CN113214302B - 3-substituted five-membered cyclic borate derivative for inhibiting metal beta-lactamase and/or serine beta-lactamase - Google Patents

3-substituted five-membered cyclic borate derivative for inhibiting metal beta-lactamase and/or serine beta-lactamase Download PDF

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CN113214302B
CN113214302B CN202110444405.4A CN202110444405A CN113214302B CN 113214302 B CN113214302 B CN 113214302B CN 202110444405 A CN202110444405 A CN 202110444405A CN 113214302 B CN113214302 B CN 113214302B
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肖友财
李国波
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Sichuan University
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Abstract

The invention provides a 3-substituted five-membered cyclic borate derivative for inhibiting metallo-beta-lactamase and/or serine beta-lactamase, belonging to the field of pharmaceutical chemistry. The structure of the 3-substituted five-membered cyclic borate derivative is shown as a formula I. Experimental results show that the compound has good inhibitory activity on SBL beta-lactamase and MBL beta-lactamase, can be used as a serine beta-lactamase inhibitor, a metal beta-lactamase and serine beta-lactamase dual inhibitor, and has wide application prospect in preparation of drugs for resisting drug-resistant bacteria.

Description

3-substituted five-membered cyclic borate derivative for inhibiting metal beta-lactamase and/or serine beta-lactamase
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a 3-substituted five-membered cyclic borate derivative with an inhibiting effect on metallo-beta-lactamase and/or serine beta-lactamase, and a pharmaceutical composition and pharmaceutical application thereof.
Background
The beta-lactam antibiotics are the most widely clinically used antibiotics (such as cephalosporins, carbapenems and the like) at present, have good bacteriostatic effect on gram-positive bacteria and gram-negative bacteria, and have the advantages of good clinical curative effect, low toxicity, wide adaptation diseases and the like. The beta-lactam antibiotics prevent cell wall peptide synthesis mainly by inhibiting the catalytic activity of bacterial cell wall peptide synthetase (namely penicillin binding protein, PBP for short), thereby causing bacterial cell wall defect and death due to expansion and cracking of thalli. However, the continuous emergence of beta-lactam antibiotic resistant 'super' bacteria with high-efficiency resistance and rapid spread in the global range become one of the main sources of current domestic and foreign refractory infections, so that the problem of beta-lactam antibiotic resistance is not easy to solve.
There are a wide variety of pathogenic beta-lactamases, and over 1300 different subtypes of beta-lactamases have been discovered and identified: these beta-lactamases are classified into A, B, C and D four classes based on amino acid sequence homology; these beta-lactamases are classified into two broad classes according to the differences in catalytic mechanisms: serine beta-lactamase (SBL) and metallo beta-lactamase (MBL). At present, a plurality of SBL inhibitors such as clavulanic acid, sulbactam, tazobactam and abamectin are approved for clinical use, and have better clinical curative effect on SBL penicillin or cephalosporin drug-resistant bacteria. Recently, the FDA in the united states approved adult treatment of the complex urinary tract infection (cluti) with the β -lactamase inhibitor, vaboractam, containing a novel structure of a six-membered cyclic boronic ester, in combination with the carbapenem antibiotic, meropenem, for the treatment of diseases including kidney infection, pyelonephritis, caused by specific bacteria; however, this treatment is not effective against MBL carbapenem-resistant bacteria.
Figure BDA0003036215480000011
At present, no medicine taking metallo-beta-lactamase as a target exists on the market, and the development of a medicine capable of effectively inhibiting MBL is urgently needed. In the face of the increasing variety of multi-drug resistant, widely-drug resistant (XDR) and even pan-drug resistant (PDR) super bacteria, the existing beta-lactamase inhibitors can not meet the clinical requirements at all, so the development of inhibitors with double inhibitory action on MBL and SBL is a key direction for solving the drug resistance of bacteria.
Disclosure of Invention
The invention aims to provide a 3-substituted five-membered cyclic borate derivative which has an inhibitory effect on MBL and an inhibitory effect on SBL, even has a dual inhibitory effect on MBL and SBL, and a pharmaceutical composition and pharmaceutical application thereof.
The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof:
Figure BDA0003036215480000021
wherein n is an integer of 0-4;
R1each independently selected from halogenated or non-halogenated C1～6Alkyl, halogenated or non-halogenated C1～6Alkoxy, halogen, nitro, amino,Hydroxy, carboxy, cyano;
the A ring is selected from 5-6-membered aryl, 5-6-membered heteroaryl, 3-6-membered saturated cycloalkyl and 3-6-membered saturated heterocyclic group;
l is none or C1～4An alkylene group;
x is NH, O or S;
R2is hydrogen or C1～6An alkyl group.
Further, the structure of the compound is shown as a formula I-1:
Figure BDA0003036215480000022
wherein, Y1、Y2、Y3、Y4、Y5Each independently is selected from N or CH;
n is an integer of 0 to 3;
R1each independently selected from halogenated or non-halogenated C1～4Alkyl, halogenated or non-halogenated C1～4Alkoxy, halogen, nitro, amino, hydroxy, carboxy, cyano;
m is 0, 1 or 2;
x is selected from O or S.
Further, the structure of the compound is shown as formula II:
Figure BDA0003036215480000031
wherein n is an integer of 0-2;
R1each independently selected from halogenated or non-halogenated C1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, halogen, nitro, cyano;
m is 0, 1 or 2;
x is selected from O or S.
Further, the structure of the compound is shown as formula III-1, formula III-2, formula III-3 or formula III-4:
Figure BDA0003036215480000032
wherein n is 0 or 1;
R1each independently selected from halogenated or non-halogenated C1～4Alkyl, halogenated or non-halogenated C1～4Alkoxy, halogen, nitro, cyano.
Further, the compound is one of the following compounds:
Figure BDA0003036215480000041
Figure BDA0003036215480000051
the present invention also provides a method for preparing a compound of formula II, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof, comprising the steps of:
Figure BDA0003036215480000061
(1) reacting the compound shown in the formula II-c with the compound shown in the formula II-d to obtain a compound shown in the formula II-e;
(2) hydrolyzing the compound shown in the formula II-e to obtain a compound shown in the formula II;
wherein n and R1As described above.
