CN114230529A

CN114230529A - Tetrahydroquinoxaline sulfonamide derivative and preparation method and application thereof

Info

Publication number: CN114230529A
Application number: CN202111293744.3A
Authority: CN
Inventors: 梁停停; 冬海洋; 王建红; 鲁露; 张亚宏; 齐建国
Original assignee: Henan University
Current assignee: Henan University
Priority date: 2021-11-03
Filing date: 2021-11-03
Publication date: 2022-03-25

Abstract

The invention discloses a compound containing a tetrahydroquinoxaline sulfonamide structure, and provides a specific preparation method of the compound and pharmaceutical application of the compound as a microtubule polymerization inhibitor. The invention discloses a tetrahydroquinoxaline sulfonamide derivative shown in a general formula (I), and pharmacological experiment results show that the sulfonamide compound (I) has proliferation inhibition activity on tumor cells, blocks the tumor cells in a G2/M stage, and can be used for preparing and treating malignant tumors caused by tubulin dynamic balance imbalance; the invention also discloses a preparation method of the tetrahydroquinoxaline sulfonamide derivative.

Description

Tetrahydroquinoxaline sulfonamide derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a microtubule polymerization inhibitor containing a tetrahydroquinoxaline sulfonamide structure, a preparation method thereof, a pharmaceutical composition containing the compounds and application thereof in medicines for treating malignant tumors and the like.

Technical Field

The pathogenesis of cancer is complex and is related to various factors such as environment, genes, obesity, infection and the like. The main characteristics of cancer are unlimited growth of cells, high mortality and recurrence rate and poor prognosis.

Microtubules are hollow cylindrical structures formed by polymerization of alpha-tubulin and beta-tubulin, and microtubules are in a dynamic equilibrium state under normal physiological conditions. Microtubules, which are important components of cytoskeleton, are involved in various biological functions such as transport of intracellular substances, cell movement, maintenance of cell morphology, and cell proliferation. Microtubules participate in spindle formation during cell proliferation, and have a close relationship with the distribution of genetic material. Tumor cells have the ability to proliferate rapidly, with frequent mitotic processes and shorter cell cycles than normal cells, and thus microtubules in tumor cells are in an abnormally activated state. Microtubule-targeting agents (MTAs) promote or inhibit microtubule polymerization by binding to microtubules, destroy the dynamic equilibrium of microtubules, interfere with mitosis of cells, and induce tumor cell death.

Disclosure of Invention

The purpose of the invention is as follows: the invention discloses a compound containing a tetrahydroquinoxaline sulfonamide structure, and provides a specific preparation method of the compound and pharmaceutical application of the compound as a microtubule polymerization inhibitor.

The technical scheme is as follows: the invention discloses a tetrahydroquinoxaline sulfamide derivative shown as a general formula (I) or pharmaceutically acceptable salt thereof:

wherein: x ═ CH or N;

R¹represents H, F, Cl, Br, -OR⁴、-COOR⁴、-OCOR⁴、-NHCOR⁴、-CONHR⁴or-OH, R¹May be mono-or di-substituted; r⁴Represents H, C1-C6 alkyl or C3-C8 cycloalkyl;

R²represents substituted C1-C6 alkyl, substituted C3-C8 cycloalkyl, substituted C2-C6 heterocycloalkyl, substituted aromatic ring or substituted aromatic heterocycle, wherein the heterocycloalkyl is a ternary, quaternary, quinary or hexahydric saturated heterocycle containing 1-3O, N or S atoms;

R³represents H, substituted C1-C6 alkyl, substituted C3-C8 cycloalkyl, substituted C2-C6 heterocycloalkyl or COR⁵(ii) a The heterocycloalkyl is a ternary, quaternary, quinary or hexahydric saturated heterocycle containing 1-3O, N or S atoms; r⁵Represents a substituted C1-C6 alkyl group or a substituted aromatic ring.

Wherein: x ═ CH or N; r¹Preferably H, F, Cl, -OMe, -OEt, -COOMe, -COOEt, -OCOMe, -OCOEt, -CONH₂、-CONHMe、-NHCOMe、-NHCOEt；R²Preference is given to

Wherein R is⁶Representative H, F, CH₃、t-Bu、CF₃、CN、OH、OCH₃、OCF₃、NH₂、NHCH₃、N(CH₃)₂、NHC₂H₅、N(C₂H₅)₂、NHCOCH₃、CONH₂、CONHCH₃，R⁶May be mono-, di-or tri-substituted; r³H, Me, Et or COMe are preferred.

The pharmaceutically acceptable salts of the compounds are acid addition salts of the compounds of the general formula (I), wherein the acid used for salt formation is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

When X is CH, R¹When H, the compounds of formula (I) may be prepared by the following method:

when R is³When H, the compounds of formula (I) may be prepared by the following method:

when R is³When not equal to H, the compounds of formula (I) can be prepared by:

wherein, X, R¹、R²And R³The definition of (1) is as before;

the method comprises the following specific steps:

preparation of target compound I-a:

(1) taking a compound II as an initial raw material, taking anhydrous DCM as a solvent, taking TEA or DIPEA as an acid-binding agent, and reacting with corresponding sulfonyl chloride III to generate a target compound.

Preparation of target Compounds I-B:

(2) preparation of Compound V

Taking a compound IV as a starting material, taking acetonitrile or DMF as a solvent, and carrying out nucleophilic substitution reaction with benzylamine under the action of potassium carbonate to generate a compound V;

(3) preparation of Compound VI

Two methods can be used for preparing compound VI from compound V: 1) reducing nitro group under the action of hydrogen by using methanol as a solvent and Pd/C as a catalyst to obtain a compound VI; 2) reducing nitro group with Fe powder and HCl (0.15M) by using ethanol as a solvent to obtain a compound VI;

(4) preparation of Compound VII

Cyclizing the compound VI with dimethyl oxalate or diethyl oxalate at 70-100 ℃ to obtain a compound VII;

(5) preparation of compound VIII

Dissolving the compound VII in anhydrous tetrahydrofuran, and reducing carbonyl by adopting a borane-tetrahydrofuran complex to obtain a compound VIII;

(6) preparation of compound IX

Dissolving the compound VIII in anhydrous DCM, and reacting TEA or DIPEA serving as an acid-binding agent with corresponding sulfonyl chloride III to generate a compound IX;

(7) preparation of the object Compounds I-B

Dissolving the compound IX in methanol, and removing benzyl to obtain the target compound I-B under the action of hydrogen by using Pd/C or Raney Ni as a catalyst.

Preparation of target Compounds I-C:

the synthesis of compound X is analogous to that of compound viii.

(8) Preparation of Compound XII

Dissolving a compound X in DMF, adding NaH, and then adding a raw material XI to react to obtain a compound XII;

(9) preparation of Compound XIII

Dissolving a compound XII in methanol, and removing benzyl by using Pd/C or Raney Ni as a catalyst under the action of hydrogen to obtain a compound XIII;

(10) preparation of the target Compounds I-C

Dissolving a compound XIII in anhydrous DCM, and reacting TEA or DIPEA serving as an acid-binding agent with corresponding sulfonyl chloride III to generate a target compound I-C.

The invention also discloses a pharmaceutical composition which contains the compound of the general formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrup, suspending agents and injections, and common pharmaceutical excipients such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.

The application of the compound of the general formula (I) and the stereoisomer, hydrate, solvate or crystal thereof in preparing the microtubule polymerization inhibitor medicament is also in the protection scope of the invention.

Furthermore, the microtubule polymerization inhibitor is used for preparing a medicine for treating malignant tumors, wherein the malignant tumors comprise breast cancer, ovarian cancer, liver cancer, lung cancer, colon cancer, prostate cancer, chronic myelocytic leukemia and the like.

