CN111187218A - Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal β -lactamase inhibitor - Google Patents

Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal β -lactamase inhibitor Download PDF

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CN111187218A
CN111187218A CN202010121054.9A CN202010121054A CN111187218A CN 111187218 A CN111187218 A CN 111187218A CN 202010121054 A CN202010121054 A CN 202010121054A CN 111187218 A CN111187218 A CN 111187218A
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李国菠
王震玲
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Sichuan University
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Abstract

The invention relates to an application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparing metal β -lactamase inhibitors, and particularly discloses an application of compounds shown in formula I in preparing metal β -lactamase inhibitors or antibacterial combined drugs, experiments prove that the compounds provided by the invention can effectively inhibit the activity of various MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-1 and VIM-5, particularly compounds 11, 13, 14, 29, 30, 34, 37 and 40, and IC of the compounds on the VIM-2 MBL enzymes50The value is below 2.13 mu M, the inhibition effect is more obvious than that of a positive control drug, and the compound has very good potential in preparing an MBL enzyme inhibitor, and meanwhile, the compound is combined with β -lactam antibiotics, so that the metal β -lactamase generated by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotics is enhanced, and the compound has very good application prospect in preparing antibacterial combined drugs.

Description

Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal β -lactamase inhibitor
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a 1-substituted-1H-imidazole-2-carboxylic acid compound and application thereof as a metal β -lactamase inhibitor.
Background
β -lactam antibiotics have the advantages of strong bactericidal activity, low toxicity, wide indications, good clinical curative effect and the like, and occupy very important positions in antibacterial drugs, the most commonly used β -lactam antibiotics in clinic mainly comprise penicillins, cephalosporins, carbapenems, monocyclic β -lactam and the like, however, in recent years, the drug resistance of bacteria to the drugs is increased, and the curative effect of the drugs is seriously influenced, serine β -lactamase (SBL) and metallo β -lactamase (MBL) generated by pathogenic bacteria are generated, a quaternary β -lactam ring in a chemical structure of the hydrolyzable antibiotics destroys a key pharmacophore structure of the antibiotics, so that the antibiotics are ineffective due to the fact that the antibiotics are the most main drug resistance mechanism at present, a β -lactamase inhibitor and β -lactam antibiotics are combined to overcome the drug resistance of bacteria, and the principle is that a β -lactamase inhibitor prevents enzymes from hydrolyzing β -lactam antibiotics, so that the antibiotics exert the original antibacterial effects of the antibiotics are improved, the SBL 6-lactam inhibitors and the resistance of the antibiotics are almost approved by vitamin B-lactam antibiotics, and the resistance of the SBL, the resistance of the antibiotics and the resistance of the antibiotics, the resistance of the SBL, the SBL and the resistance of the RRE-lactam antibiotics, the SBL and the RRE-lactam, and the SBL.
Although a large number of MBL inhibitors have been reported at present, and part of the inhibitors also show good in vitro and in vivo activity, no MBL inhibitor is approved for clinical use until now, and medicaments entering clinical research are available.
Disclosure of Invention
In order to solve the problems, the invention provides a 1-substituted-1H-imidazole-2-carboxylic acid compound and application thereof in preparing a metal β -lactamase inhibitor.
The invention provides a compound shown as a formula C, or a salt, a stereoisomer, a crystal form or a solvate thereof:
Figure BDA0002392985820000021
wherein L is substituted or unsubstituted C1～3An alkylene group;
Raselected from amino, -YRd5-6 membered unsaturated heterocyclic group substituted with 0-3 substituents, cyano group, -COORc,RcIs selected from H or C1～3An alkyl group; and when R isaWhen cyano, L is ethylene; when R isais-COORcWhen L is C1～3An alkyl-substituted methylene group;
y is selected from O, S, CO, SO or SO2；
RdIs selected from C1～3An alkyl group, a 5-to 6-membered unsaturated heterocyclic group substituted with 0 to 3 substituents;
the substituents are independently selected from C1～3Alkyl, halogen, hydroxyl, carboxyl.
Further, the structure of the compound is shown as a formula C-1:
Figure BDA0002392985820000022
wherein m is 1 or 2; z is nothing or Y, Y is selected from O, S, CO, SO or SO2Y is preferably S, SO or SO2；
The P ring is a 5-to 6-membered unsaturated heterocycle, preferably
Figure BDA0002392985820000023
Figure BDA0002392985820000024
RbSelected from H, C1～3Alkyl, halogen, hydroxyl, carboxyl.
Further, the compound is selected from one of the following compounds:
Figure BDA0002392985820000025
Figure BDA0002392985820000031
the invention also provides a medicament which is a preparation prepared by taking the compound, or the salt, the stereoisomer, the crystal form or the solvate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides an antibacterial combined medicament which contains the compound, the salt thereof, the stereoisomer thereof, the crystal form thereof, the solvate thereof and an antibacterial medicament which are administered simultaneously or respectively and have the same or different specifications, and a pharmaceutically acceptable carrier, wherein the antibacterial medicament is preferably β -lactam antibiotic, and more preferably meropenem.
The invention also provides application of the compound shown in the formula I, or a salt, a stereoisomer, a crystal form or a solvate thereof in preparing a metal β -lactamase inhibitor:
Figure BDA0002392985820000032
in the formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano-group and-L1R1、-L2XR2Substituted or unsubstituted of the following groups: c1～8Alkyl radical, C2～8Alkenyl radical, C2～8An alkynyl group; the substituent is selected from C1～3Alkyl, hydroxy, carboxy, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～5An alkyl group;
L1selected from none or C1～5An alkylene group; r1Selected from the following groups substituted with 0 to 5 substituents: a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring; the substituents are each independently selected from C1～3Alkyl, halogen, hydroxy, carboxy, amino, cyano, -L3NH2，L3Is selected from C1～3An alkylene group;
L2selected from none or C1～5An alkylene group; x is selected from O, S, CO, SO or SO2；R2Selected from amino, C1～5Alkyl radical, C1～5Alkoxy, substituted or unsubstituted saturated or unsaturated carbocycle, substituted or unsubstituted saturated or unsaturated heterocycle, the substituent is selected from C1～3Alkyl, halogen, hydroxyl, carboxyl, amino, cyano.
Further, the metal β -lactamase is VIM-2, NDM-1, IMP-1, VIM-1 and/or VIM-5.
The invention also provides application of the compound shown in the formula I, or a salt, a stereoisomer, a crystal form or a solvate thereof and an antibacterial drug in preparation of antibacterial combined drugs:
Figure BDA0002392985820000041
in the formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano-group and-L1R1、-L2XR2Substituted or unsubstituted of the following groups: c1～8Alkyl radical, C2～8Alkenyl radical, C2～8An alkynyl group; the substituent is selected from C1～3Alkyl, hydroxy, carboxy, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～5An alkyl group;
L1selected from none or C1～5An alkylene group; r1Selected from the following groups substituted with 0 to 5 substituents: a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring; the substituents are each independently selected from C1～3Alkyl, halogen, hydroxy, carboxy, amino, cyano, -L3NH2，L3Is selected from C1～3An alkylene group;
L2selected from none or C1～5An alkylene group; x is selected from O, S, CO, SO or SO2；R2Selected from amino, C1～5Alkyl radical, C1～5Alkoxy, substituted or unsubstituted saturated or unsaturated carbocycle, substituted or unsubstituted saturated or unsaturated heterocycle, the substituent is selected from C1～3Alkyl, halogen, hydroxyl, carboxyl, amino, cyano.
Further, the antibacterial drug is β -lactam antibiotic, preferably meropenem.
Further, in formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted following groups: c1～4Alkyl radical, C2～4Alkenyl radical, C2～4An alkynyl group; the substituents are selected from methyl, hydroxy, carboxyl, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～3An alkyl group.
Further, the structure of the compound shown in the formula I is shown in the formula II:
Figure BDA0002392985820000051
in the formula II, L1Selected from none or C1～3An alkylene group;
m ring is selected from 3-6 membered saturated or unsaturated carbocyclic ring, 3-6 membered saturated or unsaturated carbocyclic ringAnd a heterocyclic ring; preferably, the M ring is selected from
Figure BDA0002392985820000052
Figure BDA0002392985820000053
m is an integer of 0 to 3, preferably 0 or 1;
R1ais selected from C1～3Alkyl, halogen, hydroxy, amino, -L3NH2，L3Is selected from C1～2An alkylene group;
alternatively, the structure of the compound of formula I is shown in formula IV:
Figure BDA0002392985820000054
wherein L is2Selected from none or C1～3An alkylene group;
x is selected from O, S, CO, SO2；
R2Selected from amino, C1～3Alkyl radical, C1～3Alkoxy, substituted or unsubstituted 5-6 membered saturated or unsaturated heterocycle, the substituent is selected from C1～3An alkyl group.
Further, the structure of the compound shown in the formula II is shown in the formula III:
Figure BDA0002392985820000055
in formula III, E is selected from N or CR5，R5Selected from H, C1～3Alkyl, halogen, hydroxy, amino, -CH2NH2。
Further, the structure of the compound shown in formula I is shown in formula C:
Figure BDA0002392985820000061
in the formula C, L is substituted or unsubstituted C1～3An alkylene group;
Raselected from amino, -YRd5-6 membered unsaturated heterocyclic group substituted with 0-3 substituents, cyano group, -COORc,RcIs selected from H or C1～3An alkyl group; and when R isaWhen cyano, L is ethylene; when R isais-COORcWhen L is C1～3An alkyl-substituted methylene group;
y is selected from O, S, CO, SO or SO2；
RdIs selected from C1～3An alkyl group, a 5-to 6-membered unsaturated heterocyclic group substituted with 0 to 3 substituents;
the substituents are independently selected from C1～3Alkyl, halogen, hydroxyl, carboxyl.
Further, the structure of the compound shown in the formula C is shown in a formula C-1:
Figure BDA0002392985820000062
wherein m is 1 or 2; z is nothing or Y, Y is selected from O, S, CO, SO or SO2Y is preferably S, SO or SO2；
The P ring is a 5-to 6-membered unsaturated heterocycle, preferably
Figure BDA0002392985820000063
Figure BDA0002392985820000064
RbSelected from H, C1～3Alkyl, halogen, hydroxyl, carboxyl.