Further, in the step (1), the molar ratio of the compound represented by the formula II-a to the compound represented by the formula II-b is 1: (1-8), preferably 1: 5; the reaction temperature is room temperature;
and/or, in the step (2), the hydrolysis method is to add a base to the compound shown in the formula II-c, wherein the base is preferably an inorganic base, and is more preferably sodium hydroxide.
The invention also provides a pharmaceutical composition for inhibiting beta-lactamase, which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt thereof, or isotopic compound thereof, or stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound, or pharmaceutically acceptable salt thereof, or isotopic compound thereof, or stereoisomer thereof in preparing beta-lactamase inhibitors.
Further, the beta-lactamase inhibitor is a metallo beta-lactamase inhibitor, a serine beta-lactamase inhibitor, a metallo beta-lactamase and a serine beta-lactamase dual inhibitor.
Further, the beta-lactamase inhibitor is an antibacterial drug; the antibacterial drug is preferably a drug against drug-resistant bacteria, more preferably a drug against multi-drug resistant bacteria, a drug against widely drug resistant bacteria, or a drug against fully drug resistant bacteria.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
In the group of the compounds of the invention, Me is methyl,ipr is isopropyl.
In the compounds of formula I of the invention, n R1Can be substituted at any position on the benzene ring.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca～bAlkyl represents any alkyl group containing from "a" to "b" carbon atoms. For example, C1～6The alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic. For example, "3-to 6-membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 3 to 6 carbon atoms in the ring.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one ring heteroatom (including but not limited to O, S or N). For example, "3 to 6-membered saturated heterocyclic group" means a saturated heterocyclic group having 3 to 6 ring atoms.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring having the conjugated pi-electron system. The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. The hetero atoms referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
Halogen is fluorine, chlorine, bromine or iodine.
An "isotopic compound" refers to a compound obtained by substituting one or more atoms in the compound with its corresponding isotope. Such as compounds obtained by replacing one or more hydrogens (H) in the compound with deuterium (D) or tritium (T); such as one or more than two carbons in a compound12Quilt carbon11Or carbon13The compound obtained after replacement.
By "pharmaceutically acceptable" is meant that the carrier, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
"salts" are acid and/or base salts of a compound or a stereoisomer thereof with inorganic and/or organic acids and/or bases, and also include zwitterionic (inner) salts, as well as quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
The pharmaceutically acceptable salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
Experimental results show that the compound provided by the invention has good inhibitory activity on SBL beta-lactamase and MBL beta-lactamase, can be used as a serine beta-lactamase inhibitor, a metal beta-lactamase and serine beta-lactamase dual inhibitor, and has wide application prospect in preparation of drugs for resisting drug-resistant bacteria.
The preparation method of the compound is simple, mild in condition, easy in raw material obtaining and suitable for industrial production.
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 invention are known products, and are obtained by purchasing products sold in the market.
According to the following synthetic route I, the compounds 1-42 of the present invention are synthesized. The first synthetic route is as follows:
Figure BDA0003036215480000081
(1) preparation of 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde compound (compound shown as formula II-b)
To a round bottom flask (25mL) was added bis (pinacolato) diboron (4.8mmol,1.2 equivalents), 2-bromobenzaldehyde derivative (formula II-a, 4mmol,1.0 equivalent), PdCl2(dppf) (88mg,0.12mmol) and KOAc (12mmol,3.0 equiv.), the mixture was sealed with a septum, purged several times with argon, then dry 1, 4-dioxane (15mL) was added to the mixture and stirred at 80 ℃ for 8 h. The resulting crude reaction mixture was washed with saturated NaHCO3Diluting and extracting with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrated residue was purified by flash column chromatography to obtain 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (compound represented by the formula II-b).
(2) Preparation of 2-formylphenylboronic acid compound (compound shown in formula II-c)
The compounds represented by the formula II-c used in the present invention can be obtained by purchasing commercially available products, or can be prepared by the following method.
To a 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde compound (compound represented by the formula II-b) (1.0 equivalent) in THF/H2O mixed solution (THF: H)2O volume ratio is 10:1) adding NaIO4(1.5 eq.) the mixture was stirred at room temperature for 20 minutes until well mixed. Aqueous HCl (1.0M) was then added and stirred for 2 hours. The resulting system was then extracted with dichloromethane (3 × 50mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated in vacuo. The concentrated residue was purified by flash column chromatography to give 2-formylphenylboronic acid compounds (compounds represented by the formulae II to c).
(3) Preparation of benzoxaborole acrylate compound (compound shown as formula II-e)
To 2-formylphenylboronic acid compounds (formula II-c, 1.0 equiv.) in tetrahydrofuran (1ml) was added DABCO (triethylenediamine, 1.0 equiv.), 1,1,1,3,3, 3-hexafluoropropan-2-yl acrylate (formula II-d, 5.0 equiv.) was added dropwise, reacted at room temperature and monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the reaction was quenched with aqueous hydrochloric acid (1.0M,10mL) and extracted with ethyl acetate (3 × 10mL), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product. Then purifying the crude product by flash column chromatography to obtain the benzoxaborole acrylate compound (namely the compound shown in the formula II-e).
(4) Preparation of the end product (Compound of formula II)
The benzoxaborole acrylate compound synthesized in the step (3) (i.e., the compound represented by formula II-e) was dissolved in methanol, and an aqueous sodium hydroxide solution (1.0M) was added dropwise thereto, followed by stirring at room temperature for 2.5 hours, followed by acidification with an aqueous hydrochloric acid solution (1.0M,10 mL). The system was extracted with ethyl acetate (3 × 10mL), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product. The crude product was then purified by flash column chromatography to give the final product (i.e., the compound of formula II).
The preparation method and structural characterization of specific compounds 1-42 are as follows.
