CN106008306A - Substituted indole derivatives, and preparation method and application thereof - Google Patents

Substituted indole derivatives, and preparation method and application thereof Download PDF

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CN106008306A
CN106008306A CN201610495845.1A CN201610495845A CN106008306A CN 106008306 A CN106008306 A CN 106008306A CN 201610495845 A CN201610495845 A CN 201610495845A CN 106008306 A CN106008306 A CN 106008306A
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indole
drying
acid
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刘新泳
赵法宝
展鹏
刘娜
贾海永
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention discloses substituted indole derivatives, and a preparation method and application thereof. The substituted indole compounds or pharmaceutically acceptable salts, esters or prodrugs have the structure disclosed as General Formula I. The invention also discloses a preparation method of the substituted indole compounds and application of the composition containing one or more of the compounds in preparing drugs for treating and preventing human hepatitis C.

Description

Substituted indole derivatives, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to substituted indole derivatives, a preparation method of the derivatives and application of the derivatives in preparation of anti-hepatitis C medicines.
Background
Hepatitis C Virus (HCV) RNA polymerase (Non-Structure 5B, NS5B) has an irreplaceable important role in the HCV life cycle, and a novel NS5B inhibitor that is highly efficient, low-toxic, drug-resistant and has good pharmacokinetic properties is an important direction for the development of anti-HCV drugs. Several of the HCV NS5B Thumb Site I inhibitors are already in clinical research, but the poor pharmacokinetic properties of these inhibitors limit their clinical utility. Therefore, the research and development of the anti-hepatitis C medicament with a new structure and a new mechanism have important significance.
Heterocyclic compounds have a wide range of antiviral activities, and they are generally used as a parent nucleus of a basic structure constituting a pharmacophore to meet the spatial requirements of a target site for a particular action of a drug, or as an active substituent or as a component of a ring system to produce a corresponding biological activity. The dependence of the drug on the heterocycle is due to the fact that heterocycles are less metabolically decomposed in the body and have better biocompatibility than aliphatic or aromatic compounds. Indole is an important aromatic heterocycle, and derivatives thereof have wide biological activity and clinical application. The invention designs and synthesizes a series of substituted indole derivatives based on the good anti-HCV activity of indole analogs, and the compounds and the application thereof are not found in the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a substituted indole derivative and a preparation method thereof, and also provides an anti-hepatitis C virus activity screening result of the substituted indole derivative and application thereof in preparing anti-hepatitis C drugs.
The technical scheme of the invention is as follows:
1. substituted indole derivatives
A substituted indole derivative, or a pharmaceutically acceptable salt, ester or prodrug thereof, has a structure shown in a general formula I:
wherein,
R1、R2each independently selected from a substituted benzene ring, a substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings, various aliphatic rings, various saturated aliphatic chains or various unsaturated aliphatic chains;
R3are various carboxylic acids, carboxylic esters or amides.
Preferred according to the invention are those of the formula I in which R1、R2Each independently selected from phenyl, p-methylphenyl, p-methoxyphenyl, 2-furyl, 3-thienyl, m-methylphenyl, m-fluorophenyl or p-trifluoromethylphenyl; r3Is carboxyl or carbomethoxy.
According to the present invention, it is further preferred that the substituted indole compound is one of the following specific compounds:
as used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, are commensurate with a reasonable benefit-to-risk ratio, are generally water or oil soluble or dispersible, and are effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated herein and are compatible with the chemical nature of the compounds of formula i. A list of suitable salts is found on pages 1-19 of s.m. berge et al, j.pharm.sci.,1977, 66.
The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of the derivative is the active drug as defined for the compound of formula I.
2. Substituted indole derivatives and their preparation
The preparation method of the substituted indole derivative comprises the following steps:
route one: indole-6-methyl formate 1 is used as an initial raw material, and is subjected to affinity substitution reaction with chloroacetyl morpholine in an N, N-dimethylformamide solution to generate an intermediate compound 2; then the intermediate compound 2 reacts with N-bromosuccinimide in a dichloromethane solution to generate an intermediate compound 3; then, the intermediate compound 3 reacts with various substituted boric acids in dioxane solution to generate a target product a, and then different target products a react with sodium hydroxide solution in methanol solution to obtain a target product b;
the synthesis route one is as follows:
wherein R is1、R2The general formula I is shown in the specification;
reagents and conditions: (i) chloroacetyl morpholine, sodium hydride, N-dimethylformamide, room temperature; (ii) dichloromethane, N-bromosuccinimide; (iii) boronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (iv) methanol, aqueous sodium hydroxide solution, reflux.
The substituted boric acid is phenylboronic acid, p-methoxyphenylboronic acid, m-fluorophenylboronic acid, 3-furanboronic acid, p-methylphenylboronic acid, m-methylphenylboronic acid, 2, 4-dimethylphenylboronic acid, 2-thiopheneboronic acid, 2, 3-dimethylphenylboronic acid or 2-fluoro-3-methoxyphenylboronic acid.
And a second route: taking an intermediate compound 3 as a raw material, reacting the intermediate compound with phenylboronic acid in a dioxane solution to generate an intermediate compound 4, and then reacting the intermediate compound with different substituted boric acids to generate a target product a; then the compound a reacts with a sodium hydroxide aqueous solution in a methanol solution to generate a target product b;
the second synthetic route is as follows:
wherein R is1The general formula I is shown in the specification;
reagents and conditions: (i) phenylboronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (ii) boronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (iii) methanol, aqueous sodium hydroxide solution, reflux.
The substituted boric acid is phenylboronic acid, p-methoxyphenylboronic acid or 3-furanboronic acid.
The room temperature of the invention is 25 ℃.
The invention relates to a more detailed preparation method of substituted indole derivatives, which comprises the following steps:
route one:
(1) weighing 5.26g of raw material 6-methyl indole carboxylate, placing the raw material in a 100mL flask, adding 20mL of N, N-dimethylformamide for dissolving, adding 791.9mg of sodium hydride, stirring at room temperature for 30 minutes, then adding 3.90mL of chloroacetyl morpholine, stirring at room temperature for reaction for 12 hours, performing thin-layer detection reaction, then performing spin-drying on the solvent, adding 20mL of water and 20mL of dichloromethane, separating an organic phase, washing with 20mL of water twice, drying with anhydrous sodium sulfate, performing spin-drying on the solvent to obtain a white solid, and performing vacuum drying to obtain an intermediate compound 2;
(2) weighing 4.53g of intermediate compound 2, placing the intermediate compound 2 in a 250mL flask, adding 50mL of dichloromethane for dissolving, then adding 5.61g N-bromosuccinimide in batches, stirring at room temperature for reaction for 12 hours, adding 30mL of water for quenching reaction after the thin-layer detection reaction is completed, washing an organic phase by 30mL of water twice, drying the organic phase by anhydrous sodium sulfate, carrying out Flash column chromatography after solvent is dried in a spinning mode to obtain a white solid, and carrying out vacuum drying to obtain an intermediate 3;
(3) weighing 92.0mg of intermediate compound 3, placing the intermediate compound in a 25mL microwave reactor, adding 10mL of redistilled dioxane for dissolution, and adding 420 mu mol of different substituted phenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 89.2mg of tripotassium phosphate; reacting for 30 minutes at 150 ℃ in a microwave reactor, detecting the reaction through a thin layer, filtering the reaction liquid by using kieselguhr after the reaction is completed, spin-drying the solvent, dissolving the solid by using 10mL of dichloromethane, washing the solid twice by using 10mL of water, drying the anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain a target product a 01;
(4) weighing 200.00 mu mol of compound a01 in a 25mL flask, adding 15mL of methanol for dissolving, heating for refluxing, slowly dropwise adding 1M of sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time until the pH value is stabilized above 10, stopping dropwise adding the sodium hydroxide solution, detecting the reaction completion by using a thin-layer plate, adjusting the pH value to 1 by using 1M of hydrochloric acid, then spin-drying the solvent, adding 10mL of ethyl acetate for dissolving, washing twice by using 10mL of water, drying by using anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing by using ethanol to obtain a target product b 01.
