CN116693467A - Thiazole amine MBL inhibitor and preparation method and application thereof - Google Patents

Thiazole amine MBL inhibitor and preparation method and application thereof Download PDF

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CN116693467A
CN116693467A CN202210190185.1A CN202210190185A CN116693467A CN 116693467 A CN116693467 A CN 116693467A CN 202210190185 A CN202210190185 A CN 202210190185A CN 116693467 A CN116693467 A CN 116693467A
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substituted
alkyl
compound
amino
phenyl
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李国菠
颜宇航
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Sichuan University
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Sichuan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The invention provides a thiazole amine MBL inhibitor, and a preparation method and application thereof, and belongs to the field of medicinal chemistry. The thiazole amine MBL inhibitor is a compound shown in a formula I, or a salt, an isomer, a hydrate, a solvate or a prodrug thereof. The compounds of the invention have good inhibitory activity on metallo-beta-lactamase (MBL), especially on a plurality ofClinically relevant MBL subtype has good inhibition activity on subtype VIM, NDM, IMP and the like, has stronger gram-negative bacteria permeability, can be used for preparing a broad-spectrum MBL inhibitor, and has good development prospect as a drug molecule for overcoming antibacterial drug resistance.

Description

Thiazole amine MBL inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a thiazole amine MBL inhibitor, and a preparation method and application thereof.
Background
The beta-lactam antibiotics have the characteristics of wide antibacterial spectrum, high safety, good clinical curative effect and the like, and are the most commonly used antibiotics at present. However, due to abuse and unreasonable use of antibiotics, bacteria have serious drug resistance to antibiotics, and human health is seriously threatened. In 2019, the world health organization has listed the problem of antimicrobial drug resistance as one of ten global health threats. Among pathogenic microorganisms having drug resistance, the problem of antibiotic resistance of gram-negative bacteria is particularly serious. Gram-negative bacteria such as Acinetobacter baumannii, pseudomonas aeruginosa and Enterobacter which are resistant to carbapenem antibiotics have been classified as extremely dangerous pathogenic bacteria by the world health organization. Current studies indicate that there are a variety of mechanisms of resistance of gram-negative bacteria, including prevention of antibiotics from entering the bacteria, evacuation of antibiotics by efflux pumps, changing of antibiotic action targets, hydrolysis of antibiotics, etc., where the production of beta-lactamase hydrolyzes antibiotics as its primary mechanism against beta-lactam antibiotics. Beta-lactamases can be classified into serine-beta-lactamase (SBL) and metallo-beta-lactamase (MBL) according to differences in amino acid sequences, catalytic mechanisms, etc. The beta-lactamase inhibitor is combined with beta-lactamase to inhibit the hydrolysis of beta-lactamase and restore the antibiotic activity, so that the beta-lactamase inhibitor is an effective treatment strategy for resisting drug-resistant gram-negative bacteria infection. Six SBL inhibitors have been successfully marketed to date, and no clinically useful inhibitors have been available for MBL.
MBL can be further divided into three subclasses, B1, B2, B3, according to the amino acid sequence and the structure of the active site, wherein MBL class B1 comprises the most clinically relevant subtype VIM, NDM, IMP found in almost all major gram-negative pathogens, including klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, and other clinically common pathogens. MBL has a broad substrate specificity, hydrolyzes all but the monocyclic class of β -lactam antibiotics and β -lactam SBL inhibitors, and some MBL can hydrolyze even the non- β -lactam SBL inhibitor avibactam. And recently, it has been reported that NDM-1 can hydrolyze the monocyclic β -lactam antibiotic aztreonam slowly, which may mean that MBL has gained the ability to hydrolyze the monocyclic β -lactam antibiotic in continuous evolution. In addition, part of the MBL gene is present on the bacterial mobile genetic element and can be rapidly and widely spread among bacteria by horizontal gene transfer. Therefore, the production of MBL enzymes in bacteria is one of the most alarming drug resistance factors, and the development of effective MBL inhibitors is urgent and of great clinical significance.
At present, various types of MBL inhibitors are reported, including sulfhydryl groups, carboxylic acids, phosphoric acids and the like, but due to the numerous MBL subtypes, the structures have large differences, flexible and changeable loops exist in the active site, and most inhibitors lack broad-spectrum inhibition activity on multiple MBL subtypes, particularly clinically relevant subtypes such as VIM, NDM, IMP and the like. In addition, the low permeability of the bacterial outer membrane is also a common shortcoming of MBL inhibitors that have been reported to date. Therefore, there is a need to develop MBL inhibitors with broad-spectrum inhibitory activity as well as good inhibitory activity against bacteria, providing new lead compounds for the development of clinically effective MBL inhibitors.
Disclosure of Invention
The invention aims to provide a thiazole amine MBL inhibitor, and a preparation method and application thereof.
The present invention provides a compound of formula I, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, -NHR 1 ’；
R 1 ' is selected from 0 to 5R 3 Substituted C 1 ～C 8 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from 5-10 membered aryl, 5-10 membered heteroaryl;
R 3 ' selected from C 1 ～C 8 An alkyl group;
l is selected from none, 0 to 5R 4 Substituted C 1 ～C 8 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 8 An alkyl group;
R 2 selected from C 1 ～C 8 Alkyl, C 2 ～C 8 Alkenyl, C 2 ～C 8 Alkynyl, quilt with 0-5R 5 Substituted 5-10 membered aryl, substituted 0-5R 5 Substituted 3-to 10-membered heteroaryl groups, substituted with 0-5R 5 Substituted 3-10 membered heterocyclyl, substituted with 0-5R 5 Substituted 3-10 membered cycloalkyl;
R 5 are respectively and independently selected from 0 to 5R 6 Substituted C 1 ～C 8 Alkyl, R is 0-5 6 Substituted C 1 ～C 8 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-5R 6 Substituted 5-10 membered aryl, substituted 0-5R 6 Substituted 5-to 10-membered heteroaryl;
R 6 are respectively and independently selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 8 Alkynyl and 5-10 membered aryl;
R 7 selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxyl, amino, nitro, cyano, 5-10 membered aryl, 5-10 membered heteroaryl;
when R is 1 Selected from amino, R 2 When selected from phenyl, L 2 Not selected from C 1 An alkylene group;
when R is 1 Selected from hydrogen, R 2 When selected from phenyl, L 2 Not selected from C 1 Alkylene, 1C 1 Alkyl substituted C 1 Alkylene, C 2 An alkylene group;
when R is 1 Selected from amino groups, L being selected from none of the times, R 2 Not selected from thienyl, C 1 ～C 5 An alkyl group;
when R is 1 Selected from amino, R 2 Selected from C 1 When alkyl, L is not selected from C 2 ～C 4 Alkylene, none, 1C 1 Alkyl substituted C 2 Alkylene, 1C 1 Alkyl substituted C 1 An alkylene group;
when R is 1 Selected from hydrogen, R 2 Selected from C 1 In the case of alkyl groups, L is not selected from 1C 1 Alkyl substituted C 2 Alkylene, 1C 1 Alkyl substituted C 1 An alkylene group;
when R is 1 Selected from amino groups, L is selected from C 1 In the case of alkylene radicals, R is not selected from
Further, the method comprises the steps of,
R 1 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, -NHR 1 ’；
R 1 ' is selected from 0 to 3R 3 Substituted C 1 ～C 8 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 8 An alkyl group;
l is selected from none, 0 to 3R 4 Substituted C 1 ～C 8 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 8 An alkyl group;
R 2 Selected from C 1 ～C 8 Alkyl, C 2 ～C 8 Alkenyl, C 2 ～C 8 Alkynyl, quilt with 0-3R 5 Substituted phenyl, substituted with 0-3R 5 Substituted thienyl, substituted with 0-3R 5 Substituted piperidinyl, substituted with 0-3R 5 Substituted azetidines, substituted with 0-3R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 8 Alkyl, R is 0-3 6 Substituted C 1 ～C 8 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-3R 6 Substituted phenyl, substituted with 0-3R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 8 Alkynyl, phenyl;
R 7 selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
Further, the method comprises the steps of,
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 2 selected from C 1 ～C 7 Alkyl, C 2 ～C 4 Alkenyl, C 2 ～C 4 Alkynyl, quilt with 0-2R 5 Substituted phenyl, substituted with 0-1R 5 Substituted thienyl, substituted with 0-1R 5 Substituted piperidinyl, substituted with 0-1R 5 Substituted azetidines, substituted with 0-1R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
Further, the compound is shown as a formula II:
wherein, the liquid crystal display device comprises a liquid crystal display device,
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 2 selected from C 1 ～C 7 Alkyl, C 2 ～C 4 Alkenyl, C 2 ～C 4 Alkynyl, quilt with 0-2R 5 Substituted phenyl, substituted with 0-1R 5 Substituted thienyl, substituted with 0-1R 5 Substituted piperidinyl, substituted with 0-1R 5 Substituted azetidines, substituted with 0-1R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 Are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
Further, the compound is shown as a formula III:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 5a 、R 5b 、R 5c are respectively and independently selected from hydrogen and R of 0 to 3 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
Further, the compound is shown as a formula IV:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group.
Further, the compound is one of the following compounds:
the invention also provides application of the compound, or salt, isomer, hydrate, solvate or prodrug thereof in preparing MBL inhibitor and/or antibacterial drugs.