Further, the compound shown in the formula I is selected from one of the following compounds:
Figure BDA0002392985820000065
Figure BDA0002392985820000071
Figure BDA0002392985820000081
experiments prove that the compound provided by the invention can effectively inhibit the activity of a plurality of MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-1 and VIM-5, in particular to compounds 11, 13, 14, 29, 30, 34, 37 and 40, and IC of the compounds on the VIM-2 MBL enzyme50The value is below 2.13 mu M, the inhibition effect is more obvious than that of a positive control drug, and the compound has very good potential in preparing an MBL enzyme inhibitor, and meanwhile, the compound is combined with β -lactam antibiotics, so that the metal β -lactamase generated by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotics is enhanced, and the compound has very good application prospect in preparing antibacterial combined drugs.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a (Bruker Avance III 400) nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (d)6-DMSO) or deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
Example 11-synthesis of methyl-1H-imidazole-2-carboxylic acid (compound B):
Figure BDA0002392985820000091
ethyl imidazole-2-carboxylate 1(100mg, 0.71mmol) was dissolved in 10ml THF, activated by slow addition of sodium hydride (43mg, 1.78mmol) under ice bath for 1h, followed by addition of iodomethane (507mg, 3.57mmol), and after completion of addition, reacted at room temperature for 1 h. TLC detection reaction is complete, stop reaction, decompression concentration to remove solvent, water dissolution, ethyl acetate extraction (3X 20ml), organic layer combination, saturated saline solution washing, anhydrous sodium sulfate drying, filtration, concentration to get crude product. Purification by column chromatography (PE: EA ═ 1:1) gave compound 1-methyl-1H-imidazole-2-carboxylic acid ethyl ester 1b (98mg, yield 89%) as a yellow oily liquid.
The compound ethyl 1-methyl-1H-imidazole-2-carboxylate 1b (98mg, 0.63mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (76mg, 1.91mmol) into a mixed solvent with the O being 2:1 under stirring, reacting for 1H at normal temperature after the addition is finished, detecting the reaction completely by TLC, stopping the reaction, adjusting the Ph to about 7-8 by 3NHCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH being 10:1) to obtain a light yellow liquid, namely the compound 1-methyl-1H-imidazole-2-carboxylic acid (namely the compound B, 41mg, the yield is 81.2%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ7.35(s,1H),6.93(s,1H),3.99(s,3H)ppm.13CNMR(101MHz,DMSO-d6)δ138.28,128.58,124.67,121.00,33.28ppm.HRMS:m/z calcd forC5H6N2O2[M+H]+127.0502,found 127.0504；[M+Na]+149.0327,found 149.0243.
Example 21-synthesis of amino-1H-imidazole-2-carboxylic acid (compound 3):
Figure BDA0002392985820000092
imidazole 2-carboxylic acid (95mg, 0.86mmol) was dissolved in 10ml N, N-dimethylformamide, potassium tert-butoxide (154mg, 1.37mmol) was added with stirring, and O- (4-nitrobenzoyl) hydroxylamine (172mg, 0.94mmol) was added after 0.5h of activation. Reacting at normal temperature for 10H, detecting by TLC to complete reaction, stopping reaction, adjusting pH to about 5 with 3N HCl, separating out solid, filtering, washing with dichloromethane to obtain light yellow crystal, i.e. compound 1-amino-1HImidazole-2-carboxylic acid (i.e. compound 3, 82mg, yield 76.6%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.53(s,1H),7.08(s,1H),6.79(s,1H),6.17(s br,2H)ppm.13C NMR(101MHz,DMSO-d6)δ137.30,126.35,121.75ppm.ESI-MSm/z:128.04[M+H]+.
Example 31-synthesis of ethyl-1H-imidazole-2-carboxylic acid (compound 4):
Figure BDA0002392985820000101
dissolving imidazole-2-ethyl formate 1(100mg, 0.711mmol) in 3ml of N, N-dimethylformamide, adding potassium carbonate (295mg, 21.4mmol) for activation for 30min, then dropwise adding bromoethane (155mg, 1.41mmol), after the addition is finished, heating to 60 ℃ for reaction for 4h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1-ethyl-1H-imidazole-2-carboxylate 3b (100mg, yield 83.3%) as a pale yellow liquid.
The compound ethyl 1-ethyl-1H-imidazole-2-carboxylate 3b (100mg, 0.59mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (71mg, 1.78mmol) into a mixed solvent with O being 2:1 under stirring, reacting for 1H at normal temperature after addition, detecting by TLC that the reaction is complete, stopping the reaction, adjusting the Ph to about 7-8 with 3NHCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH being 10:1) to obtain a light yellow liquid, namely the compound 1-ethyl-1H-imidazole-2-carboxylic acid (namely the compound 4, 70mg, the yield is 84.3%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ8.74(s br,1H),7.91(s,1H),7.33(s,1H),7.04(s,1H),4.04(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ163.87,142.91,136.73,129.21,125.68,121.38,118.58,43.10,41.99,16.52 16.49ppm.HRMS:m/zcalcd for C6H8N2O2[M-H]-139.0513,found 139.0515.
EXAMPLE 41 Synthesis of cyclopropyl-1H-imidazole-2-carboxylic acid (Compound 5)
Figure BDA0002392985820000102
Imidazole-2-carboxylic acid ethyl ester (300mg, 2.14mmol), cyclopropylboronic acid (532mg, 6.42mmol) and sodium carbonate (681mg, 6.42mmol) were dissolved in 6ml of 1, 2-dichloroethane, and 2, 2-bipyridine (33mg, 2.14mmol) and copper acetate (427mg, 2.14mmol) were added thereto with stirring, and after the addition, the temperature was raised to 70 ℃ to react for 3 hours. TLC, stopped the reaction, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (PE: EA ═ 2:1) to give the compound 1-cyclopropyl-1H-imidazole-2-carboxylic acid ethyl ester 4b (320mg, yield 83.1%).
Compound 4b (100mg, 0.55mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (67mg, 1.67mmol) into a mixed solvent with the ratio of O to 2:1 under stirring, reacting at normal temperature for 1H, detecting by TLC (thin layer chromatography), stopping the reaction, adjusting the pH value to about 7-8 with 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH: 10:1) to obtain a colorless viscous liquid, namely the compound 1-cyclopropyl-1H-imidazole-2-carboxylic acid (namely the compound 5, 60mg, the yield is 71.4%, and the HPLC purity is more than 95%).1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.16(s,1H),6.99(s,1H),4.54(s br,1H),3.34(s,1H),1.02-0.98(m,2H),0.88-0.83(m,2H)ppm.HRMS:m/z calcd for C7H8N2O3[M-H]-151.0508,found 151.0513.
EXAMPLE 51 Synthesis of allyl-1H-imidazole-2-carboxylic acid (Compound 6)
Figure BDA0002392985820000111
Dissolving imidazole-2-ethyl formate (300mg, 2.14mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (1.39g, 4.28mmol) for activation for 0.5h, adding 3-bromopropionitrile, heating to 80 ℃ after the addition for reaction for 5h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1-allyl-1H-imidazole-2-carboxylate 5b (310mg, yield 80.5%) as a pale yellow liquid.
Compound 5b (100mg, 0.56mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (67mg, 1.67mmol) into a mixed solvent with O being 2:1 under stirring, reacting for 1H at normal temperature after the addition is finished, detecting the reaction completely by TLC, stopping the reaction, adjusting the pH to about 7-8 by 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH being 10:1) to obtain a light yellow viscous liquid which is the compound 1-allyl-1H-imidazole-2-carboxylic acid (namely the compound 6, 65mg, the yield is 79.3%, and the HPLC purity is more than 95%).1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.11(s,1H),6.94(s,1H),6.00-5.94(m,1H),5.30(d,J＝10.4Hz,1H),5.20(d,J＝16.8Hz,1H),4.57(d,J＝5.6Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ137.68,134.95,128.86,119.92,117.81,48.79ppm.HRMS:m/z calcd for C7H8N2O2[M+H]+153.0659,found 153.0671.
Example synthesis of 61-propyl-1H-imidazole-2-carboxylic acid (compound 7):
Figure BDA0002392985820000121
dissolving imidazole-2-ethyl formate (300mg, 2.14mmol) in 10ml acetonitrile, adding cesium carbonate (1.39g, 4.28mmol) for activation for 0.5h, adding n-propyl bromide, heating to 80 ℃ after the addition, reacting for 5h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1-propyl-1H-imidazole-2-carboxylate 6b (330mg, yield 84.6%) as a colorless liquid.
Compound 6b (100mg, 0.54mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (65mg, 1.62mmol) into a mixed solvent with the ratio of O to 2:1 under stirring, reacting at normal temperature for 1h, detecting by TLC (thin layer chromatography), stopping the reaction, adjusting the pH to about 7-8 with 3N HCl, concentrating under reduced pressure to obtain a crude product, purifying by column chromatography (DCM: MeOH: 10:1) to obtain a colorless viscous liquid,i.e., compound 1-propyl-1H-imidazole-2-carboxylic acid (i.e., compound 7, 65mg, yield 86.7%, HPLC purity > 95%).1H NMR(400MHz,CDCl3)δ7.09(s,1H),6.93(s,1H),4.44(s,2H),1.80(t,J＝7.2Hz,2H),0.87(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ160.23,143.10,124.20,49.04,24.37,11.16ppm.HRMS:m/z calcd for C7H10N2O2[M+H]+155.0821,found 155.0829；[M+Na]+177.0640,found177.0652.
Example 71-Synthesis of isopropyl-1H-imidazole-2-carboxylic acid (Compound 8):
Figure BDA0002392985820000122
dissolving imidazole-2-ethyl formate (300mg, 2.14mmol) in 5ml of N, N-dimethylformamide, adding potassium carbonate (887mg, 6.42mmol) for activation for 0.5h, adding 2-bromopropane (392mg, 3.21mmol), heating to 60 ℃ after addition for reaction for 4h, detecting complete reaction by TLC, stopping reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3 × 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1-isopropyl-1H-imidazole-2-carboxylate 7b (350mg, yield 89.7%) as a pale yellow liquid.
Compound 7b (100mg, 0.55mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (66mg, 1.65mmol) into a mixed solvent with O being 2:1 under stirring, reacting for 1H at normal temperature after the addition is finished, detecting the reaction completely by TLC, stopping the reaction, adjusting the pH to about 7-8 by 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH being 10:1) to obtain a white solid powder, namely the compound 1-isopropyl-1H-imidazole-2-carboxylic acid (namely the compound 8, 75mg, the yield is 89.3%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ7.52(s,1H),6.76(s,1H),5.87-5.81(m,1H),1.37(d,J＝6.8Hz,6H)ppm.13C NMR(101MHz,DMSO-d6)δ135.91,128.66,117.53,48.71,23.97ppm.HRMS:m/zcalcdfor C7H10N2O2[M+H]+155.0815,found 155.0807.