And a second route:
(1) weighing 92.0mg of intermediate 3 into a 50mL microwave reactor, adding 10mL of redistilled dioxane to dissolve, and adding 24.4mg of phenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 46.7mg of tripotassium phosphate; reacting for 30 minutes at 150 ℃ in a microwave reactor to obtain an intermediate 4;
(2) 220.00 mu mol of p-methoxyphenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 46.7mg of tripotassium phosphate are added into the reaction solution of the previous reaction; reacting in a microwave reactor at 150 ℃ for 30 minutes, detecting by TLC (thin layer chromatography) to complete the reaction, filtering the reaction liquid by using kieselguhr, spin-drying the solvent, dissolving the solid by using 20mL of ethyl acetate, washing by using 20mL of water twice, drying by using anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain a target product a 02;
(3) weighing 200.00 mu mol of compound a02 in a 25mL flask, adding 15mL of methanol for dissolving, heating for refluxing, slowly dropwise adding 1M of sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time until the pH value is stabilized above 10, stopping dropwise adding the sodium hydroxide solution, detecting the reaction completion by using a thin-layer plate, adjusting the pH value to 1 by using 1M of hydrochloric acid, then spin-drying the solvent, dissolving in 10mL of ethyl acetate, washing twice by using 10mL of water, drying by using anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing by using ethanol to obtain the target product b 02.
3. Application of substituted indole derivatives
An in vitro affinity assay for NS5B protein was performed using surface plasmon resonance on 23 specific compounds synthesized as described above. As can be seen from table 1, the substituted indole derivatives of the present invention are a series of non-nucleoside HCV inhibitors with novel structures, and have different affinities to NS5B, therefore, the present invention further provides:
the application of substituted indole derivatives as non-nucleoside HCV inhibitors. In particular to the application of the compound as an HCV inhibitor in the preparation of anti-hepatitis C drugs.
An anti-HCV pharmaceutical composition comprises a substituted indole derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients.
The invention provides a substituted indole derivative with a brand-new structure and a preparation method thereof, an anti-HCV activity screening result and a first application thereof in the field of antivirus. Experiments prove that the indole derivative can be used as an HCV inhibitor and has high application value. In particular to the application of the compound as an HCV inhibitor in the preparation of anti-hepatitis C drugs.
Detailed Description
The following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention.
The synthetic routes referred to in the examples are as follows:
the first synthetic route is as follows:
the second synthetic route is as follows:
example 1: preparation of intermediate 2
Weighing methyl 6-indolecarboxylate (5.26g, 30.00mmol) into a 100mL flask, adding 20mL DMF to dissolve, adding sodium hydride (791.9mg, 33.00mmol), stirring at room temperature for 30 minutes, then adding chloroacetyl morpholine (3.90mL, 30.00mmol), stirring at room temperature for reaction for 12 hours, detecting the solvent by TLC after the reaction is completed, adding 20mL water and 20mL DCM for extraction, separating the organic phase, washing with water (2X 20mL), drying with anhydrous sodium sulfate, drying with the solvent to obtain a white solid, and drying with a vacuum drying oven to obtain an intermediate 2, a light yellow solid, yield: 92%, melting point: 156 and 158 ℃.
Intermediate 2 spectral data:1H NMR(400MHz,DMSO-d6,ppm):8.06(s,1H,indole-H),7.64-7.63(m,2H,indole-H),7.49(d,J＝3.20Hz,1H,indole-H),6.55(dd,J1＝0.40Hz,J2＝2.80Hz,1H,indole-H),5.22(s,2H,CH2),3.86(s,3H,COOCH3),3.71-3.68(m,2H,CH2),3.61-3.59(m,4H,CH2,CH2),3.46-2.44(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm):167.76(COO),166.61(CON),136.55(indole-C),134.33(indole-C),132.28(indole-C),122.54(indole-C),120.55(indole-C),120.13(indole-C),112.62(indole-C),101.67(indole-C),66.53(morpholine-CH2),66.42(morpholine-CH2),52.25(CH3),47.55(CH2),445.23(morpholine-CH2),42.32(morpholine-CH2).ESI-MS:303.5[M+H]+,320.4[M+NH4]+,325.4[M+Na]+。C16H18N2O4(302.13)。
example 2: preparation of intermediate 3
Weighing intermediate 2(4.53g, 15.00mmol), dissolving in 50mL dichloromethane in a 250mL flask, adding N-bromosuccinimide (5.61g, 30.50mmol) in batches, stirring at room temperature for 12 hours for reaction, detecting by TLC, adding 30mL water for quenching reaction, washing with organic phase water (2X 30mL), drying with anhydrous sodium sulfate, carrying out Flash column chromatography after solvent spin-drying to obtain a white solid, and drying in a vacuum drying oven to obtain intermediate 3, which is a white solid and has the yield: 94%, melting point: decomposing at 195 deg.C.
Intermediate 3 spectral data:1H NMR(400MHz,DMSO-d6,ppm):8.23(s,1H,indole-H),7.80(dd,J1＝1.20Hz,J2＝12.00Hz,1H,indole-H),7.53(d,J＝8.00Hz,1H,indole-H),5.46(s,2H,CH2),3.88(s,3H,COOCH3),3.74-3.71(m,2H,CH2),3.66-3.64(m,2H,CH2),3.61-3.58(m,2H,CH2),3.46-3.43(m,2H,CH2).ESI-MS:303.5[M+H]+,320.4[M+NH4]+,325.4[M+Na]+.C16H18N2O4(302.13).ESI-MS:461.3[M+H]+,463.2[M+H]+,476.2[M+NH4]+,478.2[M+NH4]+,476.2[M+NH4]+,483.2[M+Na]+,485.3[M+Na]+.C16H16Br2N2O4(457.95)。
example 3: preparation of Compound a01
Intermediate 3(92.0mg, 200.00. mu. mol) was weighed into a 25mL microwave reactor, dissolved by adding 10mL of heavy steamed dioxane, and phenylboronic acid (420.00. mu. mol), tetrakis (triphenylphosphine) palladium (11.6mg, 10.00. mu. mol), and tripotassium phosphate (89.2mg, 420.00. mu. mol) were added. Reacting for 30 minutes at 150 ℃ in a microwave reactor, detecting by TLC (thin layer chromatography) after the reaction is completed, filtering the reaction liquid by using kieselguhr, spin-drying the solvent, dissolving the solid by using 10mL of dichloromethane, washing by using water (2X 10mL), drying by using anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain the target product a 01. White solid, yield: 64%, melting point: 252 ℃ and 254 ℃.