The invention also provides a medicine which is a preparation prepared by taking the compound, or salt, isomer, hydrate, solvate or prodrug thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides an application of the thiazole amine compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof in preparing an MBL inhibitor and/or an antibacterial drug, which is characterized in that: the thiazole amine compound is one of the following compounds:
the compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a ～C b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1 ～C 8 Alkyl "refers to an alkyl group containing 1 to 8 carbon atoms; "C 1 ～C 8 Alkoxy "refers to an alkoxy group containing 1 to 8 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C 1 ～C 8 Alkyl means an alkyl group having 1 to 8 carbon atoms, i.e. having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl), hexyl and the like.
"halogen" is fluorine, chlorine, bromine or iodine.
The compound has good inhibitory activity on metal beta-lactamase (MBL), particularly on a plurality of clinically relevant MBL subtypes, such as VIM, NDM, IMP and the like, has stronger gram-negative bacteria permeability, can be used for preparing a broad-spectrum MBL inhibitor, and has good development prospect as a drug molecule for overcoming antibacterial drug resistance.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
Unless otherwise indicated, the materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
Example 1 Synthesis of Compounds 1, 2, 11-14, 18, 20-22, 26, 28, 29, 39, 40, 42, 45, 48, 49, 67-69 and 71-74
The synthetic route is as follows: the substrate is the corresponding aldehyde
1. Synthesis of Compound 39
Ethyl bischloroformate (1 eq) and n-hexanal (0.8 eq) were dissolved in diethyl ether (10 ml), then sodium methoxide (1.1 eq) was added dropwise at 0 ℃ and after stirring for two hours, after stirring for 5 hours at room temperature, saturated brine (about 50 ml) was added to the reaction solution, then extracted with diethyl ether (3×30 ml), after concentrating, dissolved in methanol, thiourea (0.8 eq) was added and refluxed at 65 ℃ for 5 hours, the reaction was stopped, methanol was dried by spinning, dissolved in water, adjusted to slight basicity (ph=8) with aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (PE: ea=1:1, v/v) gave intermediate a (yellow solid, yield about 70%).
Intermediate a (1 eq) was dissolved in ethanol and water (volume ratio=3:1), and sodium hydroxide (3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and then the reaction was stopped. The reaction was brought to slightly acidic (ph=5), dried by spin-drying, and chromatographed on silica gel (DCM: CH 3 Oh=30:1, v/v). Compound 39 was obtained (yield 60%).
Compound 39: 1 H NMR(400MHz,DMSO-d 6 )δ6.98(s br,2H),3.03-2.98(m,2H),1.54-1.50(m,2H),1.38-1.24(m,4H),0.86(t,J＝6.4Hz,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.37,163.99,137.86,31.27,31.13,26.62,22.25,14.32ppm.HRMS:m/z calcd for C 9 H 14 N 2 O 2 S[M+H] + 215.0849,found 215.0843；[M-H 2 O+H] + 197.0749,found 197.0737.
2. synthesis of Compounds 1, 2, 11-14, 18, 20-22, 26, 28, 29, 40, 42, 45, 48, 49, 67-69 and 71-74
According to the synthesis method described in the compound 39, the raw material n-hexanal is replaced with phenylacetaldehyde to prepare the compound 1, the raw material n-hexanal is replaced with 2-phenylpropionaldehyde to prepare the compound 2, the raw material n-hexanal is replaced with n-pentanal to prepare the compound 11, the raw material n-hexanal is replaced with n-heptanal to prepare the compound 12, the raw material n-hexanal is replaced with n-octanal to prepare the compound 13, the raw material n-hexanal is replaced with n-butanal to prepare the compound 14, the raw material n-hexanal is replaced with p-nitrophenylacetaldehyde to prepare the compound 18, the raw material n-hexanal is replaced with acetaldehyde to prepare the compound 20, the raw material n-hexanal is replaced with thiophene-2 acetaldehyde to prepare the compound 21, the raw material n-hexanal is replaced with isobutyraldehyde to prepare the compound 22, preparing a compound 26 by replacing raw material n-hexanal with 2-methyl butyraldehyde, preparing a compound 28 by replacing raw material n-hexanal with formaldehyde, preparing a compound 29 by replacing raw material n-hexanal with 3-methyl butyraldehyde, preparing a compound 40 by replacing raw material n-hexanal with 4- (2-oxo-ethyl) piperidine-1-carboxylic acid tert-butyl ester, preparing a compound 42 by replacing raw material n-hexanal with 4-pentenal, preparing a compound 45 by replacing raw material n-hexanal with 2- (1-benzoyl-piperidin-4-yl) acetaldehyde, preparing a compound 48 by replacing raw material n-hexanal with 4-aminophenylaldehyde, preparing a compound 49 by replacing raw material n-hexanal with 2- (1-furanylpiperidin-4-yl) acetaldehyde, the starting material n-hexanal was replaced with 3- (4-isopropylphenyl) -2-methylpropionaldehyde to produce compound 67, the starting material n-hexanal was replaced with 3- (3-trifluoromethylphenyl) propanal to produce compound 68, the starting material n-hexanal was replaced with convalsal aldehyde to produce compound 69, the starting material n-hexanal was replaced with 3, 5-dichlorobenzaldehyde to produce compound 71, the starting material n-hexanal was replaced with 3, 4-dichlorobenzaldehyde to produce compound 72, the starting material n-hexanal was replaced with 3, 5-dibromophenylacetaldehyde to produce compound 73, and the starting material n-hexanal was replaced with 3-chloro-5-bromo-phenylacetaldehyde to produce compound 74. The structure of each compound is shown below:
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Characterization data for each compound is shown below:
compound 1: 1 H NMR(400MHz,DMSO-d 6 )δ7.33-7.20(m,7H),4.34(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.26,163.57,140.51,136.16,136.04,129.00,128.78,127.00,32.50ppm.HRMS:m/z calcd for C 11 H 10 N 2 O 2 S[M+H] + 235.0536,found 235.0541；[M-H 2 O+H] + 217.0436,found 217.0433.
compound 2: 1 H NMR(400MHz,DMSO-d 6 )δ7.33-7.28(m,4H),7.24-7.18(m,1H),7.08(s br,2H),5.22(q,J＝7.2Hz,1H),1.54(d,J＝7.2Hz,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.96,163.94,145.50,143.11,136.08,128.91,127.28,126.94,36.74,23.08ppm.HRMS:m/z calcd for C 12 H 12 N 2 O 2 S[M+H] + 249.0692,found 249.0684；[M-H 2 O+H] + 231.0592,found 231.0578.
compound 11: 1 H NMR(400MHz,DMSO-d 6 )δ12.23(s br,1H),6.88(s,2H),2.97(t,J＝2.4Hz,2H),1.54-1.47(m,2H),1.34-1.27(m,2H),0.88(t,J＝6.8Hz,3H)ppm.HRMS:m/z calcd for C 8 H 12 N 2 O 2 S[M+H] + 201.0692,found 201.0694；[M-H 2 O+H] + 183.0592,found 183.0573；[M+Na] + 223.0517,found 223.0508.
compound 12: 1 H NMR(400MHz,DMSO-d 6 )δ6.89(s,2H),2.96(t,J＝8.0Hz,2H),1.51(t,J＝8.0Hz,2H),1.26-1.23(m,6H),0.86-0.82(m,3H)ppm.HRMS:m/z calcd for C 10 H 16 N 2 O 2 S[M+H] + 229.1005,found 229.0995；[M-H 2 O+H] + 211.0905,found 211.0887；C 10 H 16 N 2 O 2 S[M+Na] + 251.0830,found 251.0521.
compound 13: 1 H NMR(400MHz,DMSO-d 6 )δ6.88(s,2H),2.96(t,J＝8.0Hz,2H),1.51(s,2H),1.25(d,J＝7.2Hz,8H),0.85(d,J＝6.0Hz,3H)ppm.HRMS:m/z calcd for C 11 H 18 N 2 O 2 S[M+H] + 243.1162,found 243.1147；[M-H 2 O+H] + 225.1062,found 225.1042.
compound 14: 1 H NMR(400MHz,DMSO-d 6 )δ8.68(s,2H),2.97(t,J＝7.2Hz,2H),1.61-1.54(m,2H),0.91(t,J＝7.2Hz,3H)ppm.HRMS:m/z calcd for C 7 H 10 N 2 O 2 S[M+H] + 187.0536,found 187.0536；[M-H 2 O+H] + 169.0436,found 169.0421.
compound 18: 1 H NMR(400MHz,DMSO-d 6 )δ8.14(d,J＝8.4Hz,2H)7.76-7.53(m,br,4H)ppm.
compound 20: 1 H NMR(400MHz,DMSO-d 6 )δ6.71(s,2H),2.31(s,3H)ppm.
compound 21: 1 H NMR(400MHz,DMSO-d 6 )δ8.82(s br,2H),7.43(d,J＝4.8Hz,1H),7.02-6.98(m,2H),4.59(s,2H)ppm.HRMS:m/z calcd for C 9 H 8 N 2 O 2 S 2 [M+H] + 241.0100,found 241.0097；[M-H 2 O+H] + 223.0000,found 222.9991.
compound 22: 1 H NMR(400MHz,DMSO-d 6 )δ7.88-7.60(m,1H),6.97(s,1H),4.25(s,1H),1.14(s,6H)ppm.HRMS:m/z calcd for C 7 H 10 N 2 O 2 S[M+H] + 187.0536,found 187.0559；[M-H 2 O+H] + 169.0436,found 169.0449.
compound 26: HRMS m/z calcd for C 8 H 12 N 2 O 2 S[M+H] + 201.0692,found 201.0702；[M-H 2 O+H] + 183.0592,found 183.0592；[M+Na] + 223.0517,found 223.0527.
