CN114195814B - Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application - Google Patents

Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application Download PDF

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CN114195814B
CN114195814B CN202210100129.4A CN202210100129A CN114195814B CN 114195814 B CN114195814 B CN 114195814B CN 202210100129 A CN202210100129 A CN 202210100129A CN 114195814 B CN114195814 B CN 114195814B
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pharmaceutically acceptable
phenylboronic acid
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CN114195814A (en
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张晓进
龚琪杰
李田
李想
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China Pharmaceutical University
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Abstract

The invention discloses a hydroxynaphthalenone-phenylboronic acid compound, a preparation method and application thereof. The compound is shown as a formula (I). The compound can be triggered and activated by high-level Reactive Oxygen Species (ROS) in tumors, so that o-naphthoquinone compounds with anti-tumor activity are released, and the compound has good anti-tumor activity at both cellular level and animal level and good safety, and can be used for preparing anti-tumor drugs.

Description

Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application
Technical Field
The invention relates to an organic compound in the field of pharmaceutical chemistry, in particular to a hydroxynaphthalenone-phenylboronic acid compound, a preparation method and application thereof.
Background
O-naphthoquinone compounds are widely present in natural products, and most natural products have a wide range of biological activities such as antioxidant, antibacterial, apoptosis-inducing activities, etc., because they contain highly reactive small molecules. In recent years, particularly in the field of antitumor drugs, natural o-naphthoquinone compounds show potent antitumor activity, such as tanshinone IIA and beta-lapachone, which enter clinical phase II research, and thus are attracting attention. (Mini-Reviews in Medicinal Chemistry,2020,20 (19), 2019-2035). Research shows that the o-naphthoquinone compounds mainly exert antitumor activity through three mechanisms: firstly, an alkylating medium is generated, and DNA synthesis is inhibited so as to generate a cytotoxic effect; secondly, inhibiting the activities of various key enzymes in tumor cells, such as pyruvate kinase, topoisomerase and the like, so that the tumor cells undergo apoptosis; thirdly, the oxidative stress level in the tumor cells is greatly improved, and the redox balance of the tumor cells is broken, so that the apoptosis of the tumor cells is induced (Current Cancer Drug Targets,2017,17 (2), 122-136). The o-naphthoquinone compound has good anti-tumor activity, but clinical experiments show that the o-naphthoquinone compound has systemic toxic and side effects on normal tissues, which greatly limits the application of the o-naphthoquinone compound in clinic. The o-quinone group which is a main cause of toxic and side effects of the compounds is not only the pharmacophore of the compounds, but also the toxic group. The o-quinone compound not only can play an anti-tumor activity through metabolism in tumor tissues, but also can reduce and metabolize the o-naphthoquinone compound under the catalysis of single electron oxidoreductase (such as cytochrome P450 reductase, xanthine oxidase and the like) in normal tissues in vivo to generate semi-quinone free radicals and ROS, so that toxicity (European Journal of Medicinal Chemistry 2017,129,27-40) is generated on normal cells. Therefore, the selectivity of the o-naphthoquinone compounds to tumor cells is improved, the toxic and side effects are reduced, and the o-naphthoquinone compound has great clinical application value.
The prodrug strategy is widely applied in the field of anti-tumor drugs, and can improve the targeting property of the anti-tumor drugs, thereby obviously reducing the systemic toxic and side effects of the anti-tumor drugs. It is currently widely accepted that ROS levels in tumor tissue can reach significantly higher concentrations, up to 100. Mu.M, than in normal tissue. (Journal of Medicinal Chemistry 2021,64 (1), 298-325). Therefore, based on this feature, ROS-responsive prodrugs can be designed to increase the selectivity of o-naphthoquinone compounds for tumor cells, thereby avoiding systemic toxic side effects from their metabolism by single electron oxidoreductase in normal cells. Boric acid or borate groups have been reported to be specific trigger groups for ROS, and have been widely used in recent years in the design of ROS-targeted fluorescent probes and anti-tumor prodrugs.
Disclosure of Invention
The invention aims to: the invention provides a hydroxynaphthone-phenylboronic acid compound which can be triggered and activated by a high-level Reactive Oxygen Species (ROS) in tumors to release o-naphthoquinone compounds with anti-tumor activity, has good anti-tumor effect at both cellular level and animal level, and has good safety. The invention also provides a preparation method and application of the compound, and the compound can be used for preparing antitumor drugs.
The technical scheme is as follows: the hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof has a structure shown in a general formula (I):
wherein R is 1 Represents hydrogen, or mono-or polysubstituted C 1 ～C 4 Alkyl or C containing single or multiple hetero atoms 1 ～C 8 Alkyl chains in which the hetero atom is chosen from nitrogen or oxygen atoms, where C 1 ～C 4 Alkyl groups may be further substituted with hydroxy groups; r is R 2 Represents hydrogen, or mono-or polysubstituted halogen, nitro, hydroxy, amino, C 1 ～C 4 Alkoxy, C 1 ～C 4 An alkyl group; r is R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b Identical or different, each representing hydrogen, C 1 ～C 4 An alkyl group; r is R 6 Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, C 1 ～C 4 Alkoxy, C 1 ～C 4 An alkyl group; b represents a single bond or a double bond, and R when B is a double bond 3b 、R 4b Absence of; n represents 0 or 1; m represents 0 to 4, and when m represents 0, R 1 The general formula of the compound is shown as (II):
wherein R is 7a 、R 7b Identical or different, each representing hydrogen or C 1 ～C 4 An alkyl group.
As a preferred embodiment of the present invention, R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b The same or different, each represents hydrogen or methyl.
As a preferred embodiment of the present invention, the R 7a 、R 7b The same or different, each represents hydrogen or methyl.
As a preferred embodiment of the present invention, the R 6 Represents hydrogen or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, methoxy or methyl.