Compound a01 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.16(s,1H,indole-H),7.78-7.74(m,2H,indole-H),7.45(s,3H,Ph-H),7.34-7.27(m,4H,Ph-H),7.26-7.20(s,3H,Ph-H),5.12(s,2H,CH2),3.89(s,3H,COOCH3),3.54-3.50(m,2H,CH2),3.48-3.45(m,2H,CH2),3.44-3.38(m,4H,CH2,CH2).ESI-MS:455.5[M+H]+,472.5[M+NH4]+,477.4[M+Na]+.C28H26N2O4(454.19)。
example 4: preparation of Compound a03
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 4-methoxyphenylboronic acid substituent. Yellow needle crystal, yield: 52.2%, melting point: 208 ℃ and 209 ℃.
Compound a03 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.09(s,1H,indole-H),7.74(d,J＝8.00Hz,1H,indole-H),7.67(d,J＝8.00Hz,1H,indole-H),7.20(t,J＝8.00Hz,4H,Ph-H),7.02(d,J＝8.00Hz,2H,Ph-H),6.91(d,J＝8.00Hz,2H,Ph-H),5.08(s,2H,CH2),3.88(s,3H,COOCH3),3.79(s,3H,OCH3),3.74(s,3H,OCH3),3.56-3.50(m,4H,CH2,CH2),3.48-3.42(m,4H,CH2,CH2).ESI-MS:515.6[M+H]+,532.6[M+NH4]+,537.5[M+Na]+.C30H30N2O6(514.21)。
example 5: preparation of Compound a04
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced with a 3-fluorophenylboronic acid substituent. Light yellow solid, yield: 84.1%, melting point: 166 ℃ and 168 ℃.
Compound a04 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.20(s,1H,indole-H),7.85-7.75(m,2H,indole-H),7.65-7.60(m,1H,Ph-H),7.55-7.50(m,1H,Ph-H),7.42-7.35(m,2H,Ph-H),7.30-7.25(m,1H,Ph-H),7.17-7.14(m,1H,Ph-H),7.10-7.07(m,1H,Ph-H),7.02-6.80(m,1H,Ph-H),5.23(s,1H,CH2),5.18(s,1H,CH2),3.90(s,3H,COOCH3),3.58(s,1H,CH2),3.53-3.45(m,5H,CH2,CH2,CH2),3.44-3.40(m,2H,CH2).ESI-MS:508.5[M+NH4]+,513.6[M+Na]+.C28H24F2N2O4(490.17)。
example 6: preparation of Compound a06
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 4-trifluoromethylphenylboronic acid substituent. White solid, yield: 92.4%, melting point: 204 ℃ and 206 ℃.
Compound a06 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.23(s,1H,indole-H),7.87(d,J＝8.00Hz,2H,Ph-H),7.83-7.78(m,2H,indole-H),7.71(d,J＝8.00Hz,2H,Ph-H),7.55(d,J＝8.00Hz,2H,Ph-H),7.46(d,J＝8.00Hz,2H,Ph-H),5.21(s,2H,CH2),3.90(s,3H,COOCH3),3.52-3.44(m,6H,CH2,CH2,CH2),3.42-3.39(m,2H,CH2).ESI-MS:591.4[M+H]+,508.3[M+NH4]+,513.3[M+Na]+.C30H24F6N2O4(590.16)。
example 7: preparation of Compound a08
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 2-thiopheneboronic acid substituent. Light yellow solid, yield: 58.9%, melting point: 210 ℃ and 212 ℃.
Compound a08 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.18(s,1H,indole-H),7.91-7.64(m,3H,indole-H,indole-H,thiophene-H),7.59-7.45(m,1H,thiophene-H),7.32-7.28(m,1H,thiophene-H),7.25-7.23(m,1H,thiophene-H),7.21-7.19(m,1H,thiophene-H),7.10-7.06(m,1H,thiophene-H),5.29(s,1H,CH2),5.18(s,1H,CH2),3.89(s,3H,COOCH3),3.60-3.53(m,4H,CH2,CH2),3.49-3.48(m,2H,CH2),3.45-3.43(m,2H,CH2).ESI-MS:467.11[M+H]+,489.09[M+Na]+.C24H22N2O4S2(466.10)。
example 8: preparation of Compound a09
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 4-methylphenylboronic acid substituent. White solid, yield: 93.7%, melting point: 144 ℃ and 146 ℃.
Compound a09 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.11(s,1H,indole-H),7.75-7.73(m,1H,indole-H),7.70-7.68(m,1H,indole-H),7.27-7.23(m,2H,Ph-H),7.18-7.15(m,2H,Ph-H),7.13-7.10(m,4H,Ph-H),5.08(s,2H,CH2),3.88(s,3H,COOCH3),3.54-3.50(m,4H,CH2,CH2),3.46-3.42(m,4H,CH2,CH2),2.35(s,3H,CH3),2.28(s,3H,CH3).ESI-MS:483.4[M+H]+.C30H30N2O4(482.22)。
example 9: preparation of Compound a10
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 3-methylphenylboronic acid substituent. Yellow solid, yield: 76.9%, melting point: 170 ℃ and 172 ℃.
Compound a10 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.13(s,1H,indole-H),7.77-7.70(m,2H,indole-H),7.30-7.26(m,2H,Ph-H),7.18-7.15(m,2H,Ph-H),7.12-7.10(m,1H,Ph-H),7.05(t,J＝8.00Hz,2H,Ph-H),6.97(d,J＝8.00Hz,1H,Ph-H),5.08(s,2H,CH2),3.88(s,3H,COOCH3),3.58-3.56(m,1H,CH2),3.54-3.52(m,1H,CH2),3.48-3.46(m,2H,CH2),3.45-3.43(m,3H,CH2,CH2),2.30(s,3H,CH3),2.25(s,3H,CH3).ESI-MS:483.4[M+H]+,500.4[M+NH4]+,505.5[M+Na]+.C30H30N2O4(482.22)。
example 10: preparation of Compound a11
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 3-methylphenylboronic acid substituent. Light yellow solid, yield: 87.2%, melting point: 176 ℃ and 178 ℃.
Compound a11 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.15(s,1H,indole-H),7.75-7.63(m,2H,indole-H),7.11(s,1H,Ph-H),7.07(s,1H,Ph-H),7.03(s,1H,Ph-H),6.88(s,1H,Ph-H),5.13(s,1H,CH2),5.05(s,1H,CH2),3.88(s,3H,COOCH3),3.59-3.56(m,2H,CH2),3.55-3.53(m,2H,CH2),3.44-3.42(m,4H,CH2,CH2),2.35(s,3H,CH3),2.34(s,3H,CH3),2.25(s,3H,CH3),2.19(s,3H,CH3).ESI-MS:511.25[M+H]+,533.24[M+Na]+.C32H34N2O4(510.25)。
example 11: preparation of Compound a12
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 3-fluoro-4-methoxyphenylboronic acid substituent. Yellow solid, yield: 60.5%, melting point: 187-189 ℃.
