=7.9,3.8Hz,1H) ,4.70(s,2H),3.30(ddt,J=10.5,7.8,3.8Hz,1H),2.00(dtt,J=9.8,6. 3,2.7Hz,3H),1.80–1.59(m,5H),1.53–1.32(m,6H),1.27–1.11(m,4H). 13 C NMR(101MHz,Chloroform-d)δ168.34,140.70,139.59,135.86,133.57,133.47,132.48,128.81,128.43,127.70,127.47, 126.36,125.41,125.31,124.20,111.39,109.73,80.10,52.70,47.04,33.93,33.38,27.77,26.16,25.26,22.81,14.09.

[0063] 13. 3-Butyl-5-(cyclohexylamino)-6-((thiophene-2-ylmethyl)amino)isobenzofuran-1(3H)-one (Compound I-7)

[0064] The synthesis method is the same as I-1, resulting in a black solid with a yield of 32%. 1 H NMR(400MHz,Chloroform-d)δ7.17(s,1H),7.04(dt,J=3.2,1.1Hz,1H),6.98(ddd,J=6.0,5.0,3.5Hz,2H),6.46(d,J=0.8Hz,1H),5 .32–5.27(m,1H),4.46(d,J=1.0Hz,2H),3.33(dq,J=9.9,5.0,4.0Hz,1H),2.10–1.92(m,4H),1.84–1.64(m,6H),1.50–1.34(m,9H). 13 CNMR(101MHz,Chloroform-d)δ168.34,141.72,140.70,139.77,135.50,127.19,126.00,125.66 ,125.31,111.38,109.73,80.10,52.70,44.16,33.93,33.38,27.77,26.16,25.26,22.81,14.09.

[0065] 14. 3-Butyl-5-(cyclohexylamino)-6-(phenethylamino)isobenzofuran-1(3H)-one (Compound I-8)

[0066] The synthesis method is the same as I-1, resulting in a black solid with a yield of 21%. 1 H NMR(400MHz,Chloroform-d)δ7.34–7.28(m,4H),7.11(s,1H),6.41(s,1H),5.30–5.26(m,1H),3.36(t,J=6.7Hz,2H),3.29 (t,J=9.7Hz,1H),2.98(t,J=6.8Hz,2H),2.06–1.90(m,4H),1.82–1.57(m,6H),1.39(dddd,J=28.8,15.2,6.5,2.6Hz,10H). 13C NMR(101MHz,Chloroform-d)δ168.34,140.89,139.32,139.01,136.89,128.86,128.80,126.65,125 .22,110.89,109.86,80.10,52.70,45.32,35.20,33.93,33.38,27.77,26.16,25.26,22.84,14.04.

[0067] 15. 6-(benzylamino)-3-butyl-5-(cyclohexylamino)isobenzofuran-1(3H)-one (Compound I-9)

[0068] The synthesis method is the same as I-1, the product is a black solid, and the yield is 17%. 1 H NMR(500MHz,Chloroform-d)δ7.38–7.23(m,5H),7.14(s,1H),7.09(s,1H),5.54–5.37(m,1H),4.42(dt,J=5.3,0.9Hz,2H),3 .45(dp,J=7.9,4.8Hz,1H),2.02(tdd,J=9.0,4.9,1.7Hz,2H),1.87–1.77(m,2H),1.67–1.33(m,12H),0.87(t,J=7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.34,140.70,139.59,138.68,135.78,128.38,127.96,127.61, 125.31,111.39,109.73,80.10,52.70,48.71,33.93,33.38,27.77,26.16,25.26,22.80,14.07.