Example 1: synthesis of Compound 1
Figure BDA0003036215480000091
(1) In a 25mL flask, 4-methylphenol (1.0 eq), 2-bromo-5-fluorobenzaldehyde (1.0 eq) and K were added2CO3(2.0 equiv.) 10mL of DMF was added under argon. The reaction was stirred at 100 ℃ and monitored by TLC. After completion of the reaction, the system was quenched with water (10mL) and extracted with ethyl acetate (3X 10mL), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product. The crude product was purified by flash column chromatography to give the compound 2-bromo-5- (4-methylphenoxy) benzaldehyde.
To a 25-mL round bottom flask was added bis (pinacol)And (ii) diboron (1.22g, 4.8mmol,1.2 equiv.), the compound 2-bromo-5- (4-methylphenoxy) benzaldehyde (1.0 equiv.), PdCl2(dppf) (0.03 eq) and KOAc (3.0 eq). Purged several times with argon, then dry 1, 4-dioxane (15mL) was added to the reaction mixture and stirred at 80 ℃ for 8 hours. The resulting crude reaction mixture was diluted with ethyl acetate and extracted with saturated sodium bicarbonate. The combined organic layers were collected, dried over sodium sulfate and concentrated in vacuo. The concentrated residue was purified by flash column chromatography using petroleum ether and ethyl acetate as eluent (petroleum ether: ethyl acetate volume ratio: 20: 1) to give the compound 5- (4-methylphenoxy) -2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde.
(2) To 5- (4-methylphenoxy) -2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.0 eq) in THF/H2O mixed solution (32mL, THF: H)2O volume ratio is 10:1) adding NaIO4(1.5 equiv.) the mixture was stirred at room temperature for 20 minutes until well mixed. Aqueous HCl (1.0M,10mL) was then added and stirred for 2 hours. The resulting mixed system was then extracted with dichloromethane (3 × 50mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated in vacuo. The residue after concentration was purified by flash column chromatography using petroleum ether and ethyl acetate as an eluent (petroleum ether: ethyl acetate volume ratio ═ 2: 1) to give the compound (5- (4-chlorophenoxy) -2-formylphenyl) boronic acid.
(3) To the compound (4- (4-methylphenoxy) -2-formylphenyl) boronic acid (1.0 equivalent) in tetrahydrofuran (1ml) was added DABCO (1.0 equivalent), and 1,1,1,3,3, 3-hexafluoropropan-2-yl acrylate (5.0 equivalents) was added dropwise, reacted at room temperature, and monitored by TLC. After completion of the reaction, the reaction was quenched with aqueous hydrochloric acid (1.0M,10mL) and extracted with ethyl acetate (3 × 10mL), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product. The crude product was then purified by flash column chromatography using petroleum ether and ethyl acetate as eluent (petroleum ether: ethyl acetate by volume ═ 7: 1) to give the product 1,1,1,3,3, 3-hexafluoropropan-2-yl-2- (1-hydroxy-5- (p-tolyloxy) -1, 3-dihydrobenzo [ c ] [1,2] oxaboron-3-yl) acrylate.
(4) 1,1,1,3,3, 3-hexafluoropropane-2-yl 2- (1-hydroxy-5- (p-tolyloxy) -1, 3-dihydrobenzo [ c ] synthesized as described above][1,2]Oxaboron-3-yl) acrylate was dissolved in methanol, aqueous sodium hydroxide (1.0M) was added dropwise, stirred at room temperature for 2.5 hours, and then acidified with aqueous hydrochloric acid (1.0M,10 mL). The system was extracted with ethyl acetate (3 × 10mL), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product. The crude product was then purified by flash column chromatography to give a pale yellow solid, i.e. the target compound 1, in 81% yield.1H NMR(400MHz,Methanol-d4):δ＝7.55(d,J＝8.1Hz,1H),7.41(d,J＝7.5Hz,2H),7.35(t,J＝7.4Hz,2H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.24(s,1H),5.99(s,1H),5.74(s,1H),2.03(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.68,161.56,158.01,140.95,136.92,131.22,128.12,127.55,127.28,124.25,115.23,107.50,79.15,23.01。
Example 2: synthesis of Compound 2
Figure BDA0003036215480000101
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 2 is obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4):δ＝7.40(m,3H),7.35(t,J＝7.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.23(s,1H),5.97(s,1H),5.74(s,1H),2.03(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.58,161.65,158.10,140.59,136.29,131.22,128.21,127.53,127.22,124.21,117.89,115.23,109.12,107.50,79.15,23.01。
Example 3: synthesis of Compound 3
Figure BDA0003036215480000102
According to the above synthesis scheme I, referring to the preparation method of the compound 1, the target compound is obtained3, yield 85%.1H NMR(400MHz,Methanol-d4):δ＝7.47-7.37(m,4H),7.35(d,J＝8.1Hz,1H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.27(s,1H),5.99(s,1H),5.76(s,1H),1.13(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.38,161.45,157.90,140.39,136.09,131.02,128.11,127.33,127.02,124.41,117.99,115.23,109.12,107.50,79.55,24.01。
Example 4: synthesis of Compound 4
Figure BDA0003036215480000111