As a preferred embodiment of the present invention, when m represents 1 to 4, the heterocyclic structure formed by two oxygen atoms to which B is attached is as follows:
as a specific embodiment of the present invention, the compounds of the present invention are shown below:
the invention relates to preparation of hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereofA method comprising the steps of: compound IIIThe target substance I is obtained by reaction, the reaction temperature is 40-100 ℃, the reaction time is 2-12 h, and the reaction solvent can be dioxane, acetone, tetrahydrofuran, DMF, acetonitrile, dichloromethane and the like. Organic or inorganic base such as triethylamine, N-diisopropylethylamine, imidazole, 4-dimethylaminopyridine, potassium hydroxide, sodium carbonate, potassium carbonate and the like are added in the reaction. Reducing agents such as palladium carbon/hydrogen, sodium hydrosulfite, lithium aluminum hydride, sodium borohydride, sodium sulfite, zinc powder and the like are also added in the reaction; meanwhile, the compound I can be purified by common separation methods, such as recrystallization, column chromatography and the like:
the pharmaceutical composition comprises the hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also includes hydrates, stereoisomers, solvates, pharmaceutically acceptable salts and the like of the compounds of formula I. They have the same pharmacological activity as the compounds of the general formula I.
The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and can be added with common medicinal auxiliary materials such as spice, sweetener, liquid or solid filler or diluent and the like.
The compound or the pharmaceutically acceptable salt thereof disclosed by the invention is used for preparing a medicament for treating malignant tumors.
The malignant tumor is pancreatic cancer, lung cancer, leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, kidney cancer and brain colloid.
The beneficial effects are that: the safety of the hydroxynaphthone-phenylboronic acid compound is obviously better than that of the o-naphthoquinone compound. The compound can be triggered and activated by high-level Reactive Oxygen Species (ROS) in tumors to release o-naphthoquinone compounds with anti-tumor activity, has the anti-tumor activity equivalent to that of the o-naphthoquinone active pharmaceutical ingredients, and is obviously superior to that of the o-naphthoquinone active pharmaceutical ingredients in selectivity. The dosage used clinically is 0.01 mg-1000 mg/day, and can be adjusted according to the disease condition or the different dosage forms.
Drawings
FIG. 1 is an X-single crystal diffraction structure of Compound I-2.
Detailed Description
1. Synthesis of intermediates
Synthetic route for compounds of general formula I:
1. preparation of 2-hydroxy-3- (3-hydroxypropyl) naphthalene-1, 4-dione (2 a)
2-hydroxynaphthalene-1, 4-dione (0.87 g,5 mmol) was dissolved in anhydrous DMF (15 mL) followed by 3-bromopropan-1-ol (0.77 g,5.5 mmol), triethylamine (0.76 mL,5.5 mmol) and sodium iodide (0.75 g,5 mmol). The reaction solution was stirred at 50℃for 8h. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, and the organic phase was taken up with saturated NaHCO, respectively 3 Aqueous solution (50 mL) and saturated NaCl solution (50 mL) were washed successively, anhydrous Na 2 SO 4 And (5) drying. Purification by petroleum ether/ethyl acetate (20:1) silica gel column chromatography gave a yellow solid (383 mg, 33%). 1 H NMR(300MHz,CDCl 3 )δ8.20(dd,J＝5.7,3.9Hz,1H),8.14(dd,J＝5.7,3.9Hz,1H),7.79(dd,J＝5.7,3.9Hz,2H),6.95(s,1H),2.31(t,J＝7.1Hz,2H),1.78(t,J＝7.1Hz,2H),1.22(s,6H)；m/z(EI-MS):232[M] + 。
2. Preparation of 3, 4-dihydro-2H-benzo [ H ] chromene-5, 6-dione (3 a)
2a (2.32 g,10 mmol) was dissolved in anhydrous DCM (50 mL), concentrated sulfuric acid (5.00 g,50 mmol) was slowly added to the reaction under ice-water bath and stirred at room temperature for 4h. The reaction was quenched with water (60 mL), extracted with ethyl acetate, and the organic phase separatedBy other means of saturated NaHCO 3 Aqueous solution (50 mL) and saturated NaCl solution (50 mL) were washed successively, anhydrous Na 2 SO 4 And (5) drying. Purification by petroleum ether/ethyl acetate (20:1) silica gel column chromatography gave a red solid (0.58 g, 25%). mp 158-160 ℃. 1 H NMR(300MHz,DMSO)δ:8.07(dd,J＝1.8Hz,1H),7.82(dd,J＝1.8Hz,1H),7.64(dt,J＝1.8Hz,1H),7.53(dt,J＝1.8Hz,1H),2.58(t,J＝6.6Hz,2H),1.86(t,J＝6.5Hz,2H),1.47(s,6H)；m/z(EI-MS):232[M] + 。
2. Preparation of the Compounds
Example 1: preparation of Compound I-1
3a (2.30 g,10 mmol), 4-bromomethylbenzoic acid (4.30 g,20 mmol) and sodium borohydride (1.51 g,40 mmol) were dissolved in N, N-dimethylformamide (100 mL) and water (100 mL), and sodium hydroxide (1.20 g,30 mmol) was added to the reaction solution. The reaction solution was stirred at 50℃for 3h. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, and the organic phase was taken up with saturated NaHCO, respectively 3 Aqueous solution (50 mL) and saturated NaCl solution (50 mL) were washed successively, anhydrous Na 2 SO 4 And (5) drying. Purification by petroleum ether/ethyl acetate (20:1) silica gel column chromatography gave a white solid (520 mg, 15%). 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.63–7.57(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.37–7.30(m,2H),7.18(dt,J＝7.4,1.0Hz,2H),4.25–4.18(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z[M+H] + calculated for C 20 H 20 BO 5 :351.1398,found:351.1398.