[0069] 16. 3-Butyl-5-(cyclohexylamino)-6-((2,6-dichlorobenzyl)amino)isobenzofuran-1(3H)-one (Compound I-10)

[0070] The synthesis method is the same as I-1, yielding a yellow solid with a yield of 87%. 1H NMR(400MHz,Chloroform-d)δ7.35(d,J=7.9Hz,2H),7.25–7.18(m,2H),6.44(s,1H),5.31(dd,J=8.0,3.8Hz,1H),4.42(s,2H),3. 33(tt,J=10.1,3.8Hz,1H),2.02(dtd,J=35.1,9.9,8.9,3.9Hz,3H),1.85–1.61(m,5H),1.51–1.32(m,8H),0.91(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.87,147.82,146.00,136.27,135.15,134.22,129.65,128.58,113.61,11 3.12,100.53,80.74,51.51,45.98,34.78,33.01,32.93,29.72,27.00,25.79,24.98,24.90,22.56,14.00.

[0071] 17. 6-((4-bromobenzyl)amino)-3-butyl-5-(cyclohexylamino)isobenzofuran-1(3H)-one (Compound I-11)

[0072] The synthesis method is the same as I-1, yielding a yellow solid with a yield of 57%. 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=8.4Hz,2H),7.24(d,J=7.5Hz,2H),7.0 6(s,1H),6.47(s,1H),5.28(dd,J=8.0,3.8Hz,1H),4.23(d,J=5.0Hz,2H),3.34( dtt,J=10.1,6.3,3.4Hz,1H),2.06(dt,J=15.3,4.5Hz,2H),2.00–1.92(m,1H), 1.83–1.75(m,2H),1.73–1.61(m,3H),1.49–1.30(m,8H),0.89(t,J=7.1Hz,3H). 13C NMR(101MHz,Chloroform-d)δ172.02,145.73,143.71,137.54,136.03,131.85,129.65,121.44,114.01 ,108.54,101.02,80.76,51.59,48.59,34.81,33.10,33.01,27.04,25.78,24.93,24.85,22.55,13.99.

[0073] 18. 3-Butyl-5-(cyclohexylamino)-6-((4-fluorobenzyl)amino)isobenzofuran-1(3H)-one (Compound I-12)

[0074] The synthesis method is the same as I-1, resulting in a black solid with a yield of 47%. 1 H NMR(400MHz,Chloroform-d)δ7.35(dd,J=8.6,5.4Hz,2H),7.11(s,1H),7.05(t,J=8.7Hz,2H),6.47(s,1H),5.32–5.27(m,1 H),4.25(s,2H),3.38–3.28(m,1H),2.10–1.91(m,4H),1.79(dd,J=11.6,6.2Hz,2H),1.73–1.48(m,5H),1.48–1.33(m,8H). 13 C NMR(101MHz,Chloroform-d)δ168.34,163.01,160.99,140.70,139.59,135.78,135.54,135.51,130.08,130.01, 125.31,115.26,115.10,111.39,109.73,80.10,52.70,47.98,33.93,33.38,27.77,26.16,25.26,22.81,14.09.

[0075] 19. 3-Butyl-5-(cyclohexylamino)-6-((4-methoxybenzyl)amino)isobenzofuran-1(3H)-one (Compound I-13)

[0076] The synthesis method is the same as I-1, yielding a yellow solid with a yield of 28%. 1H NMR(400MHz,Chloroform-d)δ7.31(d,J=8.7Hz,2H),7.14(s,1H),6.92–6.89(m,2H),6.46(s,1H),5.32–5.27(m,1H),4.20(s,2H),3. 81(s,3H),3.32(s,1H),2.11–1.92(m,2H),1.85–1.75(m,2H),1.68(dd,J=14.5,6.1Hz,2H),1.48–1.33(m,9H),0.91(d,J=7.2Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ168.34,159.03,140.70,139.59,135.78,132.87,129.42,125.31,11 3.71,111.39,109.73,80.10,55.32,52.70,48.61,33.93,33.38,27.77,26.16,25.26,22.78,14.14.

