WO2023160582A1 - Thiazolamine mbl inhibitor, and preparation method therefor and use thereof - Google Patents

Thiazolamine mbl inhibitor, and preparation method therefor and use thereof Download PDF

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WO2023160582A1
WO2023160582A1 PCT/CN2023/077670 CN2023077670W WO2023160582A1 WO 2023160582 A1 WO2023160582 A1 WO 2023160582A1 CN 2023077670 W CN2023077670 W CN 2023077670W WO 2023160582 A1 WO2023160582 A1 WO 2023160582A1
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substituted
alkyl
compound
amino
phenyl
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李国菠
颜宇航
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四川大学
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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

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a thiazolamine MBL inhibitor and its preparation method and application.
  • ⁇ -lactam antibiotics have the characteristics of broad antibacterial spectrum, high safety and good clinical efficacy, and are currently the most commonly used antibiotics.
  • bacteria due to the abuse and irrational use of antibiotics, bacteria are severely resistant to antibiotics, and human health is seriously threatened.
  • the World Health Organization listed antimicrobial resistance as one of the top ten global health threats.
  • the problem of antibiotic resistance of Gram-negative bacteria is particularly severe.
  • Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter, which are resistant to carbapenem antibiotics, have been listed as extremely dangerous pathogenic bacteria by the World Health Organization.
  • ⁇ -lactamase can be divided into serine ⁇ -lactamase (serine- ⁇ -lactamase, SBL) and metallo- ⁇ -lactamase (metallo- ⁇ -lactamase, MBL). category.
  • MBL can be further divided into three subtypes: B1, B2, and B3.
  • B1 MBL includes the most clinically relevant subtypes of VIM, NDM, and IMP. All major Gram-negative bacterial pathogens, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, were found in clinically common pathogens.
  • MBL has a wide range of substrate specificity, and can hydrolyze all ⁇ -lactam antibiotics and ⁇ -lactam SBL inhibitors except monocyclics, and some MBL can even hydrolyze non- ⁇ -lactam SBL inhibitors. Vibatam.
  • NDM-1 can slowly hydrolyze the monocyclic ⁇ -lactam antibiotic aztreonam, which may mean that MBL has acquired the ability to hydrolyze the monocyclic ⁇ -lactam antibiotic during continuous evolution.
  • MBL genes exist on bacterial mobile genetic elements, which can spread rapidly and widely among bacteria through horizontal gene transfer. Therefore, the production of MBL enzymes in bacteria is one of the most worrying drug resistance factors, and the development of effective MBL inhibitors is imminent and has important clinical significance.
  • MBL inhibitors include sulfhydryls, carboxylic acids, phosphoric acid
  • sulfhydryls due to the large number of MBL subtypes with large differences in structure, and the flexible loop in the active site, most inhibitors lack the ability to target multiple MBL subtypes, especially clinically relevant VIM, NDM, IMP, etc.
  • Broad-spectrum inhibitory activity of isoforms In addition, the low permeability of the bacterial outer membrane is also a common shortcoming of the reported MBL inhibitors. Therefore, there is an urgent need to develop MBL inhibitors with broad-spectrum inhibitory activity and good antibacterial activity, so as to provide new lead compounds for the development of clinically effective MBL inhibitors.
  • the object of the present invention is to provide a thiazolamine MBL inhibitor and its preparation method and application.
  • the present invention provides a compound represented by formula I, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof:
  • R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 5 R 3 , -C(O)R 3 ';
  • R3 are independently selected from 5-10 membered aryl groups and 5-10 membered heteroaryl groups
  • R 3 ' is selected from C 1 -C 8 alkyl, 5-10 membered aryl;
  • L is selected from none, C 1 to C 8 alkylene substituted by 0 to 5 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 8 alkyl groups
  • R 2 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 5-10 membered aryl substituted by 0-5 R 5 , 0-5 R 5- substituted 3-10-membered heteroaryl, 3-10-membered heterocyclic group substituted by 0-5 R 5 , 3-10-membered cycloalkyl substituted by 0-5 R 5 ;
  • R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-5 R 6 , C 1 -C 8 alkoxy substituted by 0-5 R 6 , halogen, carboxyl, nitro, amino, Hydroxyl, -C(O)R 7 , -C(O)OR 7 , 5-10-membered aryl substituted by 0-5 R 6 , 5-10-membered heteroaryl substituted by 0-5 R 6 ;
  • R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, 5-10 membered aryl ;
  • R 7 is selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, 5-10-membered aryl, 5-10-membered heteroaryl;
  • R 1 is selected from amino
  • R 2 is selected from phenyl
  • L 2 is not selected from C 1 alkylene
  • L 2 is not selected from C 1 alkylene, 1 C 1 alkyl substituted C 1 alkylene, C 2 alkylene;
  • R 1 is selected from amino
  • L is selected from none
  • R 2 is not selected from thienyl, C 1 ⁇ C 5 alkyl
  • R 1 is selected from amino
  • R 2 is selected from C 1 alkyl
  • L is not selected from C 2 ⁇ C 4 alkylene, none, 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 Alkyl substituted C alkylene ;
  • R 1 is selected from hydrogen and R 2 is selected from C 1 alkyl
  • L is not selected from 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 alkyl substituted C 1 alkylene;
  • R 1 is selected from amino
  • L is selected from C 1 alkylene
  • R is not selected from
  • R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 3 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 ⁇ C 8 alkyl, phenyl
  • L is selected from none, C 1 to C 8 alkylene substituted by 0 to 3 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 8 alkyl groups
  • R 2 is selected from C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, phenyl substituted by 0 to 3 R 5 , thiophene substituted by 0 to 3 R 5 radical, furanyl substituted by 0 to 3 R 5 , pyrazolyl substituted by 0 to 3 R 5 , piperidinyl substituted by 0 to 3 R 5 , nitrogen substituted by 0 to 3 R 5 Heterocyclobutane, naphthyl substituted by 0 to 3 R 5 , substituted by 0 to 3 R 5 Replaced by 0 to 3 R 5
  • R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-3 R 6 , C 1 -C 8 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 3 R 6 , pyridyl substituted by 0 to 3 R 6 ;
  • R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, phenyl;
  • R 7 is selected from C 1 ⁇ C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furfuryl Anyl.
  • R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl, phenyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
  • R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
  • R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl, phenyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 5a , R 5b , and R 5c are independently selected from hydrogen, C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen , carboxyl, nitro, amino, hydroxyl, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • R 1 is selected from hydrogen, halogen, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are each independently selected from C 1 -C 3 alkyl groups.
  • the compound is one of the following compounds:
  • the present invention also provides the use of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitor and/or the preparation of antibacterial drug.
  • the present invention also provides a drug, which is composed of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug as the active ingredient, plus pharmaceutically Preparations prepared with acceptable excipients or auxiliary ingredients.
  • the present invention also provides a thiazole amine compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitors and/or the preparation of antibacterial drugs purposes, the thiazole amine compound is one of the following compounds:
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • C a to C b alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
  • C 1 -C 8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms
  • C 1 to C 8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms.
  • Alkyl means a saturated hydrocarbon chain having the indicated number of carbon atoms.
  • C 1 -C 8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, ie, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Alkyl groups can be straight 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 base) and hexyl, etc.
  • Halogen is fluoro, chloro, bromo or iodo.
  • the compound of the present invention has good inhibitory activity to metallo- ⁇ -lactamases (MBL), especially to multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, IMP have good inhibitory activity, and has strong revolutionary
  • MBL metallo- ⁇ -lactamases
  • the permeability of Lambert-negative bacteria can be used to prepare a broad-spectrum MBL inhibitor, and has a good development prospect as a drug molecule for overcoming antibacterial drug resistance.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.
  • compound 1 was prepared by replacing the raw material n-hexanal with phenylacetaldehyde
  • compound 2 was prepared by replacing the raw material n-hexanal with 2-phenylpropanal
  • compound 11 was prepared by replacing the raw material n-hexanal with n-valeraldehyde
  • Compound 11 was prepared by replacing the raw material n-hexanal with n-heptanal to obtain compound 12, and the raw material n-hexanal was replaced with n-octylaldehyde to obtain compound 13, and the raw material n-hexanal was replaced with n-butyraldehyde to prepare compound 14, and the raw material n-hexanal was replaced
  • Compound 18 was prepared for p-nitrophenylacetaldehyde
  • compound 20 was prepared by replacing the raw material n-hexanal with acetaldehyde
  • compound 21 was prepared by replacing the raw material n-hexanal with thiophene
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with phenylpropionic acid to prepare compound 5, and the raw material 1-(tert-butoxycarbonyl)nitrogen Compound 17 was prepared by replacing heterotidine-3-acetic acid with p-nitrophenylacetic acid, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-nitrophenylacetic acid to obtain Compound 46, the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-aminophenylacetic acid to prepare compound 47, the raw material 1-(tert-butoxycarbonyl)azetidine Compound 50 was prepared by replacing alkane-3-acetic acid with 4-biphenylacetic acid, and replacing the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid with 4-(trifluoromethoxy)phenylacetic acid
  • the raw material 1-(tert-butyl Oxycarbonyl) azetidine-3-acetic acid was replaced by 3-(4-fluorophenyl) propionic acid to prepare compound 83
  • the raw material 1-(tert-butoxycarbonyl) azetidine-3- Acetic acid was replaced by 3-(3-methoxyphenyl)propionic acid to prepare compound 84
  • the starting material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(2,4- Dichlorophenyl)propionic acid was prepared to obtain compound 85
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3-(4-methoxyphenyl)propionic acid to obtain compound 86
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(1-naphthyl)propionic acid to prepare compound 87
  • Embodiment 3 the synthesis of compound 51,54,57,62
  • compound 54 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with thiophene-3-ethanol
  • compound 57 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with 3-bromophenethyl alcohol
  • Compound 62 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with p-fluorophenethyl alcohol.
  • the structure of each compound is shown below:
  • Compound 44 and Compound 41 are obtained by de-Boc of Compound 43 and Compound 40, respectively.
  • compound 41 was prepared by replacing the starting material compound 43 with compound 40.
  • the structure of compound 41 is shown below:
  • X is a bromine atom, and R is a different substituent.
  • compound 56 was prepared by replacing the raw material 3-bromopropene with 4-bromo-1-butene
  • compound 61 was prepared by replacing the raw material 3-bromopropene with Bian bromide
  • the intermediate b was directly hydrolyzed
  • Compound 63 was prepared.
  • the structure of each compound is shown below:
  • Embodiment 6 the synthesis of compound 59,70
  • R CH 3 , Br, CH 3 O, C(CH 3 ) 3
  • compound 96 was prepared by replacing the raw material 3-thiopheneboronic acid with phenylboronic acid
  • compound 97 was prepared by replacing the raw material 3-thiopheneboronic acid with 1-methyl-1H-pyrazole-5-boronic acid
  • compound 98 was prepared by replacing the starting material 3-thiopheneboronic acid with 2-furanboronic acid. The structure of each compound is shown below:
  • Test example 1 the inhibitory activity of compound of the present invention to MBL
  • the activity test reaction was carried out in a black 96-well microtiter plate, the total volume was 60 ⁇ L, and the specific operation steps were as follows:
  • the MBL enzyme is formulated into a certain concentration of enzyme solution (VIM-2, VIM-1 and VIM-5: 1.2nM; NDM-1: 0.5nM; IMP-1: 4.8nM) with the test buffer, and the substrate FC-5 uses the test buffer to prepare a 30 ⁇ M substrate solution for future use.
  • VIP-2, VIM-1 and VIM-5 1.2nM; NDM-1: 0.5nM; IMP-1: 4.8nM
  • step (3) In a 96-well ELISA plate, 10 ⁇ L of compound working solution obtained in step (1), 30 ⁇ L of test buffer and 10 ⁇ L of enzyme solution were sequentially added to each well, and incubated at room temperature for 10 min.
  • test results show that the compounds of the present invention have good inhibitory activity on MBL, especially on multiple MBL subtypes, especially clinically relevant subtypes such as VIM, NDM, and IMP, among which compound 64 is the best.
  • Test Example 2 Antibacterial activity of the compound of the present invention combined with meropenem
  • Bacterial solution dilution Use an inoculation loop to pick a single clone from the plate and place it in normal saline, adjust the OD 630 to 0.08-0.13 (equivalent to 1 ⁇ 10 8 CFU/mL), and dilute the bacterial solution 100 times with CAMHB. Add 100 ⁇ L to each well. At this time, the concentration of meropenem was 128 ⁇ g/mL to 0.25 ⁇ g/mL, and the concentration of the enzyme inhibitor was 10 ⁇ g/mL.
  • the compounds of the present invention have good inhibitory activity on metallo- ⁇ -lactamases (MBL), especially on multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, and IMP. It has strong gram-negative bacteria permeability, can be used to prepare broad-spectrum MBL inhibitors, and has good development prospects as a drug molecule for overcoming antibacterial drug resistance.
  • MBL metallo- ⁇ -lactamases

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Abstract

Provided in the present invention are a thiazolamine MBL inhibitor, and a preparation method therefor and the use thereof, which belong to the field of medical chemistry. The thiazolamine MBL inhibitor is a compound represented by formula I, or a salt, an isomer, a hydrate, a solvate, or a prodrug thereof. The compound provided in the present invention has good inhibitory activity on metallo-β-lactamase (MBL), and particularly has good inhibitory activity on multiple clinically relevant MBL subtypes, such as the subtypes of VIM, NDM, IMP, etc., has high Gram-negative bacterial permeability, can be used for preparing a broad-spectrum MBL inhibitor, can be used as a drug molecule for overcoming bacteria resistance and drug resistance, and has a good development prospect.