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 4 is obtained with a yield of 85%.1H NMR(400MHz,Methanol-d4):δ＝7.41(d,J＝7.5Hz,2H),7.35(t,J＝7.4Hz,2H),7.29(t,J＝7.2Hz,2H),7.02(d,J＝2.2Hz,1H),6.24(s,1H),5.99(s,1H),5.74(s,1H),3.77(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.01,161.50,158.23,140.92,136.95,131.22,128.12,127.58,127.25,124.23,115.25,107.50,79.15,56.01。
Example 5: synthesis of Compound 5
Figure BDA0003036215480000112
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 5 is obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4):δ＝7.48-7.34(t,J＝7.4Hz,3H),7.30(d,J＝8.1Hz,1H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,2H),6.23(s,1H),5.97(s,1H),5.74(s,1H),3.79(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.58,161.65,158.10,140.59,136.29,131.22,128.21,127.53,127.34,124.21,117.70,115.63,109.89,107.56,79.23,43.01。
Example 6: synthesis of Compound 6
Figure BDA0003036215480000113
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 6 is obtained with a yield of 84%.1H NMR(400MHz,Methanol-d4):δ＝7.49-7.36(m,4H),7.30(d,J＝8.1Hz,1H),7.26(t,J＝7.2Hz,1H),7.00(d,J＝2.2Hz,1H),6.25(s,1H),5.97(s,1H),5.76(s,1H),3.69(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝168.38,165.45,155.90,141.39,139.09,133.02,129.11,126.33,126.02,125.41,119.99,115.23,109.12,107.50,79.55,45.01。
Example 7: synthesis of Compound 7
Figure BDA0003036215480000114
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 7 is obtained with a yield of 81%.1H NMR(400MHz,Methanol-d4):δ＝7.25(d,J＝8.4Hz,1H),7.01(d,J＝1.9Hz,1H),6.95(t,J＝8.7Hz,3H),6.90–6.81(m,2H),6.15(s,1H),5.91(s,1H),5.68(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,160.03,157.64,157.45,153.24,153.22,140.76,124.52,123.26,121.44,120.23,120.15,118.50,116.03,115.80,79.51。
Example 8: synthesis of Compound 8
Figure BDA0003036215480000121
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 8 is obtained with a yield of 79%.1H NMR(400MHz,Methanol-d4):δ＝7.29(d,J＝8.4Hz,1H),7.11(d,J＝1.9Hz,1H),6.97(t,J＝8.7Hz,3H),6.90–6.80(m,2H),6.14(s,1H),5.94(s,1H),5.69(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.13,160.22,157.67,157.75,153.44,153.52,140.86,124.32,123.28,121.14,120.23,120.15,118.50,116.03,115.80,79.71。
Example 9: synthesis of Compound 9
Figure BDA0003036215480000122
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 9 was obtained with a yield of 87%.1H NMR(400MHz,Methanol-d4):δ＝7.35(d,J＝8.4Hz,1H),7.23(d,J＝1.9Hz,1H),7.10(t,J＝8.7Hz,3H),6.99–6.89(m,2H),6.10(s,1H),5.99(s,1H),5.79(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝168.00,161.22,157.37,157.76,153.43,153.22,140.96,124.12,123.38,121.18,120.33,120.25,118.90,116.03,115.80,79.77。
Example 10: synthesis of Compound 10
Figure BDA0003036215480000123
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 10 is obtained with a yield of 85%.1H NMR(400MHz,Methanol-d4):δ＝7.61(d,J＝8.6Hz,1H),7.44(d,J＝8.3Hz,2H),7.26(d,J＝2.3Hz,2H),7.14(dd,J＝8.3,2.3Hz,1H),7.05(d,J＝8.6Hz,1H),6.28(s,1H),6.06(s,1H),5.83(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.34,161.00,155.36,151.71,140.66,126.91,126.88,126.84,125.69,124.64,124.58,124.25,123.61,122.93,120.51,117.46,79.66。
Example 11: synthesis of Compound 11
Figure BDA0003036215480000131
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 11 is obtained with a yield of 79%.1H NMR(400MHz,Methanol-d4):δ＝7.54(d,J＝8.6Hz,3H),7.32(d,J＝8.3Hz,1H),7.21(d,J＝2.3Hz,1H),7.13(dd,J＝8.3,2.3Hz,1H),7.04(d,J＝8.6Hz,1H),6.29(s,1H),6.05(s,1H),5.84(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.35,161.50,155.46,151.61,140.66,126.91,126.88,126.84,125.69,124.64,124.58,124.25,123.61,122.94,120.51,117.49,79.58。
Example 12: synthesis of Compound 12
Figure BDA0003036215480000132
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 12 is obtained with a yield of 84%.1H NMR(400MHz,Methanol-d4):δ＝7.41(d,J＝8.4Hz,1H),7.30(d,J＝1.9Hz,1H),7.13(t,J＝8.7Hz,3H),6.97–6.85(m,2H),6.10(s,1H),5.99(s,1H),5.79(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.91,163.21,156.37,157.76,153.43,153.22,140.96,124.12,123.38,120.98,120.13,120.00,118.80,116.13,115.40,78.99。
Example 13: synthesis of Compound 13
Figure BDA0003036215480000133
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 13 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.25(d,J＝8.4Hz,2H),7.01(d,J＝1.9Hz,2H),6.95(t,J＝8.7Hz,1H),6.90–6.81(m,2H),6.17(s,1H),5.98(s,1H),5.67(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,157.64,153.24,140.76,124.25,123.62,121.44,120.32,120.51,118.50,116.30,115.08,79.15。
Example 14: synthesis of Compound 14
Figure BDA0003036215480000134
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 14 is obtainedThe yield thereof was found to be 79%.1H NMR(400MHz,Methanol-d4):δ＝7.30(d,J＝8.4Hz,1H),7.12(d,J＝1.9Hz,1H),6.98(t,J＝8.7Hz,3H),6.91–6.81(m,2H),6.15(s,1H),5.95(s,1H),5.70(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.13,160.22,157.67,153.44,151.52,140.86,124.32,123.28,121.18,120.20,120.15,118.40,116.93,115.89,77.71。
Example 15: synthesis of Compound 15
Figure BDA0003036215480000141