Example 2: preparation of Compound I-2
The compound I-2 (102 mg, 32%) was synthesized by the same method as the compound I-1 using 4-bromo-2-methylbutan-2-ol (10 mmol) instead of 3-bromopan-1-ol. 1 H NMR(300MHz,DMSO-d)δ:7.80(s,2H),7.64(d,J＝7.7Hz,1H),7.50(d,J＝7.7Hz,2H),7.43(d,J＝7.7Hz,2H),7.39-7.34(m,1H),6.38(d,J＝7.6Hz,2H),5.76(s,1H),3.08(d,J＝11.8Hz,1H),2.94(d,J＝11.8Hz,1H),2.39-2.25(m,1H),1.96(dt,J＝15.1,6.7Hz,1H),1.55(t,J＝6.6Hz,2H),128 (s, 3H), 0.88 (s, 3H). Compound I-2 has been structurally confirmed by X-single crystal diffraction, see FIG. 1.ESI-HRMS m/z calculated for C 22 H 24 BO 5 [M+H] + 379.1711,found 379.1715.
Example 3: preparation of Compound I-3
The compound I-3 (91 mg, 35%) was synthesized by the same method as the compound I-1 using 6-chloro-8-fluoro-2-hydroxynaphthalene-1, 4-dione (5 mmol) in place of 2-hydroxynaphthalene-1, 4-dione and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.56(d,J＝2.2Hz,1H),7.18(dd,J＝8.1,2.2Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),4.25–4.18(m,2H),3.31(q,J＝0.9Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 26 H 28 BClFO 5 :485.1697,found:485.1706.
Example 4: preparation of Compound I-4
The compound I-4 (68 mg, 34%) was synthesized in the same manner as the compound I-1 by substituting 6-methyl-2-hydroxynaphthalene-1, 4-dione (5 mmol) for 2-hydroxynaphthalene-1, 4-dione, substituting 3-bromo-2, 2-dimethylpropan-1-ol (5 mmol) for 3-bromopropan-1-ol and substituting 2- (4-bromomethylphenyl) -1,3, 2-dioxaborolan (10 mmol) for 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.40(d,J＝2.2Hz,1H),7.27(ddd,J＝8.2,1.9,0.8Hz,1H),7.16(d,J＝8.1Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),4.18(t,J＝6.1Hz,2H),3.35(dt,J＝14.1,0.9Hz,1H),3.30(dt,J＝14.1,0.9Hz,1H),2.37(s,3H),2.04–1.96(m,1H),1.86(dt,J＝12.4,6.1Hz,1H),1.28(s,3H),1.26(s,6H),1.23(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 29 H 36 BO 5 :475.2650,found:475.2652.
Example 5: preparation of Compound I-5
The compound was synthesized in the same manner as in the compound I-1 by substituting 4-bromo-2-methylbutan-2-ol (5 mmol) for 3-bromopropan-1-ol and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) for 4-bromomethylphenylboronic acidArticle I-5 (86 mg, 39%). 1 H NMR(300MHz,CDCl 3 -d)δ:7.68-7.64(m,2H),7.53-7.45(m,3H),7.35(td,J＝7.6,1.4Hz,1H),6.60(d,J＝8.0Hz,2H),4.01(s,1H),3.11(s,2H),2.54(dt,J＝17.3,5.6Hz,1H),2.10(dt,J＝17.4,7.6Hz,1H),1.62(t,J＝6.6Hz,2H),1.35(s,3H),1.32(s,12H),1.00(s,3H).ESI-HRMS m/z calculated for C 28 H 34 BO 5 [M+H] + 461.2494,found 461.2506.
Example 6: preparation of Compound I-6
Compound I-6 (163 mg, 34%) was synthesized by the same method as compound I-1 using 2-bromo-2-methylpropan-1-ol (10 mmol) instead of 3-bromo-3-methylbutan-2-ol, 5-hydroxy-2-hydroxynaphthalene-1, 4-dione (10 mmol) instead of 2-hydroxynaphthalene-1, 4-dione and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.33–7.26(m,1H),7.12(dt,J＝7.7,1.1Hz,2H),7.06(dd,J＝8.0,1.2Hz,1H),6.85(dd,J＝8.2,1.3Hz,1H),4.13–4.02(m,2H),3.35(dt,J＝1.9,1.1Hz,2H),1.30(s,3H),1.26(s,6H),1.25(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 27 H 32 BO 6 :462.2214,found:462.2217.
Example 7: preparation of Compound I-7
Compound I-7 (168 mg, 36%) was synthesized by the same method as compound I-1 using 1-bromo-2-methylpropan-2-ol (10 mmol) instead of 3-bromo-3-methylbutan-2-ol, 7-methyl-2-hydroxynaphthalene-1, 4-dione (10 mmol) instead of 2-hydroxynaphthalene-1, 4-dione and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.57(d,J＝8.3Hz,1H),7.23–7.18(m,1H),7.15–7.08(m,3H),3.34(t,J＝1.0Hz,2H),2.78(s,1H),2.63(s,1H),2.29(s,3H),1.39(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 28 H 34 BO 5 :461.2494,found:461.2497.
Example 8: preparation of Compound I-8
7-hydroxy-2-hydroxynaphthalene-1, 4-dione (5 mmol) was used instead of 2-hydroxynaphthalene-1, 4-dione and 3-bromo-2-buten-1-ol was used5 mmol) instead of 3-bromo-3-methylbutan-2-ol and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid, compound I-8 (72 mg, 34%) was synthesized in the same manner as compound I-18. 1 H NMR(300MHz,CDCl 3 -d)δ:7.95(s,1H),7.75–7.69(m,2H),7.58(d,J＝8.9Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),6.90(d,J＝2.3Hz,1H),6.72(dd,J＝8.9,2.3Hz,1H),5.65(tq,J＝4.0,1.8Hz,1H),4.49(tq,J＝4.1,1.0Hz,2H),3.42–3.31(m,2H),2.22(dt,J＝2.0,1.1Hz,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 27 H 30 BO 6 :461.2130,found:461.2131.
