CN113004187B - Compound with function of inhibiting activity of organic anion transporter 1, preparation method and application - Google Patents

Compound with function of inhibiting activity of organic anion transporter 1, preparation method and application Download PDF

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CN113004187B
CN113004187B CN202110279322.4A CN202110279322A CN113004187B CN 113004187 B CN113004187 B CN 113004187B CN 202110279322 A CN202110279322 A CN 202110279322A CN 113004187 B CN113004187 B CN 113004187B
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王绍杰
高骏
孟维宇
毛青
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Abstract

The invention provides a compound with an activity of inhibiting an organic anion transporter 1, a preparation method and application thereof, belongs to the technical field of medicines, and provides a compound with a brand-new structure shown in a general formula I and an activity of inhibiting the organic anion transporter 1, and also provides a preparation method and application thereof in medicines for treating and/or preventing hyperuricemia and gout. Provides a new product for developing a novel organic anion transporter 1 inhibitor, provides a new treatment idea for treating hyperuricemia and gout, and provides a preparation method for preparing the compound, thereby having certain guiding significance.

Description

Compound with function of inhibiting activity of organic anion transporter 1, preparation method and application
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound capable of inhibiting the activity of an organic anion transporter 1(URAT1), and a preparation method and application thereof.
Background
Uric acid is the end product of purine metabolism in humans, and is excreted mainly in the prototype via the kidney. When xanthine oxidase catalyzes hypoxanthine and xanthine to produce excessive uric acid or uric acid excretion is reduced due to body causes, serum uric acid levels will rise, with overall levels exceeding 0.42mmol/L, which is called hyperuricemia. Long-term hyperuricemia is an important factor in the induction of gout, cardiovascular diseases, chronic kidney disease, and type II diabetes. Uric acid in vivo is freely filtered through glomeruli, and more than 90% of uric acid is recovered into blood, and only less than 10% of uric acid is discharged out of the body, and the reabsorption process is mainly mediated by organic anion transporter 1(URAT 1). The inhibition of URAT1 can promote the excretion of uric acid in vivo, therefore, URAT1 is the main target for reducing uric acid. The URAT1 inhibitors currently on the market are mainly benzbromarone and rexinader. However, benzbromarone has been removed from the market in some countries due to severe hepatotoxicity. In addition, rasidone has cardiovascular toxicity and can cause liver and kidney damage. Therefore, the development of the URAT1 inhibitor with high efficiency and low toxicity has good application prospect.
Disclosure of Invention
The invention aims to provide a compound capable of inhibiting the activity of an organic anion transporter 1(URAT1) and pharmaceutically acceptable salts thereof, and also provides a preparation method of the compound and application of the compound in preparation of anti-gout drugs.
A compound having the activity of an organic anion transporter 1 represented by the general formula I, or a pharmaceutically acceptable salt, isomer, polymorph, pharmaceutically acceptable solvate thereof;
the general formula I is:
Figure BDA0002978003990000011
wherein:
R 1 h, C1-C7 alkyl, C2-C6 alkenyl, substituted or unsubstituted aromatic ring methyl, the substituent is halogen, C1-C6 alkyl or alkoxy, the aromatic ring is benzene ring or pyridine;
R 2 is H, halogen, methyl, methoxy or cyano;
R 3 is 1-2H, halogen, methyl or methoxy;
-COOH is in the para, meta or ortho position;
the halogen is fluorine, chlorine or bromine.
Further, the compound having an activity of inhibiting an organic anion transporter 1 is any one of the following compounds 1 to 44;
Figure BDA0002978003990000021
Figure BDA0002978003990000031
the invention also provides an intermediate compound shown as a general formula II, which is used for preparing the compound with the activity of inhibiting the organic anion transporter 1 or pharmaceutically acceptable salts, isomers, polymorphs and pharmaceutically acceptable solvates of the compound;
Figure BDA0002978003990000032
wherein:
R 1 h, C1-C7 alkyl, C2-C6 alkenyl, substituted or unsubstituted aromatic ring methyl, the substituent is halogen, C1-C6 alkyl or alkoxy, the aromatic ring is benzene ring or pyridine;
R 2 is H, halogen, methyl, methoxy or cyano;
R 3 is 1-2H, halogen, methyl or methoxy;
-COOH is in the para, meta or ortho position;
R 4 is-CH 3 or-CH 2 CH 3 ；
The halogen is fluorine, chlorine or bromine.
Further, the intermediate compound is any one of the following compounds 1C to 44D:
Figure BDA0002978003990000033
Figure BDA0002978003990000041
such isomers include, but are not limited to: isomers thereof.
The pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, organic salts and inorganic salts of the compounds of the present invention: sodium salt, potassium salt, ammonia salt, hydrochloride, sulfate and methanesulfonate.
The solvate of the compound refers to an association formed by one or more solvent molecules and the compound provided by the invention. Solvents that form solvates include, but are not limited to: water, methanol, ethanol, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, toluene and DMF.
The polymorphism refers to that the compound can be a single crystal form, two crystal forms or a mixed crystal form of more than two crystal forms.
The invention also provides a preparation method of the compounds 1-44 capable of inhibiting the activity of the organic anion transporter 1, which comprises the following steps:
condensing corresponding indole-3-carboxylic acid serving as an initial raw material with corresponding amine to obtain a corresponding intermediate A, wherein the intermediate A comprises intermediate compounds 1C-4C shown in a general formula II;
hydrolyzing the obtained intermediate compounds 1C-4C by LiOH to obtain corresponding compounds 1, 7-9;
or
Reacting the obtained intermediate A with a corresponding alkylation reagent to obtain a corresponding intermediate B, wherein the intermediate B comprises intermediate compounds 2D-6D and 10D-44D shown in a general formula II;
hydrolyzing the obtained intermediate B by LiOH to obtain corresponding compounds 2-6 and 10-44;
Figure BDA0002978003990000051
the invention provides a pharmaceutical composition, which comprises one or more of the compound with inhibitory activity or pharmaceutically acceptable salt, isomer, polymorph, pharmaceutically acceptable solvate, derivative and analogue of the compound; also comprises one or the combination of pharmaceutically acceptable auxiliary materials, carriers and diluents.
The routes of administration of the pharmaceutical composition include: oral, nasal, transdermal, pulmonary and parenteral administration, preferably by the oral route. In particular, so long as it is effective in delivering the active agent to the desired site of activity, for example, by rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment routes. The dosage form of the pharmaceutical composition comprises: tablets, capsules, lozenges, syrups, emulsions, injections, aerosols and dragees. The weight percentage of the compound which can inhibit the activity of URAT1 in the medicine composition is 0.5-20%, preferably 0.5-10%.
Pharmaceutical compositions containing the compounds of the present invention may be prepared by conventional methods, for example as described in Remington, the Science and Practice of Pharmacy,19th ed., 1995. In particular, the composition may be in a conventional form such as a capsule, tablet, powder, solution, suspension, syrup, aerosol or topical form. They may be formulated in solutions or suspensions for injection using a suitable solid or liquid carrier in a suitable sterile medium.
The carrier is any one or more of water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ether of cellulose, silicic acid, fatty acid amine, fatty acid monoglyceride and diglyceride, quaternary tetraol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone. The formulation may also include wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art.
The pharmaceutical compositions may be sterile and may, if desired, be mixed with adjuvants, emulsifiers, buffers and/or colorants and the like, provided that they do not react with the active compound.
For intranasal administration, the formulations may contain an aerosol for administration dissolved or suspended in a liquid carrier, particularly an aqueous carrier. The vehicle may contain additives including solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphocholine) or cyclodextrin, preservatives such as parabens.
For parenteral administration, particularly suitable are injection solutions or suspensions, preferably aqueous solutions of the active compound in a polyhydroxylated castor oil.
Tablets, dragees or capsules having talc and/or carbohydrate carriers or binders are particularly suitable for oral administration. Carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. When a sugar-added carrier can be used, a syrup or an alcoholism agent can be used.
The application of a compound with the activity of inhibiting URAT1 or the pharmaceutically acceptable salt of the compound in preparing medicines for treating and/or preventing hyperuricemia and gout.
More than 80% of uric acid produced in the human body is excreted through the kidney, uric acid is freely filtered through the glomeruli into the renal tubules, and over 90% of uric acid entering the renal tubules is reabsorbed into the blood by the organic anion transporter in the renal tubular epithelial cells, and the reabsorption process is mainly mediated by the organic anion transporter 1(URAT 1). The compound inhibits the uric acid reabsorption process by inhibiting the activity of an organic anion transporter 1(URAT1), thereby reducing uric acid in vivo and achieving the effect of treating hyperuricemia and gout.
The invention has the beneficial effects that:
the invention provides a compound with a brand-new structure and the activity of inhibiting an organic anion transporter 1(URAT1), reduces toxicity, provides a new product for developing a novel organic anion transporter 1(URAT1) inhibitor, provides a new treatment idea for treating hyperuricemia and gout, and simultaneously provides a certain guiding significance for preparing the compound.
Detailed Description
The invention will now be further illustrated by reference to specific examples, but is not to be construed as being limited thereto.