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 15 was obtained with a yield of 87%.1H NMR(400MHz,Methanol-d4):δ＝7.39(d,J＝8.4Hz,1H),7.33(d,J＝1.9Hz,1H),7.20(t,J＝8.7Hz,3H),6.79–6.69(m,2H),6.10(s,1H),5.99(s,1H),5.79(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝168.00,161.22,157.37,157.76,153.43,153.22,140.86,124.17,123.28,121.08,120.53,120.25,118.91,116.03,115.80,79.67。
Example 16: synthesis of Compound 16
Figure BDA0003036215480000142
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 16 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.24(d,J＝8.4Hz,2H),7.01(d,J＝1.9Hz,2H),6.97(t,J＝8.7Hz,1H),6.90–6.85(m,2H),6.17(s,1H),5.95(s,1H),5.67(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.73,156.64,154.24,140.76,124.25,123.62,120.51,120.44,120.32,118.50,116.30,115.08,78.95。
Example 17: synthesis of Compound 17
Figure BDA0003036215480000143
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 17 is obtained with a yield of 79%.1H NMR(400MHz,Methanol-d4):δ＝7.34(d,J＝8.4Hz,1H),7.19(d,J＝1.9Hz,1H),7.00(t,J＝8.7Hz,3H),6.99–6.81(m,2H),6.13(s,1H),5.90(s,1H),5.701(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.03,160.12,157.37,153.14,151.72,140.66,124.12,123.08,121.38,120.21,120.15,118.40,116.93,115.89,77.71。
Example 18: synthesis of Compound 18
Figure BDA0003036215480000151
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 18 is obtained with a yield of 81%.1H NMR(400MHz,Methanol-d4):δ＝7.32(d,J＝8.4Hz,1H),7.30(d,J＝1.9Hz,1H),7.27(t,J＝8.7Hz,3H),6.89–6.59(m,2H),6.10(s,1H),5.89(s,1H),5.69(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.00,160.22,156.73,156.71,152.43,152.22,139.86,123.17,122.28,120.08,119.53,119.25,117.91,115.03,114.80,78.67。
Example 19: synthesis of Compound 19
Figure BDA0003036215480000152
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 19 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.55(d,J＝8.1Hz,1H),7.41(d,J＝7.5Hz,2H),7.35(t,J＝7.4Hz,2H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.97(dd,J＝8.2,2.2Hz,1H),6.24(s,1H),5.99(s,1H),5.74(s,1H),5.07(s,2H)；13C NMR(100MHz,Methanol-d4):δ＝167.69,161.57,158.02,140.96,136.93,131.23,128.13,127.56,127.29,124.26,115.24,107.51,79.16,69.57。
Example 20: synthesis of Compound 20
Figure BDA0003036215480000153
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 20 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.55(d,J＝8.1Hz,2H),7.35(t,J＝7.4Hz,2H),7.29(t,J＝7.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.97(dd,J＝8.2,2.2Hz,1H),6.24(s,1H),5.99(s,1H),5.74(s,1H),5.07(s,2H),3.57(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.69,161.57,158.02,140.96,136.93,131.23,128.13,127.56,127.29,124.26,115.24,107.51,79.16,69.57,45.79。
Example 21: synthesis of Compound 21
Figure BDA0003036215480000154
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 21 is obtained with a yield of 75%.1H NMR(400MHz,Methanol-d4):δ＝7.57(d,J＝8.1Hz,2H),7.36(t,J＝7.4Hz,2H),7.28(t,J＝7.2Hz,1H),7.12(d,J＝2.2Hz,1H),6.87(dd,J＝8.2,2.2Hz,1H),6.34(s,1H),5.79(s,1H),5.64(s,1H),5.17(s,2H)；13C NMR(100MHz,Methanol-d4):δ＝167.99,162.57,157.02,141.96,137.93,133.23,129.13,128.56,128.29,125.26,119.24,117.51,79.19,69.87,45.70。
Example 22: synthesis of Compound 22
Figure BDA0003036215480000161
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 22 is obtained with a yield of 79%.1H NMR(400MHz,Methanol-d4):δ＝7.34(d,J＝8.4Hz,1H),7.09(d,J＝2.4Hz,1H),7.04–6.99(m,1H),6.94–6.88(m,4H),6.26(s,1H),6.02(s,1H),5.79(s,1H),1.79(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,158.35,156.11,150.22,149.49,140.91,124.24,122.97,120.71,120.24,117.54,114.57,79.43,54.64。
Example 23: synthesis of Compound 23
Figure BDA0003036215480000162
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 23 was obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4):δ＝7.41(m,3H),7.30(t,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),7.19(t,J＝7.2Hz,1H),6.99(d,J＝2.2Hz,1H),6.43(s,1H),5.77(s,1H),5.54(s,1H),2.03(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.58,161.65,158.10,140.59,136.29,131.22,128.21,127.53,127.22,124.21,117.89,115.23,109.12,107.50,79.15,43.01。
Example 24: synthesis of Compound 24
Figure BDA0003036215480000163
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 24 was obtained with a yield of 88%.1H NMR(400MHz,Methanol-d4):δ＝7.45-7.27(m,4H),7.25(d,J＝8.1Hz,1H),7.20(t,J＝7.2Hz,1H),7.12(d,J＝2.2Hz,1H),6.17(s,1H),5.79(s,1H),5.66(s,1H),2.33(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.18,160.45,157.90,140.39,136.09,131.02,128.11,127.33,127.12,124.61,119.00,115.53,109.32,108.50,80.55,25.01。
Example 25: synthesis of Compound 25
Figure BDA0003036215480000171
Preparation of reference Compound 1 according to the above Synthesis route onePreparation method, target compound 25 was obtained with 80% yield.1H NMR(400MHz,Methanol-d4):δ＝7.34(d,J＝8.4Hz,1H),7.09(d,J＝2.4Hz,1H),7.04–6.99(m,1H),6.94–6.88(m,4H),6.26(s,1H),6.02(s,1H),5.79(s,1H),3.79(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,158.35,156.11,150.22,149.49,140.91,124.24,122.97,120.71,120.24,117.54,114.57,79.43,54.64,23.80。