Compound a12 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.14(s,1H,indole-H),7.77(d,J＝8.00Hz,1H,indole-H),7.70(d,J＝8.00Hz,1H,indole-H),7.28(t,J＝8.00Hz,1H,Ph-H),7.17(t,J＝8.00Hz,2H,Ph-H),7.05(t,J＝8.00Hz,3H,Ph-H),5.13(s,2H,CH2),3.89(s,6H,COOCH3,CH3),3.83(s,3H,CH3),3.53-3.52(m,4H,CH2,CH2),3.49-3.48(m,2H,CH2),3.44-3.43(m,2H,CH2).ESI-MS:551.19[M+H]+,573.17[M+Na]+.C30H28F2N2O6(550.19)。
example 12: preparation of Compound a13
The procedure is as in example 3, except that the phenylboronic acid substituent is replaced by a 3, 4-dimethylphenylboronic acid substituent. White solid, yield: 82.9%, melting point: 116 ℃ and 118 ℃.
Compound a13 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.10(s,1H,indole-H),7.72(s,1H,indole-H),7.68(s,1H,indole-H),7.16(s,2H,Ph-H),7.07(s,1H,Ph-H),7.03(s,1H,Ph-H),6.96(s,1H,Ph-H),6.85(s,1H,Ph-H),5.06(s,2H,CH2),3.89(s,3H,COOCH3),3.56-3.54(m,3H,CH2,CH2),3.49-3.45(m,5H,CH2,CH2,CH2),2.27(s,3H,CH3),2.22(s,3H,CH3),2.19(s,6H,CH3,CH3).ESI-MS:511.6[M+H]+,528.5[M+NH4]+,533.3[M+Na]+.C32H34N2O4(510.25)。
example 13: preparation of Compound b01
Weighing a compound a01(200.00 mu mol) in a 25mL flask, adding 15mL methanol for dissolving, heating for refluxing, slowly dropwise adding 1M sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time until the pH value is stabilized above 10, stopping dropwise adding the sodium hydroxide solution, detecting the reaction completion by TLC, adjusting the pH value to 1 by 1M hydrochloric acid, then spin-drying the solvent, adding 10mL ethyl acetate for dissolving, washing with water (2X 10mL), drying with anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing with ethanol to obtain a corresponding target product b 01. White solid, yield: 87%, melting point: 200 ℃ and 202 ℃.
Compound b01 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.71(s,1H,COOH),8.15-8.12(m,1H,indole-H),7.77-7.74(m,1H,indole-H),7.71-7.69(m,1H,indole-H),7.45-7.44(m,3H,Ph-H),7.32-7.27(m,4H,Ph-H),7.25-7.18(m,3H,Ph-H),5.09(s,2H,CH2),3.52-3.51(m,2H,CH2),3.48-3.47(m,2H,CH2),3.44-3.43(m,4H,CH2,CH2).13C NMR(100MHz,DMSO-d6,ppm):168.60(COOH),166.35(CO),141.23(indole-C),137.12(Ph-C),134.57(indole-C),131.26(Ph-C),131.09(2×Ph-C),130.08(indole-C),129.78(2×Ph-C),129.32(Ph-C),129.04(2×Ph-C),128.89(2×Ph-C),125.60(Ph-C),124.64(indole-C),121.63(indole-C),118.84(indole-C),115.18(indole-C),113.22(indole-C),66.66(morpholine-CH2),66.50(morpholine-CH2),53.37(CH2),45.52(morpholine-CH2),45.39(morpholine-CH2).ESI-MS:439.6[M-H]-.C27H24N2O4(440.17)。
example 14: preparation of Compound b04
The procedure is as in example 13, except that the substituent of compound a01 is replaced by compound a 04. Light yellow solid, yield: 92.2%, melting point: 178 ℃ and 180 ℃.
Compound b04 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.76(s,1H,COOH),8.17(s,1H,indole-H),7.88(dd,J1＝1.20Hz,J2＝8.00Hz,1H,indole-H),7.83(d,J＝8.00Hz,1H,indole-H),7.54-7.48(m,1H,Ph-H),7.40-7.39(m,1H,Ph-H),7.36-7.34(m,1H,Ph-H),7.32-7.30(m,1H,Ph-H),7.15-7.13(m,1H,Ph-H),7.12-7.10(m,1H,Ph-H),7.08-7.06(m,1H,Ph-H),7.01-6.98(m,1H,Ph-H),5.16(s,2H,CH2),3.57-3.55(m,1H,CH2),3.53-3.48(m,5H,CH2,CH2,CH2),3.43-3.42(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm):168.58(COOH),166.38(CO),163.94(Ph-C-F),163.57(Ph-C-F),161.42(Ph-C-F),161.09(Ph-C-F),140.06,138.33,137.16,136.80,136.72,133.25,133.10,131.34,130.85,129.59,127.51,125.94,125.21,124.43,121.97,118.90,117.94,117.72,116.27,116.05,114.40,113.51,113.30,66.68(morpholine-CH2),66.58(morpholine-CH2),45.61(morpholine-CH2),45.43(morpholine-CH2),42.63(CH2)。
example 15: preparation of Compound b06
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a06, white solid, yield: 83.5%, melting point: 216 ℃ and 218 ℃.
Compound b06 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.91(s,1H,COOH),8.23(d,J＝12.00Hz,1H,indole-H),7.88(q,J＝4.00Hz,2H,Ph-H),7.83(t,J＝8.00Hz,1H,indole-H),7.78(t,J＝8.00Hz,1H,indole-H),7.71(d,J＝8.00Hz,2H,Ph-H),7.59(d,J＝8.00Hz,1H,Ph-H),7.55(d,J＝8.00Hz,1H,Ph-H),7.46(d,J＝8.00Hz,2H,Ph-H),5.19(s,1H,CH2),5.01(s,1H,CH2),3.51-3.47(m,3H,CH2,CH2),3.42-3.40(m,2H,CH2),3.35-3.33(m,3H,CH2,CH2).13C NMR(100MHz,DMSO-d6,ppm):170.36(COOH),168.46,168.38,166.21(CO),140.31,140.03,138.59,138.38,137.47,137.07,135.06,134.78,132.08,130.45,130.39,129.65,129.55,129.95,125.95,125.76,125.44,122.41,122.17,119.18,118.94,114.93,114.56,113.45,113.23,66.63(morpholine-CH2),66.53(morpholine-CH2),46.09(CH2),45.66(morpholine-CH2),45.41(morpholine-CH2).ESI-MS:575.4[M-H]-.C29H22F2N2O4(576.15)。
example 16: preparation of Compound b09
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a09, white solid, yield: 87.1%, melting point: decomposed at 268 ℃.