[0077] 20. 3-Butyl-5-(cyclohexylamino)-6-((pyridin-4-ylmethylene)amino)isobenzofuran-1(3H)-one (Compound I-14)

[0078] 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.64–8.61(m,2H),7.95(s,1H),7.71–7.53(m,2H),7.21(d,J=0.6Hz,1H),5.56–5.31(m ,1H),3.47(dt,J=7.0,4.7Hz,1H),2.02(tdd,J=9.0,4.9,1.7Hz,2H),1.89–1.69(m,2H),1.69–1.34(m,12H),0.87(t,J=7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ169.16,162.18,150.59,146.31,142.64,139.50,138.33,125. 64,123.32,122.61,108.45,80.43,52.89,33.93,33.38,27.77,26.13,25.25,22.78,14.07.

[0079] 21. 6-Amino-3-butyl-5-(cyclohexylamino)isobenzofuran-1(3H)-one (Compound II-1)

[0080] 1 HNMR(400MHz,Methanol-d4)δ7.04(d,J=2.9Hz,1H),6.56(d,J=2.4Hz,1H),5.35(dt,J=6.6,3.0Hz ,1H),3.44(ddt,J=10.8,7.2,3.2Hz,1H),2.15–1.94(m,5H),1.88–1.63(m,7H),1.55–1.41(m,6H). 13 C NMR (125MHz, Common NMR Solvents)δ167.66,138.67,138.51,137.98,126.12,112.66,109.72,80.02,52.88,33.93,33.38,27.77,26.16,25.26,22.81,14.09.

[0081] 22. 6-Amino-3-butyl-5-(ethylamino)isobenzofuran-1(3H)-one (II-2)

[0082] 1 H NMR(400MHz,Chloroform-d)δ7.12(s,1H),6.44(s,1H),5.29(dd,J=7.8,4.0Hz,1H),3.23(q,J= 7.2Hz,2H),2.02–1.91(m,1H),1.75–1.62(m,1H),1.35(t,J=7.2Hz,7H),0.89(t,J=7.2Hz,3H).

[0083] 23. 6-Amino-3-butyl-5-(cyclopropylamino)isobenzofuran-1(3H)-one (II-3)

[0084] 1 H NMR (400MHz, Methanol-d4) δ6.97(s,1H),6.89(s,1H),5.35(dd,J=7.5,3.9Hz,1H),3.18(q,J=7.3Hz,1H),2.0 7–1.93(m,2H),1.72–1.61(m,2H),1.41–1.38(m,2H),0.93–0.90(m,3H),0.83–0.79(m,2H),0.57–0.51(m,2H).

[0085] 24. 6-Amino-3-butyl-5-(cyclopentylamino)isobenzofuran-1(3H)-one (II-4)

[0086] 1 H NMR (400MHz, Methanol-d4) δ6.99 (s, 1H), 6.53 (s, 1H), 5.32 (dd, J = 7.5, 3.9Hz, 1H), 3. 93–3.86(m,1H),2.10–1.95(m,4H),1.81–1.71(m,3H),1.68–1.54(m,7H),0.89(s,3H). 13 C NMR (101MHz, MeOD) δ173.36,145.67,144.00,134.59,112.10,109.29,100.79,81.35,54.18,34.30,32.57,32.49,26.56,23.78,22.17,12.94.

[0087] 25. 6-Amino-3-butyl-5-(cycloheptylamino)isobenzofuran-1(3H)-one (II-5)

[0088] 1 H NMR (400MHz, Methanol-d4) δ6.99 (s, 1H), 6.41 (s, 1H), 5.31 (dd, J = 7.4, 4.0Hz, 1H), 3.57 (t t,J=8.6,4.2Hz,1H),2.00(tq,J=14.1,4.3Hz,3H),1.79–1.58(m,10H),1.40–1.27(m,5H). 13 C NMR(101MHz,MeOD)δ173.40,145.56,143.17,135.07,111.81,109.23,100.26, 81.30,53.26,34.32,33.97,33.82,28.14,28.01,26.54,24.13,22.18,12.95.