Example synthesis of 81- (2-aminoethyl) -1H-imidazole-2-carboxylic acid (compound 9):
Figure BDA0002392985820000131
dissolving imidazole-2-carboxylic acid ethyl ester (300mg, 2.14mmol) in 8ml of N, N-dimethylformamide, adding cesium carbonate (1.39g, 4.28mmol) for activation for 0.5H, adding N-Boc-bromoethylamine (716mg, 3.21mmol), heating to 80 ℃ for reaction for 5H, detecting the reaction completion by TLC, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to obtain the compound 1- (2- (((tert-butoxycarbonyl) amino) ethyl) -1H-imidazole-2-carboxylic acid ethyl ester 8b, and directly feeding to the next step without purification.
The compound ethyl 1- (2- (((tert-butoxycarbonyl) amino) ethyl) -1H-imidazole-2-carboxylate 8b was directly dissolved in 8ml of dichloromethane, 0.8ml of trifluoroacetic acid was added, the reaction was allowed to react at normal temperature for 3 hours, the reaction was detected by TLC and was stopped, the solvent was removed by concentration under reduced pressure, 50ml of water was added to dissolve the mixture, the Ph was adjusted to about 8 with sodium bicarbonate, ethyl acetate was extracted (3 × 20ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (DCM: MeOH ═ 30:1) to give a colorless viscous liquid, i.e., the compound ethyl 1- (2-aminoethyl) -1H-imidazole-2-carboxylate 8c (240mg, yield 61.2%).
Compound 8c (100mg, 0.55mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (66mg, 1.64mmol) into a mixed solvent of O2: 1 under stirring, reacting at normal temperature for 1H, detecting by TLC (thin layer chromatography), stopping the reaction, adjusting the pH to about 7-8 with 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH 3:1) to obtain a colorless viscous liquid, namely the compound 1- (2-aminoethyl) -1H-imidazole-2-carboxylic acid (namely the compound 9, 68mg, the yield is 80.9%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ7.12(s,1H),6.77(s,1H),4.44(t,J＝6.4Hz,2H),2.84(t,J＝6.4Hz,2H),1.97(s br,2H)ppm.ESI-MS m/z:156.07[M+H]+.
Example synthesis of 91- (3-aminopropyl) -1H-imidazole-2-carboxylic acid (compound 10):
Figure BDA0002392985820000141
dissolving imidazole-2-carboxylic acid ethyl ester (300mg, 2.14mmol) in 8ml of N, N-dimethylformamide, adding cesium carbonate (1.39g, 4.28mmol) for activation for 0.5H, adding N-Boc-3-aminopropyl bromide (762mg, 3.21mmol), heating to 80 ℃ for reaction for 5H, detecting the reaction completion by TLC, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3 × 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a compound of 1- (3- ((tert-butoxycarbonyl) amino) propyl) -1H-imidazole-2-carboxylic acid ethyl ester 9b, and directly putting the compound into the next step without purification.
Directly dissolving a compound 1- (3- ((tert-butoxycarbonyl) amino) propyl) -1H-imidazole-2-carboxylic acid ethyl ester 9b in 8ml of dichloromethane, adding 0.8ml of trifluoroacetic acid, reacting for 3 hours at normal temperature, detecting complete reaction by TLC, stopping the reaction, concentrating under reduced pressure to remove a solvent, adding 50ml of water for dissolving, adjusting the pH of sodium bicarbonate to about 8, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (DCM: MeOH ═ 30:1) gave the compound ethyl 1- (3-aminopropyl) -1H-imidazole-2-carboxylate 9c (280mg, 66.3% yield) as a colorless viscous liquid.
The compound ethyl 1- (3-aminopropyl) -1H-imidazole-2-carboxylate 9c (100mg, 0.51mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (61mg, 1.52mmol) into a mixed solvent with O being 2:1 under stirring, reacting for 1H at normal temperature, detecting by TLC (thin layer chromatography), stopping the reaction, adjusting the pH to about 7-8 with 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH being 3:1) to obtain a colorless viscous liquid, namely the compound 1- (3-aminopropyl) -1H-imidazole-2-carboxylic acid (namely the compound 10, 72mg, the yield is 84.0%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ8.36(s br,3H),7.24(s,1H),6.88(s,1H),4.55(t,J＝6.4Hz,2H),2.66(t,J＝6.4Hz,2H),2.05-2.01(m,2H)ppm.ESI-MS m/z:170.08[M+H]+.
Example synthesis of 101- (but-3-en-1-yl) -1H-imidazole-2-carboxylic acid (compound 11):
Figure BDA0002392985820000142
dissolving imidazole-2-ethyl formate (300mg, 2.14mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (1.39g, 4.28mmol) for activation for 0.5h, adding 4-bromo-1-butene (430mg, 3.21mmol), heating to 80 ℃ after the activation is completed, reacting for 4h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1- (but-3-en-1-yl) -1H-imidazole-2-carboxylate 10b (350mg, yield 89.7%) as a pale yellow liquid.
The compound ethyl 1- (but-3-en-1-yl) -1H-imidazole-2-carboxylate 10b (100mg, 0.51mmol) was dissolved in 6ml EtOH: H2Adding sodium hydroxide (62mg, 1.54mmol) into a mixed solvent with the ratio of O to 2:1 under stirring, reacting for 1H at normal temperature, detecting by TLC (thin layer chromatography) until the reaction is completed, stopping the reaction, adjusting the pH to about 7-8 with 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH: 10:1) to obtain a light yellow viscous liquid, namely the compound 1- (but-3-en-1-yl) -1H-imidazole-2-carboxylic acid (namely the compound 11, 75mg, the yield is 88.2%, and the HPLC purity is more than 95%).1H NMR(400MHz,DMSO-d6)δ7.61(s,1H),7.17(s,1H),6.87(s,1H),5.79-5.69(m,1H),5.06-4.96(m,2H),4.02(t,J＝7.2Hz,2H),2.46(q,J＝7.2Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ137.20,134.79,128.28,119.24,117.31,45.26,34.85ppm.HRMS:m/z calcd forC8H10N2O2[M+H]+167.0815,found 167.0808.
EXAMPLE 111 Synthesis of cyclobutyl-1H-imidazole-2-carboxylic acid (Compound 12)
Figure BDA0002392985820000151
Dissolving imidazole-2-ethyl formate (300mg, 2.14mmol) in 5ml of N, N-dimethylformamide, adding potassium carbonate (887mg, 6.42mmol) for activation for 0.5h, adding bromocyclobutane (430mg, 3.21mmol), heating to 100 ℃ after addition for reaction for 5h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1-cyclobutyl-1H-imidazole-2-carboxylate 11b (350mg, yield 89.7%) as a colorless liquid.
Using compound 1-cyclobutyl-1H-imidazole-2-carboxylic acid ethyl ester 11b as a starting material, and according to the general procedure for ester hydrolysis, purification by column chromatography (DCM: MeOH ═ 10:1) gave compound 1-cyclobutyl-1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 12, 76mg, yield 89.4%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),7.82(s,1H),7.54(s,1H),6.35(s br,1H),4.95-4.87(m,1H),2.47-2.41(m,4H),1.85-1.77(m,2H)ppm.13C NMR(101MHz,CDCl3)δ135.56,129.26,116.94,50.98,31.08,14.89ppm.HRMS:m/z calcd for C8H10N2O2[M-H]-165.0670,found 165.0672.
Example 121-synthesis of isobutyl-1H-imidazole-2-carboxylic acid (compound 13):
Figure BDA0002392985820000161
dissolving imidazole-2-ethyl formate (150mg, 1.07mmol) in 5ml acetonitrile, adding cesium carbonate (1.04g, 3.21mmol) for activation for 0.5h, adding 1-bromo-2-methylpropane (437mg, 3.21mmol), reacting at normal temperature for 4h, detecting by TLC to complete the reaction, stopping the reaction, performing rotary evaporation to remove acetonitrile, adding water, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1-isobutyl-1H-imidazole-2-carboxylate 12b (200mg, yield 95.2%) as a pale yellow liquid.
Starting from the compound 1-isobutyl-1H-imidazole-2-carboxylic acid ethyl ester 12b, purification by column chromatography is carried out according to the general procedure for ester hydrolysis (DCM: MeOH ═ 10:1)) A colorless viscous liquid was obtained, i.e., compound 1-isobutyl-1H-imidazole-2-carboxylic acid (i.e., compound 13, 75mg, yield 87.5%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.65(s,1H),7.51(s,1H),5.57(s br,1H),3.99(d,J＝7.6Hz,2H),2.14-2.04(m,1H),0.85(d,J＝6.8Hz,6H)ppm.13C NMR(101MHz,DMSO-d6)δ136.44,124.66,122.70,122.00,55.01,29.40,19.69ppm.HRMS:m/zcalcd for C8H12N2O2[M+H]+169.0972,found 169.0977.
Example synthesis of 131- (sec-butyl) -1H-imidazole-2-carboxylic acid (compound 14):
Figure BDA0002392985820000162
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding bromo-sec-butyl alkane (291mg, 2.14mmol), heating to 60 ℃ for reaction for 4h, detecting by TLC that the reaction is complete, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1- (sec-butyl) -1H-imidazole-2-carboxylate 13b (260mg, yield 92.8%) as a pale yellow liquid.
Starting from compound 1- (sec-butyl) -1H-imidazole-2-carboxylic acid ethyl ester 13b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (sec-butyl) -1H-imidazole-2-carboxylic acid as a colorless viscous liquid (i.e. compound 14, 78mg, 91.0% yield, > 95% HPLC purity).1H NMR(400MHz,CDCl3)δ7.51(s,1H),7.07(s,1H),6.93(s,1H),4.09-4.00(m,1H),1.80-1.73(m,2H),1.47(d,J＝6.8Hz,3H),0.83(t,J＝7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ136.57,128.78,117.76,54.54,30.50,21.88,10.84ppm.HRMS:m/z calcd for C8H12N2O2[M+H]+169.0972,found 169.0978；[M+Na]+191.0796,found 191.0799.
Example 141 Synthesis of cyclopentyl-1H-imidazole-2-carboxylic acid (Compound 15):
Figure BDA0002392985820000171
dissolving imidazole-2-carboxylic acid ethyl ester (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding bromocyclopentane (317mg, 2.14mmol), heating to 80 ℃ for reaction for 3h, detecting by TLC that the reaction is complete, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound 1-cyclopentyl-1H-imidazole-2-carboxylic acid ethyl ester 14b (240mg, yield 80.8%) as a pale yellow liquid.