Example 26: synthesis of Compound 26
Figure BDA0003036215480000172
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 26 was obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4):δ＝7.48(m,3H),7.37(t,J＝7.4Hz,1H),7.26(d,J＝8.1Hz,1H),7.15(t,J＝7.2Hz,1H),6.94(d,J＝2.2Hz,1H),6.43(s,1H),5.72(s,1H),5.51(s,1H),4.14(m，2H),2.03(m,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.18,161.25,158.30,140.49,136.59,131.62,128.71,127.58,127.29,124.21,117.82,115.33,109.42,107.55,79.15,59.00,43.01。
Example 27: synthesis of Compound 27
Figure BDA0003036215480000173
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 27 was obtained with a yield of 88%.1H NMR(400MHz,Methanol-d4):δ＝7.49-7.28(m,4H),7.257(d,J＝8.1Hz,1H),7.26(t,J＝7.2Hz,1H),7.15(d,J＝2.2Hz,1H),6.14(s,1H),5.73(s,1H),5.62(s,1H),4.53(m,1H),2.31(d,6H)；13C NMR(100MHz,Methanol-d4):δ＝167.18,160.45,157.90,140.39,136.09,131.12,128.91,127.73,127.52,124.63,119.01,115.23,109.34,108.50,80.55,35.89,25.01。
Example 28: synthesis of Compound 28
Figure BDA0003036215480000174
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 28 was obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.25(d,J＝8.4Hz,1H),7.01(d,J＝1.9Hz,1H),6.95(t,J＝8.7Hz,3H),6.90–6.81(m,2H),6.15(s,1H),5.91(s,1H),5.68(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,160.03,157.64,157.45,153.24,153.22,140.76,124.52,123.26,121.44,120.23,120.15,118.50,116.03,115.80,79.51。
Synthesis of Compound 29
Figure BDA0003036215480000181
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 29 is obtained with a yield of 89%.1H NMR(400MHz,Methanol-d4):δ＝7.28(d,J＝8.4Hz,1H),7.11(d,J＝1.9Hz,1H),6.99(t,J＝8.7Hz,3H),6.80–6.71(m,2H),6.25(s,1H),5.81(s,1H),5.78(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.43,160.03,157.64,157.45,153.24,153.22,140.76,124.52,123.56,121.84,120.83,120.45,118.50,116.53,115.60,79.91。
Example 30: synthesis of Compound 30
Figure BDA0003036215480000182
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 30 was obtained with a yield of 88%.1H NMR(400MHz,Methanol-d4):δ＝7.50-7.38(m,4H),7.27(d,J＝8.1Hz,1H),7.16(t,J＝7.2Hz,1H),7.05(d,J＝2.2Hz,1H),6.84(s,1H),5.93(s,1H),5.72(s,1H),；13C NMR(100MHz,Methanol-d4):δ＝167.48,160.48,157.10,140.37,136.39,131.72,128.91,127.93,127.51,124.63,119.01,115.23,109.34,108.50,80.55,35.89。
Example 31: synthesis of Compound 31
Figure BDA0003036215480000183
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 31 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.51-7.39(m,4H),7.26(d,J＝8.1Hz,1H),7.17(t,J＝7.2Hz,1H),7.10(d,J＝2.2Hz,1H),6.84(s,1H),5.93(s,1H),5.72(s,1H),；13C NMR(100MHz,Methanol-d4):δ＝167.18,160.28,157.30,140.47,136.59,131.62,128.71,127.83,127.91,124.83,119.71,115.63,109.54,108.40,80.35,35.29。
Example 32: synthesis of Compound 32
Figure BDA0003036215480000191
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 32 was obtained with a yield of 71%.1H NMR(400MHz,Methanol-d4):δ＝7.40(d,J＝8.3Hz,1H),7.36–7.28(m,2H),7.19(d,J＝2.4Hz,1H),7.10(dd,J＝8.4,2.4Hz,1H),6.98–6.86(m,2H),6.27(s,1H),6.05(s,1H),5.82(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.32,156.54,156.33,150.79,140.72,129.39,127.82,124.45,123.31,122.00,119.53,119.27,79.55。
Example 33: synthesis of Compound 33
Figure BDA0003036215480000192
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 33 was obtained with a yield of 81%.1H NMR(400MHz,Methanol-d4):δ＝7.40(d,J＝8.4Hz,1H),7.30(d,J＝1.9Hz,1H),7.190(t,J＝8.7Hz,3H),6.80–6.70(m,2H),6.09(s,1H),5.98(s,1H),5.77(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝168.30,161.52,157.77,157.36,153.53,153.12,140.96,124.77,123.68,121.58,120.53,120.25,118.91,116.03,115.80,79.67。
Example 34: synthesis of Compound 34
Figure BDA0003036215480000193
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 34 is obtained with a yield of 79%.1H NMR(400MHz,Methanol-d4):δ＝7.61(d,J＝8.6Hz,1H),7.44(d,J＝8.3Hz,2H),7.26(d,J＝2.3Hz,2H),7.14(dd,J＝8.3,2.3Hz,1H),7.05(d,J＝8.6Hz,1H),6.28(s,1H),6.06(s,1H),5.83(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.34,161.00,155.36,151.71,140.66,126.91,126.88,126.84,125.69,124.64,124.58,124.25,123.61,122.93,120.51,117.46,79.66。
Example 35: synthesis of Compound 35
Figure BDA0003036215480000194
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 35 was obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4):δ＝7.59(d,J＝8.6Hz,1H),7.46(d,J＝8.3Hz,3H),7.28(d,J＝2.3Hz,1H),7.13(dd,J＝8.3,2.3Hz,1H),7.02(d,J＝8.6Hz,1H),6.21(s,1H),6.16(s,1H),5.85(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝167.37,161.03,155.39,151.74,140.69,126.94,126.91,126.87,125.72,124.67,124.61,124.28,123.64,122.96,120.53,117.49,79.69。
Example 36: synthesis of Compound 36
Figure BDA0003036215480000201
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 36 is obtained with a yield of 89%.1H NMR(400MHz,Methanol-d4):δ＝7.30(d,J＝8.4Hz,2H),7.22(d,J＝1.9Hz,2H),6.98(t,J＝8.7Hz,1H),6.97–6.85(m,2H),6.18(s,1H),5.92(s,1H),5.63(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝168.44,158.65,152.25,149.77,124.26,123.63,121.45,120.33,120.52,118.51,116.31,115.09,79.16。