Example 9: preparation of Compound I-9
Compound I-9 (33 mg, 15%) was synthesized by the same method as compound I-1 using 5-chloro-2-hydroxynaphthalene-1, 4-dione (5 mmol) instead of 2-hydroxynaphthalene-1, 4-dione, 1-bromo-2, 3-dimethylbuten-3-ol (5 mmol) instead of 3-bromo-3-methylbutan-2-ol and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.51(t,J＝8.0Hz,1H),7.41(dd,J＝7.7,1.3Hz,1H),7.28(dd,J＝8.1,1.2Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),6.76(q,J＝1.3Hz,1H),3.38–3.34(m,2H),1.90(d,J＝1.3Hz,3H),1.45(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 29 H 33 BClO 5 :507.2104,found:507.2106.
Example 10: preparation of Compound I-10
Compound I-10 (209 mg, 32%) has been synthesized by the same method as compound I-18 using 7-methoxy-2-hydroxynaphthalene-1, 4-dione (5 mmol) instead of 2-hydroxynaphthalene-1, 4-dione, 1-bromopropen-2-ol (5 mmol) instead of 3-bromo-3-methylbutan-2-ol and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 HNMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.65(d,J＝7.9Hz,1H),7.13(dt,J＝7.8,1.0Hz,2H),6.97(d,J＝2.2Hz,1H),6.89(dd,J＝7.9,2.4Hz,1H),3.81(s,3H),3.46–3.34(m,2H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 27 H 30 BO 6 :461.2130,found:461.2133.
Example 11: preparation of Compound I-11
Compound I-11 (91 mg, 36%) was synthesized by the same method as compound I-1 using 6-bromo-2-hydroxynaphthalene-1, 4-dione (5 mmol) instead of 2-hydroxynaphthalene-1, 4-dione, 1, 3-dimethyl-2-buten-2-ol (5 mmol) instead of 3-bromo-3-methylbutan-2-ol and 4-bromomethylphenylboronic acid pinacol ester (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 HNMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.60(dd,J＝8.3,2.5Hz,1H),7.54(d,J＝2.5Hz,1H),7.24(d,J＝8.2Hz,1H),7.13(dt,J＝7.7,1.0Hz,2H),3.45–3.34(m,2H),2.29(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 27 H 29 BO 5 :523.1286,found:523.1288.
Example 12: preparation of Compound I-12
The compound I-12 (37 mg, 17%) was synthesized by the same method as the compound I-4 using 6-bromo-2-hydroxynaphthalene-1, 4-dione (5 mmol) instead of 2-hydroxynaphthalene-1, 4-dione. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.65(m,2H),7.65–7.59(m,2H),7.52(d,J＝7.9Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.06(s,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.34(q,J＝0.8Hz,2H),1.95(dddd,J＝19.8,9.3,6.2,3.3Hz,2H),1.02(s,3H),0.97(s,3H).ESI-HRMS m/z[M+H] + calculated for C 25 H 27 BIO 5 :545.0991,found:545.0995.
Example 13: preparation of Compound I-13
Compound I-13 (35 mg, 19%) was synthesized in the same manner as compound I-1 using 6-nitro-2-hydroxynaphthalene-1, 4-dione (5 mmol) instead of 2-hydroxynaphthalene-1, 4-dione, 3-bromo-2-methyl-2-buten-1-ol (5 mmol) instead of 3-bromopropan-1-ol and 2- (4-bromomethylphenyl) -1,3, 2-dioxaborolan (10 mmol) instead of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:8.52(d,J＝2.1Hz,1H),8.24(dd,J＝8.5,2.1Hz,1H),7.65–7.60(m,2H),7.57(d,J＝8.5Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.72(dq,J＝7.3,1.0Hz,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.36(dt,J＝14.3,1.1Hz,1H),3.29(dt,J＝14.3,1.1Hz,1H),2.16(p,J＝1.0Hz,3H),1.95(dddd,J＝19.8,9.3,6.1,3.3Hz,2H),1.89(q,J＝0.9Hz,3H).ESI-HRMS m/z[M+H] + calculated for C 25 H 25 BNO 7 :462.1719,found:462.1723.
Example 14: preparation of Compound I-14
Compound I-14 (33 mg, 15%) was synthesized by the same method as compound I-4 using 6-amino-2-hydroxynaphthalene-1, 4-dione (5 mmol) in place of 2-hydroxynaphthalene-1, 4-dione. 1 H NMR(300MHz,CDCl 3 -d)δ:7.65–7.59(m,2H),7.16–7.09(m,3H),7.07(d,J＝8.2Hz,1H),6.77(dd,J＝8.2,2.2Hz,1H),4.93(d,J＝5.3Hz,1H),4.80(d,J＝5.3Hz,1H),4.21(ddd,J＝7.0,5.5,4.1Hz,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),2.01–1.86(m,4H).ESI-HRMS m/z[M+H] + calculated for C 23 H 25 BNO 5 :406.1820,found:406.1823.
Example 15: preparation of Compound I-15
Compound I-15 (71 mg, 18%) was synthesized by the same method as compound I-1 using 6-cyano-2-hydroxynaphthalene-1, 4-dione (5 mmol) in place of 2-hydroxynaphthalene-1, 4-dione and 2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.89(d,J＝2.2Hz,1H),7.80(dd,J＝8.4,2.2Hz,1H),7.65–7.59(m,2H),7.29(d,J＝8.3Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.21(ddd,J＝7.0,5.5,4.1Hz,2H),3.78(dd,J＝12.3,4.2Hz,2H),3.72(dd,J＝12.4,4.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.80(m,3H),1.03(d,J＝6.5Hz,3H).ESI-HRMS m/z[M+H] + calculated for C 25 H 25 BNO 5 :430.1820,found:430.1824.