Has the advantages that: the invention discloses a tetrahydroquinoxaline sulfonamide derivative shown in a general formula (I), and pharmacological experiment results show that the sulfonamide compound (I) has proliferation inhibition activity on tumor cells, blocks the tumor cells in a G2/M stage, and can be used for preparing and treating malignant tumors caused by tubulin dynamic balance imbalance; the invention also discloses a preparation method of the tetrahydroquinoxaline sulfonamide derivative.

Detailed Description

The present application is described in further detail below with reference to specific examples, but the scope of the present invention is not limited thereto.

Example 1

Synthesis of 1- ((4-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-A-1)

II (1.00g,7.45mmol), DMAP (0.27g,2.24mmol) and TEA (1.51g,14.91mmol) were dissolved in DCM (40mL), a solution of p-methoxybenzenesulfonyl chloride (III-1) (1.46g,7.08mmol) in DCM was added dropwise at 0 ℃ and after addition was complete, stirring was carried out at room temperature and the reaction was monitored by TLC after 1.5h (PE: EA ═ 2: 1). After completion of the reaction, DCM was diluted, washed with water (100 mL. times.3), saturated NaCl solution (100 mL. times.3), anhydrous Na₂SO₄And (5) drying. Suction filtration, filtrate concentration under reduced pressure, column chromatography (PE: EA ═ 8:1) purification, to obtain 1.59g of dark brown solid, yield 70.4%.¹H NMR(300MHz,CDCl₃)δ7.69(d,J＝8.0Hz,1H),7.53(d,J＝8.6Hz,2H),7.01(t,J＝7.4Hz,1H),6.89(d,J＝8.6Hz,2H),6.72(t,J＝7.6Hz,1H),6.50(d,J＝7.9Hz,1H),3.86(s,3H),3.81(t,J＝4.9Hz,2H),2.97(t,J＝4.8Hz,2H).¹³C NMR(75MHz,CDCl₃)δ163.03,137.87,131.24,129.38,126.63,126.44,121.78,117.04,114.70,114.20,55.60,43.78,38.76。

Example 2

Synthesis of 1- ((2-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-A-2)

Using II (1.00g,7.45mmol) and 2-methoxybenzenesulfonyl chloride (III-2) (1.46g,7.08mmol) as starting materials, the procedure was the same as for the target compound I-A-1, giving 1.64g of a brown solid with a yield of 72.2%.¹H NMR(300MHz,CDCl₃)δ7.98(dd,J＝7.9,1.7Hz,1H),7.50(ddd,J＝8.3,7.4,1.7Hz,1H),7.41(dd,J＝8.2,1.4Hz,1H),7.08-6.99(m,1H),6.94-6.86(m,2H),6.66-6.59(m,1H),6.53(dd,J＝8.0,1.5Hz,1H),3.79(t,J＝4.9Hz,2H),3.56(s,3H),3.10(t,J＝5.0Hz,2H).¹³C NMR(75MHz,CDCl₃)δ157.02,136.84,134.86,131.35,128.18,125.24,124.10,123.91,120.28,117.06,114.52,112.21,55.65,43.93,40.28。

Example 3

Synthesis of 1- ((3, 4-dimethoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-A-3)

Using II (1.00g,7.45mmol) and 3, 4-dimethoxybenzenesulfonyl chloride (III-3) (1.68g,7.08mmol) as starting materials, the same procedure was followed as for the target compound I-A-1 to give 1.70g of a brown solid in 68.4% yield.¹H NMR(300MHz,CDCl₃)δ7.69(dd,J＝8.2,1.5Hz,1H),7.29(dd,J＝8.6,2.1Hz,1H),7.03-6.94(m,1H),6.84(d,J＝8.5Hz,1H),6.75(d,J＝2.1Hz,1H),6.72-6.65(m,1H),6.45(dd,J＝8.0,1.4Hz,1H),3.90(s,3H),3.77(t,J＝5.1Hz,2H),3.59(s,3H),2.88(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ152.61,148.85,138.13,131.23,126.82,126.66,121.75,120.77,116.96,114.59,110.30,109.64,56.12,55.89,43.82,38.38。

Example 4

Synthesis of 1-p-toluenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline (I-A-4)

Using II (1.00g,7.45mmol) and 4-methylbenzenesulfonyl chloride (III-4) (1.35g,7.08mmol) as starting materials, the procedure was the same as for the target compound I-A-1, giving 1.60g of a brown solid in 74.4% yield.¹H NMR(300MHz,CDCl₃)δ7.63(dd,J＝8.2,1.5Hz,1H),7.43(d,J＝8.3Hz,2H),7.17(d,J＝8.0Hz,2H),7.00-6.92(m,1H),6.70-6.62(m,1H),6.45(dd,J＝8.0,1.4Hz,1H),3.83(br,1H),3.74(t,J＝5.1Hz,2H),2.88(t,J＝5.2Hz,2H),2.36(s,3H).¹³C NMR(75MHz,CDCl₃)δ143.73,137.87,136.68,129.70,127.29,126.60,126.22,121.75,116.97,114.77,43.82,38.81,21.59。

Example 5

Synthesis of 6-methoxy-1- ((4-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-1)

Synthesis of N-benzyl-5-methoxy-2-nitroaniline (V-1)

Benzylamine (2.07g,19.28mmol) was dissolved in acetonitrile (40mL), 3-fluoro-4-nitrobenzylether (IV-1) (3.00g,17.50mmol) and anhydrous potassium carbonate (4.84g,35.02mmol) were added, and the mixture was stirred under reflux at 85 ℃. After 90min, TLC (developing agent PE: EA ═ 5:1) was used to monitor completion of the reaction, and after completion of the reaction of the starting materials, heating was stopped, the reaction mixture was cooled to room temperature, filtered with suction, and the filtrate was washed with water (20 mL. times.3), washed with a saturated sodium chloride solution (20 mL. times.3), and dried over anhydrous sodium sulfate overnight. Suction filtration is carried out, and the filtrate is concentrated under reduced pressure to obtain yellow solid 3.92g with the yield of 86.6 percent. The product was directly put to the next step without further purification.¹H NMR(300MHz,DMSO)δ8.87(t,J＝5.7Hz,1H),8.06(d,J＝9.7Hz,1H),7.46-7.41(m,2H),7.40-7.34(m,2H),7.32-7.27(m,1H),6.35-6.25(m,2H),4.64(d,J＝5.9Hz,2H),3.74(s,3H)。

N¹Synthesis of (E) -benzyl-5-methoxyphenyl-1, 2-diamine (VI-1)

V-1 (817mg,3.16mmol) is dissolved in methanol (40mL), palladium-carbon (67mg,0.63mmol) is added in portions with stirring, and hydrogen is placed in three places for reaction at room temperature. After 90min TLC (developing agent PE: EA ═ 5:1) monitored for completion of the reaction. After the raw materials completely react, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated, and the separation is carried out by column chromatography (developing agent PE: EA is 10:1), so that 679mg of dark gray oily matter is obtained, and the yield is 93.9%.¹H NMR(300MHz,CDCl₃)δ7.50-7.35(m,5H),6.73(d,J＝8.3Hz,1H),6.36(d,J＝2.7Hz,1H),6.28(dd,J＝8.3,2.7Hz,1H),4.37(s,2H),3.79(s,3H),3.16(br,3H)。

Synthesis of 1-benzyl-7-methoxy-1, 4-dihydroquinoxaline-2, 3-dione (VII-1)

VI-1 (100mg,0.44mmol) and diethyl oxalate (517mg,4.38mmol) are added into a single-neck bottle in sequence and reacted for 4h at 140 ℃. TLC (developing agent PE: EA ═ 5:1) monitored for completion of the reaction. After the reaction of the raw materials is completed, the heating is stopped, the mixture is cooled to room temperature, ether (20mL) is added and stirred for 1h, and the mixture is filtered by suction to obtain 95mg of brown solid with the yield of 76.9%. The product was directly put to the next step without further purification.