Example 37: synthesis of Compound 37
Figure BDA0003036215480000202
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 37 is obtained with a yield of 81%.1H NMR(400MHz,Methanol-d4):δ＝7.39(d,J＝8.4Hz,1H),7.29(d,J＝1.9Hz,1H),7.18(t,J＝8.7Hz,3H),6.79–6.69(m,2H),6.08(s,1H),5.97(s,1H),5.76(s,1H)；13C NMR(100MHz,Methanol-d4):δ＝168.29,161.51,157.76,157.35,153.52,153.11,140.95,124.76,123.67,121.57,120.54,120.24,118.90,116.02,115.79,79.66。
Example 38: synthesis of Compound 38
Figure BDA0003036215480000203
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 38 was obtained with a yield of 83%.1H NMR(400MHz,Methanol-d4)δ＝7.43(d,J＝7.1Hz,2H),7.39–7.33(m,2H),7.32–7.26(m,2H),7.20(d,J＝2.5Hz,1H),7.07(dd,J＝8.4,2.5Hz,1H),6.18(s,1H),6.00(s,1H),5.75(s,1H),5.08(s,2H)；13C NMR(100MHz,Methanol-d4):δ＝167.57,158.63,148.06,141.14,137.29,128.10,127.47,127.17,124.07,122.76,118.88,114.22,79.35,69.78。
Example 39: synthesis of Compound 39
Figure BDA0003036215480000211
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 39 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.58(d,J＝8.1Hz,2H),7.37(t,J＝7.4Hz,2H),7.26(t,J＝7.2Hz,1H),7.05(d,J＝2.2Hz,1H),6.94(dd,J＝8.2,2.2Hz,1H),6.23(s,1H),5.89(s,1H),5.74(s,1H),5.07(s,2H),1.57(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.89,161.97,158.62,140.56,136.23,133.23,129.13,128.56,128.29,125.26,117.24,107.61,79.16,69.97,45.89。
Example 40: synthesis of Compound 40
Figure BDA0003036215480000212
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 40 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.53(d,J＝8.1Hz,2H),7.35(t,J＝7.4Hz,2H),7.27(t,J＝7.2Hz,1H),7.06(d,J＝2.2Hz,1H),6.97(dd,J＝8.2,2.2Hz,1H),6.24(s,1H),5.85(s,1H),5.79(s,1H),5.07(s,2H),3.57(s,3H)；13C NMR(100MHz,Methanol-d4):δ＝167.09,161.97,158.02,140.56,136.23,133.23,129.13,128.06,128.29,125.26,117.24,107.01,79.16,69.97,45.79。
Example 41: synthesis of Compound 41
Figure BDA0003036215480000213
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 41 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.58(d,J＝8.1Hz,2H),7.46(t,J＝7.4Hz,2H),7.38(t,J＝7.2Hz,1H),7.16(d,J＝2.2Hz,1H),6.97(dd,J＝8.2,2.2Hz,1H),6.37(s,1H),5.99(s,1H),5.64(s,1H),5.57(s,2H)；13C NMR(100MHz,Methanol-d4):δ＝167.49,162.17,157.92,141.56,137.93,132.23,129.13,128.56,128.29,125.26,119.24,117.51,79.19,67.87,41.70。
Example 42: synthesis of Compound 42
Figure BDA0003036215480000214
According to the above synthesis scheme one, referring to the preparation method of compound 1, the target compound 42 is obtained with a yield of 80%.1H NMR(400MHz,Methanol-d4):δ＝7.44(d,J＝8.3Hz,2H),7.26(d,J＝2.3Hz,2H),7.14(dd,J＝8.3,2.3Hz,2H),7.05(d,J＝8.6Hz,1H),6.28(s,1H),6.06(s,1H),5.83(s,1H)5.07(s,2H)；13C NMR(100MHz,Methanol-d4):δ＝167.34,161.00,155.36,151.71,140.66,126.91,126.88,126.84,125.69,124.64,124.58,124.25,123.61,122.93,120.51,117.46,79.66 69.96。
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1: in vitro inhibitory Activity of Compounds of the invention on MBL and SBL enzymes
1. Experimental methods
The in vitro inhibitory activity of the compounds 1-38 of the invention on SBL-like beta-lactamases (TEM-1, KPC-2, Ampc, OXA-48) and MBL-like beta-lactamases (GOB-18, SFH-1, NDM-1, VIM-2) was tested by the following method, with a commercially available beta-lactamase inhibitor Avibactam as a control.
(1) Preparation of protein:
(1.1) preparing VIM-2 protein. VIM-2 gene (protein residue sequence: 27-266) was amplified by PCR and cloned into PET28 vector with His tag and TEV protease cleavage site at N-terminus. VIM-2 protein was expressed in E.coli (DE3), cultured at 37 ℃ for 2-4 hours until OD600 reached 0.6-0.8, induced by the addition of isopropyl beta-D-1-thiogalactopyranoside (IPTG) to a final concentration of 0.3mM, and shaken overnight at 20 ℃. The cells were collected by centrifugation at 4000r/min for 15min and resuspended in lysis buffer (20mM Tris-HCl, 250mM NaCl, pH8.0), cells were disrupted using a high pressure disrupter, cell debris was removed by centrifugation at 15,000r/min for 30min, the supernatant was collected and applied to a Ni-NTA column (Roche), and the cell debris was removed by bulk washing with Wash buffer (20mM Tris-HCl pH8.0,250 mM NaCl,5mM imidazole) containing 5mM imidazole to remove non-specifically bound proteins. Finally, the protein of interest was eluted with an elution buffer containing 250mM imidazole (20mM Tris-HCl pH8.0,250 mM NaCl, 250mM imidazole). The protein of interest is collected and concentrated, and the VIM-2 protein is desalted into a buffer of 20mM Tris-HCl pH7.5,200mM NaCl using a desalting column. VIM-2 protein was collected and concentrated to 15mg/ml and stored at-80 ℃ with the addition of 1mM tris (2-carboxyethyl) phosphine (TCEP). The purification process was monitored by SDS-PAGE and the protein concentration was determined by a Nanno Drop 2000 Spectrophotometer (Thermo Scientific).
(1.2) similar methods were used to prepare the remaining proteins (TEM-1, KPC-2, Ampc, OXA-48, GOB-18, SFH-1, NDM-1 proteins).