[0089] 26. 6-Amino-3-butyl-5-((tetrahydro-2H-pyran-4-yl)amino)isobenzofuran-1(3H)-one (II-6)

[0090] 1H NMR(400MHz,Chloroform-d)δ7.16(s,1H),6.46(s,1H),5.33–5.26(m,1H),4.04(dq,J=12.2,4.2Hz,2H),3.62– 3.54(m,3H),2.11–2.04(m,2H),2.02–1.93(m,1H),1.73–1.55(m,4H),1.48–1.38(m,3H),0.90(t,J=7.1Hz,3H). 13 CNMR(101MHz,CDCl3)δ171.75,146.24,143.50,133.95,114.12,112.71,101 .05,80.84,66.66,66.61,48.81,34.80,33.05,33.01,26.98,22.51,13.98.

[0091] 27. 5-(((1R,3S,5r,7r)-adamantane-2-yl)amino)-6-amino-3-butylisobenzofuran-1(3H)-one (II-7)

[0092] 1 H NMR(400MHz,Chloroform-d)δ7.10(s,1H),6.89(d,J=0.8Hz,1H),5.32–5.27(m,1H),3.71(q,J=7.4Hz,1H),2 .74(s,6H),2.01–1.85(m,3H),1.68(ddd,J=14.7,8.1,6.2Hz,3H),1.26–1.23(m,8H),0.91(d,J=7.3Hz,3H).

[0093] 28. 6-Amino-5-(cyclohexylamino)-3-methylisobenzofuran-1(3H)-one (II-8)

[0094] 1 H NMR(400MHz,Chloroform-d)δ7.12(s,1H),6.42(s,1H),5.37(q,J=6.6Hz,1H),3.33(tt,J=10.1,3.7Hz,1H),2.06(dt,J =11.3,4.6Hz,2H),1.79(dq,J=12.6,4.1Hz,3H),1.68(dt,J=13.0,4.3Hz,2H),1.55(d,J=6.6Hz,3H),1.47–1.31(m,4H). 13CNMR (101MHz, CDCl3) δ171.57,147.71,144.22,133.52,119.55,112.60,100.63,51.45,33.02,32.94,25.77,24.91,24.82,20.79.

[0095] 29. 6-Amino-5-(cyclohexylamino)-3-ethylisobenzofuran-1(3H)-one (II-9)

[0096] 1 H NMR (400MHz, Chloroform-d) δ7.12(s,1H),6.43(s,1H),5.30–5.27(m,1H),3.39–3.28(m,1H),2.13–1.90(m,5H),1.80(s,1H),0.96(t,J=7.4Hz,4H).

[0097] 30. 6-Amino-5-(cyclohexylamino)-3-propylisobenzofuran-1(3H)-one (II-10)

[0098] 1 H NMR (400MHz, Chloroform-d) δ7.10(s,1H),6.41(s,1H),5.24(dd,J=7.2,4.0Hz,1H),3.30(tt,J=10.0,3.8Hz,1H),2.03(ddt,J=14.5,7.2,3. 8Hz,3H),1.80–1.74(m,2H),1.65(dd,J=10.7,6.0Hz,1H),1.42–1.32(m,3H),1.24(ddt,J=15.4,8.4,3.2Hz,4H),0.95(td,J=7.3,1.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.90,146.08,144.14,133.59,113.56,112.55,100.82,81.69,51.45,32.98,32.92,27.94,25.77,24.90,24.82,8.87.

[0099] 31. 6-Amino-5-(cyclohexylamino)-3-isobutylisobenzofuran-1(3H)-one (II-11)

[0100] 1H NMR(400MHz,Chloroform-d)δ7.14(s,1H),6.42(s,1H),5.35–5.31(m,1H),3.34(d,J=10.0Hz,1H),2.13–1.98(m,4H),1.82 (td,J=8.5,4.2Hz,3H),1.70(ddd,J=14.3,8.9,3.3Hz,3H),1.49–1.33(m,4H),1.07(d,J=6.6Hz,3H),0.99(d,J=6.7Hz,3H).