Synthesis of 1-benzyl-7-methoxy-1, 2,3, 4-tetrahydroquinoxaline (VIII-1)

VII-1 (1.00g,3.55mmol) was added into a two-necked flask, dissolved in anhydrous tetrahydrofuran (60mL) under nitrogen protection, and 1mol/L borane tetrahydrofuran complex (8.80mL) was slowly added dropwise at 0 ℃ and stirred for 30min after completion of the addition. The reaction was then allowed to warm to room temperature for 12h and monitored by TLC (developing reagent PE: EA: 2:1) for completion. After the reaction of the raw materials was completed, methanol was added dropwise at 0 ℃ to quench the unreacted borane, stirring was carried out for 20min after no bubble was generated, extraction was carried out with methylene chloride (20 mL. times.3), the organic layers were combined, washed with water (20 mL. times.3), washed with a saturated sodium chloride solution (20 mL. times.3), and dried over anhydrous sodium sulfate overnight. Vacuum filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography (PE: EA is 8:1) to obtain white solid 350mg with yield 38.8%.¹H NMR(300MHz,CDCl₃)δ7.28-7.14(m,6H),6.39(d,J＝8.3Hz,1H),6.14-6.00(m,2H),4.36(s,2H),3.57(s,3H),3.33(s,4H)。

Synthesis of 4-benzyl-6-methoxy-1- ((4-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-1)

VIII-1 (300mg,1.18mmol) was dissolved in dichloromethane (40mL), DMAP (43mg,0.35mmol) and triethylamine (239mg,2.36mmol) were added, a solution of 4-methoxybenzenesulfonyl chloride (III-1) (269mg,1.30mmol) in dichloromethane was slowly added dropwise at 0 deg.C, the reaction was carried out at room temperature for 2 hours after completion of the dropwise addition, and the completion of the reaction was monitored by TLC (developing reagent PE: EA ═ 5: 1). After the starting material had reacted completely, the solvent was removed under reduced pressure, ethyl acetate (20mL) was dissolved, washed with 0.1mol/L dilute hydrochloric acid (20 mL. times.3), water (20 mL. times.3), saturated sodium chloride solution (20 mL. times.3), and dried over anhydrous sodium sulfate overnight. Suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain 393mg of white solid with the yield of 78.4 percent.¹H NMR(300MHz,CDCl₃)δ7.59(d,J＝8.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.23-7.14(m,3H),6.87(d,J＝8.9Hz,2H),6.82-6.72(m,2H),6.26(dd,J＝8.8,2.7Hz,1H),6.04(d,J＝2.6Hz,1H),4.24(s,2H),3.88-3.83(m,5H),3.68(s,3H),2.98(t,J＝5.4Hz,2H)。

IX-1 (350mg,0.83mmol), dry methanol (40mL) and Raney nickel were placed in a 100mL round-bottomed flask in this order, replaced with hydrogen three times, reacted at 60 ℃ for 4h, and the reaction was monitored by TLC (PE: EA ═ 2: 1). After the reaction, celite was filtered, the solvent was removed under reduced pressure, and column chromatography (developing agent PE: EA ═ 5:1) was performed to obtain 202mg of a white solid, and the yield was 72.9%.¹H NMR(300MHz,CDCl₃)δ7.53(d,J＝8.9Hz,1H),7.46(d,J＝8.9Hz,2H),6.85(d,J＝8.9Hz,2H),6.27(dd,J＝8.9,2.7Hz,1H),5.98(d,J＝2.7Hz,1H),3.82(s,3H),3.77-3.70(m,5H),2.86(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ162.91,158.47,138.87,131.13,129.37,127.82,115.09,114.10,102.99,99.13,55.52,55.22,43.75,38.37。

Example 6

Synthesis of 6-methoxy-1- ((2-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-2)

Synthesis of 4-benzyl-6-methoxy-1- ((2-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-2)

Using VIII-1 (300mg,1.18mmol) and 2-methoxybenzenesulfonyl chloride (III-2) (269mg,1.30mmol) as starting materials, the procedure was followed using IX-1, giving 412mg of a white solid in 82.2% yield.¹H NMR(300MHz,CDCl₃)δ7.95(dd,J＝7.8,1.7Hz,1H),7.58-7.48(m,1H),7.36(d,J＝8.8Hz,1H),7.31-7.23(m,3H),7.09-6.99(m,3H),6.89(d,J＝8.3Hz,1H),6.22(dd,J＝8.8,2.7Hz,1H),6.15(d,J＝2.7Hz,1H),4.37(s,2H),3.85(t,J＝5.2Hz,2H),3.67(s,3H),3.49(s,3H),3.12(t,J＝5.2Hz,2H)。

Using IX-2 (400mg,0.94mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 252mg of a white solid in 80.3% yield.¹H NMR(300MHz,CDCl₃)δ7.93(d,J＝7.8Hz,1H),7.55-7.45(m,1H),7.32(d,J＝8.9Hz,1H),7.00(d,J＝7.5Hz,1H),6.90(d,J＝8.3Hz,1H),6.21(dd,J＝8.9,2.6Hz,1H),6.07(d,J＝2.6Hz,1H),3.94(br,1H),3.75-3.66(m,5H),3.56(s,3H),3.01(t,J＝5.0Hz,2H).¹³C NMR(75MHz,CDCl₃)δ157.62,157.04,137.99,134.89,131.33,128.03,125.66,120.25,117.28,112.28,102.65,99.36,55.74,55.33,43.73,39.83。

Example 7

Synthesis of 1- ((3, 4-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-3)

Synthesis of 4-benzyl-1- ((3, 4-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-3)

The procedure was carried out using VIII-1 (300mg,1.18mmol) and 3, 4-dimethoxybenzenesulfonyl chloride (III-3) (308mg,1.30mmol) as starting materials with the compound IX-1 to give 424mg of a white solid in 56.9% yield.¹H NMR(300MHz,CDCl₃)δ7.68(d,J＝8.8Hz,1H),7.39-7.30(m,2H),7.26-7.23(m,2H),6.89(d,J＝8.5Hz,1H),6.82-6.76(m,3H),6.32(dd,J＝8.8,2.7Hz,1H),6.08(d,J＝2.7Hz,1H),4.28(s,2H),3.97(s,3H),3.90(t,J＝5.4Hz,2H),3.71(s,3H),3.62(s,3H),3.01(t,J＝5.4Hz,2H)。

Using IX-3 (400mg,0.88mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 256mg of a white solid in 80.1% yield.¹H NMR(300MHz,CDCl₃)δ7.60(d,J＝8.9Hz,1H),7.29(dd,J＝8.4,2.4Hz,1H),6.88(d,J＝8.5Hz,1H),6.81(d,J＝2.0Hz,1H),6.32(dd,J＝8.9,2.7Hz,1H),6.00(d,J＝2.7Hz,1H),3.94(s,3H),3.81-3.75(m,5H),3.67(s,3H),2.87(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.74,152.55,148.79,139.11,131.19,128.00,120.88,115.16,110.31,109.76,103.10,99.02,56.12,55.93,55.33,43.86,38.17。

Example 8

Synthesis of 6-methoxy-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline (I-B-4)

Synthesis of 4-benzyl-6-methoxy-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline (IX-4)

Using VIII-1 (300mg,1.18mmol) and 4-methylbenzenesulfonyl chloride (III-4) (248mg,1.30mmol) as starting materials, the procedure was identical to that of compound IX-1, giving 406mg of a white solid in 81.8% yield.¹H NMR(300MHz，CDCl₃)δ7.64(d,J＝8.8Hz,1H),7.48(d,J＝8.3Hz,2H),7.29-7.20(m,5H),6.89-6.82(m,2H),6.32(dd,J＝8.9,2.7Hz,1H),6.10(d,J＝2.7Hz,1H),4.26(s,2H),3.90(t,J＝5.4Hz,2H),3.73(s,3H),2.98(t,J＝5.4Hz,2H),2.47(s,3H)。