(2) Testing of inhibitory Activity:
(2.1) test of inhibitory Activity of Compounds on VIM-2 protein. Test compounds were dissolved in 100% DMSO solvents to prepare 100mM stock solutions, which were then diluted with VIM-2 buffer solutions to prepare three-fold dilutions of working compound solutions, e.g., 3.6mM, 1.2mM, and 400. mu.M. mu.L of the compound working solution, 30. mu.L of VIM-2 buffer solution, and 10. mu.L of VIM-2 protein (200pM) were added to each test well, and reacted at 25 ℃ for 10 minutes, and after 10. mu.L of the VIM-2 substrate was added to each test well, the fluorescence intensity of the kinetic reaction process of the above reaction solution was measured at an excitation wavelength of 380nM and an emission wavelength of 460nM using a Thermo VARIOSKAN LUX plate reader immediately. Compound concentrations from 600. mu.M to 0.03. mu.M 3-fold dilution for IC determination503 parallel groups were set for each concentration. The inhibition rate was calculated using the following formula:
Figure BDA0003036215480000231
wherein Δ FaChange in fluorescence intensity, Δ F, for the same time without test compoundcThe change in fluorescence intensity of the test compound is measured at the same time. The half-effective Inhibitory Concentration (IC) of the test compound against VIM-2 protein was obtained using Graphpad Prism software (La Jolla, Calif.)50) The value is obtained.
(2.2) Using a similar method, willReplacement of the VIM-2 protein with the remaining proteins, respectively, and determination of the IC of the test compound against the TEM-1, KPC-2, Ampc, OXA-48, GOB-18, SFH-1, NDM-1 proteins50The value is obtained.
2. Results of the experiment
IC of each compound against SBL class beta-lactamase (TEM-1, KPC-2, Ampc, OXA-48) and MBL class beta-lactamase (GOB-18, SFH-1, NDM-1, VIM-2)50The values are shown in Table 1.
TABLE 1 inhibitory Activity of the Compounds of the invention against clinical beta-lactamases
Figure BDA0003036215480000232
Figure BDA0003036215480000241
In Table 1 "+++" denotes IC50<0.1 μ M; "+ +" indicates 0.1. mu.M<IC50<10.0 μ M; "+" indicates 10.0. mu.M<IC50<100.0 mu M; "-" denotes IC50>100.0μM。
As can be seen from Table 1, the compounds of the present invention have good inhibitory activity against SBL class beta-lactamases, in particular compounds 4, 9, 20, 22, 36, 40, 41, 42, which have IC for KPC-2 or OXA-4850As low as 0.1. mu.M or less.
In addition, the compound has good inhibitory activity on MBL beta-lactamase.
As can be seen from the table 1, the compounds 1-6, 9-15, 17-20, 22-24, 27-28, 32 and 34-42 have good inhibitory activity on SBL beta-lactamases and MBL beta-lactamases, and can be used for preparing MBL/SBL dual inhibitors.
On the other hand, although commercially available beta-lactamase inhibitor Avibactam is effective in inhibiting a variety of SBL-like beta-lactamases, it has a poor inhibitory effect on MBL-like beta-lactamases and has an IC effect on SFH-1 and NDM-150>100.0μM。
The experimental results show that the compound provided by the invention can be used for preparing SBL inhibitors, MBL inhibitors and even MBL/SBL dual inhibitors.
In conclusion, the invention provides a 3-substituted five-membered cyclic borate derivative which has an inhibitory effect on MBL, an inhibitory effect on SBL and even a dual inhibitory effect on MBL and SBL, and a pharmaceutical composition and pharmaceutical application thereof. Experimental results show that the 3-substituted five-membered cyclic borate derivative not only has good inhibitory activity on SBL beta-lactamases, but also has good inhibitory activity on MBL beta-lactamases, can be used as serine beta-lactamase inhibitors, metallo beta-lactamases and serine beta-lactamase dual inhibitors, and has wide application prospects in preparation of drugs for resisting drug-resistant bacteria.

Claims (13)

1. A compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof:
Figure FDA0003554734650000011
wherein n is an integer of 0-2;
R1each independently selected from halogenated or non-halogenated C1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, halogen, nitro, cyano;
m is 0, 1 or 2;
x is selected from O or S.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as a formula III-1, a formula III-2, a formula III-3 or a formula III-4:
Figure FDA0003554734650000012
wherein n is 0 or 1;
R1each independently selected from halogenated or non-halogenated C1～4Alkyl, halogenated or non-halogenated C1～4Alkoxy, halogen, nitro, cyano.
3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof, wherein: the compound is one of the following compounds:
Figure FDA0003554734650000021
Figure FDA0003554734650000031
4. a process for preparing a compound of formula II, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof, wherein: the method comprises the following steps:
Figure FDA0003554734650000041
(1) reacting the compound shown in the formula II-c with the compound shown in the formula II-d to obtain a compound shown in the formula II-e;
(2) hydrolyzing the compound shown in the formula II-e to obtain a compound shown in the formula II;
wherein X, m, n, R1As claimed in claim 1; x is located at the 1-or 2-position of the phenyl ring.
5. The method of claim 4, wherein: in the step (1), the molar ratio of the compound shown in the formula II-c to the compound shown in the formula II-d is 1: (1-8); the reaction temperature is room temperature;
and/or, in the step (2), the hydrolysis method is to add alkali into the compound shown in the formula II-e.
6. The method of claim 5, wherein: in the step (1), the molar ratio of the compound shown as the formula II-c to the compound shown as the formula II-d is 1: 5;
and/or, in the step (2), the alkali is inorganic alkali.
7. The method of claim 6, wherein: in the step (2), the alkali is sodium hydroxide.
8. A pharmaceutical composition for inhibiting beta-lactamase, comprising: the preparation is prepared by taking the compound of any one of claims 1 to 3, or pharmaceutically acceptable salt thereof, or isotopic compound thereof, or stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
9. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, or a stereoisomer thereof, for the preparation of a β -lactamase inhibitor.
10. Use according to claim 9, characterized in that: the beta-lactamase inhibitor is a metallo beta-lactamase inhibitor, a serine beta-lactamase inhibitor, a metallo beta-lactamase and a serine beta-lactamase dual inhibitor.
11. Use according to claim 9, characterized in that: the beta-lactamase inhibitor is an antibacterial drug.
12. Use according to claim 11, characterized in that: the antibacterial drug is a drug for resisting drug-resistant bacteria.
13. Use according to claim 12, characterized in that: the antibacterial drug is a drug for resisting multiple drug-resistant bacteria, a drug for resisting wide drug-resistant bacteria or a drug for resisting full drug-resistant bacteria.
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