阅读说明：本技术 一种多取代磺酰胺类化合物、制备方法及其医药用途 (Polysubstituted sulfonamide compound, preparation method and medical application thereof ) 是由 尤启冬 姜正羽 杨伟康 赵开梅 金雨辉 郭小可 徐晓莉 王磊 于 2021-11-05 设计创作，主要内容包括：本发明公开了一种多取代磺酰胺类化合物、制备方法及其医药用途。本发明提供的多取代磺酰胺类化合物对Keap1-p62PPI具有明显的抑制活性,为一种有效的Keap1-p62PPI抑制剂,具有开发成Keap1-p62相互作用抑制剂药物的前景。(The invention discloses a polysubstituted sulfonamide compound, a preparation method and medical application thereof. The polysubstituted sulfonamide compound provided by the invention has obvious inhibitory activity on Keap1-p62PPI, is an effective Keap1-p62PPI inhibitor, and has a prospect of being developed into a Keap1-p62 interaction inhibitor drug.)

1. A polysubstituted sulfonamide compound is characterized in that the chemical structural formula is as follows:

wherein:

a ═ quinoline, isoquinoline, indene, a benzene ring, 2-methylphenyl, 3-methylphenyl, 2, 5-dimethylphenyl, 2-methoxyphenyl, or 3-methoxyphenyl;

b ═ 2-methylbenzene, 2-bromobenzene, 4-methylbenzene, 4-methoxybenzene, 4-acetylaminobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-ethylbenzene, 4-isopropylbenzene, 2, 4-dimethylbenzene, 2,4, 6-trimethylbenzene, 2, 6-dimethyl-4-bromobenzene, 2, 6-dimethyl-4-chlorobenzene, 2,4, 6-triethylbenzene, 2,4, 6-triisopropylbenzene, 2,3,5, 6-tetramethylbenzene or 2,3,4,5, 6-pentamethylbenzene.

2. The process for producing polysubstituted sulfonamide compounds according to claim 1, wherein the synthesis route is as follows:

wherein:

a ═ quinoline, isoquinoline, indene, a benzene ring, 2-methylphenyl, 3-methylphenyl, 2, 5-dimethylphenyl, 2-methoxyphenyl, or 3-methoxyphenyl;

b ═ 2-methylbenzene, 2-bromobenzene, 4-methylbenzene, 4-methoxybenzene, 4-acetylaminobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-ethylbenzene, 4-isopropylbenzene, 2, 4-dimethylbenzene, 2,4, 6-trimethylbenzene, 2, 6-dimethyl-4-bromobenzene, 2, 6-dimethyl-4-chlorobenzene, 2,4, 6-triethylbenzene, 2,4, 6-triisopropylbenzene, 2,3,5, 6-tetramethylbenzene or 2,3,4,5, 6-pentamethylbenzene;

x ═ Cl or Br.

3. Use of the polysubstituted sulfonamide compounds according to claim 1 for the preparation of Keap1-p62 interaction inhibitors.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a polysubstituted sulfonamide compound, a preparation method and a medical application thereof.

Background

The autophagy adaptor p62 is closely related to the occurrence and development of tumors and is considered as a pathogenic target of the clear cell renal cell carcinoma. p62 is often observed to be expressed in cancer cells at elevated levels and therefore can be a good biomarker for prognosis of tumours.

The Keap1 protein in the cytoplasm is an aptamer to E3 ubiquitin ligase, and is one of the components of cellular defense mechanisms. p62 competitively binds to Keap1 protein via Keap1-p62 interaction, resulting in degradation of Keap1 protein by p 62-mediated selective autophagy, resulting in sustained activation of downstream genes, thereby inducing cancer. Inhibition of the Keap1-p62 interaction may therefore be a viable strategy for the treatment of cancer.

Disclosure of Invention

The invention aims to provide a polysubstituted sulfonamide compound, a preparation method and medical application thereof.

The above purpose of the invention is realized by the following technical scheme:

a polysubstituted sulfonamide compound has the following chemical structural formula:

wherein:

a ═ quinoline, isoquinoline, indene, a benzene ring, 2-methylphenyl, 3-methylphenyl, 2, 5-dimethylphenyl, 2-methoxyphenyl, or 3-methoxyphenyl;

b ═ 2-methylbenzene, 2-bromobenzene, 4-methylbenzene, 4-methoxybenzene, 4-acetylaminobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-ethylbenzene, 4-isopropylbenzene, 2, 4-dimethylbenzene, 2,4, 6-trimethylbenzene, 2, 6-dimethyl-4-bromobenzene, 2, 6-dimethyl-4-chlorobenzene, 2,4, 6-triethylbenzene, 2,4, 6-triisopropylbenzene, 2,3,5, 6-tetramethylbenzene or 2,3,4,5, 6-pentamethylbenzene.

The preparation method of the polysubstituted sulfonamide compound has the following synthetic route:

wherein:

a ═ quinoline, isoquinoline, indene, a benzene ring, 2-methylphenyl, 3-methylphenyl, 2, 5-dimethylphenyl, 2-methoxyphenyl, or 3-methoxyphenyl;

b ═ 2-methylbenzene, 2-bromobenzene, 4-methylbenzene, 4-methoxybenzene, 4-acetylaminobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-ethylbenzene, 4-isopropylbenzene, 2, 4-dimethylbenzene, 2,4, 6-trimethylbenzene, 2, 6-dimethyl-4-bromobenzene, 2, 6-dimethyl-4-chlorobenzene, 2,4, 6-triethylbenzene, 2,4, 6-triisopropylbenzene, 2,3,5, 6-tetramethylbenzene or 2,3,4,5, 6-pentamethylbenzene;

x ═ Cl or Br.