Example 1
The preparation process of the 4- (1H-indole-3-formamido) benzoic acid (compound 1) specifically comprises the following steps:
to the reaction flask were added 3-indolecarboxylic acid (25.59g,0.159mol), dichloromethane 200mL, thionyl chloride (46.80g,0.393mol), DMF2mL in this order, and the mixture was heated to reflux and stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, 50mL of methylene chloride was added and evaporated again to dryness, and the remaining thionyl chloride was evaporated. 200mL of dichloromethane was added to prepare an acid chloride suspension for use. Another 1000mL three-necked flask was charged with methyl p-aminobenzoate (21.82g,0.144mol), triethylamine (16.07g,0.159mol) and 300mL of dichloromethane, and stirred in an ice-water bath. Slowly adding acyl chloride suspension dropwise, stirring for 30min after dropwise adding, and transferring to room temperature for reaction overnight. TLC monitoring, after the reaction is finished, evaporating the solvent under reduced pressure, adding 1M sodium carbonate solution and 1M hydrochloric acid in sequence, pulping, filtering, and drying to obtain 32.52g of solid, namely an intermediate compound 1C, with the yield of 84.2%;
adding the intermediate compound 1C (1.5g,5mmol), lithium hydroxide monohydrate (0.64g,15mmol), THF15mL and 10mL of water into a 100mL eggplant-shaped bottle, stirring at room temperature for 10min, heating to 50 ℃, reacting overnight, distilling under reduced pressure to remove THF after TLC monitoring reaction is completed, adding 1M hydrochloric acid to adjust the pH to 3-4, stirring at room temperature for 1h, filtering, and drying at 50 ℃ in vacuum to obtain a white solid, namely compound 1, and recrystallizing with anhydrous methanol and tetrahydrofuran (v: v ═ 1:1) to obtain 1.21g of a refined product with the yield of 84.6%.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
1C：M.p.>250℃； 1 H-NMR(400MHz,DMSO-d 6 )δ11.85(s,1H),10.06(s,1H),8.38(s,1H),8.27–8.17(m,1H),7.96(s,4H),7.53–7.48(m,1H),7.19(m,J＝15.8,7.1,1.4Hz,2H),3.84(s,3H).
compound 1: m.p are provided.>250℃； 1 H-NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),11.89–11.74(m,1H),10.01(d,J＝2.8Hz,1H),8.37(t,J＝2.7Hz,1H),8.29–8.19(m,1H),7.94(d,J＝2.1Hz,4H),7.50(d,J＝7.7Hz,1H),7.28–7.13(m,2H)；HRMS(ESI):m/z 279.0773[M-H] - .
Example 2
The preparation process of the 3- (1H-indole-3-formamido) benzoic acid (compound 7) specifically comprises the following steps:
3-indolecarboxylic acid (5.00g,0.031mol), dichloromethane (50 mL), thionyl chloride (11.06g,0.093mol), and DMF0.3mL were added to the reaction flask in this order, warmed to reflux, and stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, 20mL of methylene chloride was added and evaporated again to dryness, and the remaining thionyl chloride was evaporated. 50mL of dichloromethane was added to make an acid chloride suspension for use. Another 500mL three-necked flask was charged with methyl 3-aminobenzoate (3.86g,0.028mol), triethylamine (3.14g,0.031mol) and 50mL of dichloromethane, and stirred in an ice-water bath. Slowly adding acyl chloride suspension dropwise, stirring for 30min after dropwise adding, and transferring to room temperature for reaction overnight. Monitoring by TLC, after the reaction is finished, evaporating the solvent under reduced pressure, adding 1M sodium carbonate solution and 1M hydrochloric acid in sequence, pulping, filtering, and drying to obtain 7.25g of an intermediate compound 2C with the yield of 88.0%;
the intermediate compound 2C (1.0g,3.4mmol), lithium hydroxide monohydrate (0.84g,20mmol), THF5mL, and 5mL of water were added to a 100mL eggplant-shaped bottle, stirred at room temperature for 10min, heated to 66 ℃, reacted for 5h, after completion of the TLC monitoring reaction, THF was evaporated under reduced pressure, 1M hydrochloric acid was added to adjust the pH to 3-4, stirred at room temperature for 1h, filtered, and air-dried at 50 ℃ to obtain compound 7, which was recrystallized from anhydrous methanol and tetrahydrofuran (v: v ═ 1:1) to obtain 0.81g of a refined product with a yield of 84.6%.
The intermediate compound and the product obtained in the preparation process are detected, and the specific data are as follows:
2C：M.p.164.6-168.3℃； 1 H-NMR(400MHz,DMSO-d 6 )δ11.80(s,1H),9.97(s,1H),8.46(t,J＝2.0Hz,1H),8.36(d,J＝3.0Hz,1H),8.27–8.21(m,1H),8.12(td,J＝8.2,2.3,1.1Hz,1H),7.65(dt,J＝7.8,1.3Hz,1H),7.54–7.45(m,2H),7.21(td,J＝8.1,7.0,1.4Hz,1H),7.17(td,J＝8.0,7.0,1.2Hz,1H),3.89(s,3H).
compound 7: m.p are provided.>250℃； 1 H-NMR(600MHz,DMSO-d 6 )δ12.97(s,1H),11.78(d,J＝3.0Hz,1H),9.93(s,1H),8.42(t,J＝1.9Hz,1H),8.36(d,J＝3.0Hz,1H),8.27–8.20(m,1H),8.09(td,J＝8.1,2.3,1.1Hz,1H),7.64(dt,J＝7.7,1.3Hz,1H),7.52–7.44(m,2H),7.21(td,J＝8.2,7.0,1.4Hz,1H),7.17(td,J＝8.1,7.0,1.2Hz,1H).
3- (6-fluoro-1H-indole-3-carboxamido) benzoic acid (compound 8), 3- (6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 9) were prepared in the manner of example 1 or example 2. Detecting intermediate compounds and products obtained in the preparation process, specifically comprising the following steps:
3C： 1 H NMR(600MHz,DMSO-d 6 )δ11.85(d,J＝2.9Hz,1H),10.01(s,1H),8.45(t,J＝2.0Hz,1H),8.37(d,J＝2.9Hz,1H),8.21(dd,J＝8.8,5.6Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.3Hz,1H),7.49(t,J＝7.9Hz,1H),7.30(dd,J＝9.8,2.4Hz,1H),7.04(ddd,J＝9.8,8.7,2.4Hz,1H),3.89(s,3H).
compound 8: 1 H NMR(600MHz,DMSO-d 6 )δ12.97(s,1H),11.83(d,J＝2.9Hz,1H),9.96(s,1H),8.41(t,J＝1.9Hz,1H),8.36(d,J＝2.9Hz,1H),8.21(dd,J＝8.8,5.6Hz,1H),8.12–8.04(m,1H),7.64(dt,J＝7.6,1.3Hz,1H),7.47(t,J＝7.9Hz,1H),7.30(dd,J＝9.8,2.4Hz,1H),7.04(td,J＝9.3,2.4Hz,1H).
4C： 1 H NMR(600MHz,DMSO-d 6 )δ12.31(d,J＝3.0Hz,1H),10.11(s,1H),8.61(d,J＝3.0Hz,1H),8.44(t,J＝2.0Hz,1H),8.37(d,J＝8.3Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),8.04(dd,J＝1.5,0.7Hz,1H),7.66(dt,J＝7.8,1.3Hz,1H),7.54–7.47(m,2H),3.88(s,3H).
compound 9: 1 H NMR(600MHz,DMSO-d 6 )δ12.32(d,J＝3.1Hz,1H),10.11(s,1H),8.62(d,J＝3.1Hz,1H),8.41(t,J＝1.9Hz,1H),8.37(d,J＝8.3Hz,1H),8.08(ddd,J＝8.1,2.3,1.1Hz,1H),8.04(dd,J＝1.4,0.7Hz,1H),7.65(dt,J＝7.7,1.4Hz,1H),7.52(dd,J＝8.3,1.5Hz,1H),7.47(t,J＝7.9Hz,1H).
example 3
The preparation process of the 4- (1-isoamyl-1H-indole-3-formamido) benzoic acid (compound 2) specifically comprises the following steps:
intermediate compound 1C was prepared using the preparation method of example 1;
the intermediate compound 1C (2g,6.8mmol), anhydrous potassium carbonate (1.23g,13.6mmol), potassium iodide (0.11g,0.68mmol) and DMF25mL were added to a 100mL single vial, stirred at room temperature for 0.5h, bromoisopentane (0.94g,8.2mmol) was added dropwise, the temperature was raised to 60 ℃ for reaction, TLC monitored completion of the reaction, the reaction solution was cooled to room temperature, the filtrate was collected by filtration, poured into 50mL of water, and extracted with ethyl acetate (20 mL. times.2). The organic phases were combined and washed successively with saturated sodium bicarbonate (10 mL. times.3) and saturated sodium chloride (10 mL. times.2). Adding anhydrous sodium sulfate into the organic phase, drying overnight, performing suction filtration, and removing the solvent by evaporation under reduced pressure to obtain an intermediate compound 2D. Recrystallization from methanol and tetrahydrofuran (v: v ═ 1:1) gave 2.02g of purified product, 81.5% yield;
compound 2 was prepared from intermediate compound 2D as the starting material in 87.4% yield by the preparation method of example 1 with addition of lithium hydroxide monohydrate.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
2D： 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.40(s,1H),8.26–8.19(m,1H),8.02–7.87(m,4H),7.59(d,J＝8.1Hz,1H),7.33–7.13(m,2H),4.27(t,J＝7.5Hz,2H),3.84(s,3H),1.82–1.68(m,2H),1.60(dp,J＝13.3,6.6Hz,1H),0.97(d,J＝6.6Hz,6H).