IX-4 (350mg,0.86mmol) as raw material is used in the same operation process as the target compoundI-B-1, 202mg of a white solid was obtained, yield 74.3%.¹H NMR(300MHz,CDCl₃)δ7.50(d,J＝8.9Hz,1H),7.40(d,J＝8.2Hz,2H),7.16(d,J＝8.1Hz,2H),6.23(dd,J＝8.9,2.8Hz,1H),5.97(d,J＝2.7Hz,1H),3.94(br,1H),3.73-3.67(m,5H),2.80(t,J＝5.1Hz,2H),2.35(s,3H).¹³C NMR(75MHz,CDCl₃)δ158.55,143.72,139.04,136.48,129.72,127.63,127.32,114.86,103.09,99.06,55.25,43.79,38.35,21.61。

Example 9

Synthesis of 1- ((2, 4-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-5)

Synthesis of 4-benzyl-1- ((2, 4-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-5)

The procedure was carried out using VIII-1 (340mg,1.34mmol) and 2, 4-dimethoxybenzenesulfonyl chloride (III-5) (382mg,1.61mmol) as starting materials to give IX-1 as a white solid (444 mg, 72.8% yield).¹H NMR(300MHz,CDCl₃)δ7.81(d,J＝8.7Hz,1H),7.39(d,J＝8.7Hz,1H),7.31-7.15(m,3H),7.02(d,J＝6.9Hz,2H),6.47(dd,J＝8.8,2.3Hz,1H),6.36(d,J＝2.3Hz,1H),6.19(dd,J＝8.8,2.6Hz,1H),6.13(d,J＝2.7Hz,1H),4.35(s,2H),3.88-3.75(m,5H),3.63(s,3H),3.40(s,3H),3.09(t,J＝5.1Hz,2H)。

Using IX-5 (1.00g,2.23mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 603mg of a white solid in 74.3% yield.¹H NMR(300MHz,CDCl₃)δ7.91(d,J＝8.8Hz,1H),7.40(d,J＝8.9Hz,1H),6.54(dd,J＝8.8,2.3Hz,1H),6.42(d,J＝2.2Hz,1H),6.28(dd,J＝8.9,2.8Hz,1H),6.11(d,J＝2.8Hz,1H),3.88(s,3H),3.79-3.72(m,5H),3.58(s,3H),3.10(t,J＝5.0Hz,2H).¹³C NMR(75MHz,CDCl₃)δ164.94,158.55,157.51,137.70,133.15,125.89,120.29,117.58,104.19,102.78,99.50,99.29,55.74,55.73,55.34,43.61,39.74。

Example 10

Synthesis of 1- ((2, 5-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-6)

Synthesis of 4-benzyl-1- ((2, 5-dimethoxyphenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-6)

The procedure was carried out using compound VIII-1 (300mg,1.18mmol) and 2, 5-dimethoxybenzenesulfonyl chloride (III-6) (308mg,1.30mmol) as starting materials, and compound IX-1 to give 450mg of a white solid in 84.4% yield.¹H NMR(300MHz,CDCl₃)δ7.38(d,J＝3.2Hz,1H),7.29(d,J＝8.8Hz,1H),7.20-7.14(m,3H),7.02-6.94(m,3H),6.76(d,J＝9.0Hz,1H),6.14(dd,J＝8.8,2.6Hz,1H),6.07(d,J＝2.6Hz,1H),4.29(s,2H),3.76(t,J＝5.3Hz,2H),3.68(s,3H),3.58(s,3H),3.38(s,3H),3.06(t,J＝5.2Hz,2H)。

IX-6 (400mg,0.88mmol) was used as the starting material, and the procedure was performed as for the target compound I-B-1, giving 251mg of a white solid in 78.5% yield.¹H NMR(300MHz,CDCl₃)δ7.48(d,J＝3.1Hz,1H),7.33(d,J＝8.9Hz,1H),7.03(dd,J＝9.0,3.2Hz,1H),6.84(d,J＝9.0Hz,1H),6.23(dd,J＝8.9,2.7Hz,1H),6.07(d,J＝2.7Hz,1H),3.95(br,1H),3.78(s,3H),3.76-3.71(m,5H),3.55(s,3H),3.08(t,J＝5.1Hz,2H).¹³C NMR(75MHz,CDCl₃)δ157.65,152.84,151.15,137.89,128.60,125.69,120.63,117.36,115.72,113.66,102.74,99.51,56.25,56.11,55.35,43.81,39.97。

Example 11

Synthesis of 6-methoxy-1- ((4- (trifluoromethoxy) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-7)

Synthesis of 4-benzyl-6-methoxy-1- ((4- (trifluoromethoxy) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-7)

The procedure was carried out using VIII-1 (300mg,1.18mmol) and 4- (trifluoromethoxy) benzenesulfonyl chloride (III-7) (339mg,1.30mmol) as starting materials with the compound IX-1 to give 385mg of a white solid in 68.3% yield.¹H NMR(300MHz,CDCl₃)δ7.66-7.58(m,3H),7.31-7.25(m,5H),6.93-6.86(m,2H),6.34(dd,J＝8.9,2.7Hz,1H),6.13(d,J＝2.7Hz,1H),4.21(s,2H),3.92(t,J＝5.5Hz,2H),3.75(s,3H),2.99(t,J＝5.5Hz,2H)。

IX-7 (350mg,0.73mmol) was used as the starting material, and the procedure was as for the target compound I-B-1, giving 235mg of a white solid in 83.1% yield.¹H NMR(300MHz,CDCl₃)δ7.58(d,J＝8.8Hz,2H),7.50(d,J＝8.9Hz,1H),7.22(d,J＝8.4Hz,2H),6.26(dd,J＝8.9,2.7Hz,1H),5.99(d,J＝2.7Hz,1H),3.95(br,1H),3.79-3.64(m,5H),2.88(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.82,152.22(q,³J_C-F＝1.8Hz),139.08,137.81,129.45,127.58,120.70,120.18(q,¹J_C-F＝257.8Hz),114.37,103.19,99.12,55.21,43.89,38.62。

Example 12

Synthesis of 1- ((2-fluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-8)

Synthesis of 4-benzyl-1- ((2-fluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-8)

Starting from VIII-1 (300mg,1.18mmol) and 2-fluorobenzenesulfonyl chloride (III-8) (186mg,1.30mmol), the procedure was followed for IX-1 to give 357mg of a white solid in 73.5% yield.¹H NMR(300MHz,CDCl₃)δ7.82(ddd,J＝7.9,6.9,1.8Hz,1H),7.66-7.56(m,1H),7.47(d,J＝8.8Hz,1H),7.33-7.24(m,4H),7.22-7.14(m,1H),6.99(dd,J＝6.7,2.8Hz,2H),6.28(dd,J＝8.8,2.7Hz,1H),6.18(d,J＝2.7Hz,1H),4.40(s,2H),3.98(t,J＝5.3Hz,2H),3.71(s,3H),3.25(t,J＝5.4Hz,2H)。

Using IX-8 (300mg,0.73mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 180mg of a white solid in 76.6% yield.¹H NMR(300MHz,CDCl₃)δ7.83-7.71(m,1H),7.59-7.47(m,1H),7.33(d,J＝8.9Hz,1H),7.24-7.16(m,1H),7.16-7.08(m,1H),6.19(dd,J＝8.9,2.7Hz,1H),6.02(d,J＝2.7Hz,1H),3.92(br,1H),3.80(t,J＝5.0Hz,2H),3.69(s,3H),3.12(t,J＝5.1Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.80(d,¹J_C-F＝255.5Hz),158.25,138.61,135.33(d,³J_C-F＝8.3Hz),130.97,127.77(d,²J_C-F＝14.2Hz),126.17,124.55(d,³J_C-F＝3.8Hz),117.42(d,²J_C-F＝21.5Hz),115.03,103.05,99.36,55.26,43.89,39.74。