The polysubstituted sulfonamide compound is used for preparing a Keap1-p62 interaction inhibitor.

Has the advantages that:

the polysubstituted sulfonamide compound provided by the invention has obvious inhibitory activity on Keap1-p62PPI, is an effective Keap1-p62PPI inhibitor, and has a prospect of being developed into a Keap1-p62 interaction inhibitor drug.

Detailed Description

The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.

Example 1:

preparation of (S) -3- ((4- ((4-methoxyphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

Step 1: preparation of methyl (S) -3- ((4-nitroisoquinolin-1-yl) amino) butyrate

1-chloro-4-nitroisoquinoline (5.4g,25.9mmol) and methyl (S) -3-aminobutyrate (5.76g,38.8mmol) were dissolved in 30ml of DMF, potassium carbonate (10.7g,77.7mmol) was added, and the mixture was stirred at 100 ℃ for 8 h. After the reaction is completed, the mixture is cooled to room temperature, 200ml of water is added, EA is extracted for three times, organic phases are combined, the mixture is washed by saturated salt solution and dried by sodium sulfate, the organic phases are dried by spinning, sand making and column chromatography (PE: EA is 4: 1) are carried out, 7.1g of yellow solid is obtained, and the yield is 94.8%.

Step 2: preparation of methyl (S) -3- ((4-aminoisoquinolin-1-yl) amino) butyrate

Methyl (S) -3- ((4-nitroisoquinolin-1-yl) amino) butyrate (2g,7.7mmol) is dissolved in 20ml of anhydrous methanol, a catalytic amount of 10% Pd/C is added, the air in the reaction flask is replaced with hydrogen, and the mixture is stirred at normal temperature for 6 hours. After the reaction is completed, the solid is filtered out by using kieselguhr, the mixture is washed by using methanol for three times, organic phases are combined and dried by spinning to obtain a target product, and the target product can be directly put into the next step without purification.

And step 3: preparation of methyl (S) -3- ((4- ((tert-butoxycarbonyl) amino) isoquinolin-1-yl) amino) butanoate

(S) -methyl 3- ((4-aminoisoquinolin-1-yl) amino) butanoate (3g,11.5mmol) was dissolved in 30ml EA and (Boc) was added₂O (3g,13.7mmol), and stirred at room temperature for 4 h. After the reaction is completed, EA is dried in a spinning mode, sand is prepared, and column chromatography is carried out (PE: EA is 4: 1), so that 3.6g of light yellow oily liquid is obtained, and the yield is 86.5%.

And 4, step 4: preparation of methyl (S) -3- ((4- ((tert-butoxycarbonyl) amino) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butyrate

Methyl (S) -3- ((4- ((tert-butoxycarbonyl) amino) isoquinolin-1-yl) amino) butanoate (3g,7.5mmol) was dissolved in 10ml of DMF, cesium carbonate (7.4g,22.5mmol) was added, stirring was carried out at normal temperature for 5min, 3-bromopropyne (1.8g,15mmol) was added, and stirring was continued at normal temperature for 3 h. After the reaction is completed, 100ml of water is added, EA is extracted for three times, organic phases are combined, washed by saturated salt solution and dried by sodium sulfate, the organic phases are dried by spinning, sand making and column chromatography (PE: EA is 6:1) are carried out, 2.8g of yellow solid is obtained, and the yield is 84.3%.

And 5: preparation of methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate

Methyl (S) -3- ((4- ((tert-butoxycarbonyl) amino) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate (2g,5.0mmol) was dissolved in 5ml DCM, 5ml trifluoroacetic acid was added and stirred at ambient temperature for 2 h. After the reaction is completed, DCM is dried in a spinning mode, 30ml of saturated sodium bicarbonate solution is added, EA is extracted for three times, organic phases are combined, the mixture is washed by saturated salt solution and dried by sodium sulfate, the organic phase is dried in a spinning mode to obtain a target product, and the target product can be directly put into the next step without purification.

Step 6: preparation of methyl (S) -3- ((4- ((4-methoxyphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butyrate

Methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate (200mg,0.67mmol) was dissolved in anhydrous acetonitrile, 1ml of triethylamine was added, stirring was carried out at normal temperature for 5min, 4-methoxybenzenesulfonyl chloride (206mg,1mmol) was added, and reaction was carried out at 60 ℃ for 8 h. After the reaction was completed, acetonitrile was spin-dried, and sand-prepared, column chromatography (DCM) was performed to obtain 150mg of pale yellow oily liquid, the yield was 47.7%.

And 7: preparation of the title Compound

Dissolving methyl (S) -3- ((4- ((4-methoxyphenyl) sulfamide) isoquinoline-1-yl) (prop-2-yn-1-yl) amino) butyrate (100mg,0.2mmol) in 10ml of methanol, dropwise adding 2M LiOH (1ml,2mmol) at normal temperature, continuing stirring at normal temperature for 16h, after the reaction is completed, carrying out rotary drying on the methanol, adding 10ml of water, adjusting the pH to 4 by using 1M HCL, separating out a solid, filtering, washing a filter cake with water, and drying to obtain a light yellow solid, wherein the yield is 84mg and 86.6%.¹H NMR(300MHz,Methanol-d₄)δ8.30(d,J＝8.4Hz,1H),8.02(d,J＝8.3Hz,1H),7.84-7.79(m,3H),7.66(t,J＝7.7Hz,1H),7.40(d,J＝6.3Hz,1H),7.13(d,J＝8.9Hz,2H),4.78(dd,J＝17.9,2.5Hz,1H),4.64(q,J＝6.6Hz,1H),4.34(dt,J＝18.0,2.4Hz,1H),3.93(s,3H),2.86(dt,J＝16.0,7.0Hz,1H),2.74-2.63(m,2H),1.45(d,J＝3.4Hz,3H).HRMS(ESI):calcd For C₂₃H₂₄N₃O₅S[M+H]+454.14312,found 454.14247.