compound 2: 1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),9.99(s,1H),8.40(s,1H),8.24(d,J＝7.8Hz,1H),7.97–7.89(m,4H),7.58(d,J＝8.1Hz,1H),7.32–7.16(m,2H),4.27(t,J＝7.4Hz,2H),1.74(q,J＝7.2Hz,2H),1.61(dq,J＝13.3,6.6Hz,1H),0.97(d,J＝6.6Hz,6H).
example 4
The preparation process of the 4- (1-allyl-1H-indole-3-formamido) benzoic acid (compound 3) specifically comprises the following steps:
intermediate compound 1C was prepared using the preparation method of example 1;
the intermediate compound 1C (3g,10.2mmol), anhydrous potassium carbonate (2.76g,20mmol), potassium iodide (0.17g,1.0mmol) and DMF30mL were added to a 100mL single neck flask, stirred at room temperature for 0.5h, allyl bromide (1.48g,12.2mmol) was added dropwise, the reaction was warmed to 60 ℃ and after completion of the TLC monitoring reaction, the reaction was cooled to room temperature, poured into 100mL of water and extracted with ethyl acetate (30 mL. times.2). The organic phases were combined and washed successively with saturated sodium bicarbonate (10 mL. times.3) and saturated sodium chloride (10 mL. times.2). Adding anhydrous sodium sulfate into the organic phase, drying overnight, performing suction filtration, and removing the solvent by evaporation under reduced pressure to obtain an intermediate compound 3D. Recrystallization from methanol and tetrahydrofuran (v: v ═ 1:1) gave 2.84g of a purified product, yield 83.4%;
compound 3 was prepared from intermediate compound 3D as the starting material by the preparation method of example 1 with addition of lithium hydroxide monohydrate in 84.3% yield.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
3D： 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),8.36(s,1H),8.28–8.20(m,1H),7.95(d,J＝1.5Hz,4H),7.59–7.52(m,1H),7.24(dtd,J＝17.9,7.1,1.3Hz,2H),6.08(ddt,J＝17.2,10.6,5.5Hz,1H),5.26(dq,J＝10.3,1.5Hz,1H),5.16(dq,J＝17.1,1.6Hz,1H),4.94(dt,J＝5.7,1.7Hz,2H),3.84(s,3H).
compound 3: 1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),10.08(s,1H),8.37(s,1H),8.26(dd,J＝7.2,1.6Hz,1H),7.94(s,4H),7.55(d,J＝8.1Hz,1H),7.32–7.18(m,2H),6.19–6.00(m,1H),5.26(dd,J＝10.2,1.7Hz,1H),5.16(dt,J＝17.0,1.6Hz,1H),4.94(d,J＝5.5Hz,2H).
4- (1-benzyl-1H-indole-3-carboxamido) benzoic acid (compound 4), 4- [1- (4-fluorobenzyl) -1H-indole-3-carboxamido ] benzoic acid (compound 5) and 4- [1- (4-methylbenzyl) -1H-indole-3-carboxamido ] benzoic acid (compound 6) were prepared by the method of example 3 or example 4; detecting intermediates and products obtained in the preparation process, specifically comprising the following steps:
4D： 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),8.48(s,1H),8.38–8.19(m,1H),7.96(s,4H),7.68–7.51(m,1H),7.46–7.12(m,7H),5.54(s,2H),3.84(s,3H).
compound 4: 1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),10.08(s,1H),8.47(s,1H),8.24(d,J＝7.3Hz,1H),7.92(d,J＝3.3Hz,4H),7.58(d,J＝7.5Hz,1H),7.44–7.12(m,7H),5.54(s,2H).
5D： 1 H NMR(400MHz,DMSO-d 6 )δ10.12(s,1H),8.46(s,1H),8.25(dd,J＝6.9,2.1Hz,1H),7.96(d,J＝1.8Hz,4H),7.65–7.55(m,1H),7.42–7.31(m,2H),7.30–7.12(m,4H),5.53(s,2H),3.84(s,3H).
compound 5: 1 H NMR(400MHz,DMSO-d 6 )δ12.66(s,1H),10.09(s,1H),8.47(s,1H),8.25(dd,J＝6.8,2.2Hz,1H),7.95(t,J＝6.6Hz,4H),7.66–7.55(m,1H),7.36(dd,J＝8.5,5.5Hz,2H),7.29–7.13(m,4H),5.53(s,2H).
6D： 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),8.45(s,1H),8.29–8.17(m,1H),8.03–7.89(m,4H),7.63–7.50(m,1H),7.29–7.10(m,6H),5.47(s,2H),3.84(s,3H),2.26(s,3H).
compound 6: 1 H NMR(400MHz,DMSO-d 6 )δ13.71(s,1H),11.81(s,1H),8.75(dd,J＝8.5,1.1Hz,1H),8.30–8.18(m,2H),8.05(dd,J＝7.9,1.7Hz,1H),7.70–7.55(m,2H),7.28–7.18(m,4H),7.18–7.10(m,3H),5.51(s,2H),2.25(s,3H).
example 5
The preparation process of the 3- (1-methyl-6-cyano-1H-indole-3-formamido) benzoic acid (compound 10) specifically comprises the following steps:
intermediate compound 4C was prepared in 57.3% yield using 6-cyanoindole-3-carboxylic acid and methyl 3-aminobenzoate as starting materials and the procedure for preparation of intermediate compound 1C in example 1.
Using the intermediate compound 4C as a starting material, compound 10 was obtained in 87.2% yield using the preparation method of example 3 or example 4.
Detecting intermediates and products obtained in the preparation process, specifically comprising the following steps:
4C： 1 H NMR(600MHz,DMSO-d 6 )δ12.31(d,J＝3.0Hz,1H),10.11(s,1H),8.61(d,J＝3.0Hz,1H),8.44(t,J＝2.0Hz,1H),8.37(d,J＝8.3Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),8.04(dd,J＝1.5,0.7Hz,1H),7.66(dt,J＝7.8,1.3Hz,1H),7.54–7.47(m,2H),3.88(s,3H).
10D： 1 H NMR(600MHz,DMSO-d 6 )δ10.12(s,1H),8.55(s,1H),8.42(t,J＝1.9Hz,1H),8.36(dd,J＝8.3,0.7Hz,1H),8.21(dd,J＝1.4,0.7Hz,1H),8.10(ddd,J＝8.1,2.3,1.1Hz,1H),7.66(dt,J＝7.8,1.3Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),3.96(s,3H),3.89(s,3H).
compound 10: 1 HNMR(600MHz,DMSO-d 6 )δ12.98(s,1H),10.09(s,1H),8.55(s,1H),8.38(t,J＝2.0Hz,1H),8.36(dd,J＝8.3,0.7Hz,1H),8.21(dd,J＝1.5,0.7Hz,1H),8.07(ddd,J＝8.1,2.2,1.1Hz,1H),7.65(dt,J＝7.7,1.3Hz,1H),7.55(dd,J＝8.3,1.5Hz,1H),7.47(t,J＝7.9Hz,1H),3.96(s,3H).
similarly, with reference to the preparation method of compound 10, 3- (1-propyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 11) was prepared in a yield of 81.6% from intermediate compound 4C, respectively; 3- (1-butyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 12), yield 83.2%; 3- (1-pentyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 13), yield 76.9%; 3- (1-isopropyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 14) in 82.4% yield; 3- (1-isobutyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 15) in 77.2% yield; 3- (1-isopentyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 16), yield 81.4%; 3- [1- (cyclopropylmethyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 17) in 73.5% yield; 3- (1-cyclopentyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 18) in 69.6% yield; 3- (1-allyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 19) in 67.8% yield; 3- [1- (2-methylallyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 20) in 62.8% yield; 3- (1-benzyl-6-cyano-1H-indole-3-carboxamido) benzoic acid (compound 21), yield 87.6%; 3- [1- (4-fluorobenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 22) in 84.4% yield; 3- [1- (4-chlorobenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 23), yield 81.5%; 3- [1- (4-bromobenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 24) in 86.3% yield; 3- [1- (4-cyanobenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 25) in 74.6% yield; 3- [1- (4-methylbenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 26), yield 73.4%; 3- [1- (4-tert-butylbenzyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 27) in 68.5% yield.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
11D： 1 H NMR(600MHz,DMSO-d 6 )δ10.10(s,1H),8.61(s,1H),8.40(t,J＝2.0Hz,1H),8.37(d,J＝8.3Hz,1H),8.31–8.29(m,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.4Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),4.31(t,J＝7.1Hz,2H),3.88(s,3H),1.87(h,J＝7.3Hz,2H),0.90(t,J＝7.4Hz,3H).
compound 11: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.08(s,1H),8.62(s,1H),8.43–8.35(m,2H),8.33–8.28(m,1H),8.09(ddd,J＝8.1,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.4Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),4.31(t,J＝7.1Hz,2H),1.87(h,J＝7.3Hz,2H),0.90(t,J＝7.3Hz,3H).