Compound b09 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.77(s,1H,COOH),8.08(d,J＝4.00Hz,1H,indole-H),7.74(d,J＝8.00Hz,1H,indole-H),7.67(d,J＝8.00Hz,1H,indole-H),7.26(t,J＝8.00Hz,2H,Ph-H),7.16(d,J＝8.00Hz,2H,Ph-H),7.12(s,4H,Ph-H),5.06(d,J＝12.40Hz,2H,CH2),3.88(s,3H,COOCH3),3.54-3.50(m,4H,CH2,CH2),3.46-3.44(m,4H,CH2,CH2),2.35(s,3H,CH3),2.28(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm):168.67(COOH),166.52(CO),141.06(indole-C),138.60(Ph-C),137.04(Ph-C),135.41(indole-C),131.69(Ph-C),130.59(2×Ph-C),130.91(2×Ph-C),130.21(Ph-C),129.66(2×Ph-C),128.52(2×Ph-C),128.29(indole-C),124.50(indole-C),121.49(indole-C),118.75(indole-C),114.95(indole-C),113.04(indole-C),66.67(morpholine-CH2),66.53(morpholine-CH2),45.51(morpholine-CH2),45.39(morpholine-CH2),42.58(CH2),21.38(CH3),21.16(CH3).ESI-MS:467.5[M-H]-.C29H28N2O4(468.20)。
example 17: preparation of Compound b10
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a10, light yellow solid, yield: 90.2%, melting point: 246-248 ℃.
Compound b10 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.65(s,1H,COOH),8.10(d,J＝4.00Hz,1H,indole-H),7.76(dd,J1＝12.00Hz,J2＝1.20Hz,1H,indole-H),7.70(d,J＝8.00Hz,1H,indole-H),7.42-7.29(m,2H,Ph-H),7.27-7.25(m,2H,Ph-H),7.16-7.13(m,2H,Ph-H),7.11(s,1H,Ph-H),7.05(t,J＝8.00Hz,2H,Ph-H),6.97(d,J＝8.00Hz,1H,Ph-H),5.16(d,J＝40.00Hz,2H,CH2),3.54-3.52(m,2H,CH2),3.48-3.47(m,2H,CH2),3.44-3.43(m,4H,CH2,CH2),2.30(s,3H,CH3),2.25(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm):168.68(COOH),166.54(CO),141.20(Ph-C),138.05(Ph-C),137.80(Ph-C),137.12(indole-C),134.54(indole-C),131.25(Ph-C),130.37(Ph-C),130.14(Ph-C),129.88(Ph-C),128.87(Ph-C),128.70(indole-C),128.40(Ph-C),127.07(Ph-C),126.96(Ph-C),124.52(Ph-C),121.53(indole-C),118.90(indole-C),115.09(indole-C),113.12(indole-C),102.31(indole-C),66.69(morpholine-CH2),66.54(morpholine-CH2),45.59(morpholine-CH2),45.39(morpholine-CH2),42.61(CH2),21.59(CH3),21.50(CH3).ESI-MS:467.5[M-H]-.C29H28N2O4(468.20)。
example 18: preparation of Compound b11
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a11, white solid, yield: 85.9%, melting point: decomposing at 244 ℃.
Compound b11 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.67(s,1H,COOH),8.12-8.01(m,1H,indole-H),7.81(dd,J1＝8.00Hz,J2＝1.20Hz,1H,indole-H),7.69-7.65(m,1H,indole-H),7.62-7.52(m,1H,Ph-H),7.11-7.02(m,2H,Ph-H),6.88-6.84(m,3H,Ph-H),5.14-5.03(m,2H,CH2),3.58-3.53(m,4H,CH2,CH2),3.46-3.44(m,4H,CH2,CH2),2.35(s,3H,CH3),2.33(s,3H,CH3),2.25(s,3H,CH3),2.19(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm):168.70(COOH),166.64(CO),145.00(Ph-C),141.73(indole-C),137.79(2×Ph-C),137.49(2×Ph-C),134.46(indole-C),131.16(Ph-C),130.24(Ph-C),128.64(2×Ph-C),128.16(indole-C),127.65(2×Ph-C),126.96(Ph-C),124.40(indole-C),121.41(indole-C),118.97(indole-C),115.01(indole-C),113.08(indole-C),66.70(morpholine-CH2),66.61(morpholine-CH2),45.67(morpholine-CH2),45.39(morpholine-CH2),42.61(CH2),21.48(CH3),21.45(CH3),21.40(CH3),21.37(CH3)。
example 19: preparation of Compound b13
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a13, light yellow solid, yield: 84.4%, melting point: decomposing at 276 ℃.
Compound b13 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.62(s,1H,COOH),8.06(s,1H,indole-H),7.73(d,J＝8.00Hz,1H,indole-H),7.66(d,J＝8.00Hz,1H,indole-H),7.18-7.15(m,2H,Ph-H),7.06(s,1H,Ph-H),7.03(d,J＝8.00Hz,1H,Ph-H),6.96(d,J＝8.00Hz,1H,Ph-H),6.86(d,J＝8.00Hz,1H,Ph-H),5.03(s,2H,CH2),3.55-3.53(m,2H,CH2),3.49-3.47(m,2H,CH2),3.46-3.44(m,4H,CH2,CH2),2.26(s,3H,CH3),2.21(s,3H,CH3),2.19(s,3H,CH3),2.18(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm):168.71(COOH),166.63(CO),141.05(Ph-C),137.33(Ph-C),137.01(indole-C),136.68(indole-C),136.41(Ph-C),134.18(Ph-C),132.13(Ph-C),131.56(Ph-C),130.87(Ph-C),130.35(Ph-C),130.05(indole-C),129.96(Ph-C),128.74(Ph-C),128.72(Ph-C),127.32(Ph-C),124.30(indole-C),121.38(indole-C),118.84(indole-C),114.92(indole-C),113.01(indole-C),66.69(morpholine-CH2),66.55(morpholine-CH2),45.57(morpholine-CH2),45.39(morpholine-CH2),42.59(CH2),20.00(CH3),19.95(CH3),19.71(CH3),19.49(CH3).ESI-MS:495.5[M-H]-.C31H32N2O4(496.24)。
example 20: preparation of intermediate 4
Intermediate 3(92.0mg, 200.00. mu. mol) was weighed into a 50mL microwave reactor, 10mL of redistilled dioxane was added to dissolve, and phenylboronic acid (24.4mg, 200.00. mu. mol), tetrakis (triphenylphosphine) palladium (11.6mg, 10.00. mu. mol), and tripotassium phosphate (46.7mg, 220.00mmol) were added. The reaction is carried out for 30 minutes at 150 ℃ in a microwave reactor, and the next reaction is directly carried out.
Intermediate 4 spectral data: ESI-MS 457.4[ M + H ]]+,459.4[M+H]+,474.3[M+NH4]+,476.3[M+NH4]+,481.3[M+Na]+,483.3[M+Na]+.C22H21BrN2O4(456.07)。
Example 21: preparation of Compound a02
To the reaction solution of the one-step reaction, 4-methoxyphenylboronic acid substituent (220.00. mu. mol), tetrakis (triphenylphosphine) palladium (11.6mg, 10.00. mu. mol), and tripotassium phosphate (46.7mg, 220.00mmol) were added. Reacting for 30 minutes at 150 ℃ in a microwave reactor, detecting by TLC (thin layer chromatography) after the reaction is completed, filtering the reaction liquid by using kieselguhr, spin-drying the solvent, dissolving the solid by using 20mL of ethyl acetate, washing by using water (2X 20mL), drying by using anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain the corresponding target product a 02. White needle-like crystals, yield: 31.8%, melting point: 208-210 ℃.