Example 13

Synthesis of 6-methoxy-1- (naphthalene-1-sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-9)

Synthesis of 4-benzyl-6-methoxy-1- (naphthalene-1-sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-9)

Using VIII-1 (300mg,1.18mmol) and 1-naphthalenesulfonyl chloride (III-9) (295mg,1.30mmol) as raw materials, the procedure was the same as for compound IX-1, yielding 443mg of a white solid in 83.1% yield.¹H NMR(300MHz,CDCl₃)δ8.18(d,J＝1.8Hz,1H),7.94-7.80(m,3H),7.70-7.55(m,3H),7.45(dd,J＝8.6,1.9Hz,1H),7.01(t,J＝7.4Hz,1H),6.83(t,J＝7.6Hz,2H),6.55(d,J＝7.3Hz,2H),6.31(dd,J＝8.8,2.7Hz,1H),6.01(d,J＝2.7Hz,1H),4.09(s,2H),3.91(t,J＝5.4Hz,2H),3.68(s,3H),2.92(t,J＝5.4Hz,2H)。

Using IX-9 (400mg,0.90mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 218mg of a white solid in 68.5% yield.¹H NMR(300MHz,CDCl₃)δ8.24(s,1H),7.93-7.82(m,3H),7.68-7.57(m,3H),7.47(dd,J＝8.7,1.7Hz,1H),6.35(dd,J＝9.0,2.7Hz,1H),5.98(d,J＝2.7Hz,1H),3.83(t,J＝5.1Hz,2H),3.77(s,3H),2.83(t,J＝4.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.68,138.98,136.65,134.81,132.13,129.30,129.25,128.85,128.58,127.94,127.73,127.52,122.75,115.03,103.20,99.16,55.31,43.92,38.57。

Example 14

Synthesis of 4- ((6-methoxy-3, 4-dihydroquinoxalin-1 (2H) -yl) sulfonyl) aniline (I-B-10)

Synthesis of 4-benzyl-6-methoxy-1- ((4-nitrophenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-10)

Using VIII-1 (300mg,1.18mmol) and 4-nitrobenzenesulfonyl chloride (III-10) (228mg,1.30mmol) as starting materials, the procedure was identical to that of compound IX-1, giving 427mg of a white solid in 69.0% yield.¹H NMR(300MHz,CDCl₃)δ8.19(d,J＝8.8Hz,2H),7.66(d,J＝8.8Hz,2H),7.59(d,J＝8.8Hz,1H),7.20-7.10(m,3H),6.84-6.76(m,2H),6.31(dd,J＝8.9,2.6Hz,1H),6.17(d,J＝2.6Hz,1H),4.20(s,2H),3.92(t,J＝5.4Hz,2H),3.73(s,3H),2.94(t,J＝5.5Hz,2H)。

Using IX-10 (300mg,0.73mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 166mg of a white solid in 71.3% yield.¹H NMR(300MHz,CDCl₃)δ7.50(d,J＝8.9Hz,1H),7.26(d,J＝8.8Hz,2H),6.53(d,J＝8.7Hz,2H),6.24(dd,J＝8.9,2.7Hz,1H),6.00(d,J＝2.7Hz,1H),4.27(br,1H),3.72(s,3H),3.66(t,J＝4.9Hz,2H),2.83(t,J＝5.0Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.40,151.17,139.20,129.31,127.88,126.86,115.12,114.01,102.96,99.00,55.28,43.66,38.20。

Example 15

Synthesis of 6-methoxy-1- ((4- (trifluoromethyl) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-11)

Synthesis of 4-benzyl-6-methoxy-1- ((4- (trifluoromethyl) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-11)

The procedure was carried out using VIII-1 (300mg,1.18mmol) and 4-trifluoromethylbenzenesulfonyl chloride (III-11) (318mg,1.30mmol) as starting materials with the compound IX-1 to give 464mg of a white solid in 70.2% yield.¹H NMR(300MHz,CDCl₃)δ7.73-7.63(m,4H),7.59(d,J＝8.9Hz,1H),7.24-7.17(m,3H),6.85-6.78(m,2H),6.30(dd,J＝8.9,2.6Hz,1H),6.09(d,J＝2.6Hz,1H),4.18(s,2H),3.89(t,J＝5.4Hz,2H),3.70(s,3H),2.94(t,J＝5.5Hz,2H)。

Using IX-11 (400mg,0.87mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 214mg of a white solid in 66.7% yield.¹H NMR(300MHz,CDCl₃)δ7.70-7.65(m,4H),7.56(d,J＝8.9Hz,1H),6.31(dd,J＝9.0,2.7Hz,1H),6.00(d,J＝2.7Hz,1H),3.81(t,J＝5.2Hz,2H),3.75(s,3H),2.89(t,J＝5.3Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.89,143.10,138.76,134.34(q,²J_C-F＝32.9Hz),127.84,127.61,126.12(q,³J_C-F＝3.6Hz),123.23(q,¹J_C-F＝271.2Hz),114.45,103.43,99.32,55.30,44.01,38.77。

Example 16

Synthesis of 1- ((4- (tert-butyl) phenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-12)

Synthesis of 4-benzyl-1- ((4- (tert-butyl) phenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-12)

The procedure was performed using VIII-1 (300mg,1.18mmol) and 4-tert-butylbenzenesulfonyl chloride (III-12) (303mg,1.30mmol) as starting materials with compound IX-1 to give 442mg of a white solid in 76.4% yield.¹H NMR(300MHz,CDCl₃)δ7.61(d,J＝8.8Hz,1H),7.55-7.46(m,4H),7.29-7.23(m,3H),7.00-6.94(m,2H),6.33(dd,J＝8.8,2.7Hz,1H),6.11(d,J＝2.7Hz,1H),4.16(s,2H),3.88(t,J＝5.4Hz,2H),3.74(s,3H),2.92(t,J＝5.5Hz,2H),1.37(s,9H)。

IX-12 (400mg,0.89mmol) was used as the starting material, and the procedure was followed for the target compound I-B-1 to give 224mg of a white solid in 69.9% yield.¹H NMR(300MHz,CDCl₃)δ7.52(d,J＝8.9Hz,1H),7.47(d,J＝8.6Hz,2H),7.39(d,J＝8.6Hz,2H),6.24(dd,J＝8.9,2.7Hz,1H),6.00(d,J＝2.7Hz,1H),3.95(br,1H),3.75-3.68(m,5H),2.82(t,J＝5.1Hz,2H),1.29(s,9H).¹³C NMR(75MHz,CDCl₃)δ158.46,156.64,138.95,136.53,127.51,127.20,126.04,115.06,103.03,99.19,55.25,43.82,38.51,35.15,31.12。

Example 17

Synthesis of 6-methoxy-1-benzenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline (I-B-13)

Synthesis of 4-benzyl-6-methoxy-1-benzenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline (IX-13)

Starting from VIII-1 (300mg,1.18mmol) and benzenesulfonyl chloride (III-13) (230mg,1.30mmol), the procedure was identical to that for IX-1, giving 395mg of a white solid in 84.5% yield.¹H NMR(300MHz,CDCl₃)δ7.67-7.56(m,4H),7.51-7.43(m,2H),7.27-7.20(m,3H),6.86-6.78(m,2H),6.33(dd,J＝8.9,2.7Hz,1H),6.09(d,J＝2.7Hz,1H),4.23(s,2H),3.92(t,J＝5.5Hz,2H),3.73(s,3H),2.97(t,J＝5.5Hz,2H)。