Example 16: preparation of Compound I-16
Compound I-16 (71 mg, 18%) was synthesized in the same manner as compound I-5 using (2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborolan-5-yl) methanol (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.78(d,J＝12.4Hz,2H),3.71(d,J＝12.3Hz,2H),3.61(d,J＝5.9Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,5.0Hz,2H),2.42(t,J＝5.9Hz,1H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.8Hz,1H),1.34(s,3H),0.82(s,3H).ESI-HRMS m/z[M+H] + calculated for C 27 H 32 BO 6 :463.2286,found:463.2289.
Example 17: preparation of Compound I-17
Compound I-17 (91 mg, 36%) was synthesized in the same manner as compound I-1 using 3-bromo-3-methylbutan-2-ol (5 mmol) in place of 3-bromo-3-methylbutan-2-ol and (2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane-5, 5-diyl) dimethanol (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 HNMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.0,1.8Hz,1H),7.65–7.59(m,2H),7.43–7.33(m,2H),7.22(dd,J＝7.7,1.5Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.18(t,J＝6.1Hz,2H),3.75(s,2H),3.70(s,2H),3.54(dd,J＝11.4,5.3Hz,2H),3.48(dd,J＝11.4,5.3Hz,2H),3.36(dt,J＝14.3,1.1Hz,1H),3.30(dt,J＝14.3,0.9Hz,1H),3.20(t,J＝5.3Hz,2H),2.04–1.96(m,1H),1.86(dt,J＝12.4,6.1Hz,1H),1.28(s,3H),1.23(s,3H).ESI-HRMS m/z[M+H] + calculated for C 27 H 32 BO 7 :479.2236,found:479.2239.
Example 18: preparation of Compound I-18
Compound I-18 (168 mg, 36%) was synthesized by the same method as compound I-7 using 2- (4- (bromomethyl) phenyl) -5, 5-bis (methoxymethyl) -1,3, 2-dioxaborane (10 mmol) in place of 4-bromomethylphenylboronic acid pinacol ester. 1 H NMR(300MHz,CDCl 3 -d)δ:7.65–7.55(m,3H),7.23–7.18(m,1H),7.15–7.08(m,3H),3.64(s,4H),3.49(s,4H),3.34(t,J＝1.0Hz,2H),3.32(s,6H),2.78(s,1H),2.63(s,1H),2.29(s,3H),1.39(s,3H).ESI-HRMS m/z[M+H] + calculated for C 29 H 36 BO 7 :507.2549,found:507.2553.
Example 19: preparation of Compound I-19
Replacement of 2-hydroxynaphthalene-1, 4-dione with 5-bromo-2-hydroxynaphthalene-1, 4-dione (10 mmol)And compound I-19 (163 mg, 34%) was synthesized by the same method as compound I-6 using N- ((2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxolan-5-yl) methyl) -2-methoxyethane-1-amine (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.75–7.69(m,2H),7.33–7.26(m,1H),7.12(dt,J＝7.7,1.1Hz,2H),7.06(dd,J＝8.0,1.2Hz,1H),6.85(dd,J＝8.2,1.3Hz,1H),4.13–4.02(m,2H),3.35(dt,J＝1.9,1.1Hz,2H),1.30(s,3H),1.26(s,6H),1.25(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H] + calculated for C 29 H 36 BBrNO 6 :584.1814,found:584.1817.
Example 20: preparation of Compound I-20
Compound I-20 (91 mg, 35%) was synthesized by the same method as compound I-1 using 2- (2- (((2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborolan-5-yl) methyl) amino) ethoxy) -N, N-dimethylethane-1-amine (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.6Hz,1H),7.65–7.59(m,2H),7.40(td,J＝6.9,1.4Hz,1H),7.34(ddd,J＝8.4,6.9,1.6Hz,1H),7.24(dd,J＝7.9,1.4Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.25–4.18(m,2H),3.76(d,J＝12.4Hz,2H),3.69(d,J＝12.3Hz,2H),3.59–3.53(m,4H),3.49(p,J＝5.0Hz,1H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.80(dt,J＝4.9,3.4Hz,2H),2.69(d,J＝4.9Hz,2H),2.62–2.52(m,4H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),0.91(s,3H).ESI-HRMS m/z[M+H] + calculated for C 31 H 42 BN 2 O 6 :549.3130,found:549.3135.
Example 21: preparation of Compound I-21
Compound I-21 (31 mg, 15%) has been synthesized in the same manner as compound I-1 using 8-fluoro-2-hydroxynaphthalene-1, 4-dione (5 mmol) in place of 2-hydroxynaphthalene-1, 4-dione and 2- (4- (bromomethyl) phenyl) -5- (2, 5,8, 11-tetraoxododecyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.65–7.58(m,3H),7.42(td,J＝7.1,4.9Hz,1H),7.15–7.09(m,2H),7.09–7.04(m,1H),4.25–4.18(m,2H),3.80(d,J＝12.5Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.51(m,14H),3.37(s,3H),3.31(dt,J＝2.2,1.1Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),0.81(s,3H).ESI-HRMS m/z[M+H] + calculated for C 32 H 41 BFO 9 :599.2822,found:599.2827.
Example 22: preparation of Compound I-22
The compound I-22 (102 mg, 32%) was synthesized by the same method as the compound I-1 using 2-bromopropen-1-ol (10 mmol) instead of 3-bromopropen-1-ol. 1 H NMR(300MHz,CDCl 3 -d)δ:7.77(dd,J＝7.9,1.5Hz,1H),7.63–7.57(m,2H),7.53(d,J＝0.9Hz,1H),7.49–7.37(m,3H),7.19(dt,J＝7.4,1.0Hz,2H),3.45–3.34(m,2H).ESI-HRMS m/z calculated for C 20 H 18 BO 5 [M+H] + 349.1242,found 349.1246.