[0101] 32. 6-Amino-5-(cyclohexylamino)-3-pentylisobenzofuran-1(3H)-one (II-12)

[0102] 1 H NMR(400MHz,Chloroform-d)δ7.13(s,1H),6.43(s,1H),5.34–5.23(m,1H),3.32(d,J=10.3Hz,1H),2.07(d,J=12.1Hz, 2H),1.99–1.90(m,1H),1.80(d,J=13.1Hz,2H),1.67(p,J=7.6,7.1Hz,2H),1.49–1.28(m,11H),0.88(d,J=6.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.82,146.61,144.09,133.36,113.49,112.82,100.99,80 .82,51.50,35.12,32.99,32.92,31.61,25.77,24.90,24.83,24.57,22.52,14.01.

[0103] Example 2

[0104] The synthetic routes of compounds III-1 to III are partially the same as those in Example 1.

[0105] 1. 4-(cyclohexylamino)-2-(1-hydroxypentyl)-5-nitrobenzoic acid (compound 11)

[0106] Compound 10 (1.00 g, 3.01 mmol) was added to a reaction flask containing methanol (50 mL) and water (50 mL), followed by the addition of NaOH (0.24 g, 6.02 mmol) under stirring. The reaction solution was heated at 50 °C and stirred for 0.5 h. The solvent was removed under reduced pressure, and the solution was then dissolved in water (100 mL) and acidified to pH 2-3 with 5% HCl at -15 to 0 °C. The mixture was then rapidly extracted with cold Et₂O (50 mL × 3) and dried to obtain compound 1, which could be rapidly used in the next step without any purification.

[0107] 2. 2-(1-Acetoxypentyl)-4-(cyclohexylamino)-5-nitrobenzoic acid (compound 12)

[0108] A solution of Et₂O containing compound 11 (0.50 g, 1.42 mmol) was stirred at -15 °C, and then a mixture of triethylamine (0.14 g, 1.42 mmol) and DMAP (0.02 g, 0.14 mmol) in dichloromethane was added. Acetyl chloride (0.17 g, 2.13 mmol) dissolved in anhydrous CH₂Cl₂ was then added dropwise to the reaction mixture, and the solution was stirred at -15 °C for 5 hours. The mixture was acidified to pH 2 with 1 M HCl, and then stirred at room temperature for 0.5 hours. The organic phase was washed with water, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was then purified by column chromatography using EtOAc / petroleum ether (1 / 10, v / v) as eluent to give compound 12 as a pale yellow liquid (62.40%). 1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.38(s,1H),6.55(dd,J=8.4,4.2Hz,1H),3.34-3.21(m,1H),2.1 0(s,3H),2.12–2.03(m,2H),1.91–1.78(m,4H),1.44–1.32(m,8H),1.30–1.24(m,2H),0.90(t,J=7.2Hz,3H).

[0109] 3. Methyl 2-(1-acetoxypentyl)-4-(cyclohexylamino)-5-nitrobenzoate (Compound 13)

[0110] Compound 12 (0.2 g, 0.50 mmol) was dissolved in a dry dichloromethane solution, followed by the addition of DMAP (0.006 g, 0.05 mmol) and HATU (0.27 g, 0.75 mmol), and the reaction was carried out at room temperature for half an hour. Then, dry methanol (0.10 mL) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the solution was washed with water, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography as a yellow oil, with a yield of 70.20%. 1 H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.50(s,1H),6.34(dd,J=8.0,5.2Hz,1H),3.86(s,3H), 3.30-3.17(m,1H),2.21-1.96(m,6H)1.84-1.72(m,5H),1.43-1.22(m,8H),0.83(t,J=6.8Hz,3H).