IX-13 (350mg,0.89mmol) was used as the starting material, and the procedure was as for the target compound I-B-1, giving 201mg of a white solid in 74.3% yield.¹H NMR(300MHz,CDCl₃)δ7.56-7.48(m,4H),7.42-7.34(m,2H),6.25(dd,J＝8.9,2.7Hz,1H),5.97(d,J＝2.7Hz,1H),3.90(br,1H),3.75-3.68(m,5H),2.80(t,J＝4.3Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.62,139.39,139.00,132.88,129.08,127.62,127.29,114.77,103.12,99.08,55.27,43.82,38.41。

Example 18

Synthesis of 6-methoxy-1- ((3- (trifluoromethyl) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-14)

Synthesis of 4-benzyl-6-methoxy-1- ((3- (trifluoromethyl) phenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-14)

Using VIII-1 (300mg,1.18mmol) and 3-trifluoromethylbenzenesulfonyl chloride (III-14) (318mg,1.30mmol) as raw materials, the procedure was the same as that for IX-1 to obtain 449mg of a white solid with a yield of 71.4%.¹H NMR(300MHz,CDCl₃)δ7.90(d,J＝7.8Hz,1H),7.81-7.59(m,2H),7.59(dd,J＝7.8,1.4Hz,1H),7.32-7.18(m,4H),6.96(dd,J＝7.2,2.4Hz,2H),6.20(dd,J＝8.8,2.6Hz，1H),6.14(d,J＝2.6Hz,1H),4.33(s,2H),3.91(t,J＝5.3Hz,2H),3.68(s,3H),3.15(t,J＝5.3Hz,2H)。

Using IX-14 (400mg,0.87mmol) as a starting material, the procedure was performed in the same manner as for the target compound I-B-1 to give 258mg of a white solid in 79.8% yield.¹H NMR(300MHz,CDCl₃)δ7.85-7.78(m,2H),7.70(d,J＝7.9Hz,1H),7.58(d,J＝7.8Hz,1H),7.53(d,J＝8.9Hz,1H),6.31(dd,J＝8.9，2.7Hz,1H),6.00(d,J＝2.7Hz,1H),3.81(t,J＝5.2Hz，2H)，3.75(s,3H),2.91(t,J＝5.3Hz，2H).¹³C NMR(75MHz,CDCl₃)δ159.08，140.58，139.17,131.47(q，²J_C-F＝33.2Hz),130.55,129.87,129.37(q，³J_C-F＝3.5Hz),127.56，124.38(q，³J_C-F＝3.7Hz),123.18(q，¹J_C-F＝271.3Hz),114.13,103.40，99.10,55.30，44.00,38.64。

Example 19

Synthesis of 1- (ethylsulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-15)

Synthesis of 4-benzyl-1- (ethylsulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-15)

The procedure was carried out using VIII-1 (300mg,1.18mmol) and ethylsulfonyl chloride (III-15) (167mg,1.30mmol) as starting materials, and IX-1 was obtained as a white solid 342mg in 80.5% yield.¹H NMR(300MHz,CDCl₃)δ7.38-7.27(m,4H),7.25-7.20(m，2H),6.27(d,J＝2.7Hz,1H)，6.23(dd,J＝8.7，2.7Hz,1H)，4.52(s,2H),3.82(t,J＝5.4Hz，2H),3.69(s,3H),3.47(t，J＝5.4Hz,2H),2.97(q,J＝7.4Hz,2H),1.34(t，J＝7.4Hz,3H)。

IX-15 (300mg,0.87mmol) was used as the starting material, and the procedure was as for the target compound I-B-1, giving 151mg of a white solid in 68.0% yield.¹H NMR(300MHz,CDCl₃)δ7.34(d,J＝8.9Hz,1H),6.23(dd,J＝8.9,2.7Hz,1H),6.15(d,J＝2.7Hz,1H),4.33(br,1H),3.80-3.70(m,5H),3.46(t,J＝5.3Hz,2H),3.01(q,J＝7.4Hz，2H),1.36(t,J＝7.4Hz,3H).¹³C NMR(75MHz,CDCl₃)δ158.30,138.77,125.83,115.40,103.03,99.52,55.32,46.78,43.53,40.96,8.01。

Example 20

Synthesis of 1- ((3-bromophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-16)

Synthesis of 4-benzyl-1- ((3-bromophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-16)

The procedure was performed using VIII-1 (300mg,1.18mmol) and 3-bromophenylsulfonyl chloride (III-16) (332mg,1.30mmol) as starting materials with compound IX-1 to give 466mg of a white solid in 79.6% yield.¹H NMR(300MHz,CDCl₃)δ7.73-7.69(m,1H),7.66(d,J＝8.1Hz,1H),7.55(d,J＝8.8Hz，1H),7.43-7.37(m,1H),7.26-7.19(m,4H),6.87-6.80(m,2H),6.29(dd,J＝8.8,2.7Hz,1H),6.10(d,J＝2.7Hz,1H),4.21(s,2H),3.87(t,J＝5.5Hz,2H),3.70(s,3H),2.97(t,J＝5.5Hz,2H)。

IX-16 (400mg,0.85mmol) was used as the starting material, and the procedure was performed as for the target compound I-B-1, giving 245mg of a white solid in 75.5% yield.¹H NMR(300MHz,CDCl₃)δ7.79-7.76(m,1H),7.71-7.66(m,1H),7.54(d,J＝8.9Hz,1H),7.47-7.42(m,1H),7.34-7.29(m,1H),6.32(dd,J＝8.9,2.7Hz,1H),6.03(d,J＝2.8Hz,1H),3.84-3.76(m,5H),2.95(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.89,141.33,138.99,135.79,130.58,130.16,127.58,125.93,122.96,114.48,103.34,99.22,55.35,43.97,38.72。

Example 21

Synthesis of 1- ((3, 5-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-17)

Synthesis of 4-benzyl-1- ((3, 5-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-17)

Starting from VIII-1 (300mg,1.18mmol) and 3, 5-difluorobenzenesulfonyl chloride (III-17) (276mg,1.30mmol), the procedure was followed using IX-1 as the compound to give 421mg of a white solid in 75.9% yield.¹H NMR(300MHz,CDCl₃)δ7.55(d,J＝8.8Hz,1H),7.29-7.18(m,3H),7.13-7.02(m,2H),6.97(d,J＝2.3Hz,1H),6.93-6.81(m,2H),6.30(dd,J＝8.9,2.7Hz,1H),6.14(d,J＝2.7Hz,1H),4.27(s,2H),3.87(t,J＝5.5Hz,2H),3.71(s,3H),2.99(t,J＝5.5Hz,2H)。

IX-17 (400mg,0.93mmol) was used as the starting material, and the procedure was performed as for the target compound I-B-1, giving 251mg of a white solid in 79.3% yield.¹H NMR(300MHz,CDCl₃)δ7.54(d,J＝8.9Hz,1H),7.16-7.11(m,2H),7.01(tt,J＝8.5,2.3Hz,1H),6.33(dd,J＝9.0,2.7Hz,1H),6.05(d,J＝2.7Hz,1H),3.91(br,1H),3.82(t,J＝5.1Hz,2H),3.79(s,3H),3.01(t,J＝5.2Hz,2H).¹³C NMR(75MHz,CDCl₃)δ162.65(dd,¹J_C-F＝253.1Hz,³J_C-F＝11.5Hz),158.98,142.70(t,³J_C-F＝8.2Hz),138.85,127.41,114.21,110.99(d,²J_C-F＝18.3Hz),110.86(d,²J_C-F＝18.3Hz),108.39(t,²J_C-F＝24.9Hz),103.48,99.31,55.31,44.07，38.87。

Example 22

Synthesis of 6-methoxy-1- (m-toluenesulfonyl) -1,2,3, 4-tetrahydroquinoxaline (I-B-18)