Example 23: preparation of Compound I-23
The compound I-23 (36 mg, 17%) was synthesized by the same method as the compound I-2 using 2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.67-7.60(m,2H),7.51-7.42(m,3H),7.34(td,J＝7.6,1.4Hz,1H),6.59(d,J＝8.0Hz,2H),4.14(t,J＝5.5Hz,4H),4.01(s,1H),3.10(s,2H),2.54(dt,J＝17.3,5.6Hz,1H),2.21-2.10(m,1H),2.08-1.97(m,2H),1.65-1.57(m,2H),1.36(s,3H),1.07(s,3H).ESI-HRMS m/zcalculated for C 25 H 28 BO 5 [M+H] + 419.2024,found 419.2027.
Example 24: preparation of Compound I-24
The compound I-24 (45 mg, 23%) was synthesized by the same method as the compound I-2 using 2- (4- (bromomethyl) phenyl) -5, 5-dimethyl-1, 3, 2-dioxaborolan (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.49(s,4H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.9Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.86(s,6H).ESI-HRMS m/z calculated for C 27 H 32 BO 5 [M+H] + 447.2337,found 447.2339.
Example 25: preparation of Compound I-25
The compound I-25 (37 mg, 21%) was synthesized by the same method as compound I-2 using 2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.78(dd,J＝12.3,4.2Hz,2H),3.72(dd,J＝12.4,4.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.91–1.80(m,2H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),1.03(d,J＝6.5Hz,3H).ESI-HRMS m/z calculated for C 26 H 30 BO 5 [M+H] + 433.2181,found 433.2186.
Example 26: preparation of Compound I-26
The compound I-26 (67 mg, 56%) was synthesized by the same method as the compound I-2 using 2- (4- (bromomethyl) phenyl) -5- (methoxymethyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.77–3.66(m,4H),3.48(s,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),3.24(s,3H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.8Hz,1H),1.34(s,3H),0.82(s,3H).ESI-HRMS m/z calculated for C 28 H 34 BO 6 [M+H] + 477.2443,found 477.2448.
Example 27: preparation of Compound I-27
The compound I-27 (38 mg, 25%) was synthesized by the same method as the compound I-2 using (2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane-5, 5-diyl) dimethanol (10 mmol) instead of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.75(s,2H),3.70(s,2H),3.54(dd,J＝11.4,5.3Hz,2H),3.48(dd,J＝11.4,5.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),3.20(t,J＝5.3Hz,2H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H).ESI-HRMS m/z calculated for C 27 H 32 BO 7 [M+H] + 479.2236,found 479.2239.
Example 28: preparation of Compound I-28
The compound I-28 (56 mg, 34%) was synthesized by the same method as compound I-2 using 2- (4- (bromomethyl) phenyl) -5- ((2-methoxyethoxy) methyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.5Hz,2H),3.63–3.51(m,4H),3.48(t,J＝4.3Hz,2H),3.37(s,3H),3.34–3.25(m,2H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/z calculated for C 30 H 38 BO 7 [M+H] + 521.2705,found 521.2707.
Example 29: preparation of Compound I-29
The compound I-29 (25 mg, 16%) was synthesized by the same method as compound I-2 using 2- (4- (bromomethyl) phenyl) -5- ((2- (2-methoxyethoxy) ethoxy) methyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.55(m,9H),3.54(d,J＝11.5Hz,1H),3.35(d,J＝16.2Hz,4H),3.32–3.25(m,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/zcalculated for C 32 H 42 BO 8 [M+H] + 565.2967,found 565.2968.
Example 30: preparation of Compound I-30
The compound I-30 (33 mg, 21%) was synthesized by the same method as compound I-2 using 2- (4- (bromomethyl) phenyl) -5- (2, 5,8, 11-tetraoxododecyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol) in place of 4-bromomethylbenzoboric acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.51(m,14H),3.35(d,J＝16.2Hz,4H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/z calculated for C 34 H 46 BO 9 [M+H] + 609.3229,found 609.3231.
Example 31: preparation of Compound I-31
The compound I-31 (45 mg, 27%) was synthesized by the same method as the compound I-1 using dimethyl (4- (bromomethyl) phenyl) borate (10 mmol) instead of 4-bromomethyl phenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.61–7.56(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.36–7.32(m,2H),7.11(dt,J＝7.8,1.0Hz,2H),4.25–4.18(m,2H),3.64(s,6H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C 22 H 24 BO 5 [M+H] + 379.1711,found 379.1715.
Example 32: preparation of Compound I-32
The compound I-32 (63 mg, 47%) was synthesized by the same method as compound I-1 using (4- (bromomethyl) -2-chloro-6-fluorophenyl) boric acid (10 mmol) in place of 4-bromomethylbenzoic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.35(qt,J＝3.6,1.8Hz,3H),6.89(ddt,J＝8.1,2.1,1.1Hz,1H),4.25–4.18(m,2H),3.36(dt,J＝13.7,1.1Hz,1H),3.30(dt,J＝13.7,1.0Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C 20 H 18 BClFO 5 [M+H] + 403.0914,found 403.0917.
Example 33: preparation of Compound I-33
3-iodo-4-bromomethylphenylboronic acid (10 mmol) was used in place of 4-bromomethylphenylboronic acid, and compound I-33 (27 mg, 19%) was synthesized in the same manner as compound I-1. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.56(dd,J＝7.1,2.2Hz,1H),7.47(d,J＝2.1Hz,1H),7.43–7.31(m,3H),7.03(dt,J＝7.1,1.0Hz,1H),4.25–4.18(m,2H),3.48–3.37(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C 20 H 19 BIO 5 [M+H] + 477.0365,found 477.0365.