[0111] 4. 5-Amino-4-(cyclohexylamino)-2-(1-hydroxypentyl)benzoic acid (III-1)

[0112] The synthesis method is the same as that for compound 11. 1 HNMR(400MHz,Chloroform-d)δ7.41(s.1H),6.89(s,1H),4.45–4.39(m,2H),3.30–3.29 (m,1H),2.10–1.99(m,5H),1.91–1.78(m,4H),1.44–1.32(m,7H),0.90(t,J=7.2Hz,3H).

[0113] 5. Methyl 5-amino-4-(cyclohexylamino)-2-(1-hydroxypentyl)benzoate (III-2)

[0114] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.25(s,1H),6.84(s,1H),4.69(s,1H),4.41(m,1H),3.76(s,3H),3. 32–3.19(m,1H),2.82(s,5H),2.04(s,3H),1.81(s,4H),1.39–1.26(m,4H),0.88(t,J=6.4Hz,3H).

[0115] 6. Methyl 2-(1-acetoxypentyl)-5-amino-4-(cyclohexylamino)benzoate (III-3)

[0116] The synthesis method is the same as in Example 1.1 H NMR(400MHz,Chloroform-d)δ7.28(s,1H),6.84(s,1H),6.44–6.34(m,1H),3.90(s,3H),3.29–3.16(m, 1H),2.00–1.92(m,5H),1.87–1.75(m,4H),1.45–1.31(m,3H),1.28–1.20(m,3H),0.87(t,J=6.8Hz,3H).

[0117] Example 3: Test of the compound's ferroptosis inhibitory activity

[0118] GPX4 inhibitors, such as RSL-3, can induce ferroptosis in cells. This ferroptosis can be blocked by other small molecules, such as lipophilic antioxidants like Ferrostatin-1 (fer-1) and Liproxstatin. Therefore, the ability of ferroptosis inhibitors to block ferroptosis can be indicated by the reversal of ferroptosis induced by ferroptosis inducers.

[0119] Cell lines: Human fibrosarcoma cells HT1080 and mouse hippocampal neurons HT22 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0120] Methods: The MTT assay was used, specifically as follows: Human renal cell carcinoma cell lines HT1080 / HT22 in logarithmic growth phase were digested, collected, and diluted. Approximately 4000-5000 cells per well were seeded into 96-well plates, with three replicates and 80 μL per well. Cells were incubated overnight at 37°C and 5% CO2. The experiment included a DMSO control group and nine different concentrations of the compound treatment groups. Different concentrations of the compound were added to each treatment group, and a DMSO control group (diluted to the highest concentration compound) was set up. After incubation for 1 hour at 37°C and 5% CO2, 1 μM / 100 nM RSL3 was added to each compound concentration to induce ferroptosis. RSL3 and DMSO control groups were also set up. Cells were incubated for another 48 hours at 37°C and 5% CO2. Add 20 μL MTT solution (5 mg / mL) to each well and incubate the cells at 37°C for 2 hours. Then add 100 μL DMSO to each well, shake gently for 10 minutes, and mix thoroughly. Measure the optical density (OD) of each well at 570 nm using an ELISA reader. Repeat the experiment three times. Calculate the survival rate (%) using the following formula: Survival rate % = (OD value of experimental group / OD value of DMSO control group) × 100%.

[0121] The results are shown in Table 1, indicating that the various compounds of the present invention can significantly inhibit ferroptosis and have good ferroptosis inhibitory activity.

[0122] Table 1. Inhibitory activity of compounds against RSL3-induced ferroptosis in HT22 cells.

[0123]

[0124]

[0125] In the table: "A" indicates IC 50 ≤0.1μM, “B” indicates IC 50 >0.1μM and ≤0.5μM “C” indicator IC 50 >0.5μM and ≤2μM, "D" indicates IC 50 >2μM.

[0126] Table 2. Inhibitory activity of compounds against RSL3-induced ferroptosis in HT1080 cells.