Example 2:

preparation of (S) -3- ((4- ((4-methylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

Step 1: preparation of methyl (S) -3- ((4- ((4-methylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butyrate

(S) -methyl 3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate (200mg,0.67mmol) obtained in example 1 was dissolved in anhydrous acetonitrile, 1ml of triethylamine was added, and after stirring at room temperature for 5min, 4-methylbenzenesulfonyl chloride (195mg,1mmol) was added, and reaction was carried out at 60 ℃ for 8 h. After the reaction was completed, acetonitrile was spin-dried, and sand-prepared, column chromatography (DCM) was performed to obtain 138mg of pale yellow oily liquid, and the yield was 45.4%.

Step 2: preparation of the title Compound

This product was obtained by hydrolysis of methyl (S) -3- ((4- ((4-methylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate described above in the same manner as in example 1. A yellow powder was obtained in 85.6% yield.¹H NMR(300MHz,Methanol-d₄)δ8.30(d,J＝8.4Hz,1H),8.01(d,J＝8.3Hz,1H),7.84-7.74(m,3H),7.70-7.63(m,1H),7.44(d,J＝8.1Hz,2H),7.36(d,J＝5.2Hz,1H),4.79(dd,J＝17.9,2.5Hz,1H),4.64(q,J＝6.5Hz,1H),4.36(dt,J＝17.9,2.3Hz,1H),2.86(dt,J＝16.0,7.3Hz,1H),2.74-2.63(m,2H),2.49(s,3H),1.44(d,J＝3.7Hz,3H).HRMS(ESI):calcd For C₂₃H₂₄N₃O₄S[M+H]+438.14820,found 438.14753.

Example 3:

preparation of (S) -3- ((4- ((2,4, 6-trimethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 2,4, 6-trimethylbenzenesulfonyl chloride as prepared in example 1 and as for example 2. A yellow powder was obtained in 73.2% yield.¹H NMR(300MHz,DMSO-d₆)δ8.26(d,J＝8.3Hz,1H),7.68-7.54(m,3H),7.52-7.40(m,2H),6.99(s,2H),4.81(dt,J＝18.0,2.9Hz,1H),4.67(p,J＝7.0Hz,1H),4.41(dt,J＝18.0,2.7Hz,1H),2.74(dd,J＝15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),2.25(s,3H),1.31(d,J＝12.2Hz,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17860.

Example 4:

preparation of (S) -3- ((4- ((4-acetamidophenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 4-acetamidobenzenesulfonyl chloride as prepared in example 1 and in the same manner as in example 2. A yellow powder was obtained in 75.4% yield.¹HNMR(300MHz,DMSO-d₆)δ10.51(s,1H),8.42(s,1H),7.91-7.73(m,6H),7.64(s,1H),7.35(s,1H),4.73-4.55(m,2H),4.42(dt,J＝18.1,3.1Hz,1H),3.25(d,J＝2.1Hz,1H),2.85-2.75(m,1H),2.63-2.54(m,1H)2.14(s,3H),1.31(d,J＝5.7Hz,3H).HRMS(ESI):calcd For C₂₄H₂₄N₄NaO₅S[M+Na]+503.13596,found 503.13549.

Example 5:

preparation of (S) -3- ((4- ((4-fluorophenyl) sulfonamide) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and 4-fluorobenzenesulfonyl chloride in the same manner as in example 2. A yellow powder was obtained in 61.2% yield.¹H NMR(300MHz,Methanol-d₄)δ8.24(d,J＝8.2Hz,1H),8.00-7.92(m,3H),7.81-7.73(m,1H),7.62(t,J＝7.8Hz,1H),7.49(d,J＝1.7Hz,1H),7.38(t,J＝8.7Hz,2H),4.85(dd,J＝17.9,2.6Hz,1H),4.77-4.64(m,1H),4.35(dd,J＝17.9,2.1Hz,1H),2.88-2.79(m,1H),2.74(t,J＝2.5Hz,1H),2.71-2.60(m,1H),1.44(d,J＝2.9Hz,3H).HRMS(ESI):calcd For C₂₂H₂₁FN₃O₄S[M+H]+442.12313,found 442.12307.

Example 6:

preparation of (S) -3- ((4- ((4-chlorophenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 4-chlorobenzenesulfonyl chloride prepared in example 1 in the same manner as in example 2. A yellow powder was obtained in 59.8% yield.¹H NMR(300MHz,Methanol-d₄)δ8.36(d,J＝8.4Hz,1H),8.05-7.99(m,1H),7.91-7.85(m,3H),7.66(d,J＝8.6Hz,2H),7.49-7.44(m,1H),7.38(d,J＝7.1Hz,1H),4.85(dd,J＝18.0,2.4Hz,1H),4.63(q,J＝6.6Hz,1H),4.37(dt,J＝18.1,2.2Hz,1H),2.88(dt,J＝14.6,7.2Hz,1H),2.79-2.66(m,2H),1.46(d,J＝3.5Hz,3H).HRMS(ESI):calcd For C₂₂H₂₁ClN₃O₄S[M+H]+458.09358,found458.09321.