Description

一种噻唑胺类MBL抑制剂及其制备方法和用途A kind of thiazolamine MBL inhibitor and its preparation method and application 技术领域technical field
本发明属于医药化学领域，具体涉及一种噻唑胺类MBL抑制剂及其制备方法和用途。The invention belongs to the field of medicinal chemistry, and in particular relates to a thiazolamine MBL inhibitor and its preparation method and application.
背景技术Background technique
β-内酰胺类抗生素具有抗菌谱广、安全性高及临床疗效好等特点，是目前最常使用的抗生素。但因抗生素的滥用及不合理使用，使细菌对抗生素产生严重耐药，人类健康受到严重威胁。2019年，世界卫生组织将抗微生物药物的耐药问题列为全球十大健康威胁之一。在具有耐药性的病原微生物中，革兰氏阴性菌的抗生素耐药问题尤为严峻。对碳青霉烯类抗生素耐药的鲍曼不动杆菌、铜绿假单胞菌、肠杆菌等革兰氏阴性菌已被世界卫生组织被列为危险程度极高的病原菌。目前的研究表明，革兰氏阴性菌的耐药机制有多种，包括阻止抗生素进入细菌、将抗生素通过外排泵排出、改变抗生素作用靶点、将抗生素水解等，其中，产生β-内酰胺酶将抗生素水解是其对抗β-内酰胺类抗生素的主要机制。根据氨基酸序列及催化机制等的差异，β-内酰胺酶可分为丝氨酸β-内酰胺酶(serine-β-lactamase，SBL)和金属β-内酰胺酶(metallo-β-lactamase，MBL)两大类。通过研发β-内酰胺酶抑制剂，将其与β-内酰胺类抗生素联用，以抑制β-内酰胺酶的水解作用，恢复抗生素的抗菌活性，是对抗耐药革兰氏阴性菌感染的一种有效治疗策略。迄今为止，已有六种SBL抑制剂成功上市，而对于MBL，临床上尚无可用的抑制剂。β-lactam antibiotics have the characteristics of broad antibacterial spectrum, high safety and good clinical efficacy, and are currently the most commonly used antibiotics. However, due to the abuse and irrational use of antibiotics, bacteria are severely resistant to antibiotics, and human health is seriously threatened. In 2019, the World Health Organization listed antimicrobial resistance as one of the top ten global health threats. Among the resistant pathogenic microorganisms, the problem of antibiotic resistance of Gram-negative bacteria is particularly severe. Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter, which are resistant to carbapenem antibiotics, have been listed as extremely dangerous pathogenic bacteria by the World Health Organization. Current research shows that there are many drug resistance mechanisms of Gram-negative bacteria, including preventing antibiotics from entering the bacteria, expelling antibiotics through efflux pumps, changing antibiotic targets, and hydrolyzing antibiotics. Among them, β-lactam Enzymatic hydrolysis of antibiotics is the main mechanism of resistance to β-lactam antibiotics. According to the difference in amino acid sequence and catalytic mechanism, β-lactamase can be divided into serine β-lactamase (serine-β-lactamase, SBL) and metallo-β-lactamase (metallo-β-lactamase, MBL). category. By developing β-lactamase inhibitors and combining them with β-lactam antibiotics to inhibit the hydrolysis of β-lactamase and restore the antibacterial activity of antibiotics, it is effective against drug-resistant Gram-negative bacterial infections an effective treatment strategy. So far, six SBL inhibitors have been successfully marketed, while for MBL, there is no clinically available inhibitor.
根据氨基酸序列及活性位点结构等方面的不同，MBL可进一步划分为B1、B2、B3这三个亚类，其中，B1类MBL包含临床最为相关的VIM、NDM、IMP亚型，它们在几乎所有主要的革兰氏阴性菌病原体，包括肺炎克雷伯菌、铜绿假单胞菌及鲍曼不动杆菌等临床常见病原菌中都有发现。MBL具有广泛的底物特异性，可水解除单环类以外的所有β-内酰胺类抗生素以及β-内酰胺类SBL抑制剂，某些MBL甚至可以水解非β-内酰胺类SBL抑制剂阿维巴坦。且最近有报道表明，NDM-1可缓慢水解单环类β-内酰胺抗生素氨曲南，这可能意味着MBL在不断进化中获得了水解单环类β-内酰胺抗生素的能力。此外，部分MBL基因存在于细菌可移动基因元件上，可通过水平基因转移在细菌间快速广泛传播。因此，细菌内MBL酶的产生是最令人担忧的耐药因素之一，开发有效的MBL抑制剂迫在眉睫且具有重要的临床意义。According to differences in amino acid sequence and active site structure, MBL can be further divided into three subtypes: B1, B2, and B3. Among them, B1 MBL includes the most clinically relevant subtypes of VIM, NDM, and IMP. All major Gram-negative bacterial pathogens, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, were found in clinically common pathogens. MBL has a wide range of substrate specificity, and can hydrolyze all β-lactam antibiotics and β-lactam SBL inhibitors except monocyclics, and some MBL can even hydrolyze non-β-lactam SBL inhibitors. Vibatam. And recent reports have shown that NDM-1 can slowly hydrolyze the monocyclic β-lactam antibiotic aztreonam, which may mean that MBL has acquired the ability to hydrolyze the monocyclic β-lactam antibiotic during continuous evolution. In addition, some MBL genes exist on bacterial mobile genetic elements, which can spread rapidly and widely among bacteria through horizontal gene transfer. Therefore, the production of MBL enzymes in bacteria is one of the most worrying drug resistance factors, and the development of effective MBL inhibitors is imminent and has important clinical significance.
目前，已有多种类型的MBL抑制剂被报道，包括巯基类、羧酸类、磷酸 类等，但由于MBL亚型众多，结构具有较大差异，且活性位点中存在灵活多变的loop，多数抑制剂缺乏对多个MBL亚型，特别是临床相关的VIM、NDM、IMP等亚型的广谱抑制活性。此外，细菌外膜渗透性不高也是目前已报道的MBL抑制剂普遍存在的缺点。因此，目前亟需开发具有广谱抑制活性以及良好抑制细菌活性的MBL抑制剂，为临床有效的MBL抑制剂的研发提供新的先导化合物。Currently, various types of MBL inhibitors have been reported, including sulfhydryls, carboxylic acids, phosphoric acid However, due to the large number of MBL subtypes with large differences in structure, and the flexible loop in the active site, most inhibitors lack the ability to target multiple MBL subtypes, especially clinically relevant VIM, NDM, IMP, etc. Broad-spectrum inhibitory activity of isoforms. In addition, the low permeability of the bacterial outer membrane is also a common shortcoming of the reported MBL inhibitors. Therefore, there is an urgent need to develop MBL inhibitors with broad-spectrum inhibitory activity and good antibacterial activity, so as to provide new lead compounds for the development of clinically effective MBL inhibitors.
发明内容Contents of the invention
本发明的目的是提供一种噻唑胺类MBL抑制剂及其制备方法和用途。The object of the present invention is to provide a thiazolamine MBL inhibitor and its preparation method and application.
本发明提供了式I所示化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药：
The present invention provides a compound represented by formula I, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof:
其中，in,
R1选自氢、C1～C8烷基、卤素、羟基、羧基、氨基、硝基、-NHR1’；R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
R1’选自被0～5个R3取代的C1～C8烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 5 R 3 , -C(O)R 3 ';
R3分别独立选自5～10元芳基、5～10元杂芳基； R3 are independently selected from 5-10 membered aryl groups and 5-10 membered heteroaryl groups;
R3’选自C1～C8烷基、5～10元芳基；R 3 ' is selected from C 1 -C 8 alkyl, 5-10 membered aryl;
L选自无、被0～5个R4取代的C1～C8亚烷基、-S-、-O-、 L is selected from none, C 1 to C 8 alkylene substituted by 0 to 5 R 4 , -S-, -O-,
R4分别独立选自C1～C8烷基；R 4 are independently selected from C 1 -C 8 alkyl groups;
R2选自C1～C8烷基、C2～C8烯基、C2～C8炔基、被0～5个R5取代的5～10元芳基、被0～5个R5取代的3～10元杂芳基、被0～5个R5取代的3～10元杂环基、被0～5个R5取代的3～10元环烷基；R 2 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 5-10 membered aryl substituted by 0-5 R 5 , 0-5 R 5- substituted 3-10-membered heteroaryl, 3-10-membered heterocyclic group substituted by 0-5 R 5 , 3-10-membered cycloalkyl substituted by 0-5 R 5 ;
R5分别独立选自被0～5个R6取代的C1～C8烷基、被0～5个R6取代的C1～C8烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～5个R6取代的5～10元芳基、被0～5个R6取代的5～10元杂芳基；R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-5 R 6 , C 1 -C 8 alkoxy substituted by 0-5 R 6 , halogen, carboxyl, nitro, amino, Hydroxyl, -C(O)R 7 , -C(O)OR 7 , 5-10-membered aryl substituted by 0-5 R 6 , 5-10-membered heteroaryl substituted by 0-5 R 6 ;
R6分别独立选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C8炔基、C2～C8烯基、5～10元芳基；R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, 5-10 membered aryl ;
R7选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、5～10元芳基、5～10元杂芳基； R 7 is selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, 5-10-membered aryl, 5-10-membered heteroaryl;
当R1选自氨基，R2选自苯基时，L2不选自C1亚烷基；When R 1 is selected from amino, R 2 is selected from phenyl, L 2 is not selected from C 1 alkylene;
当R1选自氢、R2选自苯基时，L2不选自C1亚烷基、1个C1烷基取代的C1亚烷基、C2亚烷基；When R 1 is selected from hydrogen and R 2 is selected from phenyl, L 2 is not selected from C 1 alkylene, 1 C 1 alkyl substituted C 1 alkylene, C 2 alkylene;
当R1选自氨基，L选自无时，R2不选自噻吩基、C1～C5烷基；When R 1 is selected from amino, L is selected from none, R 2 is not selected from thienyl, C 1 ~ C 5 alkyl;
当R1选自氨基，R2选自C1烷基时，L不选自C2～C4亚烷基、无、1个C1烷基取代的C2亚烷基、1个C1烷基取代的C1亚烷基；When R 1 is selected from amino, R 2 is selected from C 1 alkyl, L is not selected from C 2 ~ C 4 alkylene, none, 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 Alkyl substituted C alkylene ;
当R1选自氢、R2选自C1烷基时，L不选自1个C1烷基取代的C2亚烷基、1个C1烷基取代的C1亚烷基；When R 1 is selected from hydrogen and R 2 is selected from C 1 alkyl, L is not selected from 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 alkyl substituted C 1 alkylene;
当R1选自氨基，L选自C1亚烷基时，R不选自 When R 1 is selected from amino, L is selected from C 1 alkylene, R is not selected from
进一步地，further,
R1选自氢、C1～C8烷基、卤素、羟基、羧基、氨基、硝基、-NHR1’；R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
R1’选自被0～3个R3取代的C1～C8烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 3 R 3 , -C(O)R 3 ';
R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
R3’选自C1～C8烷基、苯基；R 3 ' is selected from C 1 ~C 8 alkyl, phenyl;
L选自无、被0～3个R4取代的C1～C8亚烷基、-S-、-O-、 L is selected from none, C 1 to C 8 alkylene substituted by 0 to 3 R 4 , -S-, -O-,
R4分别独立选自C1～C8烷基；R 4 are independently selected from C 1 -C 8 alkyl groups;
R2选自C1～C8烷基、C2～C8烯基、C2～C8炔基、被0～3个R5取代的苯基、被0～3个R5取代的噻吩基、被0～3个R5取代的呋喃基、被0～3个R5取代的吡唑基、被0～3个R5取代的哌啶基、被0～3个R5取代的氮杂环丁烷、被0～3个R5取代的萘基、被0～3个R5取代的被0～3个R5取代的 R 2 is selected from C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, phenyl substituted by 0 to 3 R 5 , thiophene substituted by 0 to 3 R 5 radical, furanyl substituted by 0 to 3 R 5 , pyrazolyl substituted by 0 to 3 R 5 , piperidinyl substituted by 0 to 3 R 5 , nitrogen substituted by 0 to 3 R 5 Heterocyclobutane, naphthyl substituted by 0 to 3 R 5 , substituted by 0 to 3 R 5 Replaced by 0 to 3 R 5
R5分别独立选自被0～3个R6取代的C1～C8烷基、被0～3个R6取代的C1～C8烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～3个R6取代的苯基、被0～3个R6取代的吡啶基；R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-3 R 6 , C 1 -C 8 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 3 R 6 , pyridyl substituted by 0 to 3 R 6 ;
R6分别独立选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C8炔基、C2～C8烯基、苯基；R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, phenyl;
R7选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋 喃基。R 7 is selected from C 1 ~C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furfuryl Anyl.
进一步地，further,
R1选自氢、卤素、羟基、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
R3’选自C1～C3烷基、苯基；R 3 ' is selected from C 1 -C 3 alkyl, phenyl;
L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
R4分别独立选自C1～C3烷基；R 4 are independently selected from C 1 -C 3 alkyl groups;
R2选自C1～C7烷基、C2～C4烯基、C2～C4炔基、被0～2个R5取代的苯基、被0～1个R5取代的噻吩基、被0～1个R5取代的呋喃基、被0～1个R5取代的吡唑基、被0～1个R5取代的哌啶基、被0～1个R5取代的氮杂环丁烷、被0～1个R5取代的萘基、被0～1个R5取代的被0～1个R5取代的 R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
R5分别独立选自被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
进一步地，所述化合物如式II所示：
Further, the compound is shown in formula II:
其中， in,
L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
R4分别独立选自C1～C3烷基；R 4 are independently selected from C 1 -C 3 alkyl groups;
R2选自C1～C7烷基、C2～C4烯基、C2～C4炔基、被0～2个R5取代的苯基、被0～1个R5取代的噻吩基、被0～1个R5取代的呋喃基、被0～1个R5取代的吡唑基、被0～1个R5取代的哌啶基、被0～1个R5取代的氮杂环丁烷、被0～1个R5取代的萘基、被0～1个R5取代的被0～1个R5取代的 R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
R5分别独立选自被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
进一步地，所述化合物如式III所示：
Further, the compound is shown in formula III:
其中，in,
R1选自氢、卤素、羟基、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
R3’选自C1～C3烷基、苯基； R 3 ' is selected from C 1 -C 3 alkyl, phenyl;
L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
R4分别独立选自C1～C3烷基；R 4 are independently selected from C 1 -C 3 alkyl groups;
R5a、R5b、R5c分别独立选自氢、被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5a , R 5b , and R 5c are independently selected from hydrogen, C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen , carboxyl, nitro, amino, hydroxyl, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
进一步地，所述化合物如式IV所示：
Further, the compound is shown in formula IV:
其中，in,
R1选自氢、卤素、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, amino, -NHR 1 ';
R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
R3’选自C1～C3烷基；R 3 'is selected from C 1 -C 3 alkyl;
L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
R4分别独立选自C1～C3烷基。R 4 are each independently selected from C 1 -C 3 alkyl groups.
进一步地，所述化合物为如下化合物之一：