[0127] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> I-1 A II-2 D I-2 A II-3 D I-3 A II-4 B I-4 A II-5 C I-5 A II-6 B I-6 A II-7 A I-7 A II-8 A I-8 A II-9 A I-9 A II-10 A I-10 B II-11 A I-11 A II-12 A I-12 A III-1 C I-13 A III-2 B II-1 A III-3 B

[0128] In the table: "A" indicates IC 50 ≤0.1μM, “B” indicates IC 50 >0.1μM and ≤0.5μM “C” indicator IC 50 >0.5μM and ≤2μM, "D" indicates IC 50 >2μM.

[0129] Example 4: The compound exhibits good metabolic stability in vitro.

[0130] Human / rat plasma and rat liver microsomes were stored at -20°C and gradually thawed to room temperature before processing. A stock solution of 4 mg / mL was prepared by dissolving the compound in acetonitrile and then added to human / rat plasma or rat microsomes to a final concentration of 0.4 mg / mL. The solution was incubated at 37°C for 12 hours (0, 0.25, 0.5, 1, 2, 4, 8, 12 hours). Incubation was terminated at specific time points by adding acetonitrile. The mixture was vortexed for 30 seconds and centrifuged (12,000 rpm / 10 min), then filtered through a 0.22 μm filter and injected into an HPLC system (Agilent 1260HPLC) using an Alltima C18 (5 μm, 4.6 mm × 250 mm; mobile phase, methanol (20%) / water (80%) to methanol (100%) to methanol (20%) / water (80%); flow rate 1.0 mL / min; UV detection wavelength, 254–400 nm; temperature, 25 °C; injection volume, 10 μL) for 15 min.

[0131] Taking compound I-1 as an example, the results in Table 3 show that it exhibits excellent metabolic stability in human plasma, rat plasma, and rat liver microsomes, with half-lives all greater than 12 hours and drug recoveries exceeding 85% within 12 hours, indicating that I-1 has good metabolic stability in vitro. Therefore, aromatic alkylamine ferroptosis inhibitors based on the butylphthalide structure possess good metabolic properties and can be used for further pharmacological evaluation in animals.

[0132] Table 3. Evaluation of the in vitro metabolic stability of the compounds

[0133]

[0134] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An aromatic alkylamine ferroptosis inhibitor based on a butylphthalide structure, characterized in that, The structural formula of the aromatic alkylamine ferroptosis inhibitor is shown in Formula 1 or Formula 2: In the formula R 1 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, amino, phenyl, benzyl, naphthyl, C5-C 10 Aromatic heterocyclic groups or C3-C7 saturated heterocyclic groups; R 2 Selected from C0-C8 alkyl, C3-C 12 Cycloalkyl, adamantyl, or polyacetylenic; R 3 Selected from hydrogen, alkyl, aryl, C1-C6 alkyl-aryl, C1-C6 alkyl-phenolic or C3-C4 10 cycloalkyl; R 4 Selected from alkyl or haloalkyl, aryl, and heteroaryl groups of RC1-C10; R 5 Selected from C0 to C6 alkyl-C3 to C6 cycloalkyl-C0 to C6 alkyl or C0 to C6 alkyl-C3 to C6 cycloalkyl-C0 to C6 alkyl, C0 to C6 alkyl-Z-C0 to C6 alkyl or C0 to C6 alkyl-Z-C0 to C6 alkyl containing 1-3 independent substituents; wherein Z is selected from N, NR a , -SO2-, OC, OC=O, CO or C=OO; Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, phenyl, benzyl, naphthyl, C5-C 10 Aromatic heterocyclic groups, C3-C7 saturated heterocyclic groups, C3-C 12 Cycloalkyl, polyynyl, aryl, C1-C6 alkyl-aryl, C1-C6 alkyl-phenolic or C3-C 10 Cycloalkyl groups can be substituted by one or more atoms or groups; R a The group is selected from H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl or optionally substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocyclic alkyl, heteroaryl, C1-C6 alkoxy, NH (C1-C4 alkyl) and N (C1-C4 alkyl)2, wherein the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acrylate.