Compound 28: 1 H NMR(400MHz,DMSO-d 6 )δ7.20(s,2H),7.00(s,1H)ppm.HRMS:m/z calcd for C 4 H 4 N 2 O 2 S[M+H] + 145.0066,found 145.0067；[M-H 2 O+H] + 126.9966,found 126.9958；[M+Na] + 166.9881,found 166.9891.
compound 29: 1 H NMR(400MHz,DMSO-d 6 )δ6.97(s,2H),2.94(d,J＝6.8Hz,2H),1.78-1.71(m,1H),0.88(d,J＝6.8Hz,6H)ppm.HRMS:m/z calcd for C 8 H 12 N 2 O 2 S[M+H] + 201.0692,found 201.0688；[M-H 2 O+H] + 183.0592,found 183.0579；[M+Na] + 223.0517,found 223.0514.
compound 40: 1 H NMR(400MHz,DMSO-d 6 )δ3.88(s br,2H),3.03-3.00(m,2H),2.67(s br,2H),1.61-1.56(m,3H),1.38(m,9H),1.05-1.02(m,2H)ppm.HRMS:m/z calcd for C 15 H 23 N 3 O 4 S[M+H] + 342.1482,found 342.1486.[M+Na] + 364.1307,found 364.1298.
compound 42: 1 H NMR(400MHz,DMSO-d 6 )δ8.78(s br,2H),5.86-5.76(m,1H),5.08-5.00(m,2H),3.10(t,J＝7.2Hz,2H),2.31(t,J＝7.2Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ166.76,160.37,137.10,135.71,116.85,34.45,25.84ppm.HRMS:m/z calcd for C 8 H 10 N 2 O 2 S[M+H] + 199.0536,found 199.0533；[M-H 2 O+H] + 181.0436,found 181.0428.
compound 45: HRMS m/z calcd for C 17 H 19 N 3 O 3 S[M+H] + 346.1220,found 346.1211.
Compound 48: LC-MS m/z 250.1[ M+H ]] + .
Compound 49: LC-MS m/z 236.1[ M+H ]] + .
Compound 67: 1 H NMR(400MHz,DMSO-d 6 )δ7.13-7.08(m,4H),6.88(s,2H),4.14(s,1H),2.86-2.76(m,2H),2.68-2.63(m,1H),1.17(d,J＝6.8Hz,6H),1.12(d,J＝6.8Hz,3H)ppm.HRMS:m/z calcd for C 16 H 20 N 2 O 2 S[M+H] + 305.1318,found 305.1312.
compound 68: 1 H NMR(400MHz,DMSO-d 6 )δ7.58-7.51(m,4H),6.89(s,2H),3.31(t,J＝8.0Hz,2H),2.95(t,J＝8.0Hz,2H)ppm.HRMS:m/z calcd for C 13 H 11 F 3 N 2 O 2 S[M+H] + 317.0566,found 317.0528.
compound 69: 1 H NMR(400MHz,DMSO-d 6 )δ7.86(s br,2H),7.29(d,J＝7.6Hz,2H),7.10(d,J＝7.6Hz,2H),4.18-4.11(m,1H),2.83-2.78(m,1H),2.73-2.68(m,1H),1.25(s,9H),1.15(d,J＝6.8Hz,3H)ppm.HRMS:m/z calcd for C 17 H 22 N 2 O 2 S[M+H] + 319.1475,found 319.1461.
compound 71: 1 H NMR(400MHz,DMSO-d 6 )δ8.60(s br,2H),7.50(s,1H),7.38(d,J＝1.6Hz,2H),4.39(s,2H)ppm.HRMS:m/z calcd for C 11 H 8 Cl 2 N 2 O 2 S[M+H] + 302.9756,found 302.9757,304.9731.
compound 72: HRMS m/z calcd for C 11 H 8 Cl 2 N 2 O 2 S[M+H] + 302.9756,found 302.9752,304.9729.
Compound 73: HRMS m/z calcd for C 11 H 8 Br 2 N 2 O 2 S[M+H] + 390.8746,found 390.8749,392.8722,394.8707.
Compound 74: HRMS m/z calcd for C 11 H 8 BrClN 2 O 2 S[M+H] + 346.9251,found 346.9250,348.9221.
Example 2 Synthesis of Compounds 5, 17, 43, 46, 47, 50, 52, 55, 58, 60, 64, 65, 66
The synthetic route is as follows: the substrate being the corresponding carboxylic acid
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1. Synthesis of Compound 43
The method comprises the steps of placing raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid (1 eq) into a reaction bottle, dissolving the raw material in dry tetrahydrofuran, slowly adding lithium aluminum hydride (1.5 eq) under ice bath, moving to normal temperature for reaction, monitoring by TLC, stopping the reaction after the completion of the reaction, adding water which is equal to the mass percent of the lithium aluminum hydride (such as adding 200mg lithium aluminum hydride and adding 2ml water) under ice bath, adding sodium hydroxide aqueous solution which is equal to the water in volume and has the mass fraction of ten percent, adding twice the volume of the water, stirring for about 15 minutes, adding a small amount of anhydrous magnesium sulfate, stirring for 15 minutes, filtering, spinning dry tetrahydrofuran, adding a small amount of water and ethyl acetate (the volume ratio of water to ethyl acetate is 1:2), extracting 3 times, drying the organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, and spinning dry to obtain an intermediate a (the yield is about 50-70%).
Intermediate a (1 eq) was placed in a reaction flask, dissolved in methylene chloride, then dessert-martin (1.2 eq) was added, the reaction was stirred at room temperature for about 1h, monitored by TLC, the reaction was stopped after completion, the reaction was filtered through a cylindrical funnel, the filtrate was concentrated under reduced pressure, fine silica gel was added, the column was dried by spinning, and PE was taken out to give intermediate b (yield about 40-60%).
Ethyl bischloroformate (1 eq) and intermediate b (0.8 eq) were dissolved in diethyl ether, sodium methoxide (1.1 eq) was added dropwise at 0 ℃ and after stirring for two hours, after stirring for 5 hours at room temperature, a suitable amount of saturated brine (50 ml) was added, then extracted with diethyl ether (3 x 30 ml), the organic phase was concentrated and then dissolved in methanol, thiourea (0.8 eq) was added and refluxed at 65 ℃ for 5 hours, the reaction was stopped, the methanol was dried with spin, water was dissolved, adjusted to slight basicity (ph=8) with aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (PE: ea=1:1, v/v) gave intermediate c (as yellow solid, yield about 50-80%).
Dissolving intermediate c (1 eq) with ethanol and water (volume ratio 3:1), adding sodium hydroxide (3 eq), and reacting at normal temperatureAfter 2 hours, the reaction was stopped. The reaction was brought to slightly acidic (ph=5), dried by spin-drying, and chromatographed on silica gel (DCM: CH 3 Oh=30:1, v/v). Compound 43 was obtained (yield 60%). LC-MS m/z 314.1[ M+H ]] + .
2. Synthesis of Compounds 5, 17, 46, 47, 50, 52, 55, 58, 60, 64, 65, 66
According to the synthesis method described for compound 43, compound 5 was prepared by substituting benzene propionic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 17 was prepared by substituting p-nitrophenylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 46 was prepared by substituting 3-nitrophenylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 47 was prepared by substituting 3-aminophenylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 50 was prepared by substituting 4-biphenylylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 52 was prepared by substituting 4- (trifluoromethoxy) phenylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 55 was prepared by substituting 4-trifluoromethylphenylacetic acid for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 58 was prepared by substituting 4-isopropylbenzene for raw material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 64 was prepared by substituting 3- (2-thiophene) propionic acid for the starting material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, compound 65 was prepared by substituting naproxen for the starting material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid, and compound 66 was prepared by substituting ibuprofen for the starting material 1- (tert-butoxycarbonyl) azetidine-3-acetic acid. The structure of each compound is shown below:
Characterization data for each compound is shown below:
compound 5: 1 H NMR(400MHz,DMSO-d 6 )δ7.28-7.21(m,7H),3.27(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.71,163.30,141.09,136.45,135.74,128.85,128.79,126.60,37.17,28.66ppm.HRMS:m/z calcd for C 12 H 12 N 2 O 2 S[M+H] + 249.0692,found 249.0689；[M-H 2 O+H] + 231.0592,found 231.0579；[M+Na] + 271.0512,found 271.0512.
compound 17: 1 H NMR(400MHz,DMSO-d 6 )δ8.21(d,J＝8.8Hz,2H),7.68(d,J＝9.2Hz,2H),7.56(s,2H),3.67(s,2H)ppm.HRMS:m/z calcd fo C 11 H 9 N 3 O 4 S[M+H] + 280.0387,found 280.0380.
compound 46: 1 H NMR(400MHz,DMSO-d 6 )δ8.14(s,1H),8.08(d,J＝6.8Hz,1H),7.74(d,J＝6.8Hz,1H),7.61(t,J＝7.2Hz,1H),7.06(s,2H),4.58(s,2H)ppm.HRMS:m/z calcd for C 11 H 9 N 3 O 4 S[M+H] + 280.0387,found 280.0382.