Further, the compound is one of the following compounds:



本发明还提供了前述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药在制备MBL抑制剂和/或制备抗菌药物中的用途。The present invention also provides the use of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitor and/or the preparation of antibacterial drug.
本发明还提供了一种药物，它是由前述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。The present invention also provides a drug, which is composed of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug as the active ingredient, plus pharmaceutically Preparations prepared with acceptable excipients or auxiliary ingredients.
本发明还提供了一种噻唑胺类化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药在制备MBL抑制剂和/或制备抗菌药物中的用途，所述噻唑胺类化合物为如下化合物之一：
The present invention also provides a thiazole amine compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitors and/or the preparation of antibacterial drugs purposes, the thiazole amine compound is one of the following compounds:
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definition of terms used in the present invention: Unless otherwise stated, the initial definition provided by a group or term herein applies to the group or term throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context , giving the meanings a person skilled in the art can assign to them.
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C1～C8烷基”是指包含1～8个碳原子的烷基；“C1～C8烷氧基”是指包含1～8个碳原子的烷氧基。The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a to C b alkyl indicates any alkyl group containing "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 to C 8 alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.
“烷基”是指具有指定数目的碳原子的饱和烃链。例如，C1～C8烷基是指具有1至8个碳原子，即有1、2、3、4、5、6、7或8个碳原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基等。"Alkyl" means a saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C 1 -C 8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, ie, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkyl groups can be straight 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 base) and hexyl, etc.
“卤素”为氟、氯、溴或碘。"Halogen" is fluoro, chloro, bromo or iodo.
本发明化合物对金属β-内酰胺酶(MBL)有良好的抑制活性，特别是对多个临床相关MBL亚型，如对VIM、NDM、IMP等亚型具有良好的抑制活性，具有较强革兰氏阴性菌菌渗透性，可用于制备广谱MBL抑制剂，作为克服抗菌耐药的药物分子，具有良好的开发前景。 The compound of the present invention has good inhibitory activity to metallo-β-lactamases (MBL), especially to multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, IMP have good inhibitory activity, and has strong revolutionary The permeability of Lambert-negative bacteria can be used to prepare a broad-spectrum MBL inhibitor, and has a good development prospect as a drug molecule for overcoming antibacterial drug resistance.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.
具体实施方式Detailed ways
除另有说明外，本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。Unless otherwise specified, the raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.
实施例1、化合物1、2、11-14、18、20-22、26、28、29、39、40、42、45、48、49、67-69和71-75的合成Synthesis of Embodiment 1, Compounds 1, 2, 11-14, 18, 20-22, 26, 28, 29, 39, 40, 42, 45, 48, 49, 67-69 and 71-75
合成路线：底物为相应的醛
Synthetic route: the substrate is the corresponding aldehyde
1、化合物39的合成
1. Synthesis of Compound 39
将二氯甲酸乙酯(1eq)和正己醛(0.8eq)用乙醚(10ml)溶解后，在0℃下滴加甲醇钠(1.1eq)，加毕搅拌两小时后移至常温下搅拌5小时后，向反应液中加入饱和食盐水(约50ml)，然后用乙醚萃取(3×30ml)，浓缩过后用甲醇溶解，加入硫脲(0.8eq)置65℃下回流5小时，停止反应，旋干甲醇，加水溶解，用氨水调至微碱性(pH＝8)，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝1:1，v/v)得中间体a(为黄色固体，收率约70％)。Dissolve ethyl dichloroformate (1eq) and n-hexanal (0.8eq) in ether (10ml), add sodium methoxide (1.1eq) dropwise at 0°C, stir for 2 hours after the addition, then move to room temperature and stir for 5 hours Finally, add saturated brine (about 50ml) to the reaction solution, then extract with ether (3×30ml), concentrate and dissolve with methanol, add thiourea (0.8eq) and set at 65°C to reflux for 5 hours to stop the reaction and spin Dry methanol, add water to dissolve, adjust to slightly alkaline (pH=8) with ammonia water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, silica gel column chromatography (PE:EA=1:1, v/v ) to obtain intermediate a (as a yellow solid, with a yield of about 70%).
将中间体a(1eq)用乙醇和水(体积比＝3：1)溶解后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝5)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物39(收率60％)。 Intermediate a (1eq) was dissolved with ethanol and water (volume ratio = 3:1), and then sodium hydroxide (3eq) was added. After 2 hours of reaction at room temperature, the reaction was stopped. The reaction solution was adjusted to slightly acidic (pH=5), spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=30:1, v/v). Compound 39 was obtained (60% yield).
化合物39：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)δ164.37,163.99,137.86,31.27,31.13,26.62,22.25,14.32ppm.HRMS:m/z calcd for C9H14N2O2S[M+H]+215.0849,found 215.0843；[M-H2O+H]+197.0749,found 197.0737.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; [MH 2 O+H] + 197.0749, found 197.0737.
2、化合物1、2、11-14、18、20-22、26、28、29、40、42、45、48、49、67-69和71-75的合成2. Synthesis of compounds 1, 2, 11-14, 18, 20-22, 26, 28, 29, 40, 42, 45, 48, 49, 67-69 and 71-75
按照化合物39所述合成方法，将原料正己醛替换为苯乙醛制备得到化合物1，将原料正己醛替换为2-苯基丙醛制备得到化合物2，将原料正己醛替换为正戊醛制备得到化合物11，将原料正己醛替换为正庚醛制备得到化合物12，将原料正己醛替换为正辛醛制备得到化合物13，将原料正己醛替换为正丁醛制备得到化合物14，将原料正己醛替换为对硝基苯乙醛制备得到化合物18，将原料正己醛替换为乙醛制备得到化合物20，将原料正己醛替换为噻吩-2乙醛制备得到化合物21，将原料正己醛替换为异丁醛制备得到化合物22，将原料正己醛替换为2-甲基丁醛制备得到化合物26，将原料正己醛替换为甲醛制备得到化合物28，将原料正己醛替换为3-甲基丁醛制备得到化合物29，原料正己醛替换为4-(2-氧代乙基)哌啶-1-羧酸叔丁酯制备得到化合物40，将原料正己醛替换为4-戊烯醛制备得到化合物42，将原料正己醛替换为2-(1-苯甲酰哌啶-4-基)乙醛制备得到化合物45，将原料正己醛替换为4-氨基苯乙醛制备得到化合物48，将原料正己醛替换为2-(1-呋喃酰哌啶-4-基)乙醛制备得到化合物49，将原料正己醛替换为3-(4-异丙基苯基)-2-甲基丙醛制备得到化合物67，将原料正己醛替换为3-(3-三氟甲基苯基)丙醛制备得到化合物68，将原料正己醛替换为铃兰醛制备得到化合物69，将原料正己醛替换为3，5-二氯苯乙醛制备得到化合物71，将原料正己醛替换为3，4-二氯苯乙醛制备得到化合物72，将原料正己醛替换为3，5-二溴苯乙醛制备得到化合物73，将原料正己醛替换为3-氯-5-溴-苯乙醛制备得到化合物74，将原料正己醛替换为5-甲基呋喃-2-丙醛制备得到化合物75。各化合物的结构如下所示：

According to the synthesis method described in compound 39, compound 1 was prepared by replacing the raw material n-hexanal with phenylacetaldehyde, compound 2 was prepared by replacing the raw material n-hexanal with 2-phenylpropanal, and prepared by replacing the raw material n-hexanal with n-valeraldehyde Compound 11 was prepared by replacing the raw material n-hexanal with n-heptanal to obtain compound 12, and the raw material n-hexanal was replaced with n-octylaldehyde to obtain compound 13, and the raw material n-hexanal was replaced with n-butyraldehyde to prepare compound 14, and the raw material n-hexanal was replaced Compound 18 was prepared for p-nitrophenylacetaldehyde, compound 20 was prepared by replacing the raw material n-hexanal with acetaldehyde, compound 21 was prepared by replacing the raw material n-hexanal with thiophene-2 acetaldehyde, and the raw material n-hexanal was replaced with isobutyraldehyde Compound 22 was prepared by replacing the raw material n-hexanal with 2-methylbutyraldehyde to prepare compound 26, and the raw material n-hexanal was replaced with formaldehyde to obtain compound 28, and the raw material n-hexanal was replaced with 3-methylbutyraldehyde to obtain compound 29 , the raw material n-hexanal was replaced by 4-(2-oxoethyl)piperidine-1-carboxylate tert-butyl ester to prepare compound 40, and the raw material n-hexanal was replaced by 4-pentenal to prepare compound 42, and the raw material n-hexanal Aldehyde was replaced with 2-(1-benzoylpiperidin-4-yl) acetaldehyde to prepare compound 45, and the raw material n-hexanal was replaced with 4-aminophenylacetaldehyde to prepare compound 48, and the raw material n-hexanal was replaced with 2- (1-furanoylpiperidin-4-yl)acetaldehyde was prepared to obtain compound 49, and the raw material n-hexanal was replaced with 3-(4-isopropylphenyl)-2-methylpropanal to prepare compound 67, and the raw material Replace n-hexanal with 3-(3-trifluoromethylphenyl) propanal to prepare compound 68, replace the raw material n-hexanal with lilial to prepare compound 69, and replace the raw material n-hexanal with 3,5-dichlorobenzene Compound 71 was prepared from acetaldehyde, and compound 72 was prepared by replacing the raw material n-hexanal with 3,4-dichlorophenylacetaldehyde, and compound 73 was prepared by replacing the raw material n-hexanal with 3,5-dibromophenylacetaldehyde. Compound 74 was prepared by replacing aldehyde with 3-chloro-5-bromo-phenylacetaldehyde, and compound 75 was prepared by replacing the raw material n-hexanal with 5-methylfuran-2-propionaldehyde. The structure of each compound is shown below:

各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物1：1H NMR(400MHz,DMSO-d6)δ7.33-7.20(m,7H),4.34(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.26,163.57,140.51,136.16,136.04,129.00,128.78,127.00,32.50ppm.HRMS:m/z calcd for C11H10N2O2S[M+H]+ 235.0536,found 235.0541；[M-H2O+H]+217.0436,found 217.0433.Compound 1: 1 H NMR (400MHz, DMSO-d 6 ) δ7.33-7.20 (m, 7H), 4.34 (s, 2H) ppm. 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.26, 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; [ MH2O +H] + 217.0436, found 217.0433.
化合物2：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C12H12N2O2S[M+H]+249.0692,found 249.0684；[M-H2O+H]+231.0592,found 231.0578.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; [MH 2 O+H] + 231.0592, found 231.0578.
化合物11：1H NMR(400MHz,DMSO-d6)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 C8H12N2O2S[M+H]+201.0692,found 201.0694；[M-H2O+H]+183.0592,found 183.0573；[M+Na]+223.0517,found 223.0508.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 ;[ MH2O +H] + 183.0592, found 183.0573; [M+Na] + 223.0517, found 223.0508.
化合物12：1H NMR(400MHz,DMSO-d6)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 C10H16N2O2S[M+H]+229.1005,found 229.0995；[M-H2O+H]+211.0905,found 211.0887；C10H16N2O2S[M+Na]+251.0830,found 251.0521.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;[MH 2 O+H] + 211.0905, found 211.0887; C 10 H 16 N 2 O 2 S[M+Na] + 251.0830, found 251.0521.
化合物13：1H NMR(400MHz,DMSO-d6)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 C11H18N2O2S[M+H]+243.1162,found 243.1147；[M-H2O+H]+225.1062,found 225.1042.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;[MH 2 O+H ] + 225.1062, found 225.1042.
化合物14：1H NMR(400MHz,DMSO-d6)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 C7H10N2O2S[M+H]+187.0536,found 187.0536；[M-H2O+H]+169.0436,found169.0421.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; [MH 2 O+H] + 169.0436, found 169.0421.
化合物18：1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝8.4Hz,2H)7.76-7.53(m,br,4H)ppm.Compound 18: 1 H NMR (400MHz, DMSO-d 6 ) δ8.14 (d, J=8.4Hz, 2H) 7.76-7.53 (m, br, 4H) ppm.
化合物20：1H NMR(400MHz,DMSO-d6)δ6.71(s,2H),2.31(s,3H)ppm.Compound 20: 1 H NMR (400MHz, DMSO-d 6 ) δ6.71(s, 2H), 2.31(s, 3H) ppm.
化合物21：1H NMR(400MHz,DMSO-d6)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 C9H8N2O2S2[M+H]+241.0100,found 241.0097；[M-H2O+H]+223.0000,found 222.9991.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; [MH 2 O+H] + 223.0000, found 222.9991.
化合物22：1H NMR(400MHz,DMSO-d6)δ7.88-7.60(m,1H),6.97(s,1H),4.25(s,1H),1.14(s,6H)ppm.HRMS:m/z calcd for C7H10N2O2S[M+H]+187.0536,found 187.0559；[M-H2O+H]+169.0436,found 169.0449.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; [MH 2 O+H] + 169.0436, found 169.0449.
化合物26：HRMS:m/z calcd for C8H12N2O2S[M+H]+201.0692,found 201.0702；[M-H2O+H]+183.0592,found 183.0592；[M+Na]+223.0517,found 223.0527.Compound 26: HRMS: m/z calcd for C 8 H 12 N 2 O 2 S[M+H] + 201.0692, found 201.0702; [MH 2 O+H] + 183.0592, found 183.0592; [M+Na] + 223.0517 , found 223.0527.
化合物28：1H NMR(400MHz,DMSO-d6)δ7.20(s,2H),7.00(s,1H)ppm. HRMS:m/z calcd for C4H4N2O2S[M+H]+145.0066,found 145.0067；[M-H2O+H]+126.9966,found 126.9958；[M+Na]+166.9881,found 166.9891.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; [MH 2 O+H] + 126.9966, found 126.9958; [M+Na] + 166.9881, found 166.9891 .
化合物29：1H NMR(400MHz,DMSO-d6)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 C8H12N2O2S[M+H]+201.0692,found 201.0688；[M-H2O+H]+183.0592,found 183.0579；[M+Na]+223.0517,found 223.0514.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; [MH 2 O+H] + 183.0592, found 183.0579; [M+ Na] + 223.0517, found 223.0514.
化合物40：1H NMR(400MHz,DMSO-d6)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 C15H23N3O4S[M+H]+342.1482,found 342.1486.[M+Na]+364.1307,found 364.1298.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.
化合物42：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)δ166.76,160.37,137.10,135.71,116.85,34.45,25.84ppm.HRMS:m/z calcd for C8H10N2O2S[M+H]+199.0536,found 199.0533；[M-H2O+H]+181.0436,found 181.0428.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; [MH 2 O+H] + 181.0436, found 181.0428.
化合物45：HRMS:m/z calcd for C17H19N3O3S[M+H]+346.1220,found 346.1211.Compound 45: HRMS: m/z calcd for C 17 H 19 N 3 O 3 S[M+H] + 346.1220, found 346.1211.
化合物48：LC-MS m/z:250.1[M+H]+.Compound 48: LC-MS m/z:250.1[M+H] + .
化合物49：LC-MS m/z:236.1[M+H]+.Compound 49: LC-MS m/z:236.1[M+H] + .
化合物67：1H NMR(400MHz,DMSO-d6)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 C16H20N2O2S[M+H]+305.1318,found 305.1312.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.
化合物68：1H NMR(400MHz,DMSO-d6)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 C13H11F3N2O2S[M+H]+317.0566,found 317.0528.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.
化合物69：1H NMR(400MHz,DMSO-d6)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 C17H22N2O2S[M+H]+319.1475,found 319.1461.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.
化合物71：1H NMR(400MHz,DMSO-d6)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 C11H8Cl2N2O2S[M+H]+302.9756,found 302.9757,304.9731.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.
化合物72：HRMS:m/z calcd for C11H8Cl2N2O2S[M+H]+302.9756,found 302.9752,304.9729. 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.
化合物73：HRMS:m/z calcd for C11H8Br2N2O2S[M+H]+390.8746,found 390.8749,392.8722,394.8707.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.
化合物74：HRMS:m/z calcd for C11H8BrClN2O2S[M+H]+346.9251,found 346.9250,348.9221.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.
化合物75：1H NMR(400MHz,DMSO-d6)δ6.99(s br,2H),5.96-5.92(m,2H),3.28(t,J＝7.2Hz,2H),2.80(t,J＝7.2Hz,2H),2.21(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ164.51,164.20,152.76,150.27,138.29,134.99,106.85,106.67,29.71,25.62,13.73ppm.Compound 75: 1 H NMR (400MHz, DMSO-d 6 )δ6.99(s br,2H),5.96-5.92(m,2H),3.28(t,J=7.2Hz,2H),2.80(t,J ＝7.2Hz, 2H), 2.21(s, 3H)ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.51, 164.20, 152.76, 150.27, 138.29, 134.99, 106.85, 106.67, 29.71, 25.62, 13.73ppm.
实施例2、化合物5、17、43、46、47、50、52、55、58、60、64、65、66、76、83-95的合成Example 2, Synthesis of Compounds 5, 17, 43, 46, 47, 50, 52, 55, 58, 60, 64, 65, 66, 76, 83-95
合成路线：底物为相应的羧酸
Synthetic route: the substrate is the corresponding carboxylic acid
1、化合物43的合成
1. Synthesis of Compound 43
将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸(1eq)置于反应瓶中，用干燥的四氢呋喃溶解后，冰浴下缓慢加入四氢铝锂(1.5eq)，加毕，移至常温反应，TLC监测，反应完毕，停止反应，冰浴下加入四氢铝锂等质量的百分之一体积水(如加入200mg四氢铝锂，加入2ml水)，再加入与水相同体积的质量分数为百分之十的氢氧化钠水溶液后，补加之前水体积的两倍水后搅拌约15分钟，然后加入少量无水硫酸镁，搅拌15分钟后，抽滤，旋干四氢呋喃，剩余溶液加少量水和乙酸乙酯(水和乙酸乙酯的体积比为1:2)萃取3次，无水硫酸钠干燥有机相，减压浓缩，旋干得中间体a(收率约50-70％)。Put the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid (1eq) in a reaction flask, dissolve it in dry tetrahydrofuran, and slowly add lithium aluminum tetrahydride (1.5eq) under an ice bath, Add complete, move to normal temperature reaction, TLC monitors, and reaction is finished, stop reaction, add the 1% volume water of quality such as lithium tetrahydrogen under ice bath (as adding 200mg lithium tetrahydrogen, add 2ml water), then After adding the same volume of sodium hydroxide aqueous solution with a mass fraction of 10% as water, add water twice the volume of the previous water and stir for about 15 minutes, then add a small amount of anhydrous magnesium sulfate, stir for 15 minutes, and then filter with suction , spin-dried tetrahydrofuran, add a small amount of water and ethyl acetate (the volume ratio of water and ethyl acetate is 1:2) to extract the remaining solution 3 times, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and spin-dry to obtain intermediate a (yield about 50-70%).
将中间体a(1eq)置于反应瓶中，用二氯甲烷溶解后，加入戴斯马丁氧化剂(dessmartin，1.2eq)，室温搅拌反应1h左右，TLC监测，反应完毕，停止反应，筒型漏斗过滤，滤液干燥减压浓缩，加入细硅胶，旋干过柱，PE 出，得中间体b(收率约40-60％)。Put the intermediate a (1eq) in a reaction flask, dissolve it with dichloromethane, add Dessmartin oxidant (dessmartin, 1.2eq), stir and react at room temperature for about 1h, monitor by TLC, stop the reaction after the reaction is complete, and use a cylindrical funnel Filter, dry the filtrate and concentrate under reduced pressure, add fine silica gel, spin dry and pass through the column, PE to obtain intermediate b (yield about 40-60%).
将二氯甲酸乙酯(1eq)和中间体b(0.8eq)用乙醚溶解后，在0℃下滴加甲醇钠(1.1eq)，加毕搅拌两小时后移至常温下搅拌5小时后，加入适量饱和食盐水(50ml)，然后用乙醚(3×30ml)萃取，有机相浓缩过后用甲醇溶解，加入硫脲(0.8eq)置65℃下回流5小时，停止反应，旋干甲醇，加水溶解，用氨水调至微碱性(pH＝8)，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝1:1，v/v)得中间体c(为黄色固体，收率约50-80％)。Dissolve ethyl dichloroformate (1eq) and intermediate b (0.8eq) in ether, add sodium methoxide (1.1eq) dropwise at 0°C, stir for two hours after the addition, move to room temperature and stir for 5 hours, Add an appropriate amount of saturated saline (50ml), then extract with ether (3×30ml), dissolve the organic phase with methanol after concentration, add thiourea (0.8eq) and reflux at 65°C for 5 hours to stop the reaction, spin to dry methanol, add water Dissolved, adjusted to slightly alkaline (pH=8) with ammonia water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, silica gel column chromatography (PE:EA=1:1, v/v) to obtain the intermediate c (as a yellow solid, the yield is about 50-80%).
将中间体c(1eq)用乙醇和水(体积比3：1)溶解后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝5)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物43(收率60％)。LC-MS m/z:314.1[M+H]+.Dissolve intermediate c (1eq) with ethanol and water (volume ratio 3:1), add sodium hydroxide (3eq), react at room temperature for 2 hours, and stop the reaction. The reaction solution was adjusted to slightly acidic (pH=5), spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=30:1, v/v). Compound 43 was obtained (60% yield). LC-MS m/z:314.1[M+H] + .
2、化合物5、17、46、47、50、52、55、58、60、64、65、66、76、83-95的合成2. Synthesis of compounds 5, 17, 46, 47, 50, 52, 55, 58, 60, 64, 65, 66, 76, 83-95
按照化合物43所述合成方法，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为苯丙酸制备得到化合物5，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为对硝基苯乙酸制备得到化合物17，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-硝基苯乙酸制备得到化合物46，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-氨基苯乙酸制备得到化合物47，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为4-联苯乙酸制备得到化合物50，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为4-(三氟甲氧基)苯乙酸制备得到化合物52，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为4-三氟甲基苯乙酸制备得到化合物55，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为4-异丙基苯乙酸制备得到化合物58，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为4-丙基苯乙酸制备得到化合物60，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(2-噻吩)丙酸制备得到化合物64，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为萘普生制备得到化合物65，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为布洛芬制备得到化合物66，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为2,3-二氢苯并呋喃-5-乙酸制备得到化合物76，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(4-氟苯基)丙酸制备得到化合物83，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(3-甲氧基苯基)丙酸制备得到化合物84，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(2,4-二氯苯基)丙酸制备得到化合物85，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(4-甲氧基苯基)丙酸制备得到化合物86，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(1-萘基)丙酸制备得到化合物87，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(2-溴苯基) 丙酸制备得到化合物88，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3,4-二甲氧基苯丙酸制备得到化合物89，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-[3,4-(亚甲二氧基)苯基]丙酸制备得到化合物90，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(4-叔丁基苯)-丙酸制备得到化合物91，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(3-溴苯基)丙酸制备得到化合物92，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(4-溴苯基)丙酸制备得到化合物93，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(2-氟苯基)丙酸制备得到化合物94，将原料1-(叔丁氧基羰基)氮杂环丁烷-3-乙酸替换为3-(3氟苯基)丙酸制备得到化合物95。各化合物的结构如下所示：

According to the synthesis method described in compound 43, the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with phenylpropionic acid to prepare compound 5, and the raw material 1-(tert-butoxycarbonyl)nitrogen Compound 17 was prepared by replacing heterotidine-3-acetic acid with p-nitrophenylacetic acid, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-nitrophenylacetic acid to obtain Compound 46, the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-aminophenylacetic acid to prepare compound 47, the raw material 1-(tert-butoxycarbonyl)azetidine Compound 50 was prepared by replacing alkane-3-acetic acid with 4-biphenylacetic acid, and replacing the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid with 4-(trifluoromethoxy)phenylacetic acid Compound 52 was prepared, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 4-trifluoromethylphenylacetic acid to prepare compound 55, and the raw material 1-(tert-butoxycarbonyl) ) Azetidine-3-acetic acid was replaced by 4-isopropylphenylacetic acid to prepare compound 58, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 4-propyl Phenylacetic acid was prepared to obtain compound 60, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3-(2-thiophene)propionic acid to prepare compound 64, and the raw material 1-(tert-butyl Oxycarbonyl) azetidine-3-acetic acid was replaced by naproxen to prepare compound 65, and the raw material 1-(tert-butoxycarbonyl) azetidine-3-acetic acid was replaced by ibuprofen to obtain Compound 66 was prepared by replacing the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid with 2,3-dihydrobenzofuran-5-acetic acid to obtain compound 76. The raw material 1-(tert-butyl Oxycarbonyl) azetidine-3-acetic acid was replaced by 3-(4-fluorophenyl) propionic acid to prepare compound 83, the raw material 1-(tert-butoxycarbonyl) azetidine-3- Acetic acid was replaced by 3-(3-methoxyphenyl)propionic acid to prepare compound 84, and the starting material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(2,4- Dichlorophenyl)propionic acid was prepared to obtain compound 85, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3-(4-methoxyphenyl)propionic acid to obtain compound 86, the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(1-naphthyl)propionic acid to prepare compound 87, the raw material 1-(tert-butoxycarbonyl) Azetidine-3-acetic acid replaced by 3-(2-bromophenyl) Propionic acid was prepared to obtain compound 88, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3,4-dimethoxyphenylpropionic acid to prepare compound 89, and the raw material 1-( tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-[3,4-(methylenedioxy)phenyl]propionic acid to prepare compound 90, the raw material 1-(tert-butoxy Carbonyl) azetidine-3-acetic acid was replaced by 3-(4-tert-butylbenzene)-propionic acid to prepare compound 91, the raw material 1-(tert-butoxycarbonyl) azetidine-3- Acetic acid was replaced by 3-(3-bromophenyl)propionic acid to prepare compound 92, and the starting material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(4-bromophenyl) Propionic acid was prepared to obtain compound 93, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3-(2-fluorophenyl)propionic acid to prepare compound 94, and the raw material 1-( Compound 95 was prepared by replacing tert-butoxycarbonyl)azetidine-3-acetic acid with 3-(3fluorophenyl)propionic acid. The structure of each compound is shown below:

各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物5：1H NMR(400MHz,DMSO-d6)δ7.28-7.21(m,7H),3.27(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)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 C12H12N2O2S[M+H]+249.0692,found 249.0689；[M-H2O+H]+231.0592,found 231.0579；[M+Na]+271.0512,found 271.0512.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; [ MH2O +H] + 231.0592, found 231.0579; [M+Na] + 271.0512, found 271.0512.
化合物17：1H NMR(400MHz,DMSO-d6)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 C11H9N3O4S[M+H]+280.0387,found 280.0380.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.
化合物46：1H NMR(400MHz,DMSO-d6)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 C11H9N3O4S[M+H]+280.0387,found 280.0382.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 .
化合物47：1H NMR(400MHz,DMSO-d6)δ6.94-6.90(m,2H),6.41-6.36(m,3H),6.19(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.79,149.21,141.21,137.34,129.36,116.25,114.16,112.62，32.90ppm.HRMS:m/z calcd for C11H11N3O2S[M+H]+250.0645,found 250.0644；[M-H2O+H]+232.0545,found 232.0539.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 250.064 4; [ MH2O +H] + 232.0545, found 232.0539.
化合物50：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C17H14N2O2S[M+H]+311.0849,found 311.0843.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.HR MS: m/z calcd for C 17 H 14 N 2 O 2 S[M+H] + 311.0849, found 311.0843.
化合物52：1H NMR(400MHz,DMSO-d6)δ7.37(d,J＝8.8Hz,2H),7.29(d,J＝8.8Hz,2H),7.02(s br,2H),4.38(s,2H)ppm.13C NMR(101MHz,DMSO-d6)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 C12H9N3O2F3S[M+H]+319.0359,found 319.0373.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.
化合物55：1H NMR(400MHz,DMSO-d6)δ7.68(d,J＝8.0Hz,2H),7.56(s br,2H),7.48(d,J＝8.0Hz,2H),4.46(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.72,163.01,145.07,134.25,129.57,127.90,127.58,125.88,123.43,32.03 ppm.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 )δ165.72,163.01,145.07,134.25,129.57,127.90,127.58,125.88,123.43,32.03 ppm.
化合物58：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C14H16N2O2S[M+H]+277.1005,found 277.0992.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.
化合物60：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C14H16N2O2S[M+H]+277.1005,found 277.0998.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.
化合物64：1H NMR(400MHz,DMSO-d6)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 C10H10N2O2S2[M+H]+255.0256,found 255.0254；[M-H2O+H]+237.0156,found 237.0148.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;[ MH 2 O+H] + 237.0156, found 237.0148.
化合物65：1H NMR(400MHz,DMSO-d6)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 C17H16N2O3S[M+H]+329.0954,found 329.0947.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.
化合物66：1H NMR(400MHz,DMSO-d6)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 C16H20N2O2S[M+H]+305.1318,found 305.1299.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.
化合物76：1H NMR(400MHz,DMSO-d6)δ7.08(s,1H),6.96-6.94(m,3H),6.66(d,J＝8.0Hz,1H),4.48(t,J＝8.4Hz,2H),4.23(s,2H),3.12(t,J＝8.4Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.92,163.95,158.82,137.61,136.68,132.65,128.14,127.95,125.44,109.11,71.30,32.07,29.54ppm.Compound 76: 1 H NMR (400MHz, DMSO-d 6 ) δ7.08(s, 1H), 6.96-6.94(m, 3H), 6.66(d, J=8.0Hz, 1H), 4.48(t, J= 8.4Hz, 2H), 4.23(s, 2H), 3.12(t, J=8.4Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.92, 163.95, 158.82, 137.61, 136.68, 132.65, 128.14 ,127.95,125.44,109.11,71.30,32.07,29.54ppm.
化合物83：1H NMR(400MHz,DMSO-d6)δ7.25-7.22(m,2H),7.11-7.07(m,2H),6.94(s,2H),3.26(t,J＝8.0Hz,2H),2.83(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.22(d,J＝30.0Hz,1C),162.43,160.03,137.90,137.37(d,J＝3.0Hz,1C),135.86,130.62(d,J＝8.0Hz,1C),115.38(d,J＝3.0Hz,1C),36.42,28.71ppm.Compound 83: 1 H NMR (400MHz, DMSO-d 6 ) δ7.25-7.22(m, 2H), 7.11-7.07(m, 2H), 6.94(s, 2H), 3.26(t, J=8.0Hz, 2H), 2.83(t, J=8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.22(d, J=30.0Hz, 1C), 162.43, 160.03, 137.90, 137.37(d ,J=3.0Hz,1C),135.86,130.62(d,J=8.0Hz,1C),115.38(d,J=3.0Hz,1C),36.42,28.71ppm.
化合物84：1H NMR(400MHz,DMSO-d6)δ7.19(dt,J＝6.8Hz,,J＝1.2Hz,1H),7.02(s,2H),6.80-6.75(m,3H),3.73(s,3H),3.28(t,J＝8.0Hz,2H),2.82(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.45,163.65,159.74, 142.74,136.80,136.61,129.74,121.10,114.44,112.06,55.36,37.27,28.49ppm.Compound 84: 1 H NMR (400MHz, DMSO-d 6 ) δ7.19 (dt, J=6.8Hz,, J=1.2Hz, 1H), 7.02(s, 2H), 6.80-6.75(m, 3H), 3.73(s, 3H), 3.28(t, J=8.0Hz, 2H), 2.82(t, J=8.0Hz, 2H) ppm. 13 C NMR(101MHz, DMSO-d 6 )δ164.45, 163.65, 159.74, 142.74, 136.80, 136.61, 129.74, 121.10, 114.44, 112.06, 55.36, 37.27, 28.49ppm.
化合物85：1H NMR(400MHz,DMSO-d6)δ7.56(d,J＝2.0Hz,1H),7.48(s br,2H),7.37-7.31(m,2H),3.29(t,J＝7.2Hz,2H),2.96(t,J＝7.2Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.12,162.73,137.41,135.01,134.49,132.58,132.20,129.07,127.81,33.92,26.61ppm.Compound 85: 1 H NMR (400MHz, DMSO-d 6 ) δ7.56(d, J=2.0Hz, 1H), 7.48(s br, 2H), 7.37-7.31(m, 2H), 3.29(t, J =7.2Hz, 2H), 2.96(t, J=7.2Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ165.12, 162.73, 137.41, 135.01, 134.49, 132.58, 132.20, 129.07, 127.81, 33.92 ,26.61ppm.
化合物86：1H NMR(400MHz,DMSO-d6)δ7.76(s br,2H),7.13(d,J＝8.0Hz,2H),6.87-6.82(m,2H),3.72(s,3H),3.25(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.37,162.27,158.18,136.23,133.15,132.72,129.85,114.22,55.45,35.99,28.76ppm.Compound 86: 1 H NMR (400MHz, DMSO-d 6 ) δ7.76(s br, 2H), 7.13(d, J=8.0Hz, 2H), 6.87-6.82(m, 2H), 3.72(s, 3H ), 3.25 (t, J=7.6Hz, 2H), 2.79 (t, J=7.6Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ165.37, 162.27, 158.18, 136.23, 133.15, 132.72, 129.85,114.22,55.45,35.99,28.76ppm.
化合物87：1H NMR(400MHz,DMSO-d6)δ8.75(s br,2H),8.19(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,1H),7.58-7.51(m,2H),7.46-7.39(m,2H),3.80-3.32(m,4H)ppm.13C NMR(101MHz,DMSO-d6)δ166.54,160.71,136.73,135.52,133.90,131.81,129.08,127.49,126.89,126.57,126.15,126.04,124.09,33.69,27.98ppm.Compound 87: 1 H NMR (400MHz, DMSO-d 6 ) δ8.75(s br, 2H), 8.19(d, J=8.4Hz, 1H), 7.93(d, J=8.4Hz, 1H), 7.81( d,J＝8.0Hz,1H),7.58-7.51(m,2H),7.46-7.39(m,2H),3.80-3.32(m,4H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ166 .54, 160.71, 136.73, 135.52, 133.90, 131.81, 129.08, 127.49, 126.89, 126.57, 126.15, 126.04, 124.09, 33.69, 27.98ppm.
化合物88：1H NMR(400MHz,DMSO-d6)δ8.29(s br,2H),7.58(d,J＝8.0Hz,1H),7.35-7.31(m,2H),7.20-7.15(m,2H),3.29(t,J＝7.6Hz,2H),2.99(t,J＝7.6Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ166.07,161.33,139.61,134.85,133.02,131.26,129.08,128.38,124.32,36.65,26.91ppm.Compound 88: 1 H NMR (400MHz, DMSO-d 6 ) δ8.29(s br, 2H), 7.58(d, J=8.0Hz, 1H), 7.35-7.31(m, 2H), 7.20-7.15(m ,2H),3.29(t,J=7.6Hz,2H),2.99(t,J=7.6Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ166.07,161.33,139.61,134.85,133.02, 131.26, 129.08, 128.38, 124.32, 36.65, 26.91ppm.
化合物89：1H NMR(400MHz,DMSO-d6)δ6.95(s br,2H),6.85-6.82(m,2H),6.70(dd,J＝8.0Hz,J＝2.0Hz,1H),3.73(s,3H),3.71(s,3H),3.26(t,J＝7.6Hz,2H),2.77(t,J＝7.6Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.37,163.74,149.07,147.67,136.83,133.61,120.72,112.78,112.29,55.98,55.87,36.85,28.72ppm.Compound 89: 1 H NMR (400MHz, DMSO-d 6 ) δ6.95 (s br, 2H), 6.85-6.82 (m, 2H), 6.70 (dd, J=8.0Hz, J=2.0Hz, 1H), 3.73(s, 3H), 3.71(s, 3H), 3.26(t, J=7.6Hz, 2H), 2.77(t, J=7.6Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.37,163.74,149.07,147.67,136.83,133.61,120.72,112.78,112.29,55.98,55.87,36.85,28.72ppm.
化合物90：1H NMR(400MHz,DMSO-d6)δ6.90(s br,2H),6.81-6.79(m,2H),6.65(dd,J＝8.0Hz,J＝2.0Hz,1H),5.96(s,2H),3.23(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.29,163.85,147.62,145.91,137.34,136.60,135.05,121.72,109.24,108.49,101.10,36.98,28.90ppm.Compound 90: 1 H NMR (400MHz, DMSO-d 6 ) δ6.90 (s br, 2H), 6.81-6.79 (m, 2H), 6.65 (dd, J=8.0Hz, J=2.0Hz, 1H), 5.96(s, 2H), 3.23(t, J=7.6Hz, 2H), 2.76(t, J=7.6Hz, 2H) ppm. 13 C NMR(101MHz, DMSO-d 6 ) δ164.29, 163.85, 147.62, 145.91 ,137.34,136.60,135.05,121.72,109.24,108.49,101.10,36.98,28.90ppm.
化合物91：1H NMR(400MHz,DMSO-d6)δ8.32(s br,2H),7.30(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),3.26(t,J＝7.6Hz,2H),2.82(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.94,161.55,148.97,137.68,136.05,131.15,128.45,125.53,36.26,34.56,31.66,28.50ppm.Compound 91: 1 H NMR (400MHz, DMSO-d 6 ) δ8.32(s br, 2H), 7.30(d, J=8.0Hz, 2H), 7.15(d, J=8.0Hz, 2H), 3.26( t, J＝7.6Hz, 2H), 2.82 (t, J＝8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ165.94, 161.55, 148.97, 137.68, 136.05, 131.15, 128.45, 125.53, 36.26, 34.56, 31.66, 28.50ppm.
化合物92：1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.39(td,J＝7.2Hz J＝1.6Hz,2H),7.27-7.20(m,2H),6.89(s,2H),3.27(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.31,163.88,144.14, 137.61,136.22,131.62,130.87,129.43,128.01,122.06,36.75,28.35ppm.Compound 92: 1 H NMR (400MHz, DMSO-d 6 ) δ7.44(s, 1H), 7.39(td, J=7.2Hz J=1.6Hz, 2H), 7.27-7.20(m, 2H), 6.89( s, 2H), 3.27 (t, J=8.0Hz, 2H), 2.84 (t, J=8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.31, 163.88, 144.14, 137.61, 136.22, 131.62, 130.87, 129.43, 128.01, 122.06, 36.75, 28.35ppm.
化合物93：1H NMR(400MHz,DMSO-d6)δ7.44(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),7.06(s br,2H),3.33(t,J＝8.0Hz,2H),2.80(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ166.07,164.20,141.14,131.54,131.49,131.21,130.60,119.38,36.85,28.31ppm.Compound 93: 1 H NMR (400MHz, DMSO-d 6 ) δ7.44(d, J=8.0Hz, 2H), 7.19(d, J=8.0Hz, 2H), 7.06(s br, 2H), 3.33( t, J＝8.0Hz, 2H), 2.80 (t, J＝8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ166.07, 164.20, 141.14, 131.54, 131.49, 131.21, 130.60, 119.38, 36.85,28.31ppm.
化合物94：1H NMR(400MHz,DMSO-d6)δ12.30(s br,1H),7.28-7.22(m,2H),7.15-7.10(m,2H),6.91(s,2H),3.27(t,J＝8.0Hz,2H),2.88(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ164.09(d,J＝53.0Hz,1C),162.24,159.82,137.64,135.92,131.32(d,J＝5.0Hz,1C),128.70(d,J＝8.0Hz,1C),127.70(d,J＝15.0Hz,1C),124.77(d,J＝3.0Hz,1C),115.64(d,J＝21.0Hz,1C),30.30,27.26ppm.Compound 94: 1 H NMR (400MHz, DMSO-d 6 ) δ12.30(s br,1H),7.28-7.22(m,2H),7.15-7.10(m,2H),6.91(s,2H),3.27 (t, J=8.0Hz, 2H), 2.88 (t, J=8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ164.09 (d, J=53.0Hz, 1C), 162.24 ,159.82,137.64,135.92,131.32(d,J=5.0Hz,1C),128.70(d,J=8.0Hz,1C),127.70(d,J=15.0Hz,1C),124.77(d,J=3.0 Hz, 1C), 115.64(d, J=21.0Hz, 1C), 30.30, 27.26ppm.
化合物95：1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.39(td,J＝7.2Hz J＝1.6Hz,2H),7.27-7.20(m,2H),6.89(s,2H),3.27(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ167.06,163.86,161.44,145.51,144.96(d,J＝7.0Hz,1C),130.43(d,J＝9.0Hz,1C),128.51,125.07,115.51(d,J＝21.0Hz,1C),113.00(d,J＝21.0Hz,1C),37.30,28.22ppm.Compound 95: 1 H NMR (400MHz, DMSO-d 6 ) δ7.44(s, 1H), 7.39(td, J=7.2Hz J=1.6Hz, 2H), 7.27-7.20(m, 2H), 6.89( s,2H),3.27(t,J=8.0Hz,2H),2.84(t,J=8.0Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ167.06,163.86,161.44,145.51,144.96 (d,J=7.0Hz,1C),130.43(d,J=9.0Hz,1C),128.51,125.07,115.51(d,J=21.0Hz,1C),113.00(d,J=21.0Hz,1C) ,37.30,28.22ppm.
实施例3、化合物51、54、57、62的合成Embodiment 3, the synthesis of compound 51,54,57,62
合成路线：底物为相应的醇
Synthetic route: the substrate is the corresponding alcohol
1、化合物51的合成
1. Synthesis of Compound 51
将3-甲氧基苯乙醇(1eq)置于反应瓶中，用二氯甲烷(20ml)溶解后，加入戴斯马丁氧化剂(dessmartin，1.2eq)，室温搅拌反应1h左右，TLC监测， 反应完毕，停止反应，筒型漏斗过滤，滤液干燥减压浓缩，加入细硅胶，旋干过柱，PE出，得中间体a(收率约60％)。Put 3-methoxyphenethyl alcohol (1eq) in the reaction flask, dissolve it with dichloromethane (20ml), add Dessmartin oxidant (dessmartin, 1.2eq), stir and react at room temperature for about 1h, monitor by TLC, After the reaction is completed, stop the reaction, filter with a cylindrical funnel, dry the filtrate and concentrate under reduced pressure, add fine silica gel, spin dry and pass through the column, and remove it with PE to obtain intermediate a (yield about 60%).