12D： 1 H NMR(600MHz,DMSO-d 6 )δ10.09(s,1H),8.61(s,1H),8.40(t,J＝2.0Hz,1H),8.37(dd,J＝8.3,0.7Hz,1H),8.30(dd,J＝1.5,0.7Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(ddd,J＝7.7,1.7,1.1Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),4.34(t,J＝7.2Hz,2H),3.88(s,3H),1.88–1.79(m,2H),1.38–1.28(m,2H),0.93(t,J＝7.4Hz,3H).
compound 12: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.06(s,1H),8.62(s,1H),8.40–8.35(m,2H),8.31–8.27(m,1H),8.09(ddd,J＝8.1,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.3Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),4.33(t,J＝7.1Hz,2H),1.93–1.73(m,2H),1.40–1.22(m,2H),0.93(t,J＝7.4Hz,3H).
13D： 1 H NMR(600MHz,DMSO-d 6 )δ10.10(s,1H),8.61(s,1H),8.40(t,J＝2.0Hz,1H),8.37(dd,J＝8.3,0.7Hz,1H),8.29–8.27(m,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.4Hz,1H),7.53(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),4.32(t,J＝7.2Hz,2H),3.88(s,3H),1.84(p,J＝7.3Hz,2H),1.37–1.24(m,4H),0.86(t,J＝7.2Hz,3H).
compound 13: 1 H NMR(600MHz,DMSO-d 6 )δ13.00(s,1H),10.08(s,1H),8.64(s,1H),8.41–8.36(m,2H),8.32–8.28(m,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.4Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.49(t,J＝7.9Hz,1H),4.34(t,J＝7.2Hz,2H),1.86(p,J＝7.3Hz,2H),1.48–1.22(m,4H),0.87(t,J＝7.2Hz,3H).
14D： 1 H NMR(600MHz,DMSO-d 6 )δ10.06(s,1H),8.78(s,1H),8.43–8.35(m,2H),8.32(s,1H),8.14(ddd,J＝8.2,2.2,1.1Hz,1H),7.67(dt,J＝7.7,1.3Hz,1H),7.55(dd,J＝8.3,1.3Hz,1H),7.51(t,J＝7.9Hz,1H),4.98(p,J＝6.6Hz,1H),3.89(s,3H),1.55(d,J＝6.6Hz,6H).
compound 14: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.04(s,1H),8.78(s,1H),8.41–8.36(m,1H),8.35(t,J＝1.9Hz,1H),8.32(t,J＝0.9Hz,1H),8.11(ddd,J＝8.1,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.4Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.49(t,J＝7.9Hz,1H),4.98(p,J＝6.6Hz,1H),1.55(d,J＝6.7Hz,6H).
15D： 1 H NMR(600MHz,DMSO-d 6 )δ10.11(s,1H),8.59(s,1H),8.43–8.35(m,2H),8.34–8.31(m,1H),8.13–8.09(m,1H),7.67(dd,J＝7.7,1.4Hz,1H),7.54(dd,J＝8.3,1.3Hz,1H),7.51(t,J＝7.9Hz,1H),4.16(d,J＝7.3Hz,2H),3.88(s,3H),2.18(hept,J＝6.8Hz,1H),0.91(d,J＝6.6Hz,6H).
compound 15: 1 H NMR(600MHz,DMSO-d 6 )δ12.98(s,1H),10.08(s,1H),8.60(s,1H),8.46–8.35(m,2H),8.35–8.31(m,1H),8.09(ddd,J＝8.2,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.4Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),4.16(d,J＝7.4Hz,2H),2.19(hept,J＝6.8Hz,1H),0.92(d,J＝6.6Hz,6H).
16D： 1 H NMR(600MHz,DMSO-d 6 )δ10.07(s,1H),8.63(s,1H),8.39(t,J＝2.0Hz,1H),8.37(dd,J＝8.3,0.7Hz,1H),8.29(dd,J＝1.4,0.7Hz,1H),8.12(ddd,J＝8.1,2.2,1.1Hz,1H),7.66(ddd,J＝7.7,1.7,1.1Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),4.37–4.30(m,2H),3.88(s,3H),1.79–1.72(m,2H),1.60(dp,J＝13.3,6.7Hz,1H),0.97(d,J＝6.6Hz,6H).
compound 16: 1 H NMR(600MHz,DMSO-d 6 )δ13.00(s,1H),10.08(s,1H),8.66(s,1H),8.41–8.34(m,2H),8.29(dd,J＝1.4,0.7Hz,1H),8.09(ddd,J＝8.1,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.4Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.47(t,J＝7.9Hz,1H),4.37–4.31(m,2H),1.75(dt,J＝8.6,6.8Hz,2H),1.60(dp,J＝13.3,6.6Hz,1H),0.97(d,J＝6.7Hz,6H).
17D： 1 H NMR(600MHz,DMSO-d 6 )δ10.13(s,1H),8.68(s,1H),8.40(t,J＝2.0Hz,1H),8.38(dd,J＝8.3,0.7Hz,1H),8.32(dd,J＝1.4,0.7Hz,1H),8.12(ddd,J＝8.2,2.3,1.1Hz,1H),7.67(ddd,J＝7.8,1.7,1.1Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.51(t,J＝7.9Hz,1H),4.22(d,J＝7.2Hz,2H),3.89(s,3H),1.43–1.31(m,1H),0.66–0.58(m,2H),0.53–0.46(m,2H).
compound 17: 1 H NMR(600MHz,DMSO-d 6 )δ13.04(s,1H),10.14(s,1H),8.72(s,1H),8.45–8.39(m,2H),8.37–8.33(m,1H),8.13(ddd,J＝8.1,2.3,1.1Hz,1H),7.70(dt,J＝7.7,1.3Hz,1H),7.59(dd,J＝8.3,1.4Hz,1H),7.52(t,J＝7.9Hz,1H),4.26(d,J＝7.2Hz,2H),1.41(ddt,J＝9.4,7.5,3.8Hz,1H),0.78–0.61(m,2H),0.56–0.47(m,2H).
18D： 1 H NMR(600MHz,DMSO-d 6 )δ10.03(s,1H),8.73(s,1H),8.39(dd,J＝8.3,0.7Hz,1H),8.36(t,J＝2.0Hz,1H),8.30(t,J＝1.0Hz,1H),8.14(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.8,1.3Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),5.13–5.05(m,1H),3.89(s,3H),2.29(ddd,J＝13.3,9.6,3.1Hz,2H),1.97–1.86(m,4H),1.82–1.71(m,2H).
compound 18: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.02(s,1H),8.74(s,1H),8.39(d,J＝8.3Hz,1H),8.34(t,J＝1.9Hz,1H),8.30(d,J＝1.4Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.6,1.3Hz,1H),7.54(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),5.17–5.01(m,1H),2.35–2.23(m,2H),1.99–1.85(m,4H),1.77(qdd,J＝7.7,5.7,3.6Hz,2H).
19D： 1 H NMR(600MHz,DMSO-d 6 )δ10.15(s,1H),8.59(s,1H),8.41(t,J＝2.0Hz,1H),8.39(dd,J＝8.3,0.7Hz,1H),8.21(dd,J＝1.4,0.7Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(ddd,J＝7.7,1.7,1.1Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.49(t,J＝7.9Hz,1H),6.10(ddt,J＝17.1,10.2,5.6Hz,1H),5.30(dq,J＝10.2,1.4Hz,1H),5.21(dq,J＝17.1,1.6Hz,1H),5.01(dt,J＝5.7,1.6Hz,2H),3.88(s,3H).
compound 19: 1 H NMR(600MHz,DMSO-d 6 )δ12.99(s,1H),10.14(s,1H),8.60(s,1H),8.41–8.37(m,2H),8.25–8.19(m,1H),8.08(ddd,J＝8.1,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.3Hz,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.47(t,J＝7.9Hz,1H),6.10(ddt,J＝17.1,10.2,5.7Hz,1H),5.29(dq,J＝10.2,1.4Hz,1H),5.21(dq,J＝17.1,1.6Hz,1H),5.02(dt,J＝5.7,1.6Hz,2H).
20D： 1 H NMR(600MHz,DMSO-d 6 )δ10.17(s,1H),8.57(s,1H),8.41(t,J＝2.0Hz,1H),8.40(dd,J＝8.3,0.7Hz,1H),8.22(dd,J＝1.4,0.7Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.68–7.65(m,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),4.98–4.95(m,3H),4.79–4.65(m,1H),3.88(s,3H),1.70(d,J＝1.5Hz,3H).
compound 20: 1 H NMR(600MHz,DMSO-d 6 )δ13.00(s,1H),10.14(s,1H),8.58(s,1H),8.42–8.35(m,2H),8.27–8.19(m,1H),8.09(ddd,J＝8.1,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.4Hz,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),4.97(d,J＝5.2Hz,3H),4.77–4.69(m,1H),1.70(s,3H).
21D： 1 H NMR(600MHz,DMSO-d 6 )δ10.18(s,1H),8.69(s,1H),8.41–8.38(m,2H),8.34–8.31(m,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.67(dt,J＝7.7,1.4Hz,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.42–7.37(m,2H),7.36–7.30(m,3H),5.63(s,2H),3.88(s,3H).
compound 21: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.16(s,1H),8.71(s,1H),8.43–8.36(m,2H),8.32(d,J＝1.4Hz,1H),8.14–8.04(m,1H),7.67(dt,J＝7.7,1.4Hz,1H),7.57(dd,J＝8.3,1.4Hz,1H),7.49(t,J＝7.9Hz,1H),7.44–7.38(m,2H),7.38–7.30(m,3H),5.63(s,2H).