Starting from compound 1-cyclopentyl-1H-imidazole-2-carboxylic acid ethyl ester 14b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1-cyclopentyl-1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 15, 74mg, yield 86.0%, HPLC purity > 95%).1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.08(s,1H),6.95(s,1H),4.49-4.42(m,1H),2.23-2.16(m,2H),1.89-1.81(m,4H),1.77-1.71(m,2H)ppm.13C NMR(101MHz,CDCl3)δ164.74,143.72,135.95,129.21,126.24,117.75,117.41,58.36,57.35,33.83,33.67,24.18,23.78ppm.HRMS:m/z calcd for C9H12N2O2[M-H]-179.0826,found 179.0833.
Example 151 synthesis of- (2-hydroxypropyl) -1H-imidazole-2-carboxylic acid (compound 16):
Figure BDA0002392985820000172
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml ethanol, adding epoxypropane (414mg, 7.14mmol), heating to 80 ℃ for reaction for 3h, detecting by TLC that the reaction is complete, stopping the reaction, removing ethanol by rotary evaporation, adding water for dissolution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1- (2-hydroxypropyl) -1H-imidazole-2-carboxylate 15b (200mg, yield 70.9%) as a colourless solid.
Starting from compound 1- (2-hydroxypropyl) -1H-imidazole-2-carboxylic acid ethyl ester 15b, the compound was purified by column chromatography (DCM: MeOH ═ 4:1) according to the general procedure for ester hydrolysis to give the compound 1- (2-hydroxypropyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 16, 70mg, yield 83.9%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.59(s,1H),7.15(s,1H),6.87(s,1H),5.03(s,1H),4.55-4.27(m,1H),3.94-3.81(m,2H),1.00(d,J＝6.4Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ137.80,127.81,120.18,65.76,53.33,20.73ppm.HRMS:m/z calcd for C7H10N2O3[M+H]+171.0764,found 171.0770.
Example synthesis of 161- (1-carboxyethyl) -1H-imidazole-2-carboxylic acid (compound 17):
Figure BDA0002392985820000181
mixing imidazole-2-carboxylic acid ethyl ester (200 m)g1.43mmol) is dissolved in 5ml of N, N-dimethylformamide, potassium carbonate (591mg, 4.28mmol) is added for activation for 0.5h, then 2-bromopropionic acid ethyl ester (385mg, 2.14mmol) is added, the temperature is raised to 80 ℃ for reaction for 3h, TLC detection is carried out for complete reaction, the reaction is stopped, the mixture is cooled to room temperature, water is added for dilution, ethyl acetate extraction (3X 20ml) is carried out, organic layers are combined, saturated saline is washed, anhydrous sodium sulfate is dried, filtration and concentration are carried out, thus obtaining a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (1-carboxyethyl) -1H-imidazole-2-carboxylate 16b (330mg, yield 96.5%) as a colourless liquid.
Starting from compound 1- (1-carboxyethyl) -1H-imidazole-2-carboxylic acid ethyl ester 16b, the compound was purified by column chromatography (DCM: MeOH ═ 2:1) according to the general procedure for ester hydrolysis to give the compound 1- (1-carboxyethyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 17, 70mg, yield 91.3%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.19(s,1H),6.88(s,1H),4.79(q,J＝7.2Hz,3H),4.65(s br,2H),1.55(d,J＝7.6Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.35,136.90,127.15,119.32,56.84,19.60ppm.HRMS:m/z calcd for C7H8N2O4[M-H]-183.0411,found 183.0415.
Example 171 synthesis of- (2- (dimethylamino) ethyl) -1H-imidazole-2-carboxylic acid (compound 18):
Figure BDA0002392985820000182
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding potassium carbonate (591mg, 4.28mmol) for activation for 0.5h, adding N, N-dimethylamino bromoethane hydrobromide (499mg, 2.14mmol), heating to 80 ℃ for reaction for 3h, detecting by TLC that the reaction is complete, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dissolution, extracting with ethyl acetate (3 × 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (2- (dimethylamino) ethyl) -1H-imidazole-2-carboxylate 17b (264mg, yield 87.7%) as a pale yellow liquid.
Using compound 1- (2- (dimethylamino) ethyl) -1H-imidazole-2-carboxylic acid ethyl ester 17b as the starting material, and following the general procedure for ester hydrolysis, purification by column chromatography (DCM: MeOH ═ 5:1) yielded compound 1- (2- (dimethylamino) ethyl) -1H-imidazole-2-carboxylic acid as a yellow-brown viscous liquid (i.e., compound 18, 78mg, yield 89.9%, HPLC purity > 95%).1HNMR(400MHz,DMSO-d6)δ7.64(s,1H),7.18(s,1H),6.87(s,1H),4.06(t,J＝6.4Hz,2H),2.58(t,J＝6.4Hz,2H),2.18(s,6H)ppm.13C NMR(101MHz,DMSO-d6)δ137.87,128.42,120.01,59.79,45.52,44.40ppm.HRMS:m/z calcd for C8H13N3O2[M-H]-182.0935,found 182.0933.
Example 181- (3- (dimethylamino) propyl) -1H-imidazole-2-carboxylic acid (compound 19) synthesis:
Figure BDA0002392985820000191
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding N, N-dimethylamino chloropropane hydrochloride (338mg, 2.14mmol), heating to 60 ℃ for reaction for 3h, detecting the reaction by TLC (thin layer chromatography), stopping the reaction, decompressing and concentrating to remove acetonitrile, adding water for dissolution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (3- (dimethylamino) propyl) -1H-imidazole-2-carboxylate 18b (280mg, yield 87.2%) as a pale yellow liquid.
Using compound 1- (3- (dimethylamino) propyl) -1H-imidazole-2-carboxylic acid ethyl ester 18b as a starting material, and referring to the general procedure for ester hydrolysis, purification was performed by column chromatography (DCM: MeOH ═ 5:1) to give a yellow-brown viscous liquid, compound 1- (3- (dimethylamino) propyl) -1H-imidazole-2-carboxylic acid (i.e., compound 19, 75mg, yield 85.7%, HPLC purity > 95%).1HNMR(400MHz,DMSO-d6)δ7.61(s,1H),7.16(s,1H),6.88(s,1H),3.98(t,J＝7.2Hz,2H),3.85(sbr 1H),2.23(t,J＝7.2Hz,2H),2.19(s,6H),1.89-1.82(m,2H)ppm.δ7.21(s,1H),6.90(s,1H),4.45(t,J＝7.2Hz,2H),3.85(s br 1H),2.44(t,J＝7.2Hz,2H),2.34(s,6H),1.98-1.91(m,2H)ppm.13C NMR(101MHz,DMSO-d6)δ137.75,128.74,119.78,56.12,45.54,44.39,29.00ppm.HRMS:m/z calcd for C9H15N3O2[M-H]-196.1092,found 196.1091.
Example synthesis of 191- (3-cyanopropyl) -1H-imidazole-2-carboxylic acid (compound 20):
Figure BDA0002392985820000201
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 4-bromobutyronitrile (317mg, 2.14mmol), heating to 80 ℃ for reaction for 2h, detecting the reaction completion by TLC, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound 1- (3-cyanopropyl) -1H-imidazole-2-carboxylic acid ethyl ester 19b (260mg, yield 88.1%) as a pale yellow liquid.
Using compound 1- (3-cyanopropyl) -1H-imidazole-2-carboxylic acid ethyl ester 19b as a starting material, and following the general procedure for ester hydrolysis, purification was performed by column chromatography (DCM: MeOH ═ 10:1) to afford compound 1- (3-cyanopropyl) -1H-imidazole-2-carboxylic acid as a pale yellow viscous liquid (i.e., compound 20, 80mg, yield 80.7%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.32(s,1H),6.90(s,1H),4.53(t,J＝6.8Hz,2H),2.50(t,J＝7.2Hz,2H),2.09-2.01(m,2H)ppm.HRMS:m/z calcd for C8H9N3O2[M+H]+180.0768,found 180.0774.
Example 201 synthesis of- (2-cyanoethyl) -1H-imidazole-2-carboxylic acid (compound 21):
Figure BDA0002392985820000202
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 3-bromopropionitrile (287mg, 2.14mmol), heating to 80 ℃ for reaction for 4h, detecting the reaction by TLC (thin layer chromatography), stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound 1- (2-cyanoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 20b (230mg, yield 83.6%) as a pale yellow liquid.
Starting from compound 1- (2-cyanoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 20b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (3-cyanopropyl) -1H-imidazole-2-carboxylic acid as a pale yellow viscous liquid (i.e. compound 21, 78mg, yield 91.2%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.35(s,1H),6.91(s,1H),4.70(t,J＝6.4Hz,2H),3.01(t,J＝6.4Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ162.35,144.56,126.36,123.94,119.11,43.15,19.87ppm.HRMS:m/z calcd forC7H7N3O2[M+H]+166.0611,found 166.0614.
Example synthesis of 211- ((methylthio) methyl) -1H-imidazole-2-carboxylic acid (compound 22):
Figure BDA0002392985820000211
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding chloromethyl methyl sulfide (205mg, 2.14mmol), heating to 80 ℃ for reaction for 4h, detecting by TLC that the reaction is complete, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave a pale yellow viscous liquid, compound ethyl 1- ((methylthio) methyl) -1H-imidazole-2-carboxylate 21b (260mg, yield 91.2%).
Starting from compound 1- ((methylthio) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 21b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- ((methylthio) methyl) -1H-imidazole-2-carboxylic acid as a white solid (i.e. compound 22, 75mg, yield 87.2%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.43(s,1H),6.76(s,1H),5.70(s,2H),2.06(s,3H)ppm.HRMS:m/zcalcd for C6H8N2O2S[M-H]-171.0234,found 171.0238.
Example synthesis of 221- ((methylsulfonyl) methyl) -1H-imidazole-2-carboxylic acid (compound 23):
Figure BDA0002392985820000212
dissolving a compound 1- ((methylthio) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 21b (200mg, 1.00mmol) in 10ml of dichloromethane, adding m-chloroperoxybenzoic acid (173mg, 2.00mmol) under stirring, reacting at normal temperature for 30min after the addition is finished, detecting by TLC to complete the reaction, stopping the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by column chromatography (PE: EA is 1:3) to obtain a white solid, namely the compound 1- ((methylsulfonyl) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 22b (110mg, yield 47.4%).
Starting from compound 1- ((methylsulfonyl) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 22b, the general procedure for ester hydrolysis was followed and purified by column chromatography (DCM: MeOH ═ 1:1) to give the compound 1- ((methylsulfonyl) methyl) -1H-imidazole-2-carboxylic acid as a white solid (i.e., compound 23, 75mg, yield 85.3%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.27(s,1H),6.90(s,1H),6.23(s,2H),2.86(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ161.96,145.16,127.05,123.59,64.77,38.61ppm.HRMS:m/z calcd for C6H8N2O4S[M-H]-203.0132,found 203.0134.