将二氯甲酸乙酯(1eq)和中间体a(0.8eq)用乙醚(10ml)溶解后，在0℃下滴加甲醇钠(1.1eq)，加毕搅拌两小时后移至常温下搅拌5小时后，向反应液中加入饱和食盐水(50ml)，然后用乙醚萃取(3×30ml)，有机相浓缩过后用甲醇溶解，加入硫脲(0.8eq)置65℃下回流5小时，停止反应，旋干甲醇，加水溶解，用氨水调至微碱性(pH＝8)，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝1:1，v/v)得中间体b(为黄色固体，收率约50％)。Dissolve ethyl dichloroformate (1eq) and intermediate a (0.8eq) in ether (10ml), then add sodium methoxide (1.1eq) dropwise at 0°C, stir for two hours after the addition, then move to room temperature and stir for 5 After 1 hour, add saturated brine (50ml) to the reaction solution, then extract with ether (3×30ml), dissolve the organic phase with methanol after concentration, add thiourea (0.8eq) and place at 65°C for 5 hours at reflux to stop the reaction , spin dry methanol, add water to dissolve, adjust to slightly alkaline (pH=8) with ammonia water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, silica gel column chromatography (PE:EA=1:1, v /v) Intermediate b (yellow solid, yield about 50%) was obtained.
将中间体b(1eq)用乙醇和水(体积比＝3：1)溶解后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝5)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物51(收率60％)。Intermediate b (1eq) was dissolved with ethanol and water (volume ratio = 3:1), and then sodium hydroxide (3eq) was added to react at room temperature for 2 hours before stopping the reaction. The reaction solution was adjusted to slightly acidic (pH=5), spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=30:1, v/v). Compound 51 was obtained (60% yield).
化合物51：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C12H12N2O3S[M+H]+265.0641,found 265.0637.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.HR MS:m/ z calcd for C 12 H 12 N 2 O 3 S[M+H] + 265.0641, found 265.0637.
2、化合物54、57、62的合成2. Synthesis of Compounds 54, 57, and 62
按照化合物51所述合成方法，将原料3-甲氧基苯乙醇替换为噻吩-3-乙醇制备得到化合物54，将原料3-甲氧基苯乙醇替换为3-溴苯乙醇制备得到化合物57，将原料3-甲氧基苯乙醇替换为对氟苯乙醇制备得到化合物62。各化合物的结构如下所示：
According to the synthesis method described in compound 51, compound 54 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with thiophene-3-ethanol, and compound 57 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with 3-bromophenethyl alcohol, Compound 62 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with p-fluorophenethyl alcohol. The structure of each compound is shown below:
各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物54：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)δ164.93,164.19,140.94,137.41,135.79,128.69,126.71,122.16,27.50ppm.HRMS:m/z calcd for C9H8N2O2S2[M+H]+241.0100,found 241.0101.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.
化合物57：1H NMR(400MHz,DMSO-d6)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 C11H9BrN2O2S[M+H]+312.9641,found 312.9652,314.9628.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.
化合物62：1H NMR(400MHz,DMSO-d6)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 C11H9FN2O2S[M+H]+253.0442,found 253.0434；[M-H2O+H]+235.0341,found 235.0327.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; [MH 2 O+H] + 235.0341, found 235.0327.
实施例4、化合物41、44的合成Embodiment 4, the synthesis of compound 41,44
化合物44、化合物41分别为化合物43、化合物40脱Boc所得。Compound 44 and Compound 41 are obtained by de-Boc of Compound 43 and Compound 40, respectively.
1、化合物44的合成
1. Synthesis of Compound 44
将化合物43用二氯甲烷(10ml)溶解在反应瓶中，冰浴下加入三氟乙酸(1ml)，加毕，常温搅拌几小时后，TLC监测，反应完毕，停止反应，旋干溶剂，加水(30ml)溶解后用饱和碳酸氢钠调至弱碱性(pH＝8)，乙酸乙酯萃取(3×30ml)，无水硫酸钠干燥，减压浓缩，柱层析(DCM:CH3OH＝50:1；30:1；10:1，v/v)，得化合物44，收率约为80％。LC-MS m/z:214.1[M+H]+.Dissolve compound 43 in the reaction flask with dichloromethane (10ml), add trifluoroacetic acid (1ml) under ice bath, after the addition is complete, stir at room temperature for several hours, monitor by TLC, the reaction is complete, stop the reaction, spin the solvent, add water (30ml) was dissolved and adjusted to weakly alkaline (pH=8) with saturated sodium bicarbonate, extracted with ethyl acetate (3×30ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (DCM:CH 3 OH =50:1; 30:1; 10:1, v/v), to obtain compound 44 with a yield of about 80%. LC-MS m/z:214.1[M+H] + .
2、化合物41的合成2. Synthesis of Compound 41
按照化合物44所述合成方法，将原料化合物43替换为化合物40制备得到化合物41。化合物41的结构如下所示：
According to the synthesis method described in compound 44, compound 41 was prepared by replacing the starting material compound 43 with compound 40. The structure of compound 41 is shown below:
化合物41的表征数据如下所示：HRMS:m/z calcd for C10H15N3O2S[M+H]+242.0958,found 242.0956.The characterization data of compound 41 are as follows: HRMS: m/z calcd for C 10 H 15 N 3 O 2 S[M+H] + 242.0958, found 242.0956.
实施例5、化合物53、56、61和63的合成Synthesis of Embodiment 5, Compounds 53, 56, 61 and 63
合成路线：
synthetic route:
其中，X为溴原子，R为不同取代基。Wherein, X is a bromine atom, and R is a different substituent.
1、化合物53的合成
1. Synthesis of Compound 53
将中间体a(1eq)置于反应瓶中，用DCM(20ml)溶解后，冰浴下缓慢滴加三溴化硼(3eq)，加毕，常温搅拌几小时后，TLC监测，反应完毕，停止反应，旋干溶剂，加少量水(30ml)后用饱和碳酸氢钠调至弱碱性(pH＝8)，乙酸乙酯萃取(3×30ml)，无水硫酸钠干燥，减压浓缩，柱层析PE:EA＝(1:1，v/v)，得中间体b黄色固体(收率约30％)。Intermediate a (1eq) was placed in a reaction flask, dissolved with DCM (20ml), and boron tribromide (3eq) was slowly added dropwise under an ice bath. After the addition was completed, after stirring at room temperature for several hours, TLC monitoring showed that the reaction was complete. Stop the reaction, spin to dry the solvent, add a small amount of water (30ml), adjust to weakly alkaline (pH=8) with saturated sodium bicarbonate, extract with ethyl acetate (3×30ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, Column chromatography PE:EA=(1:1, v/v) gave intermediate b as a yellow solid (yield about 30%).
将中间体b(1eq)加入到反应瓶中，用二氯甲烷(10ml)溶解后，依次加入DMAP(1.05eq)，二碳酸二叔丁酯(1.5eq)，加毕，常温下搅拌反应1h。TLC监测，反应完毕，停止反应，加入少量薄层色谱硅胶粉，减压浓缩，旋干后经柱层析(纯DCM:CH3OH＝80:1，v/v)得中间体c，收率约为80％。Add intermediate b (1eq) into the reaction flask, dissolve it with dichloromethane (10ml), then add DMAP (1.05eq) and di-tert-butyl dicarbonate (1.5eq) in sequence, after the addition is complete, stir and react at room temperature for 1h . TLC monitoring, the reaction is complete, stop the reaction, add a small amount of thin-layer chromatography silica gel powder, concentrate under reduced pressure, and spin dry to obtain intermediate c through column chromatography (pure DCM:CH 3 OH=80:1, v/v). The rate is about 80%.
将中间体c(1eq)置于反应瓶中，用DMF溶解后，依次加入碳酸钾(3eq)，3-溴丙烯(1.5eq)，常温搅拌几小时后，TLC监测，反应完毕，停止反应，加入溶剂10倍体积水，乙酸乙酯萃取(3×50ml)，浓缩有机相，加入少量薄层色谱硅胶粉，减压浓缩，旋干后经柱层析PE:EA＝(2:1，v/v)，得中间体d(收率约为60％)。 Intermediate c (1eq) was placed in a reaction flask, dissolved in DMF, potassium carbonate (3eq) and 3-bromopropene (1.5eq) were added successively, stirred at room temperature for several hours, monitored by TLC, the reaction was completed, and the reaction was stopped. Add 10 times the volume of water as a solvent, extract with ethyl acetate (3×50ml), concentrate the organic phase, add a small amount of thin-layer chromatography silica gel powder, concentrate under reduced pressure, spin dry, and perform column chromatography PE:EA=(2:1, v /v) to obtain intermediate d (the yield is about 60%).
将中间体d(1eq)用二氯甲烷(10ml)溶解在反应瓶中，在低温下滴加三氟乙酸(3eq)，加毕常温下反应一小时左右，TLC监测，反应完毕，停止反应，旋干反应液，加入少量水(30ml)溶解后，用饱和碳酸氢钠调至弱碱性(pH＝8)，乙酸乙酯萃取(3×20ml)，浓缩有机相，加入少量薄层色谱硅胶粉，减压浓缩，旋干得中间体e，收率约为50％。Intermediate d (1eq) was dissolved in a reaction flask with dichloromethane (10ml), and trifluoroacetic acid (3eq) was added dropwise at low temperature, and reacted at normal temperature for about one hour after adding, monitored by TLC, the reaction was completed, and the reaction was stopped. Spin the reaction solution to dryness, add a small amount of water (30ml) to dissolve, adjust to weakly alkaline (pH=8) with saturated sodium bicarbonate, extract with ethyl acetate (3×20ml), concentrate the organic phase, add a small amount of thin-layer chromatography silica gel powder, concentrated under reduced pressure, and spin-dried to obtain intermediate e with a yield of about 50%.
将中间体e(1eq)用乙醇和水溶解(体积比＝3：1)后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝6)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物53(收率60％)。Intermediate e (1eq) was dissolved in ethanol and water (volume ratio = 3:1), and then sodium hydroxide (3eq) was added to react at room temperature for 2 hours before stopping the reaction. The reaction solution was adjusted to slightly acidic (pH=6), spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=30:1, v/v). Compound 53 was obtained (60% yield).
化合物53：1H NMR(400MHz,DMSO-d6)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 C14H14N2O3S[M+H]+291.0798,found 291.0791.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、化合物56、61、63的合成2. Synthesis of compounds 56, 61, 63
按照化合物53所述合成方法，将原料3-溴丙烯替换为4-溴-1-丁烯制备得到化合物56，将原料3-溴丙烯替换为卞溴制备得到化合物61，将中间体b直接水解制备得到化合物63。各化合物的结构如下所示：
According to the synthesis method described in compound 53, compound 56 was prepared by replacing the raw material 3-bromopropene with 4-bromo-1-butene, and compound 61 was prepared by replacing the raw material 3-bromopropene with Bian bromide, and the intermediate b was directly hydrolyzed Compound 63 was prepared. The structure of each compound is shown below:
化合物的表征数据如下所示：The characterization data for the compounds are shown below:
化合物56：1H NMR(400MHz,DMSO-d6)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 C15H16N2O3S[M+H]+305.0954,found 305.0947.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.
化合物61：1H NMR(400MHz,DMSO-d6)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 C18H16N2O3S[M+H]+341.0954,found 341.0944.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.
化合物63：1H NMR(400MHz,DMSO-d6)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 C11H10N2O3S[M+H]+251.0485,found 251.0482.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.
实施例6、化合物59、70的合成 Embodiment 6, the synthesis of compound 59,70
化合物59，70是以对溴噻唑胺为底物中间体，铃木反应合成所得。Compounds 59 and 70 were synthesized using p-bromothiazolamine as a substrate intermediate by Suzuki reaction.
1、化合物59的合成1. Synthesis of Compound 59
合成路线：
synthetic route:
将对溴噻唑胺(1eq)，苯硼酸(3eq)，碳酸钾(3eq)，双三苯基膦二氯化钯(0.1eq)置于反应瓶中，用甲苯(15ml)溶解后，Ar2保护下置100℃下回流反应几小时，TLC监测，反应完毕，停止反应，旋干溶剂，加水(50ml)溶解，乙酸乙酯萃取(3×40ml)，无水硫酸钠干燥有机相，减压浓缩旋干柱层析PE:EA＝(2:1，v/v)得黄色固体中间体a(收率约为80％)。P-bromothiazolamine (1eq), phenylboronic acid (3eq), potassium carbonate (3eq), bistriphenylphosphine palladium dichloride (0.1eq) were placed in the reaction flask, dissolved with toluene (15ml), Ar 2 Reflux reaction at 100°C under protection for several hours, TLC monitoring, the reaction is complete, stop the reaction, spin dry the solvent, add water (50ml) to dissolve, extract with ethyl acetate (3 × 40ml), dry the organic phase with anhydrous sodium sulfate, reduce pressure Concentration and spin-drying column chromatography PE:EA=(2:1, v/v) gave intermediate a as a yellow solid (yield about 80%).
将中间体a(1eq)用乙醇和水(体积比＝3：1)总体积(12ml)溶解后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝6)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物59(收率60％)。The intermediate a (1eq) was dissolved in the total volume (12ml) of ethanol and water (volume ratio = 3:1), and then sodium hydroxide (3eq) was added. After 2 hours of reaction at room temperature, the reaction was stopped. The reaction solution was adjusted to slightly acidic (pH=6), spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=30:1, v/v). Compound 59 was obtained (60% yield).
化合物59：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C20H20N2O2S[M+H]+353.1318,found 353.1317.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 ) Δ165.08,163.92,147.97,138.86,137.04,136.08,129.28,127 .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、化合物70的合成2. Synthesis of Compound 70
合成路线：
synthetic route:
将对溴噻唑胺(1eq)加入到反应瓶中，用二氯甲烷(20ml)溶解后，依次加入DMAP(1.05eq)，二碳酸二叔丁酯(1.5eq)，加毕，常温下搅拌反应1h。TLC监测，反应完毕，停止反应，加入少量薄层色谱硅胶粉，减压浓缩，旋干后经柱层析PE:EA＝10：1，8：1(v/v)，得中间体a，收率约为40％。Add p-bromothiazolamine (1eq) into the reaction flask, dissolve it with dichloromethane (20ml), then add DMAP (1.05eq) and di-tert-butyl dicarbonate (1.5eq) in sequence, after the addition is complete, stir the reaction at room temperature 1h. TLC monitoring, the reaction is complete, stop the reaction, add a small amount of thin-layer chromatography silica gel powder, concentrate under reduced pressure, spin dry, and perform column chromatography PE:EA=10:1, 8:1 (v/v) to obtain intermediate a, The yield is about 40%.
将中间体a(1eq)，苯硼酸(3eq)，碳酸铯(3eq)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.3eq)置于反应瓶中，用1，4-二氧六环(15ml)溶解后，Ar2保护下置100℃下回流反应几小时，TLC监测，反应完毕，停止反应，旋干溶剂，加水(50ml)溶解，乙酸乙酯萃取(3x40ml)，无水硫酸钠干燥有机相，减压浓缩旋干柱层析PE:EA＝(8:1，5:1，3:1，2:1，v/v)，得黄色固体中间体b(收率约为50％)。Put intermediate a (1eq), phenylboronic acid (3eq), cesium carbonate (3eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3eq) in the reaction flask In the process, after dissolving with 1,4-dioxane (15ml), put it under the protection of Ar 2 at 100°C to reflux for a few hours, monitor by TLC, stop the reaction after the reaction is complete, spin the solvent, add water (50ml) to dissolve, acetic acid Extracted with ethyl ester (3x40ml), dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure and spin-dried column chromatography PE:EA=(8:1, 5:1, 3:1, 2:1, v/v), obtained Yellow solid intermediate b (yield about 50%).
将中间体b(1eq)用二氯甲烷(15ml)溶解在反应瓶中，在低温下滴加三氟乙酸(3eq)，加毕常温下反应一小时左右，TLC监测，反应完毕，停止反应，旋干反应液，加入少量水(30ml)溶解后，用饱和碳酸氢钠调至弱碱性(pH＝8)后，乙酸乙酯萃取(3×20ml)，浓缩有机相，加入少量薄层色谱硅胶粉，减压浓缩，经柱层析(纯DCM:CH3OH＝50:1，v/v)得中间体c，收率约为70％。Intermediate b (1eq) was dissolved in a reaction flask with dichloromethane (15ml), and trifluoroacetic acid (3eq) was added dropwise at low temperature, and reacted at normal temperature for about one hour after addition, monitored by TLC, the reaction was completed, and the reaction was stopped. Spin the reaction solution to dryness, add a small amount of water (30ml) to dissolve, adjust to weakly alkaline (pH=8) with saturated sodium bicarbonate, extract with ethyl acetate (3×20ml), concentrate the organic phase, add a small amount of TLC Silica gel powder was concentrated under reduced pressure, and intermediate c was obtained by column chromatography (pure DCM:CH3OH=50:1, v/v) with a yield of about 70%.
将中间体c(1eq)用乙醇和水(体积比3：1)总体积(12ml)溶解后加入氢氧化钠(3eq)，常温反应2小时后，停止反应。将反应液调至微酸性(pH＝6)，旋干，硅胶柱层析(DCM:CH3OH＝30:1，v/v)。得化合物70(收率60％)。Intermediate c (1eq) was dissolved in total volume (12ml) of ethanol and water (volume ratio 3:1) and then sodium hydroxide (3eq) was added. After 2 hours of reaction at room temperature, the reaction was stopped. The reaction solution was adjusted to slightly acidic (pH=6), spin-dried, and subjected to silica gel column chromatography (DCM:CH3OH=30:1, v/v). Compound 70 was obtained (60% yield).
化合物70：1H NMR(400MHz,DMSO-d6)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. 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.
实施例7、化合物35-38的合成Embodiment 7, the synthesis of compound 35-38
化合物35-38合成路线：
Compound 35-38 synthetic route:
R＝CH3,Br,CH3O,C(CH3)3 R=CH 3 , Br, CH 3 O, C(CH 3 ) 3
化合物35-38的合成Synthesis of Compounds 35-38
将原料对甲基苯乙醇(204mg,1.50mmol)、对溴苯乙醇(100mg,0.50mmol)、对甲氧基苯乙醇(200mg,1.31mmol)、对叔丁基苯乙醇(200mg,1.12mmol)分别放入反应瓶中，用二氯甲烷(15mL)溶解后分别加入Dess-Martin(764mg,1.80mmol)、(253mg,0.60mmol)、(669mg,1.58mmol)、(517mg,1.35mmol)，分别升温至40℃进行回流反应，2h后进行TLC点板检测，反应完全后旋干二氯甲烷，加入饱和硫代硫酸钠水溶液和乙酸乙酯进行萃取，萃取液浓缩经柱层析(PE→PE:EA＝30:1，v/v)分别得无色液体化合物a40mg(对甲基)，收率20％；淡黄色液体化合物b 47mg(对溴)，收率47％；无色液体化合物c 110mg(对甲氧基)，收率55.8％；以及无色液体化合物d 92mg(对叔丁基)，收率46.3％。The raw material p-methylphenylethanol (204mg, 1.50mmol), p-bromophenylethanol (100mg, 0.50mmol), p-methoxyphenylethanol (200mg, 1.31mmol), p-tert-butylphenylethanol (200mg, 1.12mmol) Put them into reaction flasks respectively, dissolve them with dichloromethane (15mL) and add Dess-Martin (764mg, 1.80mmol), (253mg, 0.60mmol), (669mg, 1.58mmol), (517mg, 1.35mmol), respectively, Raise the temperature to 40°C for reflux reaction. After 2 hours, conduct TLC spot plate detection. After the reaction is complete, spin dry dichloromethane, add saturated aqueous sodium thiosulfate solution and ethyl acetate for extraction, and concentrate the extract by column chromatography (PE→PE : EA=30:1, v/v) respectively get colorless liquid compound a40mg (to methyl), yield 20%; Pale yellow liquid compound b 47mg (to bromine), yield 47%; Colorless liquid compound c 110mg (p-methoxy), yield 55.8%; and colorless liquid compound d 92mg (p-tert-butyl), yield 46.3%.
将化合物a(350mg,2.61mmol)、b(100mg,0.50mmol)、c(110mg,0.73mmol)、d(200mg,1.10mmol)分别放入反应瓶中分别用无水乙醚(15mL)溶解后加入二氯乙酸甲酯(338μL,3.26mmol)、(65μL,0.63mmol)、(99μL,0.95mmol)、(150μL,1.50mmol)，0℃下预冷后分别缓慢滴加30％甲醇钠(497μL,3.59mmol)、(86μL,0.69mmol)、(152μL,1.10mmol)、(240μL,1.72mmol)，反应1h后移至常温反应3h后TLC检测，待反应完全后分别使用饱和氯化钠溶液和无水乙醚萃取，浓缩萃取液后分别加入甲醇(10mL)溶解，再分别加入硫脲(198mg,2.61mmol)、(38mg,0.50mmol)、c(56mg,0.73mmol)、(90mg,1.13mmol)，升温至65℃进行回流反应，3h后TLC检测，待反应完全后分别浓缩经柱层析(PE:EA＝5:1→PE:EA＝1:1，v/v)纯化，分别得到淡黄色固体化合物e 70mg(对甲基)，收率10.3％；淡黄色固体化合物f 120mg(对溴)，收率73.3％；淡黄色固体化合物g 131mg(对甲氧基)，收率68.1％和黄色粘稠液体化合物h 120mg(对叔丁基)，收率36.5％。Compounds a (350mg, 2.61mmol), b (100mg, 0.50mmol), c (110mg, 0.73mmol), and d (200mg, 1.10mmol) were put into the reaction flask respectively and dissolved in anhydrous ether (15mL) and then added Methyl dichloroacetate (338μL, 3.26mmol), (65μL, 0.63mmol), (99μL, 0.95mmol), (150μL, 1.50mmol), pre-cooled at 0°C and slowly added 30% sodium methoxide (497μL, 3.59mmol), (86μL, 0.69mmol), (152μL, 1.10mmol), (240μL, 1.72mmol), after 1 hour of reaction, move to room temperature for 3 hours of reaction, TLC detection, after the reaction is complete, use saturated sodium chloride solution and no Extract with water and ether, concentrate the extract, add methanol (10mL) to dissolve, then add thiourea (198mg, 2.61mmol), (38mg, 0.50mmol), c (56mg, 0.73mmol), (90mg, 1.13mmol), Raise the temperature to 65°C for reflux reaction, TLC detection after 3 hours, concentrate and purify by column chromatography (PE:EA=5:1→PE:EA=1:1, v/v) after the reaction is complete, respectively to obtain light yellow Solid compound e 70mg (p-methyl), yield 10.3%; light yellow solid compound f 120mg (p-bromine), yield 73.3%; light yellow solid compound g 131mg (p-methoxy), yield 68.1% and yellow Viscous liquid compound h 120mg (p-tert-butyl), yield 36.5%.
将化合物e(70mg,0.27mmol)、f(120mg,0.37mmol)、g(131mg,0.47mmol)、h(120mg,0.39mmol)用EtOH:H2O(6:3mL)溶解后，分别加入氢氧化钠(22mg,0.80mmol)、(44mg,1.11mmol)、(56mg,1.41mmol)、(47mg,1.17mmol)后升温至65℃进行回流反应，1h后进行TLC点板检测，反应完全后旋干乙 醇，使用2M HCl调节pH至7左右，析出白色固体，过滤后用二氯甲烷:甲醇＝20:1(v/v)洗出固体得到白色化合物35(28mg，收率42％)；白色固体化合物36(60mg,收率52％)；固体化合物38(55mg,收率44％)；固体化合物37(52mg,收率46％)。各化合物的结构如下所示：
Compounds e (70mg, 0.27mmol), f (120mg, 0.37mmol), g (131mg, 0.47mmol), h (120mg, 0.39mmol) were dissolved in EtOH:H 2 O (6:3mL), and hydrogen was added respectively Sodium oxide (22mg, 0.80mmol), (44mg, 1.11mmol), (56mg, 1.41mmol), (47mg, 1.17mmol) was heated to 65°C for reflux reaction, and TLC spot plate detection was performed after 1h. After the reaction was complete, spin Dry B Alcohol, using 2M HCl to adjust the pH to about 7, a white solid precipitated, and after filtration, the solid was washed out with dichloromethane:methanol=20:1 (v/v) to obtain white compound 35 (28 mg, yield 42%); white solid Compound 36 (60mg, yield 52%); solid compound 38 (55mg, yield 44%); solid compound 37 (52mg, yield 46%). The structure of each compound is shown below:
各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物35：1H NMR(400MHz,DMSO-d6)δ7.12(dd,J＝13.2Hz,J＝7.2Hz,4H),4.40(s,2H),2.25(s,3H)ppm.HRMS:m/z calcd for C12H12N2O2S[M-H]-247.0546,found 247.0560.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[MH] - 247.0546,found 247.0560.
化合物36：1H NMR(400MHz,DMSO-d6)δ7.46(d,J＝8Hz 2H),7.21(d,J＝8Hz,2H),6.94(s,2H),4.38(s,2H)ppm.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.
化合物37：1H NMR(400MHz,DMSO-d6)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 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.
化合物38：1H NMR(400MHz,DMSO-d6)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.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.
实施例8、化合物3、4、6、9、10、15、19、23、25、30、32、33和34的合成
Example 8, Synthesis of Compounds 3, 4, 6, 9, 10, 15, 19, 23, 25, 30, 32, 33 and 34
将中间体a(400mg,1.6mmol,1eq)溶解在次磷酸中，在冰浴下缓慢滴加亚硝酸钠(222.3mg,3.2mmol,2eq)的水溶液，加毕0℃下反应1小时后移至常温反应2小时后，停止反应，加水稀释，用碳酸氢钠调至弱碱后，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝8：1，6：1，4：1，2：1，v/v)得中间体b(230mg,收率58％)。Intermediate a (400mg, 1.6mmol, 1eq) was dissolved in hypophosphorous acid, and an aqueous solution of sodium nitrite (222.3mg, 3.2mmol, 2eq) was slowly added dropwise in an ice bath, and after the addition was completed, it was reacted at 0°C for 1 hour and then moved to After reacting at room temperature for 2 hours, stop the reaction, dilute with water, adjust to a weak base with sodium bicarbonate, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (PE:EA=8:1 , 6:1, 4:1, 2:1, v/v) to obtain intermediate b (230mg, yield 58%).
将中间体b(200mg,0.86mmol,1eq)用乙醇和水溶解后加入氢氧化钠 (103mg,2.57mmol,3eq),常温反应2小时后，停止反应。将反应液调至微酸性，旋干，硅胶柱层析(DCM:CH3OH＝50:1,30；1，v/v)。得化合物3(160mg,收率80％)。Dissolve intermediate b (200mg, 0.86mmol, 1eq) in ethanol and water and add sodium hydroxide (103mg, 2.57mmol, 3eq), after 2 hours of reaction at room temperature, stop the reaction. The reaction solution was adjusted to slightly acidic, spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=50:1,30; 1, v/v). Compound 3 (160 mg, yield 80%) was obtained.
化合物3：1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),8.91(s,1H),7.34-7.24(m,5H),4.57(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ163.91,152.10,149.05,142.51,140.28,129.15,128.99,127.25,32.78ppm.HRMS:m/z calcd for C11H9NO2S[M+H]+220.0427,found 220.0429；[M-H2O+H]+202.0327,found 202.0317.
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; [ MH2O +H] + 202.0327, found 202.0317.
将原料(200mg,0.76mmol,1eq)用乙腈溶解后，在0℃下滴加亚硝酸叔丁酯(452μl，3.8mmol,5eq)，反应20min后加入氯化铜(260mg,1.52mmol,2eq)，移至常温下反应，12小时后，停止反应，旋干乙腈，加水和乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝20：1，v/v)得中间体a(120mg,收率60％)。Dissolve the raw material (200mg, 0.76mmol, 1eq) in acetonitrile, add tert-butyl nitrite (452μl, 3.8mmol, 5eq) dropwise at 0°C, and add copper chloride (260mg, 1.52mmol, 2eq) after reacting for 20min , moved to normal temperature to react, after 12 hours, stop the reaction, spin dry acetonitrile, add water and ethyl acetate to extract, dry over anhydrous sodium sulfate, concentrate under reduced pressure, silica gel column chromatography (PE:EA=20:1, v/ v) Intermediate a (120 mg, yield 60%) was obtained.
将中间体a(100mg,0.36mmol,1eq)用乙醇和水溶解后加入氢氧化钠(43mg,1.06mmol,3eq)，常温反应2小时后，停止反应。将反应液调至微酸性，旋干，硅胶柱层析(DCM:CH3OH＝50:1,30:1,v/v)。得固体化合物9(73mg,收率73％)。Intermediate a (100mg, 0.36mmol, 1eq) was dissolved in ethanol and water, and sodium hydroxide (43mg, 1.06mmol, 3eq) was added to react at room temperature for 2 hours, then stop the reaction. The reaction solution was adjusted to slightly acidic, spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=50:1, 30:1, v/v). Solid compound 9 (73 mg, yield 73%) was obtained.
化合物9：1H NMR(400MHz,DMSO-d6)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 C12H10ClNO2S[M-H]-266.0048,found 266.0015.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[MH] - 266.0048,found 266.0015.
化合物4、6、19、23、25、30和32的合成方法同化合物3。Compounds 4, 6, 19, 23, 25, 30 and 32 were synthesized in the same way as compound 3.
化合物10、15、33和34的合成方法同化合物9。