Example 7:

preparation of (S) -3- ((4- ((4-bromophenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and 4-bromobenzenesulfonyl chloride by the same method as in example 2. A yellow powder was obtained in 64.6% yield.¹H NMR(300MHz,Methanol-d₄)δ8.20(d,J＝8.3Hz,1H),7.93(d,J＝8.3Hz,1H),7.79-7.70(m,5H),7.62-7.56(m,1H),7.46(s,1H),4.84(dd,J＝17.9,2.5Hz,1H),4.73-4.66(m,1H),4.33(dt,J＝18.0,2.1Hz,1H),2.81(dt,J＝15.4,5.5Hz,1H),2.72(d,J＝2.5Hz,1H),2.66-2.54(m,1H),1.44(d,J＝2.9Hz,3H).HRMS(ESI):calcd For C₂₂H₂₁BrN₃O₄S[M+H]+502.04307,found 502.04296.

Example 8:

preparation of (S) -3- ((4- ((4-ethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 4-ethylbenzenesulfonyl chloride as prepared in example 1 and as for example 2. A yellow powder was obtained in 75.8% yield.¹H NMR(300MHz,Methanol-d₄)δ8.20(d,J＝8.3Hz,1H),7.94(d,J＝8.3Hz,1H),7.77(d,J＝7.9Hz,2H),7.72(t,J＝7.6Hz,1H),7.58(t,J＝7.7Hz,1H),7.48-7.43(m,3H),4.78(dd,J＝17.8,2.5Hz,1H),4.67(q,J＝6.5Hz,1H),4.35(dt,J＝17.8,2.0Hz,1H),2.80(q,J＝7.6Hz,3H),2.69-2.66(m,1H),2.65-2.55(m,1H),1.42(dd,J＝10.8,6.6Hz,3H),1.31(d,J＝7.6Hz,3H).HRMS(ESI):calcd For C₂₄H₂₆N₃O₄S[M+H]+452.16385,found452.16371.

Example 9:

preparation of (S) -3- ((4- ((4-isopropylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 4-isopropylbenzenesulfonyl chloride as prepared in example 1 and as for example 2. A yellow powder was obtained in 75.8% yield.¹H NMR(300MHz,Methanol-d₄)δ8.19(d,J＝8.4Hz,1H),7.91(d,J＝8.3Hz,1H),7.78(d,J＝8.3Hz,2H),7.73-7.66(m,1H),7.61-7.53(m,1H),7.48(dd,J＝5.6,2.6Hz,3H),4.78(dd,J＝17.9,2.4Hz,1H),4.68(q,J＝6.5Hz,1H),4.35(dt,J＝17.9,2.2Hz,1H),3.06(p,J＝6.9Hz,1H),2.86-2.75(m,1H),2.69-2.54(m,2H),1.42(dd,J＝11.0,6.5Hz,3H),1.34(s,3H),1.32(s,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17884.

Example 10:

preparation of (S) -3- ((4- ((2-methylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and o-toluenesulfonyl chloride, prepared as in example 2. A yellow powder was obtained in 84.2% yield.¹H NMR(300MHz,Methanol-d₄)δ8.46(s,1H),8.26(dd,J＝8.7,1.6Hz,1H),8.13-8.09(m,1H),7.76(dd,J＝8.5,1.6Hz,1H),7.66-7.55(m,2H),7.47-7.37(m,2H),7.32-7.30(m,1H),4.32-4.25(m,3H),2.73(dd,J＝15.4,7.7Hz,1H),2.68-2.61(m,5H),1.31(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₃H₂₄N₃O₄S[M+H]+438.14820,found438.14842.

Example 11:

preparation of (S) -3- ((4- ((2-bromophenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and o-bromobenzenesulfonyl chloride by the same method as in example 2. A yellow powder was obtained in 62.8% yield.¹H NMR(300MHz,Methanol-d₄)δ8.46(s,1H),8.26(d,J＝8.7Hz,1H),8.11(d,J＝8.0Hz,1H),7.91(d,J＝8.4Hz,1H),7.69(d,J＝7.9Hz,1H),7.66-7.61(m,1H),7.60-7.51(m,2H),7.42-7.37(m,1H),4.33-4.21(m,3H),2.77-2.57(m,3H),1.31(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₂H₂₁BrN₃O₄S[M+H]+502.04307,found 502.04328.

Example 12:

preparation of (S) -3- ((4- ((2, 4-dimethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 2, 4-dimethylbenzenesulfonyl chloride prepared in example 1 in the same manner as in example 2. A yellow powder was obtained in 43.8% yield.¹H NMR(300MHz,Methanol-d₄)δ8.19(d,J＝8.4Hz,1H),7.88(d,J＝8.4Hz,1H),7.74-7.66(m,2H),7.60-7.52(m,2H),7.21(s,1H),7.14(d,J＝8.2Hz,1H),4.88-4.78(m,1H),4.66(q,J＝6.5,6.0Hz,1H),4.37(d,J＝17.9Hz,1H),2.81(dd,J＝15.9,6.1Hz,1H),2.70(d,J＝2.8Hz,1H),2.66-2.59(m,1H),2.48(s,3H),2.38(s,3H),1.31(d,J＝7.6Hz,3H).HRMS(ESI):calcd For C₂₄H₂₆N₃O₄S[M+H]+452.16385,found452.16307.