Example 34: preparation of Compound I-34
3-methyl-4-bromomethylphenylboronic acid (10 mmol) was used in place of 4-bromomethylphenylboronic acid, and compound I-34 (35 mg, 24%) was synthesized in the same manner as compound I-1. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.54(dd,J＝7.5,2.2Hz,1H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.37–7.32(m,2H),7.30(d,J＝2.2Hz,1H),7.05(dt,J＝7.5,1.1Hz,1H),4.25–4.18(m,2H),3.38–3.28(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C 21 H 22 BO 5 [M+H] + 365.1555,found 365.1558.
Example 35: preparation of Compound I-35
2-amino-4-bromomethylphenylboronic acid (10 mmol) was used in place of 4-bromomethylphenylboronic acid, and compound I-35 (67 mg, 36%) was synthesized in the same manner as compound I-1. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.43–7.35(m,2H),7.35–7.30(m,2H),6.78(dt,J＝2.1,1.0Hz,1H),6.73(ddt,J＝7.9,2.0,1.0Hz,1H),5.49(d,J＝6.6Hz,1H),5.28(d,J＝6.6Hz,1H),4.25–4.18(m,2H),3.23(dt,J＝2.0,1.0Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C 20 H 21 BNO 5 [M+H] + 366.1507,found366.1511.
Example 36: preparation of Compound I-36
With 2-nitro-4-bromomethylbenzoboronAcid (10 mmol) was synthesized in the same manner as compound I-1, except that 4-bromomethylphenylboronic acid was replaced, to give compound I-36 (72 mg, 39%). 1 H NMR(300MHz,CDCl 3 -d)δ:8.20(dt,J＝2.0,1.1Hz,1H),7.74(dd,J＝7.1,1.4Hz,1H),7.42(d,J＝7.6Hz,1H),7.40–7.37(m,1H),7.37–7.30(m,3H),4.25–4.18(m,2H),3.38(dt,J＝2.0,0.9Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C 20 H 19 BNO 7 [M+H] + 396.1249,found 396.1254.
Example 37: preparation of Compound I-37
2-methoxy-4-bromomethylphenylboronic acid (10 mmol) was used in place of 4-bromomethylphenylboronic acid, and compound I-37 (38 mg, 21%) was synthesized in the same manner as compound I-1. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.45–7.30(m,4H),7.02(q,J＝1.1Hz,1H),6.93–6.87(m,1H),4.25–4.18(m,2H),3.77(s,3H),3.32–3.28(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C 21 H 22 BO 6 [M+H] + 381.1504,found 381.1507.
Example 38: preparation of Compound I-38
The compound I-38 (42 mg, 24%) was synthesized by the same method as compound I-1 using 2-methoxy-3-cyano-4-bromomethylphenylboronic acid (10 mmol) in place of 4-bromomethylphenylboronic acid. 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.65–7.59(m,2H),7.40(ddd,J＝7.2,6.1,2.0Hz,1H),7.38–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),4.25–4.18(m,2H),3.83–3.75(m,2H),3.75–3.69(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H),1.67–1.56(m,4H).ESI-HRMS m/zcalculated for C 24 H 26 BO 5 [M+H] + 405.1868,found 405.1870.
Example 39: preparation of Compound I-39
The compound was synthesized in the same manner as in the compound I-1 by using 2-methoxy-3-cyano-4-bromomethylphenylboronic acid (10 mmol) in place of 4-bromomethylphenylboronic acidI-39(38mg,21％)。 1 H NMR(300MHz,CDCl 3 -d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.66–7.60(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.38–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),5.45(s,2H),4.72(s,1H),4.25–4.18(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C 21 H 20 BO 5 [M+H] + 363.1398,found 363.1399.
3. Pharmacological experiments and results of some of the compounds of the present invention:
(1) The compound is H 2 O 2 Activation release profile determination
In a 1.5mL microcentrifuge tube, the prodrug of interest (1 mM), internal standard solution (1 mM, diclofenac), and appropriate amount of PBS buffer solution were added to dilute, ensuring a final total volume of 1mL. Placing the centrifuge tube in a constant temperature mixer, adding H 2 O 2 (5 mM,5 equiv) and then started to mix at 37℃and started to count with this as a reference, and samples were taken after 1h and 2h. The concentration change of the prodrug is detected by using an island body fluid mass spectrometer LC-MS at 254nm wavelength. More than three replicates are required for each test.
TABLE 1 variation of the content of partial Compounds of the invention over time
From the above results, it can be seen that the compounds of the present invention can be found in H 2 O 2 Under the stimulation, the o-quinone compound is released rapidly and quantitatively.
In addition, the study of the invention also finds that the compounds in the examples are incubated for 24 hours in the test buffer solution and the plasma, and all show extremely high stability and can not release the o-quinone compound, so that the compounds have the potential advantages of being released in blood and normal tissues but selectively released in tumor tissues with high ROS level, thereby having selectivity.
The hydroxynaphthone-phenylboronic acid compound can be selectively oxidized and broken by high-level ROS in tumor cells, so that a connecting chain releases o-naphthoquinone original drugs through 1, 6-elimination and autoxidation, and the selective anti-tumor effect is exerted. The mechanism of activation and release of hydroxynaphthalenone-phenylboronic acid derivatives triggered by high ROS of tumor cells is shown as follows:
(2) Determination of toxicity of Compounds to tumor cells
The experimental method comprises the following steps: and adopting an MTT colorimetric method, wherein the culture time is 48-72 h. Adding H with non-cytotoxicity concentration into tumor cell culture medium 2 O 2 (50. Mu.M-100. Mu.M) to stimulate tumor cells, mimicking the high oxidative stress and high ROS level state of tumor cells in tumor tissue. The antiproliferative activity of the compounds on various tumor cells is then measured by adding different concentrations of the test compounds. At 3.0X10 in 96-well plates, respectively 3 Well inoculation, each compound was H at non-cytotoxic concentration 2 O 2 After incubation, six concentration gradients (100,33.3,11.1,3.7,1.2,0.4. Mu.M) were set, with three duplicate wells per concentration. Optical Density (OD) was measured at 570nm using a microplate reader. Calculation of IC with Grapad Prism 8 software using solvent control treated tumor cells as control group 50 。
TABLE 2 inhibition of tumor cells A549, mia PaCa-2, PANC-1, MV4-11 and Normal cells L02, HUVEC by some of the compounds of the invention (IC 50 :μM)：
A549: human lung cancer cells; mia PaCa-2, PANC-1: human pancreatic cancer cells; MV4-11: human leukemia cells; l02: human normal hepatocytes; HUVEC: human umbilical vein endothelial cells
As can be seen from table 2, the compounds of the present invention have a strong activity against tumor cell proliferation, which is comparable to that of β -lapachone; meanwhile, the compound has no killing effect on normal cells, and the safety is obviously better than that of the o-quinone compound positive drug beta-lapachone.