compound 47: 1 H NMR(400MHz,DMSO-d 6 )δ6.94-6.90(m,2H),6.41-6.36(m,3H),6.19(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.79,149.21,141.21,137.34,129.36,116.25,114.16,112.62，32.90ppm.HRMS:m/z calcd for C 11 H 11 N 3 O 2 S[M+H] + 250.0645,found 250.0644；[M-H 2 O+H] + 232.0545,found 232.0539.
compound 50: 1 H NMR(400MHz,DMSO-d 6 )δ7.65-7.59(m,4H),7.45(t,J＝7.6Hz,2H),7.37-7.32(m,3H),7.04(s br,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.13,163.95,140.37,139.98,138.85,137.13,136.01,129.38,129.33,127.78,127.28,127.02,32.12ppm.HRMS:m/z calcd for C 17 H 14 N 2 O 2 S[M+H] + 311.0849,found 311.0843.
compound 52: 1 H NMR(400MHz,DMSO-d 6 )δ7.37(d,J＝8.8Hz,2H),7.29(d,J＝8.8Hz,2H),7.02(s br,2H),4.38(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.31,164.05,147.37,140.25,130.51,121.82,121.54,119.28,116.73,31.66ppm.HRMS:m/z calcd for C 12 H 9 N 3 O 2 F 3 S[M+H] + 319.0359,found 319.0373.
compound 55: 1 H NMR(400MHz,DMSO-d 6 )δ7.68(d,J＝8.0Hz,2H),7.56(s br,2H),7.48(d,J＝8.0Hz,2H),4.46(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.72,163.01,145.07,134.25,129.57,127.90,127.58,125.88,123.43,32.03ppm.
compound 58: 1 H NMR(400MHz,DMSO-d 6 )δ7.17-7.14(m,4H),6.90(s,2H),4.29(s,2H),2.87-2.80(m,1H),1.17(d,J＝6.8Hz,6H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.88,164.18,146.94,138.24,129.39,128.67,126.82,118.77,33.52,32.14,24.39ppm.HRMS:m/z calcd for C 14 H 16 N 2 O 2 S[M+H] + 277.1005,found 277.0992.
compound 60: 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s br,1H),6.91(s,2H),4.29(s,2H),2.51(t,J＝7.6Hz,2H),1.60-1.51(m,2H),0.87(t,J＝7.6Hz,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.93,164.11,140.66,138.06,137.29,136.69,128.88,128.61,37.35,32.21,24.58,14.13ppm.HRMS:m/z calcd for C 14 H 16 N 2 O 2 S[M+H] + 277.1005,found 277.0998.
compound 64: 1 H NMR(400MHz,DMSO-d 6 )δ7.32(d,J＝4.8Hz,1H),6.94-6.92(m,2H),6.87(d,J＝6.4Hz,2H),3.39-3.37(m,2H),3.05(t,J＝7.6Hz,2H)ppm.HRMS:m/z calcd for C 10 H 10 N 2 O 2 S 2 [M+H] + 255.0256,found 255.0254；[M-H 2 O+H] + 237.0156,found 237.0148.
compound 65: 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s br,2H),7.83(d,J＝9.2Hz,1H),7.79-7.73(m,2H),7.41(d,J＝8.4Hz,1H),7.29(s,1H),7.16(dd,J＝9.2Hz,J＝2.0Hz,1H),5.32(t,J＝7.6Hz,1H),3.86(s,3H),1.67(d,J＝7.2Hz,3H)ppm.HRMS:m/z calcd for C 17 H 16 N 2 O 3 S[M+H] + 329.0954,found 329.0947.
compound 66: 1 H NMR(400MHz,DMSO-d 6 )δ7.19(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,2H),6.92(s,2H),5.19-5.17(m,1H),2.40(d,J＝7.2Hz,2H),1.82-1.74(m,1H),1.52(d,J＝6.8Hz,3H),0.84(d,J＝6.8Hz,6H)ppm.HRMS:m/z calcd for C 16 H 20 N 2 O 2 S[M+H] + 305.1318,found 305.1299.
example 3 Synthesis of Compounds 51, 54, 57, 62
The synthetic route is as follows: the substrate is the corresponding alcohol
1. Synthesis of Compound 51
3-Methoxyphenethyl alcohol (1 eq) was placed in a reaction flask, dissolved in methylene chloride (20 ml), and then, dessert-Martin (1.2 eq) was added, the reaction was stirred at room temperature for about 1 hour, monitored by TLC, and after completion of the reaction, the reaction was stopped, the reaction was filtered through a cylindrical funnel, the filtrate was concentrated under reduced pressure, and fine silica gel was added, and the mixture was dried by spin-drying through a column, followed by PE to give intermediate a (yield: about 60%).
Ethyl bischloroformate (1 eq) and intermediate a (0.8 eq) were dissolved in diethyl ether (10 ml), sodium methoxide (1.1 eq) was added dropwise at 0 ℃ and after stirring for two hours, after stirring for 5 hours at room temperature, saturated brine (50 ml) was added to the reaction solution, then extracted with diethyl ether (3 x 30 ml), the organic phase was concentrated and then dissolved in methanol, thiourea (0.8 eq) was added and refluxed at 65 ℃ for 5 hours, the reaction was stopped, methanol was dried by spinning, dissolved in water, adjusted to slight basicity (ph=8) with aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (PE: ea=1:1, v/v) gave intermediate b (as a yellow solid, yield about 50%).
Intermediate b (1 eq) was treated with ethanol and water (volume ratio =3: 1) Sodium hydroxide (3 eq) was added after dissolution, and after reacting for 2 hours at normal temperature, the reaction was stopped. The reaction was brought to slightly acidic (ph=5), dried by spin-drying, and chromatographed on silica gel (DCM: CH 3 Oh=30:1, v/v). Compound 51 was obtained (yield 60%).
Compound 51: 1 H NMR(400MHz,DMSO-d 6 )δ8.20(s br,2H),7.28(t,J＝8.0Hz,1H),6.89-6.85(m,3H),4.37(s,2H),3.78(s,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ166.13,162.01,159.90,141.19,135.63,131.98,130.19,121.09,114.77,112.54,55.48,32.34ppm.HRMS:m/z calcd for C 12 H 12 N 2 O 3 S[M+H] + 265.0641,found 265.0637.
2. synthesis of Compounds 54, 57, 62
According to the synthesis method of the compound 51, the compound 54 is prepared by replacing the raw material 3-methoxyphenylethanol with thiophene-3-ethanol, the compound 57 is prepared by replacing the raw material 3-methoxyphenylethanol with 3-bromophenylethanol, and the compound 62 is prepared by replacing the raw material 3-methoxyphenylethanol with p-fluorophenylethanol. The structure of each compound is shown below:
characterization data for each compound is shown below:
compound 54: 1 H NMR(400MHz,DMSO-d 6 )δ7.46-7.45(m,1H),7.22(s,1H),7.03(s,2H),6.99(d,J＝4.4Hz,1H),4.34(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ164.93,164.19,140.94,137.41,135.79,128.69,126.71,122.16,27.50ppm.HRMS:m/z calcd for C 9 H 8 N 2 O 2 S 2 [M+H] + 241.0100,found 241.0101.
compound 57: 1 H NMR(400MHz,DMSO-d 6 )δ7.45-7.41(m,2H),7.26(d,J＝4.0Hz,2H),7.01-6.90(m,2H),4.44-4.36(m,2H)ppm.HRMS:m/z calcd for C 11 H 9 BrN 2 O 2 S[M+H] + 312.9641,found 312.9652,314.9628.
compound 62: 1 H NMR(400MHz,DMSO-d 6 )δ7.76(s br,2H),7.32-7.29(m,2H),7.17-7.11(m,2H),4.34(s,2H)ppm.HRMS:m/z calcd for C 11 H 9 FN 2 O 2 S[M+H] + 253.0442,found 253.0434；[M-H 2 O+H] + 235.0341,found 235.0327.
EXAMPLE 4 Synthesis of Compounds 41 and 44
Compound 44 and compound 41 were obtained by removing Boc from compound 43 and compound 40, respectively.
1. Synthesis of Compound 44
Dissolving compound 43 in dichloromethane (10 ml) in a reaction bottle, adding trifluoroacetic acid (1 ml) under ice bath, stirring at normal temperature for several hours, monitoring by TLC, stopping the reaction after completion of the reaction, spin-drying the solvent, dissolving with water (30 ml), adjusting to alkalescence (pH=8) with saturated sodium bicarbonate, extracting with ethyl acetate (3×30 ml), drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (DCM: CH) 3 Oh=50:1; 30:1;10:1, v/v) to give compound 44 in about 80% yield. LC-MS m/z 214.1[ M+H ]] + .
2. Synthesis of Compound 41
Compound 41 was prepared by substituting starting compound 43 with compound 40 according to the synthetic procedure described for compound 44. The structure of compound 41 is shown below:
characterization data for compound 41 are shown below: HRMS m/z calcd for C 10 H 15 N 3 O 2 S[M+H] + 242.0958,found 242.0956.
Example 5 Synthesis of Compounds 53, 56, 61 and 63
The synthetic route is as follows:
wherein X is a bromine atom and R is different substituents.
1. Synthesis of Compound 53
Intermediate a (1 eq) was placed in a reaction flask, after dissolution with DCM (20 ml), boron tribromide (3 eq) was slowly added dropwise under ice bath, after addition, stirring for several hours at normal temperature, TLC monitoring was performed, after completion of the reaction, the reaction was stopped, the solvent was dried by spinning, after addition of a small amount of water (30 ml), was adjusted to weak base (ph=8) with saturated sodium bicarbonate, extracted with ethyl acetate (3×30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography PE: ea= (1:1, v/v), to give intermediate b as a yellow solid (yield about 30%).