2. The aromatic alkylamine ferroptosis inhibitor based on the butylphthalide structure according to claim 1, characterized in that, The inhibitors are compounds I-1 to I-14, II-1 to II-12, and III-1 to III-3, and their structural formulas are as follows:

3. The preparation method of the aromatic alkylamine ferroptosis inhibitor based on the butylphthalide structure according to claim 2, characterized in that, The preparation method includes the following steps: The synthesis of compounds I-1 to I-14 is as follows: 5-bromophthalide was used as a starting material, and under the catalysis of AIBN, a free radical substitution reaction was carried out via NBS to obtain compound 2, which was then hydrolyzed to obtain compound 3; compound 3 reacted with the corresponding Grignard reagent to obtain compound 4; compound 4 reacted with potassium nitrate under concentrated sulfuric acid conditions to generate compound 5; compound 5 and cyclohexylamine underwent a substitution reaction in a mixed solution of DMF / tetrahydrofuran to obtain compound 6; compound 7 was obtained by reducing the nitro group of compound 6 with zinc powder, and then subjected to a reductive amination reaction with the corresponding aldehydes and ketones to obtain compounds I-1 to I-14, and II-1 to II-12; Reagents and reaction conditions: (a) NBS, AIBN, chloroform, reflux; (b) water, 110℃; (c) butyl magnesium bromide, tetrahydrofuran; (d) concentrated sulfuric acid, potassium nitrate; (e) cyclohexylamine, triethylamine, DMF, tetrahydrofuran; (f) zinc powder, hydrochloric acid, methanol; (g) the corresponding amine, acetic acid, sodium triacetoxyborohydride, dichloromethane.

4. The method for preparing the aromatic alkylamine ferroptosis inhibitor based on the butylphthalide structure according to claim 2, characterized in that, The preparation method includes the following steps: The synthesis of compounds III-1 to III-3 is as follows: compound 10 is hydrolyzed under alkaline conditions to give compound 11, which is further reacted with acyl chloride to give the corresponding ester 12. Compound 13 is formed by the condensation of compound 12 and the corresponding alcohol in the presence of HDTU and DIEPA, and then reduced to give the target compounds III-2 to III-3. Reagents and reaction conditions: (a) NBS, AIBN, chloroform, reflux; (b) water, 110°C; (c) butyl magnesium bromide, tetrahydrofuran; (d) concentrated sulfuric acid, potassium nitrate; (e) cyclohexylamine, triethylamine, DMF, tetrahydrofuran; (h) sodium hydroxide, methanol, water, 50°C; (i) acetyl chloride, triethylamine, dichloromethane, -10°C; (j) HATU, DMAP, dichloromethane, room temperature -50°C; (f) zinc powder, hydrochloric acid, methanol; (g) the corresponding amine, acetic acid, sodium triacetoxyborohydride, dichloromethane.

5. The use of the inhibitor according to claim 1 or 2 in the preparation of ferroptosis inhibitors and / or butylphthalide analog drugs.

6. The use of the inhibitor according to claim 1 or 2 in the preparation of a treatment for ferroptosis-related diseases and / or diseases treated with butylphthalide.

7. The application according to claim 6, characterized in that, The iron death-related diseases include neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, liver and kidney failure, inflammation, diabetic complications, and cardiovascular diseases.

8. The application according to claim 6, characterized in that, The diseases that butylphthalide can treat include resisting ischemic brain damage, improving neurodegenerative diseases, improving cerebral microcirculation, inhibiting platelet aggregation, protecting mitochondria, regulating energy metabolism, and reducing oxidative stress damage.

9. A drug for treating ferroptosis-related diseases, characterized in that, The drug contains the compound of claim 1 or 2 and a pharmaceutically acceptable salt, carrier, or adjuvant.

Images