Example 13:

preparation of (S) -3- ((4- ((2, 6-dimethyl-4-bromophenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and 2, 6-dimethyl-4-bromobenzenesulfonyl chloride by the same method as in example 2. A yellow powder was obtained in 35.4% yield.¹H NMR(300MHz,DMSO-d₆)δ8.26(d,J＝8.3Hz,1H),7.68-7.54(m,3H),7.52-7.39(m,2H),6.95(s,2H),4.81(dt,J＝18.0,2.9Hz,1H),4.67(p,J＝7.0Hz,1H),4.41(dt,J＝18.0,2.7Hz,1H),2.74(dd,J＝15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),1.31(d,J＝7.8Hz,3H).HRMS(ESI):calcd For C₂₄H₂₅BrN₃O₄S[M+H]+530.07436,found 530.07468

Example 14:

preparation of (S) -3- ((4- ((2, 6-dimethyl-4-chlorophenyl) sulfonylamino) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 2, 6-dimethyl-4-chlorobenzenesulfonyl chloride prepared in example 1 in the same manner as in example 2. A yellow powder was obtained in 28.5% yield.¹H NMR(300MHz,DMSO-d₆)δ8.46(s,1H),8.26(dd,J＝8.7,1.6Hz,1H),8.15-8.08(m,1H),7.67-7.52(m,2H),7.37(s,2H),4.32-4.20(m,3H),2.76-2.62(m,3H),2.60(s,6H),1.31(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₄H₂₅ClN₃O₄S[M+H]+486.12487,found486.12496.

Example 15:

preparation of (S) -3- ((4- ((2,3,5, 6-tetramethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and 2,3,5, 6-tetramethylbenzenesulfonyl chloride in the same manner as in example 2. A yellow powder was obtained in 42.6% yield.¹H NMR(300MHz,Methanol-d₄)δ8.22(t,J＝8.0Hz,1H),7.81-7.72(m,2H),7.65(q,J＝7.1,6.2Hz,1H),7.59-7.52(m,1H),7.16(s,1H),4.93-4.88(m,1H),4.70-4.60(m,1H),4.45(dt,J＝18.4,2.6Hz,1H),2.89-2.75(m,2H),2.72-2.58(m,1H),2.34(s,6H),2.20(s,6H),1.42(d,J＝7.6Hz,3H).HRMS(ESI):calcd For C₂₆H₃₀N₃O₄S[M+H]+480.19515,found 480.19449.

Example 16:

preparation of (S) -3- ((4- ((2,3,4,5, 6-pentamethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate prepared in example 1 and 2,3,4,5, 6-pentamethylbenzenesulfonyl chloride in the same manner as in example 2. A yellow powder was obtained in 41.5% yield.¹H NMR(300MHz,Methanol-d₄)δ8.21(dd,J＝8.4,5.2Hz,1H),7.82(dd,J＝14.8,9.3Hz,2H),7.70-7.62(m,1H),7.60-7.51(m,1H),4.99(d,J＝3.3Hz,1H),4.72-4.59(m,1H),4.47(dt,J＝17.8,2.8Hz,1H),2.89-2.76(m,2H),2.71-2.61(m,1H),2.38(s,6H),2.27(d,J＝1.7Hz,3H),2.20(s,6H),1.43(d,J＝3.3Hz,3H).HRMS(ESI):calcd For C₂₇H₃₂N₃O₄S[M+H]+494.21080,found 494.20973.

Example 17:

preparation of (S) -3- ((4- ((2,4, 6-triethylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 2,4, 6-triethylbenzenesulfonyl chloride as prepared in example 1 and as for example 2. A yellow powder was obtained in 54.2% yield.¹H NMR(300MHz,Methanol-d₄)δ8.46(s,1H),8.27-8.24(m,1H),8.12-8.09(m,1H),7.68-7.52(m,2H),7.11(q,J＝1.0Hz,2H),4.34-4.21(m,3H),2.85-2.70(m,5H),2.68-2.58(m,4H),1.31(d,J＝6.6Hz,3H),1.25-1.19(m,9H).HRMS(ESI):calcd For C₂₈H₃₄N₃O₄S[M+H]+508.22645,found 508.22631.

Example 18:

preparation of (S) -3- ((4- ((2,4, 6-triisopropylphenyl) sulfonamido) isoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from methyl (S) -3- ((4-aminoisoquinolin-1-yl) (prop-2-yn-1-yl) amino) butanoate and 2,4, 6-triisopropylbenzenesulfonyl chloride as prepared in example 1 and as for example 2. A yellow powder was obtained in 67.5% yield.¹H NMR(300MHz,Methanol-d₄)δ8.46(s,1H),8.26(dd,J＝8.7,1.6Hz,1H),8.13-8.07(m,1H),7.66-7.55(m,2H),7.19(d,J＝0.7Hz,2H),4.32-4.23(m,3H),4.15-4.10(m,2H),2.99-2.92(m,1H),2.73(dd,J＝15.4,7.7Hz,1H),2.69-2.59(m,2H),1.31(d,J＝6.6Hz,3H),1.25-1.18(m,18H).HRMS(ESI):calcd For C₃₁H₄₀N₃O₄S[M+H]+550.27340,found 550.27386.

Example 19:

preparation of (S) -3- ((5- ((2,4, 6-trimethylphenyl) sulfonamido) quinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroquinoline, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as in example 1 to give a yellow solid in 37.5% yield.¹HNMR(300MHz,DMSO-d₆)δ8.69(dd,J＝4.2,1.6Hz,1H),8.04(dd,J＝8.6,1.7Hz,1H),7.42(dd,J＝8.5,4.2Hz,1H),7.27(d,J＝8.4Hz,1H),6.95(s,2H),6.78(d,J＝7.9Hz,1H),6.65(dd,J＝8.7,2.0Hz,1H),4.73(dd,J＝17.9,1.2Hz,1H),4.53(dd,J＝18.0,2.5Hz,1H),4.06(t,J＝7.5Hz,1H),3.27(q,J＝2.3Hz,1H),2.74-2.58(m,2H),2.27(d,J＝2.3Hz,6H),2.22(s,3H),1.31(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17884.