Compound a02 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.13(s,1H,indole-H),7.76(d,J＝8.00Hz,1H,indole-H),7.69(d,J＝8.00Hz,1H,indole-H),7.44(s,3H,Ph-H),7.29(s,2H,Ph-H),7.17(d,J＝8.00Hz,2H,Ph-H),6.89(d,J＝8.00Hz,2H,Ph-H),5.09(s,2H,CH2),3.88(s,3H,COOCH3),3.73(s,3H,OCH3),3.52-3.50(m,2H,CH2),3.47-3.46(m,2H,CH2),3.43-3.41(m,4H,CH2,CH2)。
example 22: preparation of Compound a05
The procedure is as in example 21 except that the 4-methoxyphenylboronic acid substituent is replaced by a 3-furanboronic acid substituent. White solid, yield: 33.2%, melting point: 170 ℃ and 172 ℃.
Compound a05 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):8.16(s,1H,indole-H),8.02(s,1H,furan-H),7.93(s,1H,furan-H),7.80(s,1H,indole-H),7.75-7.73(m,1H,indole-H),7.67-7.65(m,1H,Ph-H),7.56-7.54(m,1H,Ph-H),7.39-7.37(m,2H,Ph-H),7.28(s,1H,Ph-H),6.71-6.36(m,1H,furan-H),5.32(s,1H,CH2),5.24(s,1H,CH2),3.88(s,3H,COOCH3),3.64-3.61(m,2H,CH2),3.58-3.56(m,4H,CH2,CH2),3.46-3.44(m,2H,CH2)。
example 23: preparation of Compound b02
Weighing a compound a02(200.00 mu mol) in a 25mL flask, adding 15mL methanol for dissolving, heating for refluxing, slowly dropwise adding 1M sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time, stopping dropwise adding the sodium hydroxide solution when the pH value is stabilized to be more than 10, detecting the reaction completion by TLC, adjusting the pH value to be 1 by using 1M hydrochloric acid, then spin-drying the solvent, dissolving in 10mL ethyl acetate, washing with water (2X 10mL), drying with anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing with ethanol to obtain the corresponding target product b 02. White solid, yield: 92.3%, melting point: decomposing at 232 deg.C.
Compound b02 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.72(s,1H,COOH),8.12(d,J＝8.00Hz,1H,indole-H),7.76(dd,J1＝8.00Hz,J2＝8.00Hz,1H,indole-H),7.67(d,J＝8.00Hz,1H,indole-H),7.45(t,J＝4.00Hz,3H,Ph-H),7.30-7.27(m,2H,Ph-H),7.17(d,J＝8.00Hz,2H,Ph-H),6.89(d,J＝8.00Hz,2H,Ph-H),5.07(s,2H,CH2),3.73(s,3H,CH3),3.52-3.50(m,2H,CH2),3.47-3.46(m,2H,CH2),3.43-3.42(m,4H,CH2,CH2).13C NMR(100MHz,DMSO-d6,ppm):168.68(COOH),166.48(CO),158.00(Ph-C-O),140.79(indole-C),137.04(indole-C),131.35(Ph-C),131.09(2×Ph-C),130.89(2×Ph-C),130.35(Ph-C),129.23(indole-C),129.01(2×Ph-C),126.69(Ph-C),124.49(indole-C),121.45(indole-C),118.85(indole-C),114.91(indole-C),114.43(2×Ph-C),113.06(indole-C),66.69(morpholine-CH2),66.50(morpholine-CH2),55.45(CH3),45.50(morpholine-CH2),45.38(morpholine-CH2),42.59(CH2)。
example 24: preparation of Compound b05
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a05, white solid, yield: 89.5%, melting point: decomposing at 204 ℃.
Compound b05 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.73(s,1H,COOH),8.15(d,J＝8.00Hz,1H,indole-H),8.01(s,1H,furan-H),7.92(t,J＝1.60Hz,1H,furan-H),7.81(td,J1＝8.00Hz,J2＝1.60Hz,1H,indole-H),7.73(dd,J1＝8.00Hz,J2＝1.60Hz,1H,indole-H),7.64(d,J＝8.00Hz,1H,Ph-H),7.53(d,J＝8.00Hz,1H,Ph-H),7.41-7.35(m,2H,Ph-H),7.29(tt,J1＝8.00Hz,J2＝1.60Hz,1H,Ph-H),6.71-6.36(d,J＝180.00Hz,1H,furan-H),5.29(s,1H,CH2),5.22(s,1H,CH2),3.62-3.60(m,2H,CH2),3.57-3.55(m,4H,CH2,CH2),3.46-3.44(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm):168.66(COOH),166.18(CO),158.00(Ph-C-O),144.67(furan-C),144.59(furan-C),136.81(indole-C),134.55(indole-C),133.05(indole-C),130.11(Ph-C),129.87(2×Ph-C),128.89(2×Ph-C),126.72(furan-C),122.57(Ph-C),121.50(indole-C),118.48(indole-C),115.51(indole-C),114.51(indole-C),112.47(indole-C),111.46(furan-C),70.59(morpholine-CH2),69.96(morpholine-CH2),66.82(CH2),45.53(morpholine-CH2),45.51(morpholine-CH2)。
example 25: preparation of Compound a07
Weighing intermediate 4(200.00 mu mol), adding 10mL of anhydrous tetrahydrofuran to dissolve the intermediate 4, then adding 10 mu mol of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 340 mu mol of tetramethylethylenediamine and 340 mu mol of sodium borohydride in a 25mL flask under the nitrogen protection environment, stirring at room temperature for 19 hours, stopping reaction, pouring the reaction solution into 20mL of cold water, adding 10mL of ethyl acetate to extract twice, combining organic phases, spin-drying a solvent, and performing Flash column chromatography to obtain a compound a07, namely a white solid, wherein the yield is as follows: 51.5%, melting point: 218 ℃ and 219 ℃.
Compound a07 spectroscopic data:1H NMR(400MHz,CDCl3,ppm):7.97(s,1H,indole-H),7.84(d,J＝8.00Hz,1H,indole-H),7.65(d,J＝8.00Hz,1H,indole-H),7.46-7.44(m,5H,Ph-H),6.63(s,1H,indole-H),4.88(s,2H,CH2),3.93(s,3H,COOCH3),3.69-3.68(m,2H,CH2),3.65-3.62(m,4H,CH2,CH2),3.42-3.40(m,2H,CH2).ESI-MS:379.5[M+H]+,396.5[M+NH4]+,401.5[M+Na]+.C22H22N2O4(378.16)。
example 26: preparation of Compound b07
The procedure is as in example 13, except that the substituent of compound a01 is replaced with compound a07, yield: 89.4%, melting point: decomposition at 266 ℃.