Example synthesis of 231- ((methylsulfinyl) methyl) -1H-imidazole-2-carboxylic acid (compound 24):
Figure BDA0002392985820000221
dissolving a compound 1- ((methylthio) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 21b (200mg, 1.00mmol) in 10ml of dichloromethane, adding m-chloroperoxybenzoic acid (173mg, 2.00mmol) under stirring, reacting at normal temperature for 30min after the addition is finished, detecting by TLC to complete the reaction, stopping the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by column chromatography (PE: EA is 1:3) to obtain a white solid, namely the compound 1- ((methylsulfinyl) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 23b (120mg, yield 55.5%).
Starting from compound 1- ((methylsulfinyl) methyl) -1H-imidazole-2-carboxylic acid ethyl ester 23b, the compound was purified by column chromatography (DCM: MeOH ═ 1:1) according to the general procedure for ester hydrolysis to give the compound 1- ((methylsulfinyl) methyl) -1H-imidazole-2-carboxylic acid as a white solid (i.e. compound 24, 75mg, yield 85.3%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.17(s,1H),6.85(s,1H),5.89(d,J＝12.0Hz,1H),5.71(d,J＝12.0Hz,1H),2.45(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ162.40,145.10,138.75,129.20,126.55,123.69,120.91,66.24,64.55,35.98,35.65ppm.HRMS:m/z calcd for C6H8N2O3S[M-H]-187.0177,found 187.0185.
Example 241 synthesis of- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylic acid (compound 25):
Figure BDA0002392985820000231
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 2-bromoacetamide (295mg, 2.14mmol), heating to 80 ℃ for reaction for 4h, detecting the reaction completion by TLC, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylate 24b (240mg, yield 85.4%) as a pale yellow liquid.
Starting from the compound 1- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 24b, the compound was purified by column chromatography (DCM: MeOH ═ 4:1) according to the general procedure for ester hydrolysis to give the compound 1- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylic acid as a pale yellow viscous liquid (i.e. compound 25, 78mg, yield 91.2%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.27(s,1H),7.14(d,J＝0.4Hz,1H),6.85(d,J＝0.8Hz,1H),4.80(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ176.33,161.75,139.00,126.61,25.43ppm.HRMS:m/z calcd forC6H7N3O3[M-H]-168.0415,found 168.0418.
Example synthesis of 251- (2- (1H-1,2, 3-triazol-1-yl) ethyl) -1H-imidazole-2-carboxylic acid (compound 26):
Figure BDA0002392985820000232
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding potassium carbonate (591mg, 4.28mmol) for activation for 0.5h, adding 1, 2-dibromoethane (531mg, 2.85mmol), heating to 60 ℃ for reaction for 4h, detecting complete reaction by TLC, stopping reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (2-bromoethyl) -1H-imidazole-2-carboxylate 25b (320mg, yield 91.1%) as a pale yellow liquid.
Dissolving compound 1- (2-bromoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 25b (200mg, 0.81mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (530mg, 1.62mmol) for activation for 0.5H, adding 1H-1,2, 3-triazole (112mg, 1.62mmol), heating to 80 ℃ for reaction for 4H, detecting by TLC that the reaction is complete, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave a colorless viscous liquid, i.e. compound ethyl 1- (2- (1H-1,2, 3-triazol-1-yl) ethyl) -1H-imidazole-2-carboxylate 25c (170mg, 88.6 yield%).
Starting from compound 1- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 24b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) to give the compound 1- (2-amino-2-oxoethyl) -1H-imidazole-2-carboxylic acid (i.e. compound 26, 78mg, yield 89.0%, HPLC purity > 95%) as a pale yellow viscous liquid, according to the general procedure for ester hydrolysis.1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝11.6,2H),7.23(s,1H),6.94(s,1H),6.79(s,1H),4.79(t,J＝6.0Hz,2H),4.51(t,J＝6.0Hz,2H)ppm.13CNMR(101MHz,DMSO-d6)δ137.75,135.13,135.04,128.78,119.70,55.11,45.74ppm.HRMS:m/z calcd for C8H7N5O2[M-H]-206.0673,found206.0680.
Example synthesis of 261- (2-hydroxyethyl) -1H-imidazole-2-carboxylic acid (compound 27):
Figure BDA0002392985820000241
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 2-bromoethyl acetate (385mg, 2.14mmol), heating to 80 ℃ for reaction for 2h, detecting the reaction by TLC (thin layer chromatography), stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (2-acetoxyethyl) -1H-imidazole-2-carboxylate 26b (300mg, 92.8% yield) as a pale yellow liquid.
Starting from compound 1- (2-acetoxyethyl) -1H-imidazole-2-carboxylic acid ethyl ester 26b, the compound was purified by column chromatography (DCM: MeOH ═ 3:1) according to the general procedure for ester hydrolysis to give the compound 1- (2-hydroxyethyl) -1H-imidazole-2-carboxylic acid as a white solid (i.e. compound 27, 62mg, yield 89.8%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝0.8,1H),6.84(s,1H),5.22(s br,1H),4.52(t,J＝5.6Hz,2H),3.66(t,J＝5.6Hz,2H)ppm.HRMS:m/z calcd for C6H8N2O3[M+H]+157.0608,found 157.0610.
Example 271 synthesis of- (2-methoxyethyl) -1H-imidazole-2-carboxylic acid (compound 28):
Figure BDA0002392985820000251
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 2-bromoethyl methyl ether (295mg, 2.14mmol), heating to 80 ℃ for reaction for 3h, detecting the reaction by TLC (thin layer chromatography), stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (2-methoxyethyl) -1H-imidazole-2-carboxylate 27b (260mg, yield 92.9%) as a pale yellow liquid.
Starting from compound 1- (2-methoxyethyl) -1H-imidazole-2-carboxylic acid ethyl ester 27b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (2-methoxyethyl) -1H-imidazole-2-carboxylic acid as a white solid (i.e. compound 28, 78mg, yield 90.9%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.58(s,1H),7.14(s,1H),6.86(s,1H),4.11(t,J＝5.2Hz,2H),3.57(t,J＝5.2Hz,2H),3.23(s,3H)ppm.δ7.10(s,1H),6.77(s,1H),4.62(t,J＝5.2Hz,2H),3.60(t,J＝5.2Hz,2H),3.21(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ137.95,128.56,120.07,71.71,58.43,46.28ppm.HRMS:m/z calcd for C7H10N2O3[M+H]+171.0764,found 171.0759.
Example 281- (furan-2-ylmethyl) -1H-imidazole-2-carboxylic acid (compound 29):
Figure BDA0002392985820000252
dissolving compound 28a furfuryl alcohol (200mg, 2.04mmol) in 5ml dichloromethane, slowly adding thionyl chloride (485mg, 4.08mmol) dropwise in ice bath, reacting at normal temperature for 2h after the addition is finished, detecting by TLC to complete the reaction, stopping the reaction, and concentrating under reduced pressure to obtain a crude product, namely compound 2- (chloromethyl) furan 28b, which is directly put into the next step.
Dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding a compound 2- (chloromethyl) furan 28b, heating to 80 ℃ for reaction for 3h, detecting by TLC to complete the reaction, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1- (furan-2-ylmethyl) -1H-imidazole-2-carboxylate 28b (200mg, yield 63.7%) as a white solid.
The compound 1- (furan-2-ylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester 28b is used as a raw materialMaterial was purified by column chromatography (DCM: MeOH ═ 8:1) to give the compound 1- (furan-2-ylmethyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 29, 80mg, yield 91.9%, HPLC purity > 95%) according to the general procedure for ester hydrolysis.1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.33(s,1H),6.84(s br,1H),6.42(s,2H),5.82(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ150.48,143.70,143.02,132.11,124.50,111.16,109.57,43.51ppm.HRMS:m/z calcd for C9H8N2O3[M-H]-191.0462,found 191.0460.
Example 291- (3- (1-methyl-1H-tetrazol-5-yl) propyl) -1H-imidazole-2-carboxylic acid (compound 30) synthesis:
Figure BDA0002392985820000261
dissolving a compound 1- (2-bromoethyl) -1H-imidazole-2-carboxylic acid ethyl ester 25b (200mg, 0.81mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (530mg, 1.62mmol) for activation for 0.5H, adding 1-methyl-5-mercapto-1H-tetrazole (188mg, 1.62mmol), heating to 80 ℃ for reaction for 5H, detecting by TLC (thin layer chromatography) for complete reaction, stopping reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3 x 20ml), combining organic layers, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave a colorless viscous liquid, compound 1- (3- (1-methyl-1H-tetrazol-5-yl) propyl) -1H-imidazole-2-carboxylic acid ethyl ester 29b (180mg, 84.1%).
Starting from the compound ethyl 1- (3- (1-methyl-1H-tetrazol-5-yl) propyl) -1H-imidazole-2-carboxylate 29b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (3- (1-methyl-1H-tetrazol-5-yl) propyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 30, 78mg, yield 87.6%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.13(s,1H),6.78(s,1H),4.78(t,J＝6.0Hz,2H),3.90(s,3H),3.68(t,J＝6.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ162.69,153.56,145.13,138.06,128.99,126.32,123.22,119.83,46.38,45.51,34.62,34.23,34.10ppm.HRMS:m/zcalcd for C8H10N6O2S[M-H]-253.0513,found 253.0513.
Example 301 synthesis of- (1-ethoxy-1-oxopropan-2-yl) -1H-imidazole-2-carboxylic acid (compound 31):
Figure BDA0002392985820000271
the compound ethyl 1- (1-ethoxy-1-oxopropan-2-yl) -1H-imidazole-2-carboxylate 16b (100mg, 0.41mmol) was dissolved in 6ml EtOH: H2Adding lithium hydroxide monohydrate (35mg, 0.83mmol) into a mixed solvent of O2: 1 under stirring, reacting for 1H at normal temperature after addition, detecting the reaction completely by TLC, stopping the reaction, adjusting the pH to about 7-8 by 3N HCl, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography (DCM: MeOH 10:1) to obtain a white solid powder, namely 1- (1-ethoxy-1-oxopropane-2-yl) -1H-imidazole-2-carboxylic acid (namely the compound 31, 45mg, the yield is 51.1%, and the HPLC purity is more than 95%).1H NMR(400MHz,CDCl3)δ7.29(s,1H),7.19(s,1H),6.17(s br,1H),4.32-4.22(m,3H),1.77(d,J＝2.4Hz,3H),1.33(t,J＝6.4Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ172.23,159.28,136.32,128.97,124.55,61.15,56.01,18.10,14.52ppm.HRMS:m/z calcd for C9H12N2O4[M+H]+213.0870,found 213.0873；C9H12N2O4[M+Na]+235.0695,found 235.0692.