Example 20:

preparation of (S) -3- ((5- ((2,3,4,5, 6-pentamethylphenyl) sulfonamido) quinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroquinoline, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,3,4,5, 6-pentamethylbenzenesulfonyl chloride by the same method as in example 1 to give a yellow solid in 37.5% yield.¹H NMR(300MHz,Chloroform-d)δ8.68(dd,J＝4.2,1.7Hz,1H),8.30(dt,J＝8.6,1.8Hz,1H),7.48(t,J＝8.8Hz,1H),7.33(dd,J＝8.4,4.0Hz,1H),6.64(dd,J＝8.4,2.9Hz,1H),4.83(dt,J＝17.5,2.9Hz,1H),4.55(dd,J＝17.6,2.5Hz,1H),4.18(q,J＝6.4Hz,1H),2.90(d,J＝15.4Hz,1H),2.60(dd,J＝16.5,9.0Hz,1H),2.33(d,J＝2.2Hz,6H),2.25(d,J＝3.2Hz,3H),2.22(d,J＝2.4Hz,1H),2.18(d,J＝2.4Hz,6H),1.47(d,J＝6.4Hz,3H).HRMS(ESI):calcd For C₂₇H₃₂N₃O₄S[M+H]+494.21080,found 494.21019.

Example 21:

preparation of (S) -3- ((5- ((2,3,5, 6-tetramethylphenyl) sulfonamido) quinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroquinoline, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,3,5, 6-tetramethylbenzenesulfonyl chloride by the same method as in example 1 to give a yellow solid in 54.6% yield.¹H NMR(300MHz,Chloroform-d)δ8.68(d,J＝4.2Hz,1H),8.24(dt,J＝8.7,2.3Hz,1H),7.44(t,J＝8.5Hz,1H),7.34(dd,J＝4.2,1.8Hz,1H),7.10(s,1H),6.64(dd,J＝8.5,3.1Hz,1H),4.82(dt,J＝17.5,2.8Hz,1H),4.56(dd,J＝17.5,2.3Hz,1H),4.27-4.11(m,1H),2.98-2.86(m,1H),2.60(dt,J＝15.3,7.5Hz,1H),2.30(s,6H),2.24-2.19(m,7H),1.49(d,J＝6.4Hz,3H).HRMS(ESI):calcd For C₂₆H₂₉N₃NaO₄S[M+Na]+502.17710,found 502.17621.

Example 22:

preparation of (S) -3- ((5- ((2, 6-dimethyl-4-bromophenyl) sulfonamido) quinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroquinoline, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2, 6-dimethyl-4-bromobenzenesulfonyl chloride by the same method as example 1 to give a yellow solid in 48.2% yield.¹H NMR(300MHz,Chloroform-d)δ8.69(dd,J＝4.2,1.6Hz,1H),8.04(dd,J＝8.6,1.7Hz,1H),7.42(dd,J＝8.5,4.2Hz,1H),7.25(d,J＝8.4Hz,1H),6.87(s,2H),6.78(d,J＝7.9Hz,1H),6.65(dd,J＝8.7,2.0Hz,1H),4.73(dd,J＝17.9,1.2Hz,1H),4.53(dd,J＝18.0,2.5Hz,1H),4.06(t,J＝7.5Hz,1H),3.27(q,J＝2.3Hz,1H),2.74-2.58(m,2H),2.27(d,J＝2.3Hz,6H),1.31(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₄H₂₅BrN₃O₄S[M+H]+530.07436,found 530.07403.

Example 23:

preparation of (S) -3- ((5- ((2, 6-dimethyl-4-chlorophenyl) sulfonylamino) quinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroquinoline, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2, 6-dimethyl-4-chlorobenzenesulfonyl chloride by the same method as example 1 to give a yellow solid in 25.6% yield.¹H NMR(300MHz,Chloroform-d)δ8.68(d,J＝4.2Hz,1H),8.02(dd,J＝8.6,1.7Hz,1H),7.43(dd,J＝8.5,4.3Hz,1H),7.27(d,J＝8.2Hz,1H),6.90(s,2H),6.75(d,J＝7.7Hz,1H),6.65(dd,J＝8.6,2.1Hz,1H),4.74(dd,J＝17.7,1.2Hz,1H),4.53(dd,J＝18.0,2.5Hz,1H),4.07-4.03(m,1H),3.25(q,J＝2.5Hz,1H),2.74-2.58(m,2H),2.27(d,J＝2.3Hz,6H),1.34(d,J＝7.2Hz,3H).HRMS(ESI):calcd For C₂₄H₂₅ClN₃O₄S[M+H]+486.12487,found486.12454.

Example 24:

preparation of (S) -3- ((5- ((2,4, 6-trimethylphenyl) sulfonamido) isoquinolin-8-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-nitro-8-chloroisoquinoline, methyl (S) -3-aminobutyric acid, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as in example 1 to give a yellow solid in 67.4% yield.¹H NMR(300MHz,Chloroform-d)δ9.88(d,J＝3.3Hz,1H),8.30(s,1H),8.13(dd,J＝8.3,6.3Hz,1H),7.76-7.58(m,2H),6.84(d,J＝7.2Hz,2H),6.60(t,J＝8.9Hz,1H),4.79(dt,J＝17.6,1.9Hz,1H),4.56(ddd,J＝17.5,8.8,2.5Hz,1H),4.14(s,1H),2.95(dt,J＝11.9,6.3Hz,1H),2.77(dd,J＝15.4,3.3Hz,1H),2.38(d,J＝7.9Hz,6H),2.26(t,J＝4.3Hz,4H),1.46(d,J＝6.3Hz,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17919.