22D： 1 H NMR(600MHz,DMSO-d 6 )δ10.18(s,1H),8.68(s,1H),8.40–8.37(m,2H),8.34(d,J＝1.3Hz,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.67(dt,J＝7.7,1.4Hz,1H),7.57(dd,J＝8.3,1.4Hz,1H),7.51(t,J＝7.9Hz,1H),7.47–7.40(m,2H),7.24(t,J＝8.8Hz,2H),5.61(s,2H),3.89(s,3H).
compound 22: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.14(s,1H),8.68(s,1H),8.38(d,J＝8.3Hz,1H),8.37–8.30(m,2H),8.07(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.3Hz,1H),7.57(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),7.45–7.40(m,2H),7.30–7.19(m,2H),5.61(s,2H).
23D： 1 H NMR(600MHz,DMSO-d 6 )δ10.17(s,1H),8.67(s,1H),8.41–8.37(m,2H),8.31(dd,J＝1.4,0.7Hz,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.67(ddd,J＝7.7,1.7,1.1Hz,1H),7.57(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.48–7.44(m,2H),7.38–7.35(m,2H),5.63(s,2H),3.88(s,3H).
compound 23: 1 H NMR(600MHz,DMSO-d 6 )δ12.99(s,1H),10.15(s,1H),8.67(s,1H),8.39(dd,J＝8.3,0.7Hz,1H),8.36(t,J＝1.9Hz,1H),8.32–8.29(m,1H),8.07(ddd,J＝8.1,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.3Hz,1H),7.57(dd,J＝8.3,1.4Hz,1H),7.51–7.44(m,3H),7.41–7.35(m,2H),5.63(s,2H).
24D： 1 H NMR(600MHz,DMSO-d 6 )δ10.17(s,1H),8.66(s,1H),8.42–8.37(m,2H),8.31(dd,J＝1.4,0.7Hz,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.67(ddd,J＝7.7,1.7,1.1Hz,1H),7.63–7.58(m,2H),7.57(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.34–7.28(m,2H),5.61(s,2H),3.88(s,3H).
compound 24: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.15(s,1H),8.67(s,1H),8.39(d,J＝8.3Hz,1H),8.36(t,J＝1.9Hz,1H),8.34–8.30(m,1H),8.07(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.3Hz,1H),7.62–7.59(m,2H),7.57(dd,J＝8.3,1.4Hz,1H),7.48(t,J＝7.9Hz,1H),7.35–7.28(m,2H),5.61(s,2H).
25D： 1 H NMR(600MHz,DMSO-d 6 )δ10.19(s,1H),8.68(s,1H),8.42–8.38(m,2H),8.29(d,J＝1.0Hz,1H),8.10(ddd,J＝8.2,2.3,1.1Hz,1H),7.92–7.82(m,2H),7.67(dt,J＝7.7,1.4Hz,1H),7.58(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.47(d,J＝8.3Hz,2H),5.75(s,2H),3.88(s,3H).
compound 25: 1 H NMR(600MHz,DMSO-d 6 )δ13.01(s,1H),10.20(s,1H),8.72(s,1H),8.40(d,J＝8.3Hz,1H),8.38(t,J＝1.9Hz,1H),8.32–8.29(m,1H),8.08(ddd,J＝8.1,2.3,1.1Hz,1H),7.88(d,J＝8.4Hz,2H),7.67(dt,J＝7.7,1.4Hz,1H),7.59(dd,J＝8.3,1.4Hz,1H),7.49(dd,J＝8.2,7.1Hz,3H),5.76(s,2H).
26D： 1 H NMR(600MHz,DMSO-d 6 )δ10.16(s,1H),8.66(s,1H),8.42–8.34(m,2H),8.28(d,J＝1.3Hz,1H),8.14–8.07(m,1H),7.66(dt,J＝7.7,1.3Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.26(d,J＝7.9Hz,2H),7.19(d,J＝7.9Hz,2H),5.55(s,2H),3.88(s,3H).
compound 26: 1 H NMR(600MHz,DMSO-d 6 )δ13.00(s,1H),10.14(s,1H),8.67(s,1H),8.38(dd,J＝8.3,0.7Hz,1H),8.36(t,J＝1.9Hz,1H),8.32–8.28(m,1H),8.08(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(dt,J＝7.7,1.3Hz,1H),7.55(dd,J＝8.3,1.4Hz,1H),7.47(t,J＝7.9Hz,1H),7.28–7.24(m,2H),7.19(d,J＝7.9Hz,2H),5.56(s,2H),2.27(s,3H).
27D： 1 H NMR(600MHz,DMSO-d 6 )δ10.17(s,1H),8.70(s,1H),8.41–8.38(m,2H),8.35(dd,J＝1.4,0.7Hz,1H),8.11(ddd,J＝8.2,2.3,1.1Hz,1H),7.66(ddd,J＝7.7,1.7,1.1Hz,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.50(t,J＝7.9Hz,1H),7.43–7.36(m,2H),7.28(d,J＝8.4Hz,2H),5.58(s,2H),3.88(s,3H),1.24(s,9H).
compound 27: 1 H NMR(600MHz,DMSO-d 6 )δ13.00(s,1H),10.15(s,1H),8.71(s,1H),8.39(dd,J＝8.3,0.7Hz,1H),8.37–8.35(m,2H),8.08(ddd,J＝8.2,2.3,1.1Hz,1H),7.65(dt,J＝7.7,1.3Hz,1H),7.56(dd,J＝8.3,1.4Hz,1H),7.47(t,J＝7.9Hz,1H),7.43–7.37(m,2H),7.32–7.24(m,2H),5.57(s,2H),1.24(s,9H).
example 6
A process for preparing 2- [ 5-methyl-1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 28) comprising:
starting from 5-methylindole-3-carboxylic acid and methyl 2-aminobenzoate, the preparation method of example 3 was used to obtain compound 28 with a yield of 86.9%.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
28D： 1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.65(dd,J＝8.5,1.1Hz,1H),8.57–8.51(m,1H),8.20(s,1H),8.04(dt,J＝1.7,0.8Hz,1H),8.01(dd,J＝8.0,1.6Hz,1H),7.76(td,J＝7.7,1.8Hz,1H),7.69–7.62(m,1H),7.42(d,J＝8.4Hz,1H),7.33–7.27(m,1H),7.23–7.14(m,2H),7.05(dd,J＝8.4,1.6Hz,1H),5.63(s,2H),3.90(s,3H),2.42(s,3H).
compound 28: m.p.217.5-219.3 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.67(s,1H),11.80(s,1H),8.76(dd,J＝8.5,1.1Hz,1H),8.54(dd,J＝5.4,1.5Hz,1H),8.18(s,1H),8.10–8.02(m,2H),7.76(td,J＝7.7,1.8Hz,1H),7.67–7.61(m,1H),7.43(d,J＝8.4Hz,1H),7.33–7.27(m,1H),7.22(d,J＝7.8Hz,1H),7.14(td,J＝7.6,1.2Hz,1H),7.06(dd,J＝8.4,1.6Hz,1H),5.62(s,2H),2.43(s,3H).
similarly, 2- [ 6-methyl-1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 29) was prepared in 79.6% yield according to the preparation method of compound 28; 2- [ 5-methoxy-1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 30) in 86.3% yield; 2- [1- (pyridin-2-ylmethyl) -5-fluoro-1H-indole-3-carboxamido ] benzoic acid (compound 31) in 82.6% yield; 2- [1- (pyridin-2-ylmethyl) -6-fluoro-1H-indole-3-carboxamido ] benzoic acid (compound 32) in 89.6% yield; 2- [1- (pyridin-2-ylmethyl) -5-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 33) in 92.6% yield; 2- [1- (pyridin-2-ylmethyl) -6-cyano-1H-indole-3-carboxamido ] benzoic acid (compound 34) in 94.3% yield; 5-methyl-2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 35) in 73.6% yield; 4-methyl-2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 36) in 78.6% yield; 3-methyl-2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 37) in 91.6% yield; 2-methyl-6- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] benzoic acid (compound 38) in 86.1% yield; 2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -5-fluorobenzoic acid (compound 39), yield 83.2%; 2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -4-fluorobenzoic acid (compound 40) in 86.7% yield; 2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -3-fluorobenzoic acid (compound 41), yield 83.9%; 6- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -2-fluorobenzoic acid (compound 42) in 79.6% yield.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
29D： 1 H NMR(400MHz,DMSO-d 6 )δ11.25(s,1H),8.64(dd,J＝8.5,1.1Hz,1H),8.58–8.52(m,1H),8.17(s,1H),8.10(d,J＝8.1Hz,1H),8.01(dd,J＝8.0,1.6Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.69–7.62(m,1H),7.37–7.32(m,1H),7.33–7.28(m,1H),7.21(dt,J＝7.9,1.1Hz,1H),7.19–7.14(m,1H),7.07(dd,J＝8.1,1.4Hz,1H),5.63(s,2H),3.90(s,3H),2.39(s,3H).
compound 29: m.p.245.0-246.2 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.68(s,1H),11.82(s,1H),8.77(d,J＝8.4Hz,1H),8.55(d,J＝5.8Hz,1H),8.13(d,J＝9.2Hz,2H),8.05(dd,J＝7.9,1.7Hz,1H),7.77(td,J＝7.7,1.9Hz,1H),7.67–7.60(m,1H),7.37(s,1H),7.31(dd,J＝7.5,4.9Hz,1H),7.22(d,J＝7.8Hz,1H),7.14(t,J＝7.6Hz,1H),7.06(d,J＝8.2Hz,1H),5.62(s,2H),2.40(s,3H).