The intermediate b (1 eq) was added to a reaction flask, dissolved in methylene chloride (10 ml), and then DMAP (1.05 eq) and di-tert-butyl dicarbonate (1.5 eq) were added in this order, followed by stirring at room temperature for 1 hour. TLC monitoring, stopping reaction after completion, adding small amount of thin layer chromatography silica gel powder, concentrating under reduced pressure, spin-drying, and subjecting to column chromatography (pure DCM: CH) 3 Oh=80:1, v/v) to give intermediate c in about 80% yield.
Intermediate c (1 eq) was placed in a reaction flask, dissolved in DMF, followed by the addition of potassium carbonate (3 eq), 3-bromopropene (1.5 eq) and stirring at room temperature for several hours, monitored by TLC, after completion of the reaction, the reaction was stopped, solvent 10 volumes of water was added, ethyl acetate was extracted (3×50 ml), the organic phase was concentrated, a small amount of thin layer chromatography silica gel powder was added, concentrated under reduced pressure, and after spin-drying, purified by column chromatography PE: ea= (2:1, v/v) to give intermediate d (yield about 60%).
Intermediate d (1 eq) was dissolved in methylene chloride (10 ml) in a reaction flask, trifluoroacetic acid (3 eq) was added dropwise at low temperature, the reaction was completed for about one hour at room temperature after the addition, monitored by TLC, the reaction was stopped, the reaction solution was dried by spinning, a small amount of water (30 ml) was added to dissolve, then the mixture was adjusted to weakly basic (ph=8) with saturated sodium bicarbonate, extracted with ethyl acetate (3×20 ml), the organic phase was concentrated, a small amount of thin layer chromatography silica gel powder was added, and concentrated under reduced pressure, and the intermediate e was dried by spinning to give a yield of about 50%.
Intermediate e (1 eq) was dissolved in ethanol and water (volume ratio=3:1), and sodium hydroxide (3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction was brought to slightly acidic (ph=6), dried by spin-drying, and chromatographed on silica gel (DCM: CH 3 Oh=30:1, v/v). Compound 53 was obtained (yield 60%).
Compound 53: 1 H NMR(400MHz,DMSO-d 6 )δ8.88(s br,3H),7.03(d,J＝8.4Hz,2H),6.66(d,J＝8.4Hz,2H),5.89-5.76(m,1H),5.25(d,J＝16.8Hz,1H),5.12(d,J＝10.4Hz,1H),4.32(s,2H),3.82(d,J＝5.2Hz,2H)ppm.HRMS:m/z calcd for C 14 H 14 N 2 O 3 S[M+H] + 291.0798,found 291.0791.
2. synthesis of Compounds 56, 61, 63
According to the synthesis method of the compound 53, the compound 56 is prepared by replacing raw material 3-bromopropene with 4-bromo-1-butene, the compound 61 is prepared by replacing raw material 3-bromopropene with benzyl bromide, and the compound 63 is prepared by directly hydrolyzing the intermediate b. The structure of each compound is shown below:
characterization data for the compounds are shown below:
compound 56: 1 H NMR(400MHz,DMSO-d 6 )δ9.25(s,2H),7.03(d,J＝6.4Hz,2H),6.67(d,J＝8.0Hz,2H),5.87-5.77(m,1H),5.11-5.01(m,2H),4.39-4.22(m,2H),3.24-3.17(m,2H),2.28-2.26(m,2H)ppm.HRMS:m/z calcd for C 15 H 16 N 2 O 3 S[M+H] + 305.0954,found 305.0947.
compound 61: 1 H NMR(400MHz,DMSO-d 6 )δ7.14-7.09(m,4H),7.37-7.26(m,5H),7.05(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,2H),4.50(s,2H),4.23(s,2H)ppm.HRMS:m/z calcd for C 18 H 16 N 2 O 3 S[M+H] + 341.0954,found 341.0944.
compound 63: 1 H NMR(400MHz,DMSO-d 6 )δ9.53(s br,1H),8.94(s br,1H),7.09(d,J＝8.4Hz,2H),6.74(d,J＝8.4Hz,2H),4.24(s,2H)ppm.HRMS:m/z calcd for C 11 H 10 N 2 O 3 S[M+H] + 251.0485,found 251.0482.
EXAMPLE 6 Synthesis of Compounds 59, 70
The compound 59, 70 is synthesized by taking p-bromothiazole amine as a substrate intermediate and by the reaction of the bell wood.
1. Synthesis of Compound 59
The synthetic route is as follows:
para-bromothiazole amine (1 eq), phenylboric acid (3 eq), potassium carbonate (3 eq), bis triphenylphosphine palladium dichloride (0.1 eq) were placed in a reaction flask and dissolved in toluene (15 ml), ar 2 Reflux reaction at 100deg.C for several hours under protection, TLC monitoring, stopping reaction, spin drying solvent, dissolving in water (50 ml), extracting with ethyl acetate (3×40 ml), drying the organic phase with anhydrous sodium sulfate, concentrating spin-dried column chromatography PE: EA= (2:1, v/v) under reduced pressure to give yellow solid intermediate a (yield about 80%).
Intermediate a (1 eq) was dissolved in the total volume (12 ml) of ethanol and water (volume ratio=3:1), sodium hydroxide (3 eq) was added thereto, and the reaction was stopped after 2 hours at room temperature. The reaction was brought to slightly acidic (ph=6), dried by spin-drying, and chromatographed on silica gel (DCM: CH 3 Oh=30:1, v/v). Compound 59 was obtained (yield 60%).
Compound 59: 1 H NMR(400MHz,DMSO-d 6 )δ7.58-7.54(m,4H),7.32-7.30(m,4H),7.01(s,2H),4.37(s,2H),2.93-2.90(m,1H),1.23(d,J＝6.8Hz,6H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.08,163.92,147.97,139.64,138.86,137.96,137.04,136.08,129.28,127.30,127.09,126.97,33.55,32.13,24.32ppm.HRMS:m/z calcd for C 20 H 20 N 2 O 2 S[M+H] + 353.1318,found 353.1317.
2. synthesis of Compound 70
The synthetic route is as follows:
the p-bromothiazole amine (1 eq) was added to a reaction flask, dissolved in methylene chloride (20 ml), and then DMAP (1.05 eq) and di-tert-butyl dicarbonate (1.5 eq) were added in this order, followed by stirring at room temperature for 1 hour. TLC monitoring, stopping reaction after the reaction is finished, adding a small amount of thin layer chromatography silica gel powder, concentrating under reduced pressure, and carrying out column chromatography PE after spin-drying, wherein EA=10: 1,8:1 (v/v), intermediate a, in about 40% yield.
Intermediate a (1 eq), phenylboronic acid (3 eq), cesium carbonate (3 eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.3 eq) was placed in a reaction flask and dissolved in 1, 4-dioxane (15 ml), ar 2 Reflux reaction at 100deg.C for several hours under protection, TLC monitoring, reaction completion, stopping reaction, spin drying solvent, adding water (50 ml) for dissolution, ethyl acetate extraction (3×40 ml), drying the organic phase with anhydrous sodium sulfate, concentrating spin drying column chromatography PE: EA= (8:1, 5:1,3:1,2:1, v/v) under reduced pressure to obtain yellow solid intermediate b (yield about 50%).
Intermediate b (1 eq) was dissolved in methylene chloride (15 ml) in a reaction flask, trifluoroacetic acid (3 eq) was added dropwise at low temperature, the reaction was completed for about one hour at room temperature after the addition, monitored by TLC, the reaction was stopped after completion, the reaction solution was dried by spinning, a small amount of water (30 ml) was added to dissolve, and after adjusting to weak basicity (ph=8) with saturated sodium bicarbonate, ethyl acetate was extracted (3×20 ml), the organic phase was concentrated, a small amount of thin layer chromatography silica gel powder was added, and concentrated under reduced pressure to obtain intermediate c by column chromatography (pure DCM: ch3oh=50:1, v/v) in a yield of about 70%.
Intermediate c (1 eq) was dissolved in the total volume (12 ml) of ethanol and water (volume ratio 3:1), sodium hydroxide (3 eq) was added thereto, and the reaction was stopped after 2 hours at room temperature. The reaction was brought to slightly acidic (ph=6), dried by spin-drying and chromatographed on silica gel (DCM: ch3oh=30:1, v/v). Compound 70 was obtained (60% yield).
Compound 70: 1 H NMR(400MHz,DMSO-d 6 )δ8.64(d,J＝6.0Hz,2H),7.78-7.73(m,4H),7.39(d,J＝8.4Hz,2H),7.05(s,2H),4.41(s,2H)ppm.
EXAMPLE 7 Synthesis of Compounds 35-38
Compound 35-38 synthetic route:
R＝CH 3 ,Br,CH 3 O,C(CH 3 ) 3
synthesis of Compounds 35-38
The raw materials of p-methyl phenethyl alcohol (204 mg,1.50 mmol), p-bromophenyl alcohol (100 mg,0.50 mmol), p-methoxyphenethyl alcohol (200 mg,1.31 mmol) and p-tert-butylphenyl alcohol (200 mg,1.12 mmol) are respectively put into a reaction bottle, after being dissolved by methylene dichloride (15 mL), dess-Martin (764 mg,1.80 mmol), (255 mg,0.60 mmol), (669 mg,1.58 mmol) and (517 mg,1.35 mmol) are respectively added, reflux reaction is carried out after being respectively heated to 40 ℃, TLC spot plate detection is carried out after 2h, saturated sodium thiosulfate aqueous solution and ethyl acetate are added for extraction, and colorless liquid compound a40mg (p-methyl) is respectively obtained after the concentration of the extract and the column chromatography (PE-PE: EA=30:1, v/v) are carried out, and the yield is 20%; 47mg (p-bromo) of pale yellow liquid compound b, yield 47%; 110mg (p-methoxy) of a colorless liquid compound c, yield 55.8%; and 92mg (p-tert-butyl) of a colorless liquid compound d, yield 46.3%.