Example 311 synthesis of- (oxetan-3-yl) -1H-imidazole-2-carboxylic acid (compound 32):
Figure BDA0002392985820000272
dissolving imidazole-2-carboxylic acid ethyl ester (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 3-iodooxetane (1.30g, 7.14mmol), heating to 100 ℃ for reaction for 3h, detecting the reaction by TLC (thin layer chromatography), stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (DCM: MeOH ═ 30:1) gave the compound 1- (oxetan-3-yl) -1H-imidazole-2-carboxylic acid ethyl ester 31b (200mg, yield 71.4%) as a yellow solid.
Starting from compound 1- (oxetan-3-yl) -1H-imidazole-2-carboxylic acid ethyl ester 31b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (2-methoxyethyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 32, 78mg, yield 91.0%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.59(d,J＝1.2Hz,1H),7.28(d,J＝0.8Hz,1H),5.35(t,J＝5.6Hz,1H),4.75(dd,J＝12.0Hz,J＝3.6Hz,1H),4.61(dd,J＝12.0Hz,J＝3.6Hz,1H),4.58-4.54(m,1H),3.81-3.69(m,2H)ppm.13C NMR(101MHz,DMSO-d6)δ136.05,138.81,131.72,122.73,67.9,54.88ppm.HRMS:m/z calcd for C7H8N2O3[M+H]+169.0608,found 169.0601.
Example 321- (azetidin-3-yl) -1H-imidazole-2-carboxylic acid (compound 33) synthesis:
Figure BDA0002392985820000281
dissolving imidazole-2-carboxylic acid ethyl ester (200mg, 1.43mmol) in 5ml of N, N-dimethylformamide, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding N-Boc-3-bromocyclobutane (671mg, 2.85mmol), heating to 80 ℃ for reaction for 5h, detecting the reaction completion by TLC, stopping the reaction, cooling to room temperature, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a light yellow liquid, namely the compound 32b, and directly feeding into the next step.
Compound 32b was dissolved in 10ml of dichloromethane, and trifluoroacetic acid was added in a 10% solvent amount, followed by reaction overnight at ordinary temperature. TLC detected the reaction was complete, the reaction was stopped, dichloromethane was removed by concentration under reduced pressure, diluted with water, adjusted to weak alkalinity with solid sodium bicarbonate, extracted with ethyl acetate (3 × 20ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to give a colorless liquid, and purified by column chromatography (DCM: MeOH ═ 30:1) to give the compound ethyl 1- (azetidin-3-yl) -1H-imidazole-2-carboxylate 32e (180mg, yield 64.7%).
Using compound 1- (azetidin-3-yl) -1H-imidazole-2-carboxylic acid ethyl ester 32e as a starting material, and referring to the general method of ester hydrolysis, purification was performed by column chromatography (DCM: MeOH ═ 2:1) to obtain a colorless viscous liquid, i.e., compound 1- (azetidin-3-yl) -1H-imidazole-2-carboxylic acid (i.e., compound 33, 75mg, yield 82.3%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.55(s,1H),6.86(s,1H),6.37-6.30(m,1H),3.78(t,J＝7.6Hz,2H),3.62(t,J＝7.2Hz,2H)ppm.HRMS:m/z calcd for C7H10N3O2[M+H]+168.0768,found 168.0771.
Example 331-Synthesis of benzyl-1H-imidazole-2-carboxylic acid (Compound 34):
Figure BDA0002392985820000282
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding potassium carbonate (591mg, 4.28mmol) for activation for 0.5h, adding benzyl bromide (485mg, 2.85mmol), heating to 80 ℃ for reaction for 2h, detecting by TLC to complete reaction, stopping reaction, cooling to room temperature, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1-benzyl-1H-imidazole-2-carboxylate 33b (310mg, yield 94.5%) as a white solid.
Using compound 1-benzyl-1H-imidazole-2-carboxylic acid ethyl ester 33b as a starting material, and referring to the general method of ester hydrolysis, purification by column chromatography (DCM: MeOH ═ 10:1) yielded compound 1-benzyl-1H-imidazole-2-carboxylic acid as a white solid powder (i.e., compound 34, 80mg, yield 91.1%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.34-7.28(m,6H),6.69(s,1H),5.75(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ138.29,137.87,129.13,129.10,128.17,127.91,120.05,49.93ppm.HRMS:m/z calcd for C11H10N2O2[M+H]+203.0815,found203.0818.
Example synthesis of 341- (4-methylbenzyl) -1H-imidazole-2-carboxylic acid (compound 35):
Figure BDA0002392985820000291
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 4-methylbenzyl chloride (400mg, 2.85mmol), heating to 60 ℃ for reaction for 3h, detecting by TLC to complete the reaction, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1- (4-methylbenzyl) -1H-imidazole-2-carboxylate 34b (326mg, yield 93.6%) as a colorless viscous liquid.
Starting from compound 1- (4-methylbenzyl) -1H-imidazole-2-carboxylic acid ethyl ester 34b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (4-methylbenzyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 35, 83mg, yield 94.3%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.16-7.15(m,5H),6.89(s,1H),5.14(s,2H),2.27(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ137.78,137.40,135.27,129.65,129.05,127.99,119.93,49.69,21.14ppm.HRMS:m/z calcd forC12H12N2O2[M-H]-215.0826,found 215.0825.
Example 351- (4-ethylbenzyl) -1H-imidazole-2-carboxylic acid (compound 36) synthesis:
Figure BDA0002392985820000301
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 4-ethylbenzyl chloride (440mg, 2.85mmol), heating to 60 ℃ for reaction for 4h, detecting by TLC to complete the reaction, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave a colorless, viscous liquid, i.e. compound ethyl 1- (4-ethylbenzyl) -1H-imidazole-2-carboxylate 35b (340mg, yield 92.3%, HPLC purity > 95%).
Starting from compound 1- (4-ethylbenzyl) -1H-imidazole-2-carboxylic acid ethyl ester 35b, the compound was purified by column chromatography (DCM: MeOH ═ 10:1) according to the general procedure for ester hydrolysis to give the compound 1- (4-ethylbenzyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 36, 80mg, yield 89.8%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.28-7.18(m,5H),6.91(s,1H),5.15(s,2H),2.57(q,J＝7.6Hz,2H),1.14(t,J＝7.6Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ143.77,137.77,135.53,128.50,128.02,124.68,119.99,49.74,28.29,16.08ppm.HRMS:m/z calcd for C13H14N2O2[M-H]-229.0983,found229.0980.
Example 361 synthesis of- (4-hydroxybenzyl) -1H-imidazole-2-carboxylic acid (compound 37):
Figure BDA0002392985820000302
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 4-methoxybenzyl bromide (343mg, 1.71mmol), reacting at normal temperature for 4h, detecting by TLC that the reaction is complete, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dilution, extracting with ethyl acetate (3X 20ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 2:1) gave the compound ethyl 1- (4-hydroxybenzyl) -1H-imidazole-2-carboxylate 36b (320mg, 86.2% yield) as a colorless viscous liquid.
Dissolving a compound 1- (4-hydroxybenzyl) -1H-imidazole-2-carboxylic acid ethyl ester 36b (200mg, 0.76mmol) in 5ml of dichloromethane, cooling to-78 ℃, slowly dropwise adding boron tribromide (384mg, 1.53mmol), after addition, heating to room temperature for reaction for 30min, detecting by TLC (thin layer chromatography) to complete the reaction, stopping the reaction, concentrating under reduced pressure to remove dichloromethane, adding water for dilution, adjusting pH to be neutral by sodium bicarbonate, extracting by ethyl acetate (3 × 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (DCM: MeOH: 80:1) gave the compound ethyl 1- (4-hydroxybenzyl) -1H-imidazole-2-carboxylate 36c (150mg, yield 79.4%) as a colorless viscous liquid.
Using compound 1- (4-hydroxybenzyl) -1H-imidazole-2-carboxylic acid ethyl ester 36c as starting material, and following the general procedure for ester hydrolysis, purification by column chromatography (DCM: MeOH ═ 3:1) gave compound 1- (4-hydroxybenzyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 37, 80mg, yield 90.9%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ9.52(s br,1H),7.14(d,J＝8.0Hz,2H),7.08(s,1H),6.73(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.63(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ157.11,129.45,129.19,127.72,124.22,115.38,115.23,49.41ppm.HRMS:m/z calcd for C11H10N2O3[M-H]-217.0619,found217.0618.
Example 371- (4-aminobenzyl) -1H-imidazole-2-carboxylic acid (compound 38) synthesis:
Figure BDA0002392985820000311
dissolving imidazole-2-ethyl formate (200mg, 1.43mmol) in 10ml acetonitrile, adding cesium carbonate (931mg, 2.85mmol) for activation for 0.5h, adding 4-nitrobenzyl bromide (368mg, 1.71mmol), heating to 60 ℃ for reaction for 3h, detecting by TLC to complete the reaction, stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding water for dilution, extracting by ethyl acetate (3X 20ml), combining organic layers, washing by saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1) gave the compound ethyl 1- (4-nitrobenzyl) -1H-imidazole-2-carboxylate 37b (360mg, 91.8% yield) as a colorless viscous liquid.
The compound ethyl 1- (4-nitrobenzyl) -1H-imidazole-2-carboxylate 37b (200mg, 0.73mmol) was dissolved in 12ml EtOH: H2Adding ammonium chloride (19mg, 0.36mmol) and reduced iron powder (122mg, 2.18mmol) into a mixed solvent of 0 ═ 2:1 under stirring, heating to 80 ℃ after adding, reacting for 1h, detecting by TLC that the reaction is complete, stopping the reaction, filtering while hot, and washing with ethanol. The filtrate was concentrated under reduced pressure to remove ethanol, and then diluted with water and extracted with ethyl acetate (3X 20ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purification by column chromatography (PE: EA ═ 1:1) gave the compound ethyl 1- (4-aminobenzyl) -1H-imidazole-2-carboxylate 37c (150mg, 84.2% yield) as a pale yellow viscous liquid.
Using compound 1- (4-aminobenzyl) -1H-imidazole-2-carboxylic acid ethyl ester 37c as a starting material, and according to the general procedure for ester hydrolysis, purification was performed by column chromatography (DCM: MeOH ═ 1:1) to give compound 1- (4-aminobenzyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e., compound 38, 78mg, yield 88.6%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.70(s,1H),7.12(s,1H),6.98(d,J＝8.0Hz,2H),6.88(s,1H),6.52(d,J＝8.0Hz,2H),4.95(s,2H),4.86(s br,3H)ppm.13C NMR(101MHz,DMSO-d6)δ148.87,137.36,129.27,128.70,124.76,119.71,114.21,49.96ppm.HRMS:m/z calcd for C11H11N3O2[M-H]-216.0779,found216.0778.