30D： 1 H NMR(400MHz,DMSO-d 6 )δ11.26(s,1H),8.68(dd,J＝8.5,1.2Hz,1H),8.57–8.51(m,1H),8.21(s,1H),8.02(dd,J＝8.0,1.6Hz,1H),7.81–7.73(m,2H),7.68–7.62(m,1H),7.44(d,J＝8.9Hz,1H),7.33–7.28(m,1H),7.22(dt,J＝7.9,1.1Hz,1H),7.20–7.15(m,1H),6.86(dd,J＝8.9,2.5Hz,1H),5.63(s,2H),3.90(s,3H),3.82(s,3H).
compound 30: m.p.155.3-158.7 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.65(s,1H),11.80(s,1H),8.77(dd,J＝8.5,1.1Hz,1H),8.54(dt,J＝4.8,1.3Hz,1H),8.17(s,1H),8.05(dd,J＝8.0,1.7Hz,1H),7.81–7.72(m,2H),7.66–7.60(m,1H),7.46(d,J＝9.0Hz,1H),7.35–7.26(m,1H),7.23(d,J＝7.8Hz,1H),7.19–7.10(m,1H),6.88(dd,J＝9.0,2.5Hz,1H),5.61(s,2H),3.82(s,3H).
31D： 1 H NMR(400MHz,DMSO-d 6 )δ11.22(s,1H),8.59(dd,J＝8.5,1.1Hz,1H),8.56–8.52(m,1H),8.33(s,1H),8.00(dd,J＝8.0,1.7Hz,1H),7.91(dd,J＝10.0,2.6Hz,1H),7.79(td,J＝7.7,1.8Hz,1H),7.68–7.63(m,1H),7.58(dd,J＝9.0,4.5Hz,1H),7.36–7.26(m,2H),7.21–7.16(m,1H),7.11(td,J＝9.2,2.7Hz,1H),5.69(s,2H),3.90(s,3H).
compound 31: m.p.228.5-230.0 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.72(s,1H),11.83(s,1H),8.75(dd,J＝8.5,1.1Hz,1H),8.57–8.51(m,1H),8.30(s,1H),8.06(dd,J＝8.0,1.6Hz,1H),7.96(dd,J＝10.1,2.6Hz,1H),7.79(td,J＝7.7,1.8Hz,1H),7.68–7.57(m,2H),7.35–7.27(m,2H),7.20–7.07(m,2H),5.68(s,2H).
32D： 1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.58(dd,J＝8.5,1.1Hz,1H),8.56–8.53(m,1H),8.26(s,1H),8.20(dd,J＝8.8,5.5Hz,1H),8.00(dd,J＝8.0,1.7Hz,1H),7.80(td,J＝7.7,1.8Hz,1H),7.69–7.62(m,1H),7.48(dd,J＝10.1,2.4Hz,1H),7.35–7.30(m,2H),7.22–7.15(m,1H),7.13–7.06(m,1H),5.65(s,2H),3.90(s,3H).
compound 32: m.p.222.9-223.6 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.70(s,1H),11.84(s,1H),8.73(dd,J＝8.5,1.1Hz,1H),8.58–8.52(m,1H),8.26–8.20(m,2H),8.05(dd,J＝7.9,1.7Hz,1H),7.80(td,J＝7.7,1.8Hz,1H),7.68–7.60(m,1H),7.50(dd,J＝10.0,2.4Hz,1H),7.32(dd,J＝7.6,4.1Hz,2H),7.15(td,J＝7.6,1.2Hz,1H),7.10(td,J＝9.3,2.3Hz,1H),5.64(s,2H).
33D： 1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.62(d,J＝1.5Hz,1H),8.57–8.49(m,2H),8.44(s,1H),7.99(dd,J＝8.0,1.7Hz,1H),7.84–7.77(m,2H),7.69–7.60(m,2H),7.39–7.30(m,2H),7.21(td,J＝7.6,1.2Hz,1H),5.76(s,2H),3.90(s,3H).
compound 33: m.p.190.7-191.0 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.75(s,1H),11.88(s,1H),8.71(d,J＝8.4Hz,1H),8.64(s,1H),8.52(d,J＝4.8Hz,1H),8.41(s,1H),8.09–8.03(m,1H),7.84–7.77(m,2H),7.71–7.61(m,2H),7.40–7.29(m,2H),7.18(t,J＝7.6Hz,1H),5.75(s,2H).
34D： 1 H NMR(400MHz,DMSO-d 6 )δ11.23(s,1H),8.56–8.49(m,3H),8.36(d,J＝8.6Hz,1H),8.26(d,J＝1.0Hz,1H),7.99(dd,J＝8.0,1.7Hz,1H),7.83(td,J＝7.7,1.8Hz,1H),7.69–7.63(m,1H),7.58(dd,J＝8.3,1.4Hz,1H),7.41(dt,J＝7.8,1.0Hz,1H),7.35–7.31(m,1H),7.23–7.17(m,1H),5.77(s,2H),3.89(s,3H).
compound 34: m.p.263.5-265.7 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.74(s,1H),11.89(s,1H),8.71(dd,J＝8.5,1.1Hz,1H),8.56–8.52(m,1H),8.47(s,1H),8.40(d,J＝8.4Hz,1H),8.28(d,J＝1.3Hz,1H),8.06(dd,J＝8.0,1.7Hz,1H),7.82(td,J＝7.7,1.8Hz,1H),7.69–7.61(m,1H),7.59(dd,J＝8.3,1.4Hz,1H),7.42(d,J＝7.8Hz,1H),7.37–7.30(m,1H),7.18(td,J＝7.7,1.2Hz,1H),5.76(s,2H).
35D： 1 H NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.56–8.50(m,2H),8.27–8.21(m,2H),7.81(d,J＝2.1Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.57–7.52(m,1H),7.47(dd,J＝8.6,2.1Hz,1H),7.30(dd,J＝7.6,4.9Hz,1H),7.26–7.21(m,3H),5.67(s,2H),3.89(s,3H),2.32(s,3H).
compound 35: m.p.244.0-245.9 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.63(s,1H),11.73(s,1H),8.66(d,J＝8.5Hz,1H),8.56–8.51(m,1H),8.27–8.24(m,1H),8.22(s,1H),7.86(d,J＝2.3Hz,1H),7.76(td,J＝7.7,1.9Hz,1H),7.60–7.53(m,1H),7.45(dd,J＝8.6,2.3Hz,1H),7.30(dd,J＝7.6,4.9Hz,1H),7.27–7.19(m,3H),5.65(s,2H),2.32(s,3H).
36D： 1 H NMR(400MHz,DMSO-d 6 )δ11.33(s,1H),8.58–8.50(m,2H),8.28–8.20(m,2H),7.91(d,J＝8.1Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.58–7.52(m,1H),7.31(dd,J＝7.6,4.9Hz,1H),7.27–7.21(m,3H),7.00(dd,J＝8.2,1.7Hz,1H),5.68(s,2H),3.89(s,3H),2.40(s,3H).
compound 36: m.p.252.8-253.8 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.53(s,1H),11.88(s,1H),8.65(d,J＝1.7Hz,1H),8.54(dt,J＝4.7,1.4Hz,1H),8.30–8.24(m,1H),8.22(s,1H),7.94(d,J＝8.1Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.59–7.55(m,1H),7.33–7.20(m,4H),6.97(dd,J＝8.2,1.7Hz,1H),5.66(s,2H),2.40(s,3H).
37D： 1 H NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),8.55(d,J＝4.8Hz,1H),8.38(s,1H),8.14(d,J＝7.6Hz,1H),7.79(td,J＝7.6,1.7Hz,1H),7.65(d,J＝7.7Hz,1H),7.52(t,J＝8.9Hz,2H),7.35–7.24(m,3H),7.23–7.12(m,2H),5.61(s,2H),3.68(s,3H),2.31(s,3H).
compound 37: m.p.191.8-192.2 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ12.86(s,1H),9.77(s,1H),8.57–8.52(m,1H),8.39(s,1H),8.17(dd,J＝6.8,2.2Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.71(dd,J＝7.8,1.6Hz,1H),7.57–7.45(m,2H),7.35–7.28(m,1H),7.25(dt,J＝7.7,3.8Hz,2H),7.22–7.14(m,2H),5.61(s,2H),2.29(s,3H).