Compound a (350 mg,2.61 mmol), b (100 mg,0.50 mmol), c (110 mg,0.73 mmol), d (200 mg,1.10 mmol) are respectively put into a reaction bottle, respectively dissolved by absolute ethyl ether (15 mL), methyl dichloroacetate (338 μl,3.26 mmol), (65 μl,0.63 mmol), (99 μl,0.95 mmol), (150 μl,1.50 mmol) is added, respectively precooled at 0 ℃ and slowly added with 30% sodium methoxide (497 μl,3.59 mmol), (86 μl,0.69 mmol), (152 μl,1.10 mmol), (240 μl,1.72 mmol) respectively, after reaction for 1h, transferred to normal temperature for reaction for 3h, respectively extracted by saturated sodium chloride solution and absolute ethyl ether, respectively added with thiourea (39 mg,2.61 mmol), (38 mg,0.50 mmol), c (56 mg,0.73 mmol), (1.13 ℃ C) respectively added with thiourea (39 mg, 0.13 mmol) respectively, and then added with 1:1:1:5 v=5:1:1:1:1:1:1:1:5 mmol respectively, after the reaction is completely transferred to room temperature for reaction, the TLC is respectively detected by TLC, saturated sodium chloride solution and absolute ethyl ether is used, respectively, the solution is concentrated, the extract is dissolved, and the solution is respectively, the thiourea is added; pale yellow solid compound f 120mg (p-bromo), yield 73.3%; 131mg (p-methoxy) of pale yellow solid compound, yield 68.1% and 120mg (p-tert-butyl) of yellow viscous liquid compound h, yield 36.5%.
Compounds e (70 mg,0.27 mmol), f (120 mg,0.37 mmol), g (131 mg,0.47 mmol), H (120 mg,0.39 mmol) were treated with EtOH: H 2 After O (6:3 mL) was dissolved, sodium hydroxide (22 mg,0.80 mmol), (44 mg,1.11 mmol), (56 mg,1.41 mmol) and (47 mg,1.17 mmol) were added respectively, and after heating to 65℃for reflux reaction, TLC plate detection was performed after 1h, ethanol was dried after the reaction was completed, pH was adjusted to around 7 with 2M HCl, white solid was precipitated, and after filtration, solid was eluted with dichloromethane: methanol=20:1 (v/v) to give white compound 35 (28 mg, yield 42%); white solid compound 36 (60 mg, yield 52%); solid compound 38 (55 mg, 44% yield); solid compound 37 (52 mg, yield 46%). The structure of each compound is shown below:
characterization data for each compound is shown below:
compound 35: 1 H NMR(400MHz,DMSO-d 6 )δ7.12(dd,J＝13.2Hz,J＝7.2Hz,4H),4.40(s,2H),2.25(s,3H)ppm.HRMS:m/z calcd for C 12 H 12 N 2 O 2 S[M-H] - 247.0546,found 247.0560.
compound 36: 1 H NMR(400MHz,DMSO-d 6 )δ7.46(d,J＝8Hz 2H),7.21(d,J＝8Hz,2H),6.94(s,2H),4.38(s,2H)ppm.
compound 37: 1 H NMR(400MHz,DMSO-d 6 )δ7.31(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),6.90(s,2H),4.28(s,2H),1.25(s,9H)ppm.
compound 38: 1 H NMR(400MHz,DMSO-d 6 )δ7.16(d,J＝8.0Hz,2H),6.95(s,1H),6.86(d,J＝8.4Hz,2H),4.26(s,2H),3.72(s,3H)ppm.
example 8 Synthesis of Compounds 3, 4, 6, 9, 10, 15, 19, 23, 25, 30, 32, 33 and 34
Intermediate a (400 mg,1.6mmol,1 eq) was dissolved in hypophosphorous acid, an aqueous solution of sodium nitrite (222.3 mg,3.2mmol,2 eq) was slowly added dropwise under ice bath, after 1 hour of reaction at 0 ℃ and shifting to room temperature for 2 hours, the reaction was stopped, diluted with water, adjusted to weak base with sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (PE: ea=8:1, 6:1,4:1,2:1, v/v) afforded intermediate b (230 mg, yield 58%).
Intermediate b (200 mg,0.86mmol,1 eq) was dissolved in ethanol and water, and then sodium hydroxide (103 mg,2.57mmol,3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction mixture was slightly acidic, dried by spin-drying and chromatographed on silica gel (DCM: CH 3 Oh=50:1, 30;1, v/v). Compound 3 (160 mg, yield 80%) was obtained.
Compound 3: 1 H NMR(400MHz,DMSO-d 6 )δ13.10(s,1H),8.91(s,1H),7.34-7.24(m,5H),4.57(s,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ163.91,152.10,149.05,142.51,140.28,129.15,128.99,127.25,32.78ppm.HRMS:m/z calcd for C 11 H 9 NO 2 S[M+H] + 220.0427,found 220.0429；[M-H 2 O+H] + 202.0327,found 202.0317.
the raw material (200 mg,0.76mmol,1 eq) was dissolved in acetonitrile, tert-butyl nitrite (452. Mu.l, 3.8mmol,5 eq) was added dropwise at 0℃and copper chloride (260 mg,1.52mmol,2 eq) was added after 20min of reaction, the reaction was allowed to proceed to room temperature, after 12 hours, the reaction was stopped, acetonitrile was dried by spin-drying, extraction with water and ethyl acetate, drying over anhydrous sodium sulfate, concentration under reduced pressure, silica gel column chromatography (PE: EA=20:1, v/v) to give intermediate a (120 mg, yield 60%).
Intermediate a (100 mg,0.36mmol,1 eq) was dissolved in ethanol and water, and then sodium hydroxide (43 mg,1.06mmol,3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction mixture was slightly acidic, dried by spin-drying and chromatographed on silica gel (DCM: CH 3 Oh=50:1, 30:1, v/v). Solid compound 9 (73 mg, yield 73%) was obtained.
Compound 9: 1 H NMR(400MHz,DMSO-d 6 )δ13.27(s,1H),7.32-7.28(m,2H),7.23-7.21(m,3H),3.47(t,J＝8.0,Hz,2H),2.92(t,J＝8.0,Hz,2H)ppm.HRMS:m/z calcd for C 12 H 10 ClNO 2 S[M-H] - 266.0048,found 266.0015.
compounds 4, 6, 19, 23, 25, 30 and 32 were synthesized in the same manner as compound 3.
The synthesis of compounds 10, 15, 33 and 34 was identical to that of compound 9.
Characterization data for each compound is shown below:
compound 4: 1 H NMR(400MHz,DMSO-d 6 )δ13.08(s,1H),8.94(s,1H),7.32(d,J＝4.4Hz,4H),7.26-7.20(m,1H),5.37(q,J＝7.2Hz,1H),1.64(d,J＝7.2Hz,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ163.85,155.33,151.87,145.12,141.79,129.07,127.45,127.22,37.14,23.79ppm.HRMS m/z calcd for C 12 H 11 NO 2 S[M+H] + 234.0583,found 234.0583；[M-H 2 O+H] + 216.0483,found216.0470；[M+Na] + 256.0408,found 256.0401.
compound 6: 1 H NMR(400MHz,DMSO-d 6 )δ12.95(s,1H),8.88(s,1H),7.31-7.18(m,5H),3.50(t,J＝8.0Hz,2H),2.94(t,J＝8.0Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ163.78,151.28,148.65,142.69,140.83,128.88,128.82,126.68,37.26,28.93ppm.HRMS:m/z calcd for C 12 H 11 NO 2 S[M+H] + 234.0583,found 234.0599；[M-H 2 O+H] + 216.0483,found 216.0477；[M+Na] + 256.0408,found 256.0408.
compound 10: 1 H NMR(400.MHz,DMSO-d 6 )δ13.25(s,1H),7.31-7.28(m,2H),7.21-7.19(m,3H),3.47(t,J＝8.0Hz,2H),2.92(t,J＝8.0Hz,2H)ppm.HRMS:m/z calcd for C 12 H 10 BrNO 2 S[M+H] + 311.9688,found 311.9679,313.9659；[M-H 2 O+H] + 293.9588,found 293.9570,295.9550.
compound 15: HRMS m/z calcd for C 12 H 10 INO 2 S[M+H] + 359.9550,found 359.9554；C 12 H 10 INO 2 S[M+H] + 360.9583,found 360.9595；C 12 H 10 INO 2 S[M+Na] + 381.9369,found 381.9363；C 12 H 10 INO 2 S[M+Na] + 382.9403,found 3882.9408.