Example 381- (4- (aminomethyl) benzyl) -1H-imidazole-2-carboxylic acid (compound 39) synthesis:
Figure BDA0002392985820000321
4-Aminomethylbenzyl alcohol (200mg, 1.46mmol) was dissolved in 10ml of dichloromethane, thionyl chloride (344mg, 2.92mmol) was added with stirring, and after reaction at normal temperature for 2 hours, the solvent was removed by concentration under reduced pressure to obtain compound 38b, 38b was dissolved in 5ml of N, N-dimethylformamide, and after addition of imidazole-2-carboxylic acid ethyl ester (204mg, 1.46mmol) and cesium carbonate (1.42g, 4.38mmol), the temperature was raised to 80 ℃ and reaction was carried out for 5 hours. TLC detection reaction is complete, stop reaction, cool to room temperature, add water to dilute, ethyl acetate extract (3X 20ml), combine organic layers, saturated saline solution wash, anhydrous sodium sulfate drying, filtration, concentration to get crude product. Purification by column chromatography (DCM: MeOH ═ 500: 1) gave compound 1- (4- (aminomethyl) benzyl) -1H-imidazole-2-carboxylic acid ethyl ester 38c (230mg, yield 60.8%) as a colorless oily liquid.
Starting from compound 1- (4- (aminomethyl) benzyl) -1H-imidazole-2-carboxylic acid ethyl ester 38c, the compound was purified by column chromatography (DCM: MeOH ═ 1:1) according to the general procedure for ester hydrolysis to give the compound 1- (4- (aminomethyl) benzyl) -1H-imidazole-2-carboxylic acid (i.e. compound 39, 82mg, yield 92.1%, HPLC purity > 95%) as a white solid powder. HRMS m/zcalcdfor C12H13N3O2[M-H]-230.0935,230.0929.
Example 391 synthesis of (pyridin-4-ylmethyl) -1H-imidazole-2-carboxylic acid (compound 40):
Figure BDA0002392985820000322
4-pyridinemethanol (200mg, 1.83mmol) was dissolved in 2ml of thionyl chloride, and after heating to 70 ℃ and reacting for 1h, thionyl chloride was removed by concentration under reduced pressure to obtain compound 39b, which was dissolved in 5ml of N, N-dimethylformamide, and after adding imidazole-2-carboxylic acid ethyl ester (256mg, 1.83mmol) and cesium carbonate (1.78g, 5.49mmol), heating to 80 ℃ and reacting for 4 h. TLC detection reaction is complete, stop reaction, cool to room temperature, add water to dilute, ethyl acetate extract (3X 20ml), combine organic layers, saturated saline solution wash, anhydrous sodium sulfate drying, filtration, concentration to get crude product. Purification by column chromatography (DCM: MeOH ═ 30:1) gave compound 1- (pyridin-4-ylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester 39c (240mg, yield 56.7%) as a colorless oily liquid.
Starting from compound 1- (pyridin-4-ylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester 39c, the compound was purified by column chromatography (DCM: MeOH ═ 1:1) according to the general procedure for ester hydrolysis to give the compound 1- (pyridin-4-ylmethyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 40, 76mg, yield 86.5%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ9.52(s br,1H),8.47(dd,J＝4.4Hz,J＝1.6Hz,2H),7.19(d,J＝0.8Hz,1H),7.07(d,J＝6.0Hz,2H),6.84(d,J＝0.8Hz,1H),5.84(s,2H)ppm.HRMS:m/z calcd for C10H9N3O2[M-H]-202.0622,found 202.0615.
Example 401 synthesis of- (thiophen-2-ylmethyl) -1H-imidazole-2-carboxylic acid (compound 41):
Figure BDA0002392985820000331
2-Thiophenemethanol (200mg, 1.75mmol) was dissolved in 5ml of dichloromethane, thionyl chloride (414mg, 0.335mmol) was slowly added dropwise with stirring to react for 3 hours, then the solvent was removed by concentration under reduced pressure to obtain compound 40b, 40b was dissolved in 5ml of N, N-dimethylformamide, and then imidazole-2-carboxylic acid ethyl ester (196mg, 1.40mmol) and cesium carbonate (1.71g, 5.26mmol) were added thereto and the temperature was raised to 80 ℃ to react for 5 hours. TLC detection reaction is complete, stop reaction, cool to room temperature, add water to dilute, ethyl acetate extract (3X 20ml), combine organic layers, saturated saline solution wash, anhydrous sodium sulfate drying, filtration, concentration to get crude product. Purification by column chromatography (DCM: MeOH ═ 50: 1) gave compound 1- (thiophen-2-ylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester 40c (260mg, yield 62.8%) as a colorless oily liquid.
Starting from compound 1- (thien-2-ylmethyl) -1H-imidazole-2-carboxylic acid 40c, the compound was purified by column chromatography (DCM: MeOH ═ 2:1) according to the general procedure for ester hydrolysis to give the compound 1- (thien-2-ylmethyl) -1H-imidazole-2-carboxylic acid as a white solid powder (i.e. compound 41, 80mg, yield 90.9%, HPLC purity > 95%).1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.49(dd,J＝5.2Hz,J＝1.2Hz,1H),7.20(t,J＝1.2Hz,1H),7.01(q,J＝3.6Hz,1H),6.90(d,J＝1.2Hz,1H),5.41(s,2H)ppm.HRMS:m/z calcd for C9H8N2O2S[M-H]-207.0234,found 207.0221.
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1 in vitro inhibitory Activity of the Compounds of the invention against various MBL enzymes
(1) Experimental materials:
WHB all-black 96-hole flat-bottom luminescent plate (specification: WHB-96-02); l-captopril, a positive control product of Dalian Meiren Biotechnology Ltd. (product No. MB 1527); the compound synthesized in the embodiment of the invention, and imidazole-2-formic acid (namely compound A).
(2) The experimental method comprises the following steps:
construction of recombinant plasmid: VIM-2(aa:27-266), NDM-1(aa:1-270), IMP-1 (aa: 1-246) and VIM-5(aa:1-266) genes with N-terminal His6-tag and TEV restriction enzyme sites and VIM-1(aa:1-266) genes with C-terminal His6-tag and TEV restriction enzyme sites are respectively cloned into a pET28 prokaryotic expression vector to construct a recombinant plasmid for expressing corresponding target proteins.
Expression and purification of protein of interest the recombinant plasmid is transferred to E.coli Transetta (DE3) for expression, incubated at 37 ℃ to OD 6000.6-0.8, reduced to 20 ℃ (VIM-2 and NDM-1), 16 ℃ (IMP-1), 18 ℃ (VIM-1, VIM-5) with addition of isopropyl β -D-1-thiogalactopyranoside (IPTG) at a final concentration of 0.5mM to induce expression of the protein of interest, incubated for 18-20 hours, centrifuged at 4000rpm for 15 minutes to collect the cells, resuspended in Buffer A (20mM Tris-lpH8.0, 250mM NaCl) and, after lysis of the bacteria with a low temperature high pressure continuous flow cell disruptor (JNBIO), centrifuged at 15,000rpm for 30min to remove cell debris, the supernatant is collected and the Ni-NTA column is pretreated before purification using Ni-NTA column (20mM Buffer B-Buffer; 20mM NaCl; centrifugation column (JNBO 8.0,250 mM) to remove the residual protein of interest, and the Buffer is eluted with a Buffer solution of 10mM Buffer, washed with a Buffer solution containing the protein of 10mM Buffer, and the Buffer is eluted from the Buffer of Buffer containing the Buffer of Buffer, washed with 10mM NaCl, the Buffer containing the Buffer of the Buffer containing the protein of Tris-NTA, the Buffer containing the Buffer, the Buffer containing the Buffer, the Buffer containing the protein of the Buffer, the Buffer after centrifugation, the Buffer containing the Buffer is removed and the protein of the Buffer containing the protein of the Buffer of the protein of the Buffer of interest is washed with the Buffer of 10mM Buffer of Tris-Buffer of the.
Activity test experiment:
(a) single concentration activity assay
All test compounds were dissolved in 100% DMSO solvent to make 100mM stock solution, which was diluted with DMSO to 10mM/1mM compound working solution, respectively. The total reaction volume was 60. mu.L. mu.L of the compound working solution (final concentration: 100. mu.M/10. mu.M), 39.4. mu.L of Buffer C and 10. mu.L of the MBL enzyme solution (final enzyme concentration: 0.2nM) were added to the test wells, and 40. mu.L of Buffer C and 10. mu.L of the MBL enzyme solution (final enzyme concentration: 0.2nM) were added to the control wells in this order, and after reaction at room temperature for 10 minutes and further addition of 10. mu.L of the FC-5 substrate solution (final substrate concentration: 5. mu.M), the fluorescence intensity during the course of the enzyme kinetic reaction was measured immediately using a Thermo VARIOSKAN LUX plate reader at an excitation wavelength of 380nM and an emission wavelength of 460 nM. Calculating and obtaining the inhibition rate of the tested compound to various MBL enzymes at 100 mu M/10 mu M according to the measured fluorescence intensity change; the results of the test inhibition are shown in table 1.
(b) Half maximal effective Inhibitory Concentration (IC)50) Measurement experiment
The fluorescence intensity of the test compounds during the course of the enzyme kinetic reaction was measured at 10 concentration gradients, respectively, with reference to the single concentration activity assay described above. IC was calculated from the measured change in fluorescence intensity and the concentration of compound using GraphPad Prism software50The value is obtained. Correlation IC50The values are shown in Table 2.
TABLE 1 inhibitory Activity of Compounds on various MBL enzymes
Figure BDA0002392985820000351
Figure BDA0002392985820000361
aEach compound was tested in triplicate(ii) a Data are mean ± SD (n ═ 3), "-" indicates the value of the term for the untested compound.
Table 2 IC of some of the compounds50Value (μ M)
Figure BDA0002392985820000362
Figure BDA0002392985820000371
Figure BDA0002392985820000381
"-" indicates the value of the term for the untested compound.
It can be seen that the compounds of the present invention are effective in inhibiting the activity of a number of MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-5, and in particular compounds 11, 13, 14, 29, 30, 34, 37, 40, their IC for MBL enzymes of the VIM-2 type50The value is below 2.13 mu M, the inhibition effect is more obvious than that of a positive control drug, and the MBL enzyme inhibitor has very good potential in preparation.