In addition, the representative compounds of the invention have good anti-tumor cell proliferation activity on leukemia cells (HL-60), breast cancer cells (MCF-7), gastric cancer cells (HGC-27), liver cancer cells (HepG 2), colon cancer cells (HCT 116), kidney cancer cells (A498), brain glioma cells (U251) and the like, and the compounds of the invention have broad-spectrum anti-tumor effect and have therapeutic potential on the tumors.
TABLE 3 inhibition of growth of several other tumor cell lines by some of the compounds of the invention (IC 50 :μM)
(3) In vivo anti-tumor Activity Studies
The experimental method comprises the following steps: collecting the human pancreatic cancer cells in the vigorous growth period, preparing a cell suspension under the aseptic condition, and inoculating the cell suspension to the armpit of a nude mouse. The diameter of the transplanted tumor of the nude mice is measured by a vernier caliper, and after the tumor grows to a certain size, animals are grouped, and 5 animals are grouped in each group. The antitumor effect of the test object is dynamically observed by using a method for measuring tumor diameters. Saline was administered to the blank control; group of compounds: tail vein injection is carried out once every other day for 21 days. Tumor-bearing nude mice were sacrificed 21 days later and tumor masses were isolated and weighed. The data obtained were statistically processed (t-test) to calculate the relative tumor proliferation rate. And simultaneously, photographing the finally peeled tumor blocks to preserve pictures.
TABLE 4 relative tumor proliferation rates of Mia PaCa-2 transplants of representative Compounds of the invention
As can be seen from Table 4, the representative compounds I-12 and I-22 of the present invention have good inhibitory effect on Mia PaCa-2 transplantation tumor in nude mice, and have equivalent inhibitory activity to beta-lapachone.
(4) In vivo safety study
The experimental method comprises the following steps: mice were tested for acute toxicity. The in vivo safety of the compounds was assessed by testing the median lethal dose of I-12, I-22 and beta-lapachone. The mice used in the experiments were ICR mice, 10 in each group, male and female halves. Saline was administered to the blank control; animals were observed for clinical signs and mortality every hour for 14 days, within 4 hours of the day of dosing.
TABLE 5 half of the mortem mass (LD) of representative compounds of the invention on normal ICR mice 50 ) Data
Group of Half lethal dose (mg/kg)
Ⅰ-7 3500.0
Ⅰ-12 3200.0
I-14 3700.0
I-22 3300.0
Beta-lapachone 160.0
As can be seen from Table 5, the representative compounds I-12, I-22 of the present invention have significantly better safety than beta-lapachone and significantly less toxic side effects than beta-lapachone.
Therefore, the hydroxynaphthone-phenylboronic acid derivative has the anti-tumor activity equivalent to that of the o-naphthoquinone original drug, is obviously superior to that of the o-naphthoquinone original drug in selectivity, and can be used for preparing the anti-tumor drug.

Claims (10)

1. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof is characterized in that the structure of the compound is shown as a general formula (I):
wherein R is 1 Represents hydrogen, or mono-or polysubstituted C 1 ～C 4 Alkyl or C containing single or multiple hetero atoms 1 ～C 8 Alkyl chains in which the hetero atom is chosen from nitrogen or oxygen atoms, where C 1 ～C 4 Alkyl groups may be further substituted with hydroxy groups; r is R 2 Represents hydrogen, or mono-or polysubstituted halogen, nitro, hydroxy, amino, C 1 ～C 4 Alkoxy, C 1 ～C 4 An alkyl group; r is R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b Identical or different, each representing hydrogen, C 1 ～C 4 An alkyl group; r is R 6 Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, C 1 ～C 4 Alkoxy, C 1 ～C 4 An alkyl group; b represents a single bond or a double bond, and R when B is a double bond 3b 、R 4b Absence of; n represents 0 or 1; m represents 0 to 4, and when m represents 0, R 1 The general formula of the compound is shown as (II):
wherein R is 7a 、R 7b Identical or different, each representing hydrogen or C 1 ～C 4 An alkyl group.
2. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b The same or different, each represents hydrogen or methyl.
3. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is 7a 、R 7b The same or different, each represents hydrogen or methyl.
4. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is 6 Represents hydrogen or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, methoxy or methyl.
5. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein when m represents 0 to 4, the heterocyclic structure formed by two oxygen atoms to which B is attached is as follows:
6. the hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is as follows:
7. a process for the preparation of hydroxynaphthalenone-phenylboronic acid compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of: compound IIIThe target substance I is obtained by reaction, the reaction temperature is 40-100 ℃, wherein R is 1 、R 2 、R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b 、R 6 The definition of ∈ B, n or m is the same as claim 1:
8. a pharmaceutical composition comprising a hydroxynaphthalenone-phenylboronic acid compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a malignancy.
10. The use according to claim 9, wherein the malignancy is pancreatic cancer, lung cancer, leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, renal cancer, and glioma.
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