Example 25:

preparation of (S) -3- ((8- ((2,4, 6-trimethylphenyl) sulfonamido) isoquinolin-5-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 5-chloro-8-nitroisoquinoline, methyl (S) -3-aminobutyrate, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as example 1 to give a yellow solid in 56.4% yield.¹HNMR(300MHz,Chloroform-d)δ10.46(s,1H),7.61(d,J＝9.1Hz,1H),7.31(s,1H),7.01(s,3H),6.84-6.75(m,2H),4.99(q,J＝6.9Hz,1H),4.14(d,J＝2.5Hz,2H),2.99(dd,J＝15.9,6.9Hz,1H),2.85(dd,J＝16.0,7.1Hz,1H),2.69(s,6H),2.35(s,3H),2.26(t,J＝2.5Hz,1H),1.65(d,J＝6.8Hz,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17934.

Example 26:

preparation of (S) -3- ((1- ((2,4, 6-trimethylphenyl) sulfonamido) isoquinolin-4-yl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 4-chloro-1-nitroisoquinoline, methyl (S) -3-aminobutyrate, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as in example 1 to give a yellow solid in 15.2% yield.¹HNMR(300MHz,DMSO-d₆)δ8.28(d,J＝8.1Hz,1H),7.68-7.51(m,3H),7.49-7.40(m,2H),7.02(s,2H),4.83(dt,J＝18.0,2.9Hz,1H),4.56(p,J＝7.0Hz,1H),4.41(dt,J＝18.0,2.7Hz,1H),2.82(dd,J＝15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),2.25(s,3H),1.32(d,J＝11.8Hz,3H).HRMS(ESI):calcd For C₂₅H₂₈N₃O₄S[M+H]+466.17950,found466.17848.

Example 27:

preparation of (S) -3- ((7- ((2,4, 6-trimethylphenyl) sulfonamido) -2, 3-dihydro-1H-inden-4-yl) (prop-2-yn-1-yl) amino) butanoic acid

Step 1: preparation of methyl (S) -3- ((7-nitro-2, 3-dihydro-1H-inden-4-yl) amino) butyrate

Dissolving 7-nitro-4-bromo-2, 3-dihydro-1H-indene (1g,3.2mmol) in 30ml of toluene, and adding Pd under stirring₂(dba)₃(147mg,0.16mmol), BINAP (300mg,0.54mmol), cesium carbonate (3.14g,9.6mmol), heated at reflux for 16 h. After completion of the reaction, toluene was spin-dried, 100ml of water was added, EA was extracted three times, the organic phases were combined, washed with saturated brine, dried over sodium sulfate, and the organic phases were spin-dried, made into sand, and subjected to column chromatography (PE: EA ═ 6:1) to obtain 650mg of a yellow solid, with a yield of 64.3%.

Step 2: preparation of the title Compound

This was prepared from methyl (S) -3- ((7-nitro-2, 3-dihydro-1H-inden-4-yl) amino) butanoate, 3-bromopropyne, and 2,4, 6-trimethylbenzenesulfonyl chloride as described above in example 1 to give a yellow solid in 24.3% yield.¹H NMR(300MHz,Chloroform-d)δ7.31(s,1H),6.97(s,2H),6.64(d,J＝7.9Hz,1H),6.43(d,J＝7.9Hz,1H),3.88(d,J＝2.4Hz,3H),2.98(t,J＝7.3Hz,2H),2.85(t,J＝7.5Hz,2H),2.72(d,J＝14.8Hz,3H),2.56(s,6H),2.34(s,3H),2.13-2.06(m,2H),1.48-1.26(m,3H).HRMS(ESI):calcd For C₂₅H₃₀N₂NaO₄S[M+Na]+477.18185,found 477.18166.

Example 28:

preparation of (S) -3- ((4- ((2,4, 6-trimethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from p-bromonitrobenzene, (S) -methyl-3-aminobutyrate, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 75.9% yield.¹H NMR(300MHz,Chloroform-d)δ7.10-7.01(m,2H),6.91(s,2H),6.60-6.51(m,2H),4.49(d,J＝2.5Hz,2H),3.99-3.88(m,1H),2.75-2.63(m,1H),2.56-2.50(m,1H),2.47(s,6H),2.32(s,3H),2.28(t,J＝2.4Hz,1H),1.33(d,J＝6.4Hz,3H).HRMS(ESI):calcd For C₂₂H₂₆N₂NaO₄S[M+Na]+437.15055,found 437.14998.

Example 29:

preparation of (S) -3- ((2-methyl-4- ((2,3,5, 6-tetramethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2-bromo-5-nitrotoluene, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,3,5, 6-tetramethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 68.3% yield.¹H NMR(300MHz,DMSO-d₆)δ9.99(s,1H),7.23(s,1H),7.10(d,J＝8.6Hz,1H),6.80(d,J＝2.6Hz,1H),6.71(dd,J＝8.5,2.7Hz,1H),3.79-3.58(m,3H),2.99-2.96(m,1H),2.46(s,6H),2.40(dd,J＝14.9,4.1Hz,1H),2.22(s,6H),2.19-2.12(m,1H),2.11(s,3H),1.07(d,J＝6.4Hz,3H).HRMS(ESI):calcd For C₂₄H₃₀N₂NaO₄S[M+Na]+465.18185,found 465.18154.

Example 30:

preparation of (S) -3- ((3-methyl-4- ((2,3,5, 6-tetramethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2-nitro-5-bromotoluene, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,3,5, 6-tetramethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 58.6% yield.¹H NMR(300MHz,DMSO-d₆)δ9.14(s,1H),7.22(s,1H),6.74-6.63(m,2H),6.57(dd,J＝8.8,2.9Hz,1H),4.23(q,J＝7.1,6.5Hz,1H),4.03-3.89(m,2H),3.07-3.02(m,1H),2.44(t,J＝6.8Hz,2H),2.29(s,6H),2.21(s,6H),2.05(s,3H),1.19(d,J＝6.5Hz,3H).HRMS(ESI):calcd For C₂₄H₃₀N₂NaO₄S[M+Na]+465.18185,found465.18158.