Compound b07 spectroscopic data:1H NMR(400MHz,DMSO-d6,ppm):12.62(s,1H,COOH),8.03(s,1H,indole-H),7.71(dd,J1＝8.00Hz,J2＝4.00Hz,1H,indole-H),7.64(d,J＝8.00Hz,1H,indole-H),7.52(d,J＝4.00Hz,2H,Ph-H),7.49-7.47(m,3H,Ph-H),6.67(s,1H,indole-H),5.17(s,2H,CH2),3.58-3.56(m,4H,CH2,CH2),3.54-3.53(m,2H,CH2),3.47-3.46(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm):168.75(COOH),166.64(CO),144.88(indole-C),138.20(indole-C),132.10(Ph-C),131.49(Ph-C),129.31(2×Ph-C),129.28(2×Ph-C),129.08(indole-C),124.02(indole-C),121.20(indole-C),120.11(indole-C),113.02(indole-C),102.48(indole-C),66.73(morpholine-CH2),66.64(morpholine-CH2),45.83(morpholine-CH2),45.41(morpholine-CH2),42.58(CH2).ESI-MS:363.4[M-H]-.C21H20N2O4(364.14)。
example 27: affinity determination experiment of target compound and NS5B
Principle of experiment
Optical Surface Plasmon Resonance (SPR) is an optical physical phenomenon. When a beam of P-polarized light is incident on the prism end face within a certain angle range, surface plasmon waves are generated at the interface between the prism and the metal thin film (Au or Ag). When the propagation constant of the incident light wave matches the propagation constant of the surface plasmon wave, free electrons in the metal film are caused to resonate, i.e., surface plasmon resonance. During analysis, a layer of biomolecule recognition membrane is fixed on the surface of a sensing chip, then a sample to be detected flows on the surface of the chip, if molecules capable of interacting with the biomolecule recognition membrane on the surface of the chip exist in the sample, the refractive index of the surface of the gold membrane changes, and finally SPR angle changes are caused, and information such as the concentration, affinity, kinetic constant, specificity and the like of an analyte is obtained by detecting the SPR angle changes.
Materials and methods
Experimental material and instrument and equipment
Experimental methods
Surface activation and protein coupling of CM5 chips
The CM5 chip surface was activated with 0.2 mol/L1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.05mol/L N-succinimide (NHS) solutions. Then, Anti-histadine antibody in the His Capture Kit is diluted to 50 mu g/mL by using an Immobilization buffer in the Kit, injection is carried out by adopting a set flow rate (10 mu L/min) and time (7min) mode, carboxyl on the surface of the chip is activated by adopting 0.05mmol/L NHS and 0.2mol/L EDC, and Anti-histadine antibody protein is coupled to Fc1 and Fc2 channels of the chip until the two channels reach a set coupling level (9000-15000 RU). Finally, the chip surface was blocked with ethanolamine for 7min, and the chip was washed twice with 1.05 XPBS (5% DMSO), and the mobile phase in the system was replaced with a system with DMSO while removing the unconjugated protein.
Solvent correction
Placing the prepared DMSO gradient solution in a detector, simultaneously adding sufficient NS5B dilution solution and chip regeneration solution into the instrument, calling capture mode in Knitic assay tool of the instrument, simultaneously injecting the DMSO gradient solution into a reference channel Fc1 and a working channel Fc2, and carrying out binding reaction at 25 ℃ and under the environment of pH 7.4. The flow rate of NS5B diluent is set at 10 μ L/min, the sample injection time is 2min, and the stabilization time is 4 min. The flow rate of the DMSO gradient solution is set to be 30 mu L/min, the sample injection time is 2min, and the stabilization time is 1 min. The flow rate of the regeneration liquid is set to be 30 mu L/min, the sample introduction time is 1min, and the stabilization time is 1 min.
Affinity kinetic analysis of small molecule inhibitors with NS5B
And (3) placing the prepared micromolecule sample with gradient concentration to be detected in a detector, and setting 12.5 mu M of each sample as the repeated concentration. The small molecule inhibitor activity determination step is completely the same as the solvent correction operation step.
Affinity kinetic data analysis
Solvent correction
(1) A solvent calibration curve was established. The solvent correction results file is opened using BIAevaluation software and the Rpoint table is selected. Using the Data/filter command in the open table, Fc1 was selected in the Data for the channel column, Binding1 was selected in the Id column Data, and the Data for the RelResp column was then copied into a newly created table and named Fc 1. Returning to the original table at channel column selection Fc2-1, the data of the RelResp column is then copied into the newly created table and named Fc 2-1. In the newly created table, the Data/Generation Calibration command is used, X is set to Fc2-1, the Y column is set to Fc1, and the Line command in the Other drop-down menu is selected and confirmed to obtain the solvent Calibration standard curve.
(2) The sample detection results were free of the influence of solvent correction. And after the solvent correction curve is established, directly opening a result file of the small molecule test, and selecting an Rpoint table mode to open. Selecting Fc1 from Data of a channel column, selecting Binding1 from Data of an Id column by using a Data/filter command, copying Data of a RelResp column into a newly-built table, naming the column as Fc1, copying the column to obtain Fc2-1 and naming the Fc2-1 by the same method, then selecting a solvent correction curve just obtained in a popup dialog box by using a Data/calibration values command, clicking next, setting Y to be Fc1 to obtain a corresponding solvent correction factor, naming the column of the solvent correction factor as corr, subtracting the corresponding solvent correction factor from Data of Fc2-1 in the next column to obtain a real value of Fc2-1, and naming the column as True.
Establishment of sample small molecule curve and calculation of equilibrium dissociation constant
The obtained response value (True column) data of the solvent removal effect is copied into a newly-created table, and the corresponding small molecule sample concentration of each data is copied into the next column and named as Conc, and note that the data in the Conc column cannot have units. Then using Creat Curve command, setting X as Conc column and Y as True column, confirming to obtain relation Curve point between response value and concentration, then using fitting function in software, using Fit/general command, selecting steady state affinity in pop-up dialog box to Fit Curve data, thus obtaining small molecule compoundEquilibrium dissociation constant K ofD. The constant means the concentration of ligand required to bind half of the total protein to the ligand, and a smaller value indicates a stronger binding of the compound to the protein.
Experimental result of affinity determination of target compound and NS5B
TABLE 1 results of affinity experiments of target compounds with NS5B
The active compound has been thickened.
aKD: represents the equilibrium dissociation constant of a compound and a protein, and the smaller the value, the stronger the affinity between the compound and the protein.
And (4) conclusion:
as shown in Table 1, the substituted indole derivatives of the present invention are a series of non-nucleoside HCV inhibitors with novel structures, and have different affinities with NS 5B. Wherein compounds a02, a03, a11 and b05 all have an affinity comparable to or even slightly better than that of the positive control compound. In particular compound a10 (K)D2.8 μ M) and b13 (K)D2.3 μ M), which had an affinity for NS5B, respectively, was a positive control compound 121 (K)D90.8 mu M), far exceeds the positive control compound, so the substituted indole derivatives have further development value and can be used as lead compounds for resisting HCV.

Claims (7)

1. A substituted indole derivative, or a pharmaceutically acceptable salt, ester or prodrug thereof, characterized by having a structure shown in general formula I:
wherein,
R1、R2each independently selected from substituted benzene ring, substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings,Various substituted six-membered and five-membered heterocyclic rings, various substituted six-membered and six-membered heterocyclic rings, various substituted five-membered and five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings, various aliphatic rings, various saturated aliphatic chains or various unsaturated aliphatic chains;
R3are various carboxylic acids, carboxylic esters or amides.