Experimental example 2 antibacterial Activity of the Compound of the present invention in combination with Meropenem against various drug-resistant bacteria
(1) Experimental materials:
the positive control product L-captopril (Dalian biotech Co., Ltd., product No. MB 1527); the positive control product abamectin (zilu day and heyday pharmaceuticals ltd); meropenem (Dalian Meiren, product number: D1204A); mueller Hinton II Broth (Cation-Adjusted), Cation-Adjusted Miller-Xinton Broth (CAMHB), available from BD corporation; MHA medium, purchased from BD; the compounds synthesized in the examples of the present invention;
drug-resistant strains: coli BAA-2452 (capable of producing NDM-1 enzyme), MF C1274 (capable of producing VIM-1 enzyme), PAW35 (capable of producing VIM-2 enzyme), PA 5621 (capable of producing VIM-2 enzyme).
(2) The experimental method comprises the following steps:
a. resuscitating the strain-80 deg.C, resuscitating the drug-resistant strain on MHA plate, and culturing at 35 deg.C for 18-20 h.
b. Preparing stock solution, namely preparing 10mg/ml stock solution according to the amount of the compound, and taking a part of the stock solution as the stock solution according to the dosage to dilute the stock solution by 10 times to 1 mg/ml; preparing the reference medicaments of abamectin and captopril into stock solution of 10 mg/ml; meropenem was prepared as a 12.8mg/ml stock solution.
c. Diluting the medicine, namely adding 100 mu L of CAMHB into a 96-well plate, diluting the meropenem stock solution into liquid medicine with the concentration of 1024 mu g/ml by using the CAMHB, respectively adding 100 mu L of diluted meropenem liquid medicine into a first column, uniformly mixing, sucking 100 mu L of diluted meropenem liquid medicine respectively, adding the liquid medicine into a second column, performing serial dilution by using a 2-fold dilution method until the liquid medicine reaches a 10 th column, sucking 100 mu L, discarding the last two columns, wherein one column is a growth control, and one column is a blank control, and the concentration of the meropenem is respectively 512, 256, 128, 64, 32, 16, 8, 4, 2, 1 mu g/ml, and adding 2 mu L of corresponding β -lactamase inhibitor (namely each tested compound or positive control product of the invention) into each 1-10 column.
d. And (3) bacterial liquid dilution, namely, selecting a bacterial monoclonal colony, suspending the bacterial monoclonal colony in physiological saline, adjusting the OD630 to be 0.5 McFahrenheit turbidity (0.08-0.13 OD/mL) to be equivalent to 1 × 108CFU/mL, diluting the suspension by using CAMHB to be 200 times to 5 × 105CFU/mL, adding 100 μ L of the bacterial liquid into each hole, and adding no bacterial liquid into blank holes, wherein the concentration of meropenem is respectively 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 μ g/mL, and the concentration of β -lactamase inhibitor is 100 μ g/mL.
e. And (3) performing static culture, namely putting the 96-well plate into a 35 ℃ incubator, and performing static culture for 16-20 h.
f. The result judges that the minimum concentration which can completely or obviously inhibit the bacterial growth is the MIC of the meropenem when the combination is used.
g. The experiment was repeated twice and the average was taken and the results are shown in table 3. In table 3, "fold" represents the ratio of the MIC of meropenem alone to the MIC of meropenem when used in combination, and a larger value of the fold "indicates that the compound used in combination with meropenem has a more significant effect of enhancing the bacteriostatic effect.
TABLE 3 MIC of meropenem when compound (100. mu.g/ml) is used in combination with meropenem
Figure BDA0002392985820000391
"-" indicates the value of the term for the untested compound.
The compound disclosed by the invention can be combined with meropenem, so that the MIC of meropenem to drug-resistant bacteria can be effectively reduced, the compound disclosed by the invention can inhibit metal β -lactamase generated by the drug-resistant bacteria, the inhibition effect of meropenem to the drug-resistant bacteria is further enhanced, the problem that antibiotic is ineffective due to the fact that the drug-resistant bacteria generate metal β -lactamase is solved, and the compound has very good potential in preparation of antibacterial combined medicines.
In conclusion, the invention provides 1-substituted-1H-imidazole-2-carboxylic acid compounds which can effectively inhibit the activity of various MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-1 and VIM-5, in particular compounds 11, 13, 14, 29, 30, 34, 37 and 40, and IC of the compounds on VIM-2 MBL enzymes50The value is below 2.13 mu M, the inhibition effect is more obvious than that of a positive control drug, and the compound has very good potential in preparing an MBL enzyme inhibitor, and meanwhile, the compound is combined with β -lactam antibiotics, so that the metal β -lactamase generated by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotics is enhanced, and the compound has very good application prospect in preparing antibacterial combined drugs.

Claims (10)

1. Use of a compound of formula I, or a salt, or a stereoisomer, or a crystal form, or a solvate thereof, in the preparation of a metal β -lactamase inhibitor:
Figure FDA0002392985810000011
in the formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano-group and-L1R1、-L2XR2Substituted or unsubstituted of the following groups: c1～8Alkyl radical, C2～8Alkenyl radical, C2～8An alkynyl group; the substituent is selected from C1～3Alkyl radicalHydroxy, carboxy, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～5An alkyl group;
L1selected from none or C1～5An alkylene group; r1Selected from the following groups substituted with 0 to 5 substituents: a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring; the substituents are each independently selected from C1～3Alkyl, halogen, hydroxy, carboxy, amino, cyano, -L3NH2，L3Is selected from C1～3An alkylene group;
L2selected from none or C1～5An alkylene group; x is selected from O, S, CO, SO or SO2；R2Selected from amino, C1～5Alkyl radical, C1～5Alkoxy, substituted or unsubstituted saturated or unsaturated carbocycle, substituted or unsubstituted saturated or unsaturated heterocycle, the substituent is selected from C1～3Alkyl, halogen, hydroxyl, carboxyl, amino, cyano.
2. The use according to claim 1, wherein the metallo β -lactamase is VIM-2, NDM-1, IMP-1, VIM-1 and/or VIM-5.
3. The application of the compound shown in the formula I, or a salt, a stereoisomer, a crystal form or a solvate thereof and an antibacterial drug in the preparation of antibacterial combined drugs:
Figure FDA0002392985810000012
in the formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano-group and-L1R1、-L2XR2Substituted or unsubstituted of the following groups: c1～8Alkyl radical, C2～8Alkenyl radical, C2～8An alkynyl group; the substituent is selected from C1～3Alkyl, hydroxy, carboxy, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～5An alkyl group;
L1selected from none or C1～5An alkylene group; r1Selected from the following groups substituted with 0 to 5 substituents: a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring; the substituents are each independently selected from C1～3Alkyl, halogen, hydroxy, carboxy, amino, cyano, -L3NH2，L3Is selected from C1～3An alkylene group;
L2selected from none or C1～5An alkylene group; x is selected from O, S, CO, SO or SO2；R2Selected from amino, C1～5Alkyl radical, C1～5Alkoxy, substituted or unsubstituted saturated or unsaturated carbocycle, substituted or unsubstituted saturated or unsaturated heterocycle, the substituent is selected from C1～3Alkyl, halogen, hydroxyl, carboxyl, amino, cyano.
4. The use according to claim 3, wherein the antibacterial agent is β -lactam antibiotic, preferably meropenem.
5. Use according to any one of claims 1 to 4, characterized in that:
in formula I, R is selected from H, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted following groups: c1～4Alkyl radical, C2～4Alkenyl radical, C2～4An alkynyl group; the substituents are selected from methyl, hydroxy, carboxyl, amino, cyano, -NR3R4；R3、R4Each independently selected from C1～3An alkyl group.
6. Use according to any one of claims 1 to 4, characterized in that: the structure of the compound shown in the formula I is shown in the formula II:
Figure FDA0002392985810000021
in the formula II, L1Selected from none or C1～3An alkylene group;
m ring is selected fromA 3-6 membered saturated or unsaturated carbocyclic ring, a 3-6 membered saturated or unsaturated heterocyclic ring; preferably, the M ring is selected from
Figure FDA0002392985810000022
Figure FDA0002392985810000023
m is an integer of 0 to 3, preferably 0 or 1;
R1ais selected from C1～3Alkyl, halogen, hydroxy, amino, -L3NH2，L3Is selected from C1～2An alkylene group;
alternatively, the structure of the compound of formula I is shown in formula IV:
Figure FDA0002392985810000031
wherein L is2Selected from none or C1～3An alkylene group;
x is selected from O, S, CO, SO2；
R2Selected from amino, C1～3Alkyl radical, C1～3Alkoxy, substituted or unsubstituted 5-6 membered saturated or unsaturated heterocycle, the substituent is selected from C1～3An alkyl group.
7. Use according to claim 6, characterized in that: the structure of the compound shown in the formula II is shown in the formula III:
Figure FDA0002392985810000032
in formula III, E is selected from N or CR5，R5Selected from H, C1～3Alkyl, halogen, hydroxy, amino, -CH2NH2。
8. Use according to any one of claims 1 to 4, characterized in that: the structure of the compound is shown as a formula C:
Figure FDA0002392985810000033
in the formula C, L is substituted or unsubstituted C1～3An alkylene group;
Raselected from amino, -YRd5-6 membered unsaturated heterocyclic group substituted with 0-3 substituents, cyano group, -COORc,RcIs selected from H or C1～3An alkyl group; and when R isaWhen cyano, L is ethylene; when R isais-COORcWhen L is C1～3An alkyl-substituted methylene group;
y is selected from O, S, CO, SO or SO2；
RdIs selected from C1～3An alkyl group, a 5-to 6-membered unsaturated heterocyclic group substituted with 0 to 3 substituents;
the substituents are independently selected from C1～3Alkyl, halogen, hydroxyl, carboxyl.
9. The compound according to claim 8, or a salt thereof, or a stereoisomer thereof, or a crystalline form thereof, or a solvate thereof, characterized in that: the structure of the compound is shown as a formula C-1:
Figure FDA0002392985810000041
wherein m is 1 or 2; z is nothing or Y, Y is selected from O, S, CO, SO or SO2Y is preferably S, SO or SO2；
The P ring is a 5-to 6-membered unsaturated heterocycle, preferably
Figure FDA0002392985810000042
Figure FDA0002392985810000043
RbSelected from H, C1～3Alkyl, halogen, hydroxyl, carboxyl.
10. Use according to any one of claims 1 to 4, characterized in that: the compound is selected from one of the following compounds:
Figure FDA0002392985810000044
Figure FDA0002392985810000051
Figure FDA0002392985810000061
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