Synthesis of 4-benzyl-6-methoxy-1- (m-toluenesulfonyl) -1,2,3, 4-tetrahydroquinoxaline (IX-18)

Using VIII-1 (300mg,1.18mmol) and 3-methylbenzenesulfonyl chloride (III-18) (364mg,1.30mmol) as starting materials, the procedure was identical to that of compound IX-1 to give 407mg of a white solid in 83.3% yield.¹H NMR(300MHz,CDCl₃)δ7.64-7.55(m,1H),7.42-7.28(m,4H),7.24-7.16(m,3H),6.85-6.74(m,2H),6.33-6.25(m,1H),6.09-6.03(m,1H),4.20(s,2H),3.86(t,J＝5.6Hz,2H),3.69(s,3H),2.95(t,J＝5.2Hz,2H),2.32(s,3H)。

Using IX-18 (350mg,0.86mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 222mg of a white solid in 81.2% yield.¹H NMR(300MHz,CDCl₃)δ7.50(d,J＝8.9Hz,1H),7.38-7.24(m,4H),6.25(dd,J＝8.9,2.8Hz,1H),5.98(d,J＝2.8Hz,1H),3.74-3.66(m,5H),2.82(t,J＝5.3Hz,2H),2.30(s,3H).¹³C NMR(75MHz,CDCl₃)δ158.61,139.28,139.22,139.02,133.63,128.93,127.69,127.57,124.47,114.92,103.10,99.08,55.29,43.82,38.46,21.33。

Example 23

Synthesis of 1- ((3, 4-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-19)

Synthesis of 4-benzyl-1- ((3, 4-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-19)

Starting from VIII-1 (300mg,1.18mmol) and 3, 4-difluorobenzenesulfonyl chloride (III-19) (276mg,1.30mmol), the procedure was followed using IX-1 as the compound to give 424mg of a white solid in 78.6% yield.¹H NMR(300MHz,CDCl₃)δ7.55(d，J＝8.8Hz，1H),7.39-7.31(m,1H),7.30-7.20(m,4H),7.17-7.10(m,1H),6.88-6.80(m,2H),6.28(dd,J＝8.9,2.6Hz,1H),6.14(d,J＝2.6Hz,1H),4.25(s,2H),3.87(t,J＝5.4Hz,2H),3.70(s,3H),2.98(t,J＝5.5Hz,2H)。

IX-19 (400mg,0.93mmol) was used as the starting material, and the procedure was performed as for the target compound I-B-1, giving 245mg of a white solid in 77.3% yield.¹H NMR(300MHz,CDCl₃)δ7.50(d,J＝8.9Hz,1H),7.43-7.35(m,1H),7.35-7.28(m,1H),7.25-7.15(m,1H),6.28(dd,J＝9.0,2.8Hz,1H),6.00(d,J＝2.8Hz,1H)，3.81-3.73(m,5H),2.94(t,J＝5.4Hz,2H).¹³C NMR(75MHz,CDCl₃)δ158.94,153.19(dd,¹J_C-F＝255.7Hz,²J_C-F＝12.5Hz),150.03(dd,¹J_C-F＝253.0Hz,²J_C-F＝13.2Hz),138.97,136.30(d,³J_C-F＝8.6Hz),127.63,124.49(dd,²J_C-F＝7.4Hz,³J_C-F＝4.0Hz),118.14(d,²J_C-F＝18.2Hz),117.20(dd,²J_C-F＝19.7Hz,³J_C-F＝1.5Hz),114.30,103.38,99.22,55.30,43.98,38.74。

Example 24

Synthesis of 1- ((2, 6-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (I-B-20)

Synthesis of 4-benzyl-1- ((2, 6-difluorophenyl) sulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroquinoxaline (IX-20)

Using VIII-1 (300mg,1.18mmol) and 2, 6-difluorobenzenesulfonyl chloride (III-20) (276mg,1.30mmol) as starting materials, the procedure was identical to that of compound IX-1 to give 427mg of a white solid in 81.2% yield.¹H NMR(300MHz,CDCl₃)δ7.54-7.38(m，2H),7.27-7.17(m,3H),7.02-6.89(m,4H),6.22(dd,J＝8.8,2.7Hz,1H),6.14(d,J＝2.7Hz,1H),4.36(s,2H),3.97(t,J＝5.0Hz,2H),3.65(s,3H),3.27(t,J＝5.0Hz,2H)。

Using IX-20 (400mg,0.93mmol) as a starting material, the procedure was performed as for the target compound I-B-1 to give 242mg of a white solid in 76.6% yield.¹H NMR(300MHz,CDCl₃)δ7.58-7.47(m,1H),7.43(d,J＝9.0Hz,1H),7.01(t,J＝8.5Hz,2H),6.29(dd,J＝9.0,2.8Hz,1H),6.09(d,J＝2.8Hz,1H),3.99(br,1H),3.95(t,J＝5.0Hz,2H),3.76(s,3H),3.30(t,J＝5.1Hz,2H).¹³C NMR(75MHz,CDCl₃)δ159.73(dd,¹J_C-F＝258.3Hz,³J_C-F＝3.9Hz),158.22,138.17,134.77(t,³J_C-F＝10.9Hz),125.72,118.04(t,²J_C-F＝16.3Hz),115.05,113.27(d,²J_C-F＝23.7Hz),113.23(d,²J_C-F＝23.7Hz),103.17,99.64,55.28,44.15,39.95。

Example 25

Synthesis of methyl 1- ((4-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline-6-carboxylate (I-B-21)

Synthesis of methyl 3-benzylamino-4-nitrobenzoate (V-2)

The procedure was carried out using 3-fluoro-4-nitrobenzoic acid methyl ester (IV-2) (1.00g,5.02mmol) and benzylamine (0.65g,6.03mmol) as starting materials to give compound V-1 as an orange solid 1.21g with a yield of 84.2%.¹H NMR(300MHz,CDCl₃)δ8.34(t,J＝5.6Hz,1H),8.24(d,J＝8.9Hz,1H),7.59(d,J＝1.5Hz,1H),7.41-7.30(m,5H),7.26(dd,J＝8.9,1.7Hz,1H),4.59(d,J＝5.5Hz,2H),3.91(s,3H).

Synthesis of methyl 4-amino-3-benzylamino-benzoic acid (VI-2)

The operation process is the same as that of compound VI-1 with V-2 (1.20g,4.19mmol) as material to obtain orange red oil 0.75g in 70.1% yield. The product was directly put on to the next step without further purification.¹H NMR(300MHz,CDCl₃)δ7.48(dd,J＝8.0,1.8Hz,1H),7.45-7.27(m,6H),6.71(d,J＝8.0Hz,1H),4.33(s,2H),3.85(s,3H),3.78(br,2H),3.41(s,1H)。

Synthesis of 4-benzyl-2, 3-dioxo-1, 2,3, 4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (VII-2)

VI-2 (1.00g,3.90mmol) and diethyl oxalate (11.40g,78.03mmol) are used as raw materials, the operation process is the same as that of the compound VII-1, and 857mg of offwhite powder is obtained, and the yield is 70.8%. The product was directly put on to the next step without further purification.