2. The substituted indole derivative of claim 1, wherein in formula I, R is1、R2Each independently selected from phenyl, p-methylphenyl, p-methoxyphenyl, 2-furyl, 3-thienyl, m-methylphenyl, m-fluorophenyl or p-trifluoromethylphenyl; r3Is carboxyl or carbomethoxy.
3. The substituted indole derivative according to claim 1 or 2, which is one of the following specific compounds:
4. the process for preparing substituted indole derivatives according to claim 1 or 2, comprising one of the following steps:
route one: indole-6-methyl formate 1 is used as an initial raw material, and is subjected to affinity substitution reaction with chloroacetyl morpholine in an N, N-dimethylformamide solution to generate an intermediate compound 2; then the intermediate compound 2 reacts with N-bromosuccinimide in a dichloromethane solution to generate an intermediate compound 3; then, the intermediate compound 3 reacts with various substituted boric acids in dioxane solution to generate a target product a, and then different target products a react with sodium hydroxide solution in methanol solution to obtain a target product b;
the synthesis route one is as follows:
wherein R is1、R2The general formula I is shown in the specification;
reagents and conditions: (i) chloroacetyl morpholine, sodium hydride, N-dimethylformamide, room temperature; (ii) dichloromethane, N-bromosuccinimide; (iii) boronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (iv) refluxing methanol and sodium hydroxide water solution;
the substituted boric acid is phenylboronic acid, p-methoxyphenylboronic acid, m-fluorophenylboronic acid, 3-furanboronic acid, p-methylphenylboronic acid, m-methylphenylboronic acid, 2, 4-dimethylphenylboronic acid, 2-thiopheneboronic acid, 2, 3-dimethylphenylboronic acid or 2-fluoro-3-methoxyphenylboronic acid;
and a second route: taking an intermediate compound 3 as a raw material, reacting the intermediate compound with phenylboronic acid in a dioxane solution to generate an intermediate compound 4, and then reacting the intermediate compound with different substituted boric acids to generate a target product a; then the compound a reacts with a sodium hydroxide aqueous solution in a methanol solution to generate a target product b;
the second synthetic route is as follows:
wherein R is1The general formula I is shown in the specification;
reagents and conditions: (i) phenylboronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (ii) boronic acid, tetrakis (triphenylphosphine) palladium, potassium phosphate, dioxane, 90 ℃; (iii) refluxing methanol and sodium hydroxide water solution;
the substituted boric acid is phenylboronic acid, p-methoxyphenylboronic acid or 3-furanboronic acid.
5. The process for preparing substituted indoles derivative of claim 4, comprising the step of one of the following schemes:
route one:
(1) weighing 5.26g of raw material 6-methyl indole carboxylate, placing the raw material in a 100mL flask, adding 20mL of N, N-dimethylformamide for dissolving, adding 791.9mg of sodium hydride, stirring at room temperature for 30 minutes, then adding 3.90mL of chloroacetyl morpholine, stirring at room temperature for reaction for 12 hours, performing thin-layer detection reaction, then performing spin-drying on the solvent, adding 20mL of water and 20mL of dichloromethane for extraction, separating an organic phase, washing with 20mL of water twice, drying with anhydrous sodium sulfate, performing spin-drying on the solvent to obtain a white solid, and performing vacuum drying to obtain an intermediate compound 2;
(2) weighing 4.53g of intermediate compound 2, placing the intermediate compound 2 in a 250mL flask, adding 50mL of dichloromethane for dissolving, then adding 5.61g N-bromosuccinimide in batches, stirring at room temperature for reaction for 12 hours, adding 30mL of water for quenching reaction after the thin-layer detection reaction is completed, washing an organic phase by 30mL of water twice, drying the organic phase by anhydrous sodium sulfate, carrying out Flash column chromatography after solvent is dried in a spinning mode to obtain a white solid, and carrying out vacuum drying to obtain an intermediate 3;
(3) weighing 92.0mg of intermediate compound 3, placing the intermediate compound in a 25mL microwave reactor, adding 10mL of redistilled dioxane for dissolution, and adding 420 mu mol of different substituted phenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 89.2mg of tripotassium phosphate; reacting for 30 minutes at 150 ℃ in a microwave reactor, detecting the reaction through a thin layer, filtering the reaction liquid by using kieselguhr after the reaction is completed, spin-drying the solvent, dissolving the solid by using 10mL of dichloromethane, washing the solid twice by using 10mL of water, drying the anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain a target product a 01;
(4) weighing 200.00 mu mol of compound a01 in a 25mL flask, adding 15mL of methanol for dissolving, heating for refluxing, slowly dropwise adding 1M of sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time until the pH value is stabilized above 10, stopping dropwise adding the sodium hydroxide solution, detecting the reaction completion by using a thin-layer plate, adjusting the pH value to 1 by using 1M of hydrochloric acid, then spin-drying the solvent, adding 10mL of ethyl acetate for dissolving, washing twice by using 10mL of water, drying by using anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing by using ethanol to obtain a target product b 01;
and a second route:
(1) weighing 92.0mg of intermediate 3 into a 50mL microwave reactor, adding 10mL of redistilled dioxane to dissolve, and adding 24.4mg of phenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 46.7mg of tripotassium phosphate; reacting for 30 minutes at 150 ℃ in a microwave reactor to obtain an intermediate 4;
(2) 220.00 mu mol of p-methoxyphenylboronic acid, 11.6mg of tetrakis (triphenylphosphine) palladium and 46.7mg of tripotassium phosphate are added into the reaction solution of the previous reaction; reacting in a microwave reactor at 150 ℃ for 30 minutes, detecting by TLC (thin layer chromatography) to complete the reaction, filtering the reaction liquid by using kieselguhr, spin-drying the solvent, dissolving the solid by using 20mL of ethyl acetate, washing by using 20mL of water twice, drying by using anhydrous sodium sulfate, spin-drying the solvent, carrying out Flash column chromatography, and recrystallizing the chromatographic product by using ethanol to obtain a target product a 02;
(3) weighing 200.00 mu mol of compound a02 in a 25mL flask, adding 15mL of methanol for dissolving, heating for refluxing, slowly dropwise adding 1M of sodium hydroxide solution into the reaction solution, monitoring the pH value of the solution in real time until the pH value is stabilized above 10, stopping dropwise adding the sodium hydroxide solution, detecting the reaction completion by using a thin-layer plate, adjusting the pH value to 1 by using 1M of hydrochloric acid, then spin-drying the solvent, dissolving in 10mL of ethyl acetate, washing twice by using 10mL of water, drying by using anhydrous sodium sulfate, spin-drying the solvent, and recrystallizing by using ethanol to obtain the target product b 02.
6. Substituted indole derivatives as claimed in any of claims 1 to 3 for use as HCV inhibitors for the preparation of anti-hepatitis c medicaments.
7. An anti-HCV pharmaceutical composition comprising a substituted indole derivative according to any of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
CN201610495845.1A 2016-06-28 2016-06-28 Substituted indole derivatives, and preparation method and application thereof Pending CN106008306A (en)

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