Compound 19: 1 H NMR(400MHz,DMSO-d 6 )δ13.16(s,1H),9.21(s,1H),8.28(dd,J＝6.8,J＝1.6,2H),7.83(d,J＝8.4,2H)ppm.HRMS:m/z calcd for C 10 H 6 N 2 O 4 S[M-H] - 248.9976,found 248.9973.
compound 23: 1 H NMR(400MHz,CDCl 3 )δ8.81(s,1H),4.33(s,1H),1.25(d,J＝16.4,6H)ppm.HRMS:m/z calcd for C 10 H 9 NO 2 S[M+H] + 172.0427,found 172.0432；[M-H 2 O+H] + 154.0327,found 154.0323.
compound 25: LC-MS m/z 186.1[ M+H ] +.
Compound 30: 1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H),3.18(s,2H),1.86(s,1H),0.88(s,6H)ppm.
compound 32: 1 H NMR(400MHz,DMSO-d 6 )δ9.17(s,1H),8.52(s,1H)ppm.HRMS:m/z calcd for C 4 H 3 NO 2 S[M-H] - 127.9812,found 127.9915,[M-H 2 O] - 110.9778,found 110.9760.
compound 33: 1 H NMR(400MHz,DMSO-d 6 )δ7.30-7.24(m,5H),4.61(s,2H)ppm.HRMS:m/z calcd for C 11 H 8 ClNO 2 S[M-H] - 251.9892,found 251.9854.
compound 34: 1 H NMR(400MHz,DMSO-d 6 )δ7.29-7.23(m,5H),4.62(s,2H)ppm.HRMS:m/z calcd for C 11 H 8 BrNO 2 S[M-H] - 295.9386,found 295.9349,297.9327.
EXAMPLE 9 Synthesis of Compound 7
After dissolving ethyl 2-amino-5-bromoformate (300 mg,1.19mmol,1 eq) in 5ml of toluene, thiophene-boronic acid (455 mg,3.58mmol,3 eq), cesium carbonate (1.17 g,3.58mmol,3 eq), pd (pph) were added 3 ) 4 (138 mg,0.119mmol,0.1 eq) and then heated to 110℃for 5 hours under reflux. Stopping the reaction, spin-drying toluene, extracting with water and ethyl acetate, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting to silica gel column chromatography (PE: ea=8:1, 6:1,4:1,2:1, v/v) to obtain intermediate a (210 mg, yield 70%).
Intermediate a (200 mg,0.83mmol,1 eq) was dissolved in ethanol and water, and sodium hydroxide (100 mg,2.5mmol,3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction mixture was slightly acidic, dried by spin-drying and chromatographed on silica gel (DCM: CH 3 Oh=50:1, 30:1,10:1, v/v). Compound 7 (40 mg, yield 20%) was obtained.
Compound 7: 1 H NMR(400MHz,DMSO-d 6 )δ8.56(s br,2H),7.89(d,J＝2.0Hz,1H),7.63-7.61(m,1H),7.36(dd,J＝4.8Hz,J＝0.8Hz,1H)ppm.HRMS:m/z calcd for C 8 H 6 N 2 O 2 S 2 [M+H] + 226.9943,found 226.9945；[M-H 2 O+H] + 208.9843,found 258.9767；[M+Na] + 248.9768,found 258.9767.
example 10 Synthesis of Compounds 8 and 16
Sodium flake (69 mh,2.9mmol,1.5 eq) was added to ethanol, after complete dissolution, ethyl 2 amino 5 bromoformate (500 mg,1.99mmol,1 eq), p-chlorophenylthiol (230 mg,1.6mmol,0.8 eq) were added, the reaction was stopped by moving to 80 ℃ for two hours, filtration, spin-drying of the filtrate, dissolution with ethyl acetate, and silica gel column chromatography (PE: ea=7:1, 5:1,3:1,1:1, v/v) gave yellow solid intermediate a (230 mg, yield 46%).
Intermediate a (120 mg,0.38mmol,1 eq) was dissolved in ethanol and water, and sodium hydroxide (46 mg,1.14mmol,3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction was brought to slightly acidic, dried by spin-drying and chromatographed on silica gel (DCM: ch3oh=50:1, 30:1, 10:1). Compound 8 was obtained as a red solid (80 mg, yield 76%).
Compound 8: 1 H NMR(400MHz,DMSO-d 6 )δ7.45-7.38(m,6H)ppm.HRMS:m/z calcd for C 10 H 7 ClN 2 O 2 S 2 [M+H] + 286.9710,found 286.9700；[M-H 2 O+H] + 268.9610,found 268.9590.
intermediate a (200 mg,0.64mmol,1 eq) was dissolved in dry dichloromethane, MCPBA (328 mg,1.9mmol,3 eq) was added at 0deg.C, after stirring for 6 hours at ambient temperature, the reaction was stopped, filtered and the filtrate was chromatographed on silica gel (DCM: CH 3 Oh=40:1) to afford intermediate b as a pale yellow solid (130 mg, 65% yield).
Intermediate b (100 mg,0.29mmol,1 eq) was dissolved in ethanol and water, and then sodium hydroxide (35 mg,0.87mmol,3 eq) was added thereto, followed by reaction at room temperature for 2 hours, and the reaction was stopped. The reaction mixture was slightly acidic, dried by spin-drying and chromatographed on silica gel (DCM: CH 3 Oh=50:1, 30:1, v/v). Yellow solid compound 16 (37 mg, yield 37%) was obtained.
Compound 16: 1 H NMR(400MHz,DMSO-d 6 )δ13.75(s,1H),8.23(s,2H),7.94(d,J＝8.4Hz,2H),7.72(d,J＝8.4Hz,2H)ppm.HRMS:m/z calcd for C 10 H 7 ClN 2 O 4 S 2 [M+H] + 318.9609,found 318.9607；[M-H 2 O+H] + 300.9509,found 300.9509；[M+Na] + 340.9433,found 340.9436.
EXAMPLE 11 Synthesis of Compound 27
The compound 2-amino-5- (sec-butyl) thiazole-4-carboxylic acid methyl ester 7b (200 mg,0.9 mmol) was accurately weighed into 8ml of dry DCM, triethylamine (283 mg,2.8 mmol) and acetyl chloride (110 mg,1.4 mmol) were added under ice-bath, the reaction was warmed to room temperature after addition, TLC detection was complete after 3h, the reaction was stopped, the DCM was removed by concentration under reduced pressure, and the compound 2-acetamido-5- (sec-butyl) thiazole-4-carboxylic acid methyl ester 9b (190 mg, yield 79.5%) was purified by column chromatography (PE: EA=4:1) as an off-white solid.
Starting from compound 2-acetamido-5- (sec-butyl) thiazole-4-carboxylic acid methyl ester 9b, the white solid, compound 2-acetamido-5- (sec-butyl) thiazole-4-carboxylic acid 9 (compound 27, 82mg, 86.7% yield) was purified by column chromatography (DCM: meoh=10:1) with reference to the general method of ester hydrolysis.
Compound 27: HRMS m/z calcd for C 10 H 14 N 2 O 3 S[M+H] + 243.0798,found 243.0814；[M-H 2 O+H] + 225.0698,found 225.0708；[M+Na] + 265.0623,found 265.0622.
Replacement of acetyl chloride with benzoyl chloride compound 31 was synthesized following the procedure for the synthesis of compound 27.
Compound 31: 1 H NMR(400MHz,DMSO-d 6 )δ7.41-7.22(m,5H),4.07(s,2H),2.92(s,2H),1.69(s,1H),0.83(d,J＝3.2Hz,6H)ppm.HRMS:m/z calcd for C 15 H 18 N 2 O 2 S[M+H] + 291.1162,found 291.1152；[M-H 2 O+H] + 273.1062,found 273.1054；[M+Na] + 313.0987,found 313.0979.
the following demonstrates the beneficial effects of the present invention through specific test examples.
Test example 1 inhibition Activity of the Compounds of the invention against MBL
1. Test method
The activity test reactions were performed in a black 96-well elisa plate, generally 60 μl, and the specific procedure was as follows:
(1) Preparing a mother solution with the concentration of 100mM of the compound solid to be tested by using DMSO, diluting the mother solution into a working solution with the concentration of 3.6mM or 600 mu M by using a test buffer (20 mM Tris-HCl pH 7.5, 200mM NaCl,0.01%Triton X-100), and then three times diluting the working solution by using the test buffer for 9 concentration gradients to obtain working solutions with 10 different concentrations.
(2) MBL enzyme was prepared as a solution of enzyme at a concentration (VIM-2, VIM-1 and VIM-5:1.2nM; NDM-1:0.5nM; IMP-1:4.8 nM) using a test buffer, and substrate FC-5 was prepared as a 30. Mu.M substrate solution using a test buffer for use.
(3) In a 96-well ELISA plate, 10. Mu.L of the compound working solution obtained in the step (1), 30. Mu.L of the test buffer and 10. Mu.L of the enzyme solution are sequentially added to each well, and incubated for 10min at room temperature.
(4) 10. Mu.L of substrate solution was added to each well of a 96-well microplate, and the fluorescence value (. Lamda.) was continuously measured for 6 minutes using a Tecan microplate reader ex ＝380nm,λ em =460 nm).
Each experiment was run with a control well without compound and all assays contained three replicates. From the change in fluorescence intensity measured by the microplate reader, the residual activity of the enzyme in each well was calculated, and the calculation was shown as: residual activity (%) = (Δf) I )/(ΔF C )×100，ΔF I For a certain period of time, the fluorescence change value of the compound-containing hole, delta F C The change in fluorescence in control wells without compound added over the same period of time. Fitting the processed data with Graphpad Prism 5 software to obtain IC 50 Values.