Synthesis of 4-benzyl-1, 2,3, 4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (VIII-2)

Using VII-2 (800mg,2.58mmol) and BH₃The starting material was THF complex (6.45mL) in the same procedure as compound VIII-1 to give 490mg of a yellow oil in 67.3% yield.¹H NMR(300MHz,CDCl₃)δ7.36-7.21(m,7H),6.42(d,J＝8.0Hz,1H),4.42(s,2H),4.28(s,1H),3.77(s,3H),3.40(t,J＝5.1Hz,2H),3.22(t,J＝5.1Hz,2H)。

Synthesis of methyl 4-benzyl-1- ((4-methoxyphenyl) sulfonyl) -1,2,3, 4-tetrahydroquinoxaline-6-carboxylate (IX-21)

Using VIII-2 (330mg,1.17mmol) and 4-methoxybenzenesulfonyl chloride (III-1) (266mg,1.29mmol) as starting materials, the procedure was identical to that of compound IX-1, giving 280mg of a white solid in 53.0% yield.¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝8.4Hz,1H),7.48(d,J＝8.9Hz,2H),7.36(dd,J＝8.4,1.6Hz,1H),7.29(d,J＝1.4Hz,1H),7.24-7.17(m,3H),6.90-6.78(m,4H),4.39(s,2H),3.89(t,J＝5.0Hz,2H),3.85(s,3H),3.84(s,3H),3.01(t,J＝5.2Hz,2H)。

IX-21 (280mg, 0.62mmol) was used as the starting material, and the procedure was the same as for compound I-B-1, giving 68mg of a white solid in 30.4% yield.¹H NMR(300MHz,CDCl₃)δ7.75(d,J＝8.6Hz,1H),7.51(d,J＝8.6Hz,2H),7.34(dd,J＝8.6,1.9Hz,1H),7.17(d,J＝2.0Hz,1H),6.87(d,J＝8.6Hz,2H),3.88(s,3H),3.85-3.78(m,5H),2.96(t,J＝5.1Hz,2H).¹³C NMR(75MHz,CDCl₃)δ167.02,163.23,137.27,130.92,129.33,127.77,126.01，125.60,118.26,115.89,114.34,55.61,52.12,43.75,38.81。

Example 26

Synthesis of 1-p-toluenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (I-B-22)

Synthesis of 4-benzyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (IX-22)

Using VIII-2 (330mg,1.17mmol) and 4-methylbenzenesulfonyl chloride (III-4) (246mg,1.29mmol) as starting materials, the procedure was identical to that of compound IX-1 to give 259mg of a white solid in 60.8% yield.¹H NMR(300MHz,CDCl₃)δ7.78(d,J＝8.4Hz,1H),7.44(d,J＝8.2Hz,2H),7.36(dd,J＝8.4,1.4Hz,1H),7.31-7.27(m,1H),7.24-7.16(m,5H),6.89-6.79(m,2H),4.37(s,2H),3.88(t,J＝5.1Hz,2H),3.83(s,3H),2.97(t,J＝5.2Hz,2H),2.41(s,3H)。

IX-22 (250mg,0.60mmol) was used as the starting material, and the procedure was the same as for compound I-B-1, giving 69mg of a white solid in 35.4% yield.¹H NMR(300MHz,CDCl₃)δ7.75(d,J＝8.6Hz,1H),7.47(d,J＝8.2Hz,2H),7.35(dd,J＝8.6,1.9Hz,1H),7.20(d,J＝8.0Hz,2H),7.17(d,J＝2.0Hz,1H),3.94(s,1H),3.88(s,3H),3.82(t,J＝5.1Hz,2H),3.00-2.91(m,2H),2.38(s,3H).¹³C NMR(75MHz,CDCl₃)δ167.01,144.04,137.21,136.37,129.84,127.78,127.23,125.97,125.47,118.29，115.91,52.12,43.79，38.83,21.61。

In the above examples, the product may be any addition salt of hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

The following are some of the pharmacological experiments and results described in the present invention:

experiment 1: proliferation inhibition assay for tumor cells (MTT assay)

The compounds of the present invention were tested for cell proliferation inhibitory activity against human chronic myelogenous leukemia cells (K562), human liver cancer cells (HepG2), human breast cancer cells (MCF-7) and human cervical cancer cells (Hela). The above cell lines were all frozen and passaged in this laboratory. Inoculating 4000-5000 tumor cells in logarithmic growth phase to 96-well plate, adding target compound or control drug (compound ABT-751 as positive control drug) with different concentrations after 24 hr, and adding 5% CO at 37 deg.C₂And culturing for 72 h. mu.L of MTT solution (5mg/mL) was added to each well, and the culture was continued for 4 hours and the medium and MTT solution were discarded. Adding 100 mu L of DMSO solution into each hole, measuring the absorbance (OD value) of each hole at the wavelength of 570nm by using a microplate reader after shaking, and calculating the cell inhibition rate: growth inhibition rate (OD control-OD experiment)/(OD control-OD blank) × 100% (OD control, OD experiment and OD blank represent the average of each groupLight absorption values) and then fit IC of the compounds using GraphPad software₅₀。

The results of the experiments are shown in table 1, and show that part of the compounds have stronger proliferation inhibition activity.

A:IC₅₀﹤20μM；B:20<IC₅₀<100μM；C:IC₅₀>100μM

Experiment 2: cell cycle experiments

The compounds of the invention were tested for their effect on the cell cycle of cancer cells (Hela). Hela cells were seeded in 6-well plates at 37 ℃ with 5% CO₂Incubating for 24 hr, adding compounds or positive control with different concentrations into each well, respectively, at 37 deg.C and 5% CO₂The culture was continued for 24 hours. The cells were harvested, centrifuged, and slowly dropped vertically into 10mL of pre-chilled 70% (v/v) ethanol and fixed at-20 ℃ for 48 h. PBS wash, 500. mu.L of stain (50. mu.g/mL PI and 100. mu.g/mL RNaseA) was added to each sample, incubated at 4 ℃ in the dark for 1h, centrifuged to remove the dye, washed with PBS, filtered through a 300 mesh screen, and detected using a flow cytometer at 580 nm.

The experimental results are as follows: the results show that the compounds can dose-dependently arrest the cell cycle in the G2/M phase, as shown in FIG. 1.

Experiment 3: binding Pattern study

The binding mode of the compound and the microtubules was studied by molecular docking using maestro11.5 software. Cocrystal complexes of colchicine and microtubules (PDB: 1SA0) were first downloaded from PDB databases and energy minimization was performed by protein preparation options for protein hydrogenation, dehydration, supplementation of missing residues or fragments. The grid is then generated using the recipient grid generation options, by standard operations recommended by the software. Compounds were hydrogenated, 3D structured, ionized and optimized by OPLS3 force field, and then molecularly docked using the standard precision mode in Glide Docking.

Results of the experiment

The molecular docking results show that tetrahydroquinoxaline ring occupies a hydrophobic cavity of colchicine binding site, NH on the ring forms hydrogen bond with alpha tubulin Thr179, and benzene ring connected with sulfonyl group occupies hydrophobic pocket in beta tubulin. FIG. 2 shows the diagram of the binding of compound I-B-1 to microtubules. FIG. 3 shows the docking scheme of compound I-B-21 with microtubules.

Claims

1. The tetrahydroquinoxaline sulfonamide derivative or the pharmaceutically acceptable salt thereof has a structural general formula shown as a formula (I):

wherein: x ═ CH or N;

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: x ═ CH or N; r¹Selected from H, F, Cl, -OMe, -OEt, -COOMe, -COOEt, -OCOMe, -OCOEt, -CONH₂、-CONHMe、-NHCOMe、-NHCOEt；R²Selected from substituted aromatic rings or substituted aromatic heterocycles；R³Selected from H, Me, Et or COMe.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: r²Is selected from

Wherein R is⁶Representative H, F, CH₃、t-Bu、CF₃、CN、OH、OCH₃、OCF₃、NH₂、NHCH₃、N(CH₃)₂、NHC₂H₅、N(C₂H₅)₂、NHCOCH₃、CONH₂、CONHCH₃，R⁶It may be mono-, di-or tri-substituted.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of a compound of general formula (I) wherein the acid used to form the salt is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of microtubule polymerization.

7. The pharmaceutical use of claim 6, wherein said microtubule polymerization inhibitor is used for the treatment of a malignant tumor, wherein said malignant tumor is breast cancer, ovarian cancer, liver cancer, lung cancer, colon cancer, prostate cancer, or chronic myelogenous leukemia.