38D： 1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),8.55(d,J＝4.8Hz,1H),8.33(s,1H),8.17–8.12(m,1H),7.78(td,J＝7.7,1.7Hz,1H),7.53(dd,J＝7.5,4.5Hz,2H),7.39(t,J＝7.8Hz,1H),7.31(dd,J＝7.5,5.0Hz,1H),7.25(d,J＝7.8Hz,1H),7.23–7.15(m,2H),7.09(d,J＝7.5Hz,1H),5.61(s,2H),3.74(s,3H),2.37(s,3H).
compound 38: m.p.193.3-195.5 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.48(s,1H),10.11(s,1H),8.55(dt,J＝4.8,1.4Hz,1H),8.29(s,1H),8.21–8.15(m,1H),7.88(d,J＝8.2Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.57–7.49(m,1H),7.38(t,J＝7.9Hz,1H),7.34–7.28(m,1H),7.26–7.17(m,3H),7.06(d,J＝7.6Hz,1H),5.62(s,2H),2.44(s,3H).
39D： 1 H NMR(400MHz,DMSO-d 6 )δ11.01(s,1H),8.59–8.52(m,2H),8.28(s,1H),8.23–8.18(m,1H),7.78(td,J＝7.7,1.8Hz,1H),7.72(dd,J＝9.4,3.2Hz,1H),7.59–7.52(m,2H),7.33–7.28(m,1H),7.27–7.20(m,3H),5.67(s,2H),3.89(s,3H).
compound 39: m.p.222.2-223.1 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ14.02(s,1H),11.65(s,1H),8.78(dd,J＝9.3,5.1Hz,1H),8.55(d,J＝4.8Hz,1H),8.26(d,J＝7.2Hz,2H),7.76(d,J＝8.4Hz,2H),7.62–7.46(m,2H),7.39–7.18(m,4H),5.66(s,2H).
40D： 1 H NMR(400MHz,DMSO-d 6 )δ11.52(s,1H),8.58–8.52(m,2H),8.27(s,1H),8.25–8.21(m,1H),8.10(dd,J＝9.0,6.7Hz,1H),7.78(td,J＝7.7,1.8Hz,1H),7.59–7.53(m,1H),7.33–7.29(m,1H),7.28–7.22(m,3H),7.06–6.98(m,1H),5.69(s,2H),3.92(s,3H).
compound 40: m.p.244.8-245.7 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ12.13(s,1H),8.64(dd,J＝12.5,2.7Hz,1H),8.54(dd,J＝4.9,1.6Hz,1H),8.30–8.24(m,2H),8.13(dd,J＝8.8,6.8Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.63–7.54(m,1H),7.34–7.21(m,4H),6.98(td,J＝8.4,2.8Hz,1H),5.67(s,2H).
41D： 1 H NMR(400MHz,DMSO-d 6 )δ9.77(s,1H),8.58–8.53(m,1H),8.44(s,1H),8.14(dd,J＝7.2,1.8Hz,1H),7.79(td,J＝7.7,1.8Hz,1H),7.64(d,J＝7.8Hz,1H),7.58–7.51(m,2H),7.38(td,J＝8.1,5.1Hz,1H),7.34–7.26(m,2H),7.19(pd,J＝7.2,1.4Hz,2H),5.62(s,2H),3.72(s,3H).
compound 41: m.p.218.5-220.9 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.20(s,1H),9.82(s,1H),8.57–8.53(m,1H),8.44(s,1H),8.19–8.14(m,1H),7.78(td,J＝7.7,1.9Hz,1H),7.70(dd,J＝7.9,1.4Hz,1H),7.59–7.48(m,2H),7.39–7.25(m,3H),7.20(tt,J＝7.2,5.6Hz,2H),5.62(s,2H).
42D： 1 H NMR(400MHz,DMSO-d 6 )δ10.33(s,1H),8.55(dd,J＝4.9,1.6Hz,1H),8.35(s,1H),8.19–8.14(m,1H),7.78(td,J＝7.7,1.8Hz,1H),7.71(d,J＝8.2Hz,1H),7.62–7.52(m,2H),7.31(dd,J＝7.6,4.9Hz,1H),7.27(d,J＝7.8Hz,1H),7.25–7.17(m,2H),7.07(dd,J＝10.5,8.3Hz,1H),5.63(s,2H),3.79(s,3H).
compound 42: m.p.184.1-186.7 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.84(s,1H),10.88(s,1H),8.55(d,J＝4.8Hz,1H),8.29(s,1H),8.25–8.18(m,1H),8.14(d,J＝8.4Hz,1H),7.82–7.72(m,1H),7.65–7.51(m,2H),7.36–7.18(m,4H),7.03(dd,J＝10.8,8.2Hz,1H),5.64(s,2H).
example 7
The preparation process of 2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -4, 5-difluorobenzoic acid (compound 43) specifically comprises the following steps:
3-indolecarboxylic acid (5.0g,0.031mol), dichloromethane (50 mL), thionyl chloride (11.07g,0.093mol), and DMF0.3mL were added to the reaction flask in this order, warmed to reflux, and stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, 50mL of methylene chloride was added and evaporated again to dryness, and the residual thionyl chloride was evaporated. 50mL of dichloromethane was added to make an acid chloride suspension for use. Another 500mL three-necked flask was charged with methyl 2-amino-4, 5-difluorobenzoate (5.27g,0.028mol), triethylamine (3.14g,0.031mol), and 50mL of dichloromethane, and stirred in an ice-water bath. Slowly adding acyl chloride suspension dropwise, stirring for 30min after dropwise adding, and transferring to room temperature for reaction overnight. Monitoring by TLC, after the reaction is finished, evaporating the solvent under reduced pressure, adding 1M sodium carbonate solution and 1M hydrochloric acid in sequence, pulping, filtering, and drying to obtain 8.34g of an intermediate compound A (4, 5-difluoro-2- (1H-indole-3-formamido) methyl benzoate), wherein the yield is 90.2%;
the intermediate compound A (4, 5-difluoro-2- (1H-indole-3-carboxamido) methyl benzoate) (2.0g,6.1mmol), anhydrous potassium carbonate (1.69g,12.2mmol), potassium iodide (0.10g,0.6mmol) and DMF20mL were added to a 100mL eggplant-shaped bottle, stirred at room temperature for 0.5H, added with 2-chloromethylpyridine hydrochloride (1.20g,7.3mmol), heated to 65 ℃ for reaction, after TLC monitoring of the reaction was complete, the reaction solution was cooled to room temperature, poured into 100mL of water, and extracted with ethyl acetate (30 mL. times.2). The organic phases were combined and washed successively with saturated sodium bicarbonate (10 mL. times.3) and saturated sodium chloride (10 mL. times.2). Adding anhydrous sodium sulfate into the organic phase, drying overnight, performing suction filtration, and removing the solvent by evaporation under reduced pressure to obtain an intermediate compound 43D. Recrystallization from methanol and tetrahydrofuran (v: v ═ 1:1) gave 2.05g of purified product, yield 79.6%;
the intermediate compound 43D (1.5g,3.6mmol), lithium hydroxide monohydrate (0.75g,17.8mmol), THF8mL, and water 8mL were added to a 100mL eggplant-shaped bottle, stirred at room temperature for 10min, heated to 60 ℃, reacted overnight, monitored by TLC for completion of the reaction, THF was evaporated under reduced pressure, 1M hydrochloric acid was added to adjust pH to 3-4, stirred at room temperature for 1h, filtered, and air-dried at 50 ℃ to obtain compound 43, which was recrystallized from anhydrous methanol and tetrahydrofuran (v: v ═ 1:1) to obtain 1.21g of a refined product with a yield of 84.4%.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
a (4, 5-difluoro-2- (1H-indole-3-carboxamido) benzoic acid methyl ester): m.p.193.0-194.8 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),11.32(s,1H),8.71(dd,J＝13.9,7.7Hz,1H),8.20–8.15(m,1H),8.06(d,J＝3.0Hz,1H),7.97(dd,J＝11.3,9.0Hz,1H),7.57–7.50(m,1H),7.22(pd,J＝7.1,1.4Hz,2H),3.91(s,3H).
43D：M.p.173.0-178.4℃； 1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),8.70(dd,J＝13.8,7.7Hz,1H),8.54(d,J＝4.8Hz,1H),8.26(s,1H),8.21(dd,J＝6.4,2.9Hz,1H),7.98(dd,J＝11.3,9.0Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.55(dd,J＝6.5,2.9Hz,1H),7.35–7.19(m,4H),5.68(s,2H),3.91(s,3H).
compound 43: m.p.222.9-224.3 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ12.12(s,1H),8.80(dd,J＝14.0,7.7Hz,1H),8.53(dd,J＝5.0,1.7Hz,1H),8.30–8.21(m,2H),7.98(dd,J＝11.4,9.2Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.60–7.52(m,1H),7.29(dd,J＝7.6,4.9Hz,1H),7.24(td,J＝5.8,4.9,3.1Hz,3H),5.66(s,2H).
using indole-3-carboxylic acid and methyl 4, 5-dimethoxy-2-aminobenzoate as starting materials, the preparation process of example 6 was carried out to give 2- [1- (pyridin-2-ylmethyl) -1H-indole-3-carboxamido ] -4, 5-dimethoxybenzoic acid (compound 44) in a yield of 76.3%.