Example 31:

preparation of (S) -3- ((2, 5-dimethyl-4- ((2,3,5, 6-tetramethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2, 5-dimethyl-4-bromonitrobenzene, (S) -methyl-3-aminobutyrate, 3-bromopropyne and 2,3,5, 6-tetramethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 72.6% yield.¹H NMR(300MHz,DMSO-d₆)δ7.21(s,1H),6.99(s,1H),6.75(s,1H),3.81-3.62(m,2H),3.44(ddd,J＝10.1,6.6,3.7Hz,1H),2.96-2.90(m,1H),2.33(dd,J＝14.5,3.6Hz,1H),2.26(s,6H),2.19(s,6H),2.11(d,J＝9.9Hz,1H),2.06(s,3H),1.97(s,3H),1.06(d,J＝6.3Hz,3H).HRMS(ESI):calcd For C₂₅H₃₂N₂NaO₄S[M+Na]+479.19750,found 479.19669.

Example 32:

preparation of (S) -3- ((3-methoxy-4- ((2,3,5, 6-tetramethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2-methoxy-4-bromonitrobenzene, (S) -methyl 3-aminobutyric acid, 3-bromopropyne and 2,3,5, 6-tetramethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 42.8% yield.¹H NMR(300MHz,Methanol-d₄)δ7.19-7.14(m,2H),6.51(dd,J＝8.8,2.7Hz,1H),6.45(d,J＝2.6Hz,1H),4.37(dt,J＝8.0,6.2Hz,1H),4.01(t,J＝2.2Hz,2H),3.40(s,3H),2.66(dd,J＝15.2,5.9Hz,1H),2.58-2.48(m,2H),2.40(s,6H),2.25(s,6H),1.32(d,J＝6.7Hz,3H).HRMS(ESI):calcd For C₂₄H₃₀N₂NaO₅S[M+Na]+481.17676,found481.17605.

Example 33:

preparation of (S) -3- ((3-methyl-4- ((2,4, 6-trimethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2-nitro-5-bromotoluene, (S) -3-aminobutyric acid methyl ester, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as in example 27 to give a yellow solid in 84.3% yield.¹H NMR(300MHz,DMSO-d₆)δ9.13(s,1H),7.00(s,2H),6.74(d,J＝8.7Hz,1H),6.66-6.56(m,2H),4.24(q,J＝6.8Hz,1H),3.98(d,J＝2.4Hz,2H),3.06(d,J＝2.2Hz,1H),2.49(d,J＝7.7Hz,2H),2.37(s,6H),2.28(s,3H),1.94(s,3H),1.20(d,J＝6.6Hz,3H).HRMS(ESI):calcd For C₂₃H₂₈N₂NaO₄S[M+Na]+451.16620,found451.16551.

Example 34:

preparation of (S) -3- ((2, 5-dimethyl-4- ((2,4, 6-trimethylphenyl) sulfonamido) phenyl) (prop-2-yn-1-yl) amino) butanoic acid

This was prepared from 2, 5-dimethyl-4-bromonitrobenzene, (S) -methyl-3-aminobutyrate, 3-bromopropyne and 2,4, 6-trimethylbenzenesulfonyl chloride by the same method as example 27 to give a yellow solid in 64.8% yield.¹H NMR(300MHz,Methanol-d₄)δ7.15(s,1H),6.99(s,2H),6.72(s,1H),3.83(dd,J＝17.6,2.4Hz,1H),3.77-3.67(m,2H),2.60-2.49(m,2H),2.41(s,6H),2.33(s,3H),2.31-2.24(m,1H),2.08(d,J＝13.6Hz,6H),1.23(d,J＝6.4Hz,3H).HRMS(ESI):calcd For C₂₄H₃₀N₂NaO₄S[M+Na]+465.18185,found465.18116.

The drug effect example:

the compounds were tested for inhibitory activity against Keap1-p62PPI using fluorescence polarization (FP assay).

The assay used a 384 well blackboard (model Corning 3575) and 40. mu.L of final volume selection was added to the wells in the order of 20. mu.L of each of the different concentrations of compound, 10. mu.L of Keap1 Kelch domain protein (40nM, final concentration 10nM), and 10. mu.L of the LFITC-Acp-VDPpSTGEL fluorescent probe (16nM, final concentration 4 nM). A blank control (30. mu.L Tris buffer + 10. mu.L FITC-Acp-VDPpSTGEL fluorescent probe) and a negative control (20. mu.L Tris buffer + 10. mu.L Keap1 Kelch domain protein + 10. mu.L FITC-Acp-VDPpSTGEL fluorescent probe) were set for each experiment. After the addition, the plate is covered on a shaking table and incubated for 30min, a polarization value P is obtained by using a multifunctional microplate reader under the condition that the excitation wavelength is 485nm and the emission wavelength is 525nm, the inhibition rate is calculated by using the following formula, and IC is calculated by using GraphPad software₅₀Values, results are shown in Table 1(^aSee the specific examples for structures of compounds). Inhibition rate ═ 1- (P)_{Compound (I)}-P_{Blank space})/(P_{Negative control}-P_{Blank space})]X 100%. The small molecules prevent the continuous activation of downstream genes by inhibiting Keap1-p62PPI, thereby inhibiting the occurrence and development of hepatocellular carcinoma.

TABLE 1 IC of compounds of the invention on Keap1-p62PPI₅₀Value of

In conclusion, the polysubstituted sulfonamide compound provided by the invention has obvious inhibitory activity on Keap1-p62PPI, is an effective Keap1-p62PPI inhibitor, and has a prospect of being developed into a Keap1-p62 interaction inhibitor drug.

The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.