2. Test results
TABLE 1 inhibitory Activity of Compounds against MBL a
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a * ***: representing good inhibitory activity (IC) 50 <1 μm); * **: represents moderate inhibitory activity (1. Mu.M)<IC 50 <100 μm); * *: representing weak inhibitory activity (IC) 50 >100μM)
The test results show that: the compound of the invention has good inhibitory activity on MBL, particularly on a plurality of MBL subtypes, particularly on clinically relevant subtypes VIM, NDM, IMP and the like, wherein the compound 64 is optimal.
Test example 2 antibacterial Activity of the inventive Compounds in combination with meropenem
1. Test method
(1) Resuscitating the strain: strains were resuscitated from-80℃refrigerator and streaked onto non-resistant MHA plates with an inoculating loop and incubated at 35℃for 18-20h.
(2) And (3) diluting the liquid medicine: meropenem solid was weighed and dissolved in DMSO to prepare a mother liquor of 12.8mg/mL, and the mother liquor was diluted with CAPHB medium to a working solution of 512. Mu.g/mL. 100 mu L of CAMHB and 100 mu L of meropenem working solution are added into a transparent 96-well plate, 9 concentrations are diluted by 2 times, and a growth control well without meropenem is arranged. mu.L of compound at a concentration of 1mg/mL was added to each well.
(3) And (3) bacterial liquid dilution: the OD was adjusted by picking up a single clone from the plate with an inoculating loop in physiological saline 630 To 0.08-0.13 (corresponding to 1X 10) 8 CFU/mL), the bacterial suspension was diluted 100-fold with camdb, and 100 μl was added to each well. At this time, the meropenem concentration was 128. Mu.g/mL to 0.25. Mu.g/mL, respectively, and the enzyme inhibitor concentration was 10. Mu.g/mL.
(4) Stationary culture and result judgment: placing the 96-well plate into a 35 ℃ incubator, and standing for culturing for 16-20h. The next day observations, the Minimum Inhibitory Concentration (MIC) of meropenem was at the minimum concentration that could completely or significantly inhibit bacterial growth.
2. Test results
TABLE 2 antibacterial Activity of Compounds in combination with meropenem for the expression of clinically isolated strains of MBL
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The test results above demonstrate that: among the compounds of the present invention, most of the compounds used in combination with meropenem have good antibacterial activity against clinically isolated strains such as MBL expressing E.coli and Klebsiella pneumoniae, such as compounds 1, 2, 21, 54, 64, etc.
In conclusion, the compound disclosed by the invention has good inhibitory activity on metal beta-lactamase (MBL), particularly has good inhibitory activity on a plurality of clinically relevant MBL subtypes, such as VIM, NDM, IMP subtype and the like, has stronger gram-negative bacteria permeability, can be used for preparing a broad-spectrum MBL inhibitor, and has good development prospect as a drug molecule for overcoming antibacterial drug resistance.

Claims (10)

1. A compound of formula I, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, -NHR 1 ’；
R 1 ' is selected from 0 to 5R 3 Substituted C 1 ～C 8 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from 5-10 membered aryl, 5-10 membered heteroaryl;
R 3 ' selected from C 1 ～C 8 An alkyl group;
l is selected from none, 0 to 5R 4 Substituted C 1 ～C 8 Alkylene, -S-, -O-,
R 4 Are respectively and independently selected from C 1 ～C 8 An alkyl group;
R 2 selected from C 1 ～C 8 Alkyl, C 2 ～C 8 Alkenyl, C 2 ～C 8 Alkynyl, quilt with 0-5R 5 Substituted 5-10 membered aryl, substituted 0-5R 5 Substituted 3-to 10-membered heteroaryl groups, substituted with 0-5R 5 Substituted 3-10 membered heterocyclyl, substituted with 0-5R 5 Substituted 3-10 membered cycloalkyl;
R 5 are respectively and independently selected from 0 to 5R 6 Substituted C 1 ～C 8 Alkyl, R is 0-5 6 Substituted C 1 ～C 8 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-5R 6 Substituted 5-10 membered aryl, substituted 0-5R 6 Substituted 5-to 10-membered heteroaryl;
R 6 are respectively and independently selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 8 Alkynyl and 5-10 membered aryl;
R 7 selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxyl, amino, nitro, cyano, 5-1%0-membered aryl, 5-10 membered heteroaryl;
when R is 1 Selected from amino, R 2 When selected from phenyl, L 2 Not selected from C 1 An alkylene group;
when R is 1 Selected from hydrogen, R 2 When selected from phenyl, L 2 Not selected from C 1 Alkylene, 1C 1 Alkyl substituted C 1 Alkylene, C 2 An alkylene group;
when R is 1 Selected from amino groups, L being selected from none of the times, R 2 Not selected from thienyl, C 1 ～C 5 An alkyl group;
when R is 1 Selected from amino, R 2 Selected from C 1 When alkyl, L is not selected from C 2 ～C 4 Alkylene, none, 1C 1 Alkyl substituted C 2 Alkylene, 1C 1 Alkyl substituted C 1 An alkylene group;
when R is 1 Selected from hydrogen, R 2 Selected from C 1 In the case of alkyl groups, L is not selected from 1C 1 Alkyl substituted C 2 Alkylene, 1C 1 Alkyl substituted C 1 An alkylene group;
when R is 1 Selected from amino groups, L is selected from C 1 In the case of alkylene radicals, R is not selected from
2. The compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof according to claim 1, wherein:
R 1 selected from hydrogen, C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, -NHR 1 ’；
R 1 ' is selected from 0 to 3R 3 Substituted C 1 ～C 8 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 8 An alkyl group;
l is selected from none, 0 to 3R 4 Substituted C 1 ～C 8 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 8 An alkyl group;
R 2 selected from C 1 ～C 8 Alkyl, C 2 ～C 8 Alkenyl, C 2 ～C 8 Alkynyl, quilt with 0-3R 5 Substituted phenyl, substituted with 0-3R 5 Substituted thienyl, substituted with 0-3R 5 Substituted piperidinyl, substituted with 0-3R 5 Substituted azetidines, substituted with 0-3R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 8 Alkyl, R is 0-3 6 Substituted C 1 ～C 8 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-3R 6 Substituted phenyl, substituted with 0-3R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 8 Alkynyl, phenyl;
R 7 selected from C 1 ～C 8 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
3. The compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof according to claim 2, wherein:
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 2 selected from C 1 ～C 7 Alkyl, C 2 ～C 4 Alkenyl, C 2 ～C 4 Alkynyl, quilt with 0-2R 5 Substituted phenyl, substituted with 0-1R 5 Substituted thienyl, substituted with 0-1R 5 Substituted piperidinyl, substituted with 0-1R 5 Substituted azetidines, substituted with 0-1R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
4. The compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof according to claim 1, wherein: the compound is shown as a formula II:
wherein, the liquid crystal display device comprises a liquid crystal display device,
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 2 selected from C 1 ～C 7 Alkyl, C 2 ～C 4 Alkenyl, C 2 ～C 4 Alkynyl, quilt with 0-2R 5 Substituted phenyl, substituted with 0-1R 5 Substituted thienyl, substituted with 0-1R 5 Substituted piperidinyl, substituted with 0-1R 5 Substituted azetidines, substituted with 0-1R 5 Substituted naphthyl;
R 5 are respectively and independently selected from 0 to 3R 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
5. The compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof according to claim 1, wherein: the compound is shown in a formula III:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group;
R 5a 、R 5b 、R 5c are respectively and independently selected from hydrogen and R of 0 to 3 6 Substituted C 1 ～C 4 Alkyl, R is 0-3 6 Substituted C 1 ～C 3 Alkoxy, halogen, carboxyl, nitro, amino, hydroxyl, -C (O) R 7 、-C(O)OR 7 Is covered with 0-1R 6 Substituted phenyl, substituted with 0-1R 6 Substituted pyridinyl;
R 6 are respectively and independently selected from C 1 ～C 3 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, C 2 ～C 4 Alkynyl, phenyl;
R 7 selected from C 1 ～C 4 Alkyl, halogen, hydroxy, carboxy, amino, nitro, cyano, phenyl, furyl.
6. The compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof according to claim 4, wherein: the compound is shown in a formula IV:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, halogen, amino, -NHR 1 ’；
R 1 ' is selected from 0 to 1R 3 Substituted C 1 ～C 3 Alkyl, -C (O) R 3 ’；
R 3 Each independently selected from phenyl, pyridyl, thienyl, pyrazolyl, and furyl;
R 3 ' selected from C 1 ～C 3 An alkyl group;
l is selected from none, 0 to 1R 4 Substituted C 1 ～C 6 Alkylene, -S-, -O-,
R 4 are respectively and independently selected from C 1 ～C 3 An alkyl group.
7. The compound according to any one of claims 1 to 6, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, wherein: the compound is one of the following compounds:
8. use of a compound according to any one of claims 1 to 7, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, for the preparation of an MBL inhibitor and/or for the preparation of an antibacterial drug.
9. A medicament, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into the compound, or salt, isomer, hydrate, solvate or prodrug of any one of claims 1 to 7.
10. The application of thiazole amine compounds, or salts, or isomers, or hydrates, or solvates, or prodrugs thereof in preparing MBL inhibitors and/or antibacterial drugs is characterized in that: the thiazole amine compound is one of the following compounds:
CN202210190185.1A 2022-02-28 2022-02-28 Thiazole amine MBL inhibitor and preparation method and application thereof Pending CN116693467A (en)

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