Detecting intermediate compounds and products obtained in the preparation process, wherein the specific data are as follows:
44D： 1 H NMR(400MHz,DMSO-d 6 )δ11.45(s,1H),8.54(dd,J＝4.9,1.6Hz,1H),8.49(s,1H),8.26–8.21(m,2H),7.77(td,J＝7.7,1.8Hz,1H),7.57–7.51(m,1H),7.46(s,1H),7.31(dd,J＝7.6,4.9Hz,1H),7.27–7.20(m,3H),5.67(s,2H),3.89(s,3H),3.89(s,3H),3.79(s,3H).
compound 44: m.p.256.0-258.4 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ13.43(s,1H),11.93(s,1H),8.57(s,1H),8.54(dd,J＝5.1,1.6Hz,1H),8.30–8.25(m,1H),8.20(s,1H),7.77(td,J＝7.7,1.8Hz,1H),7.59–7.54(m,1H),7.49(s,1H),7.33–7.28(m,1H),7.28–7.19(m,3H),5.65(s,2H),3.89(s,3H),3.79(s,3H).
test example 1
Investigation of organic anion Transporter 1(URAT1) inhibitory Activity
1. Test materials
1.1 reagent: human URAT1 transporter over-expression cell strain HEK293-URAT1, 14 C-Uric acid
1.2 Instrument: electronic analytical balance (AR1140 type), electric constant temperature water bath (DK-98-1 type), enzyme mark instrument (Varioskan Flash type)
1.3 test samples: positive drugs of Racinidide and tranilast and prepared compounds 1-44
2. Test method
2.1 preparation method
The administration concentration of the prepared compound 1-44 is 10 mu mol/L, and the concentration of the positive control group rasilanid and tranilast is 10 mu mol/L.
Preparation of 20mmol/L stock solutions of the respective compounds: DMSO is used as a solvent of a tested compound, each compound and a positive control drug are prepared into 20mmol/L stock solution, and the stock solution is stored at-20 ℃ for standby after being uniformly mixed.
Preparation of respective working liquids
1) The stock solution was diluted to 200-fold working solution of each administration concentration using DMSO as a vehicle.
2) With HBSS (Cl-free) - ) The buffer solution was used as a solvent, and 200-fold working solution in 1) was diluted 100-fold to obtain 2-fold working solution for each administration concentration.
3) With HBSS (Cl-free) - ) Preparing buffer solution and placing label substrate 14 And (3) mixing the 2-time working solution of the C-Uric acid with the 2-time working solution of each compound in equal volume, and uniformly mixing for later use.
2.2 methods of administration
After cell lines (HEK293-URAT1) expressing human drug transporter URAT1 and Mock cells were recovered and subcultured, the cells were inoculated into 24-well cell culture plates and cultured for about 40 hours to allow the cells to grow over each well.
The plate medium was removed for administration, washed with 37 ℃ buffer and incubated. Starting administration after the incubation is finished; after 2min, the reaction was stopped with cold buffer, and 0.1mol/LNaOH was added per well to lyse the cells; the cell lysate is taken out in a scintillation vial, the scintillation fluid is added, and the radioactivity intensity in the sample is measured. Each compound and positive and blank controls were set in 2 duplicate wells (n-2).
2.3 data processing
Will contain only the labelling substrate 14 The value of the transport value Uc of C-Uric acid administration group (control) cells after deducting the transport value U0 of background Mock cells is defined as 100%, the percentage (In) of the transport value U and Uc of each administration group after adding the test compound is calculated by taking the value as a standard, and the inhibition effect rate IR is calculated to characterize the inhibition effect of the compound on transporters, and the formula is as follows:
Figure BDA0002978003990000231
IR＝100-In
each set was set with 2 wells (n ═ 2), and Mean ± standard error (SD) was calculated using Excel statistical formula. Each value represents the mean of one experimental group.
2.4 statistical methods
All data were examined using the SPSS (17.0) statistical software package. Results are expressed as mean ± sd, comparisons of mean between groups for homogeneity of variance analysis, and Dunnett's test analysis for comparison between groups
3. The experimental results are as follows:
the experimental results show that most of the prepared 44 target compounds show stronger organic anion transporter 1(URAT1) inhibition activity (the experimental data are shown in Table 1).
TABLE 1 Effect of Compounds 1 to 44 on URAT1 Activity (M + -SD)
Figure BDA0002978003990000232
Figure BDA0002978003990000241
Formulation example 1
Medicine tablets for preventing or treating hyperuricemia or gout by using compound 34
Prescription composition and content
Figure BDA0002978003990000242
The prescription of the coating liquid is as follows:
opadry (03B28796) 21g
Proper amount of 95% ethanol
Making into about 430ml
Process for the preparation of a coating
Mixing the auxiliary materials which are sieved by a 100-mesh sieve and the main medicine which are sieved by a 60-mesh sieve, preparing soft materials by 95% ethanol, granulating by a 18-mesh sieve, ventilating and drying at 60 ℃, granulating by a 16-mesh sieve, uniformly mixing with magnesium stearate, and punching tablets by shallow recesses with phi of 6 mm.
Preparing a coating solution: adding a proper amount of 95% ethanol into a proper container, starting a stirrer, uniformly adding the Opadry (03B28796) solid powder into the vortex according to the prescription amount, simultaneously avoiding the powder from floating on the liquid surface as much as possible, if necessary, increasing the rotating speed to keep a proper vortex, reducing the stirring speed after all the Opadry (03B28796) are added, eliminating the vortex, and continuously stirring for 45min to obtain the product.
Preparation of film-coated tablets: placing the tablet core in a coating pan, maintaining the temperature at 60 + -5 deg.C, and coating.

Claims (7)

1. A compound having an activity of inhibiting an organic anion transporter 1, or a pharmaceutically acceptable salt thereof, wherein the compound having an activity of inhibiting an organic anion transporter 1 has the structural formula:
Figure FDA0003781311810000011
wherein:
R 1 is C1-C7 alkyl, C2-C6 alkenyl, substituted or unsubstituted aromatic ring methyl, the substituent is halogen, C1-C6 alkyl or alkoxy, the aromatic ring is benzene ring or pyridine;
R 2 is H, halogen, methyl, methoxy or cyano;
R 3 is 1-2H, halogen, methyl or methoxy;
-COOH is in the para, meta or ortho position;
the halogen is fluorine, chlorine or bromine.
2. A compound having an activity of inhibiting an organic anion transporter 1 or a pharmaceutically acceptable salt thereof, wherein the compound having an activity of inhibiting an organic anion transporter 1 is any one of the following compounds 2 to 6 and 10 to 44;
Figure FDA0003781311810000012
Figure FDA0003781311810000021
3. an intermediate compound for preparing the compound having an activity of inhibiting the organic anion transporter 1 according to claim 1 or a pharmaceutically acceptable salt thereof; the intermediate compound has a structural formula as follows:
Figure FDA0003781311810000022
wherein:
R 1 is C1-C7 alkyl, C2-C6 alkenyl, substituted or unsubstituted aromatic ring methyl, the substituent is halogen, C1-C6 alkyl or alkoxy, the aromatic ring is benzene ring or pyridine;
R 2 is H, halogen, methyl, methoxy or cyano;
R 3 is 1-2H, halogen, methyl or methoxy;
-COOR 4 at the para, meta or ortho position;
R 4 is-CH 3 or-CH 2 CH 3 ；
The halogen is fluorine, chlorine or bromine.
4. An intermediate compound for preparing the compound having an activity of inhibiting the organic anion transporter 1 according to claim 2 or a pharmaceutically acceptable salt thereof; the intermediate compound is any one of the following compounds 2D to 6D and 10D to 44D:
Figure FDA0003781311810000031
5. a process for preparing a compound or a pharmaceutically acceptable salt of a compound having an activity of inhibiting organic anion transporter 1 according to claim 2, which comprises:
condensing corresponding indole-3-carboxylic acid serving as an initial raw material with corresponding amine to obtain a corresponding intermediate A;
reacting the obtained intermediate A with a corresponding alkylation reagent to obtain a corresponding intermediate B, wherein the intermediate B is intermediate compounds 2D-6D and 10D-44D, and the corresponding structural formula is shown in claim 4;
hydrolyzing the obtained intermediate B by LiOH to obtain corresponding compounds 2-6 and 10-44;
Figure FDA0003781311810000041
6. a pharmaceutical composition comprising one or more of the compounds having an activity of inhibiting organic anion transporter 1 or pharmaceutically acceptable salts thereof according to any one of claims 1 to 2; also comprises one or the combination of pharmaceutically acceptable auxiliary materials, carriers and diluents; the routes of administration of the pharmaceutical composition include: oral, nasal, transdermal, pulmonary and parenteral administration; the dosage form of the pharmaceutical composition comprises: tablets, capsules, lozenges, syrups, emulsions, injections, aerosols and dragees; the weight percentage of the compound or the pharmaceutically acceptable salt of the compound which can inhibit the activity of the organic anion transporter 1 in the pharmaceutical composition is 0.5-20%.
7. The application of a compound capable of inhibiting the activity of an organic anion transporter 1 or a pharmaceutically acceptable salt of the compound to preparation of a medicament for treating and/or preventing hyperuricemia and gout, wherein the compound capable of inhibiting the activity of the organic anion transporter 1 or the pharmaceutically acceptable salt of the compound is the compound capable of inhibiting the activity of the organic anion transporter 1 according to any one of claims 1-2 or the pharmaceutically acceptable salt of the compound.
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WO2003029212A1 (en) * 2001-09-27 2003-04-10 F. Hoffmann-La Roche Ag Indole derivatives as cox ii inhibitors
WO2004018428A1 (en) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Antibacterial benzoic acid derivatives

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