Compounds 10, 15, 33 and 34 were synthesized in the same way as compound 9.

各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物4：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C12H11NO2S[M+H]+234.0583,found 234.0583；[M-H2O+H]+216.0483,found 216.0470；[M+Na]+256.0408,found 256.0401.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;[MH 2 O+H] + 216.0483,found 216.0470;[M+Na] + 256.0408,found 256.0401.
化合物6：1H NMR(400MHz,DMSO-d6)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.13C NMR(101MHz,DMSO-d6)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 C12H11NO2S[M+H]+234.0583,found 234.0599；[M-H2O+H]+216.0483,found 216.0477；[M+Na]+256.0408,found 256.0408.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; [MH 2 O+H] + 216.0483, found 216.0477; [M+Na] + 256.0408, found 256.0408.
化合物10：1H NMR(400.MHz,DMSO-d6)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 C12H10BrNO2S[M+H]+311.9688,found 311.9679,313.9659；[M-H2O+H]+293.9588,found 293.9570,295.9550.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=8.0 Hz,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; [MH 2 O+ H] + 293.9588, found 293.9570, 295.9550.
化合物15：HRMS:m/z calcd for C12H10INO2S[M+H]+359.9550,found359.9554；C12H10INO2S[M+H]+360.9583,found 360.9595；C12H10INO2S[M+Na]+381.9369,found 381.9363；C12H10INO2S[M+Na]+382.9403,found 3882.9408.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.
化合物19：1H NMR(400MHz,DMSO-d6)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 C10H6N2O4S[M-H]-248.9976,found 248.9973.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[MH] - 248.9976,found 248.9973.
化合物23：1H NMR(400MHz,CDCl3)δ8.81(s,1H),4.33(s,1H),1.25(d,J＝16.4,6H)ppm.HRMS:m/z calcd for C10H9NO2S[M+H]+172.0427,found 172.0432；[M-H2O+H]+154.0327,found 154.0323.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; [MH 2 O+H] + 154.0327, found 154.0323.
化合物25：LC-MS m/z:186.1[M+H]+.Compound 25: LC-MS m/z:186.1[M+H]+.
化合物30：1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),3.18(s,2H),1.86 (s,1H),0.88(s,6H)ppm.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.
化合物32：1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.52(s,1H)ppm.HRMS:m/z calcd for C4H3NO2S[M-H]-127.9812,found 127.9915,[M-H2O]-110.9778,found 110.9760.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[MH] - 127.9812 ,found 127.9915,[MH 2 O] - 110.9778,found 110.9760.
化合物33：1H NMR(400MHz,DMSO-d6)δ7.30-7.24(m,5H),4.61(s,2H)ppm.HRMS:m/z calcd for C11H8ClNO2S[M-H]-251.9892,found 251.9854.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[MH] - 251.9892, found 251.9854.
化合物34：1H NMR(400MHz,DMSO-d6)δ7.29-7.23(m,5H),4.62(s,2H)ppm.HRMS:m/z calcd for C11H8BrNO2S[M-H]-295.9386,found 295.9349,297.9327.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[MH] - 295.9386,found 295.9349,297.9327.
实施例9、化合物7、96、97、98的合成Embodiment 9, the synthesis of compound 7,96,97,98
合成路线：
synthetic route:
1、化合物7的合成
1. Synthesis of Compound 7
将2-氨基-5-溴甲酸乙酯(300mg,1.19mmol,1eq)用甲苯5ml溶解后，加入3-噻吩硼酸(456mg,3.58mmol,3eq)、碳酸铯(1.17g，3.58mmol,3eq)、Pd(pph3)4(138mg,0.119mmol,0.1eq),后升温至110℃回流反应5小时。停止反应，旋干甲苯，加水和乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝8：1，6：1，4：1，2：1，v/v)得中间体a(210mg,收率70％)。After dissolving ethyl 2-amino-5-bromoformate (300mg, 1.19mmol, 1eq) in 5ml of toluene, add 3-thiopheneboronic acid (456mg, 3.58mmol, 3eq), cesium carbonate (1.17g, 3.58mmol, 3eq) , Pd(pph 3 ) 4 (138mg, 0.119mmol, 0.1eq), and then heated to 110°C for 5 hours under reflux. Stop the reaction, spin dry toluene, add water and ethyl acetate to extract, dry over anhydrous sodium sulfate, concentrate under reduced pressure, perform silica gel column chromatography (PE:EA=8:1, 6:1, 4:1, 2:1, v /v) Intermediate a (210 mg, yield 70%) was obtained.
将中间体a(200mg,0.83mmol,1eq)用乙醇和水溶解后加入氢氧化钠(100mg,2.5mmol,3eq),常温反应2小时后，停止反应。将反应液调至微酸性，旋干，硅胶柱层析(DCM:CH3OH＝50:1,30:1,10:1，v/v)。得化合物7(40mg,收率20％)。Intermediate a (200mg, 0.83mmol, 1eq) was dissolved in ethanol and water, and sodium hydroxide (100mg, 2.5mmol, 3eq) was added to react at room temperature for 2 hours, then stop the reaction. The reaction solution was adjusted to slightly acidic, spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=50:1, 30:1, 10:1, v/v). Compound 7 (40 mg, yield 20%) was obtained.
化合物7：1H NMR(400MHz,DMSO-d6)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 C8H6N2O2S2[M+H]+226.9943,found 226.9945；[M-H2O+H]+208.9843,found 258.9767；[M+Na]+248.9768,found 258.9767.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; [MH 2 O+H] + 208.9843 , found 258.9767; [M+Na] + 248.9768, found 258.9767.
2、化合物96、97、98的合成 2. Synthesis of Compounds 96, 97, and 98
按照化合物7所述合成方法，将原料3-噻吩硼酸替换为苯硼酸制备得到化合物96，将原料3-噻吩硼酸替换为1-甲基-1H-吡唑-5-硼酸制备得到化合物97，将原料3-噻吩硼酸替换为2-呋喃硼酸制备得到化合物98。各化合物的结构如下所示：
According to the synthesis method described in compound 7, compound 96 was prepared by replacing the raw material 3-thiopheneboronic acid with phenylboronic acid, and compound 97 was prepared by replacing the raw material 3-thiopheneboronic acid with 1-methyl-1H-pyrazole-5-boronic acid. Compound 98 was prepared by replacing the starting material 3-thiopheneboronic acid with 2-furanboronic acid. The structure of each compound is shown below:
各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物96：1H NMR(400MHz,DMSO-d6)δ12.45(s br,1H),7.42-7.31(m,5H),7.18(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ166.05,164.08,137.47,131.89,131.55,129.77,128.57,128.24ppm.Compound 96: 1 H NMR (400MHz, DMSO-d 6 ) δ12.45(s br, 1H), 7.42-7.31(m, 5H), 7.18(s, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ166.05, 164.08, 137.47, 131.89, 131.55, 129.77, 128.57, 128.24ppm.
化合物97：1H NMR(400MHz,DMSO-d6)δ7.42-7.41(m,3H),6.31(d,J＝1.6Hz,2H)3.65(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ167.66,162.88,141.19,138.04,132.76,119.06,108.54,37.15ppm.Compound 97: 1 H NMR (400MHz, DMSO-d 6 ) δ7.42-7.41 (m, 3H), 6.31 (d, J=1.6Hz, 2H) 3.65 (s, 3H) ppm. 13 C NMR (101MHz, DMSO-d 6 )δ167.66, 162.88, 141.19, 138.04, 132.76, 119.06, 108.54, 37.15ppm.
化合物98：1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝1.6Hz,1H),7.28(s,2H),7.17(d,J＝2.8Hz,1H),6.56(q,J＝1.6Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ165.53,164.27,146.46,142.95,132.00,129.17,112.69,110.89,40.62,40.41,40.20,39.99,39.78,39.57,39.36ppm.Compound 98: 1 H NMR (400MHz, DMSO-d 6 ) δ7.66(d, J=1.6Hz, 1H), 7.28(s, 2H), 7.17(d, J=2.8Hz, 1H), 6.56(q ,J＝1.6Hz,1H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ165.53,164.27,146.46,142.95,132.00,129.17,112.69,110.89,40.62,40.41,40.20,39.99,39.78, 39.57,39.36 ppm.
实施例10、化合物8和16的合成
The synthesis of embodiment 10, compound 8 and 16
将钠片(69mh,2.9mmol,1.5eq)加入到乙醇中，待完全溶解后，加入2氨基5溴甲酸乙酯(500mg,1.99mmol,1eq)、对氯苯硫酚(230mg,1.6mmol,0.8eq)，移至80℃下反应两小时，停止反应，过滤，旋干滤液，用乙酸乙酯溶解后，硅胶柱层析(PE:EA＝7:1,5:1,3:1,1:1，v/v)得黄色固体中间体a(230mg,收率 46％)。Sodium tablets (69mh, 2.9mmol, 1.5eq) were added to ethanol, and after being completely dissolved, ethyl 2-amino-5-bromoformate (500mg, 1.99mmol, 1eq), p-chlorothiophenol (230mg, 1.6mmol, 0.8eq), moved to 80°C to react for two hours, stopped the reaction, filtered, spin-dried the filtrate, dissolved with ethyl acetate, and performed silica gel column chromatography (PE:EA=7:1,5:1,3:1, 1:1, v/v) to obtain yellow solid intermediate a (230mg, yield 46%).
将中间体a(120mg,0.38mmol,1eq)用乙醇和水溶解后加入氢氧化钠(46mg,1.14mmol,3eq),常温反应2小时后，停止反应。将反应液调至微酸性，旋干，硅胶柱层析(DCM:CH3OH＝50:1,30:1,10:1)。得红色固体化合物8(80mg,收率76％)。Intermediate a (120mg, 0.38mmol, 1eq) was dissolved in ethanol and water, and sodium hydroxide (46mg, 1.14mmol, 3eq) was added to react at room temperature for 2 hours, then stop the reaction. The reaction solution was adjusted to slightly acidic, spin-dried, and subjected to silica gel column chromatography (DCM:CH3OH=50:1, 30:1, 10:1). Red solid compound 8 (80 mg, yield 76%) was obtained.
化合物8：1H NMR(400MHz,DMSO-d6)δ7.45-7.38(m,6H)ppm.HRMS:m/z calcd for C10H7ClN2O2S2[M+H]+286.9710,found 286.9700；[M-H2O+H]+268.9610,found 268.9590.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; [MH 2 O+H] + 268.9610, found 268.9590.
将中间体a(200mg,0.64mmol,1eq)用干燥的二氯甲烷溶解后，在0℃下加入MCPBA(328mg,1.9mmol,3eq)，移至常温搅拌6小时后，停止反应，过滤，滤液硅胶柱层析(DCM:CH3OH＝40:1)，得淡黄色固体中间体b(130mg,收率65％)。Dissolve intermediate a (200mg, 0.64mmol, 1eq) in dry dichloromethane, add MCPBA (328mg, 1.9mmol, 3eq) at 0°C, move to room temperature and stir for 6 hours, stop the reaction, filter, and the filtrate Silica gel column chromatography (DCM:CH 3 OH=40:1) gave intermediate b (130mg, yield 65%) as light yellow solid.
将中间体b(100mg,0.29mmol,1eq)用乙醇和水溶解后加入氢氧化钠(35mg,0.87mmol,3eq),常温反应2小时后，停止反应。将反应液调至微酸性，旋干，硅胶柱层析(DCM:CH3OH＝50:1,30:1,v/v)。得黄色固体化合物16(37mg,收率37％)。Intermediate b (100mg, 0.29mmol, 1eq) was dissolved in ethanol and water, and sodium hydroxide (35mg, 0.87mmol, 3eq) was added to react at room temperature for 2 hours, then stop the reaction. The reaction solution was adjusted to slightly acidic, spin-dried, and subjected to silica gel column chromatography (DCM:CH 3 OH=50:1, 30:1, v/v). Compound 16 (37 mg, yield 37%) was obtained as a yellow solid.
化合物16：1H NMR(400MHz,DMSO-d6)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 C10H7ClN2O4S2[M+H]+318.9609,found 318.9607；[M-H2O+H]+300.9509,found 300.9509；[M+Na]+340.9433,found 340.9436.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; [MH 2 O+H] + 300.9509, found 300.9509; [M+Na ] + 340.9433, found 340.9436.
实施例11、化合物27、78、80、81的合成Embodiment 11, the synthesis of compound 27,78,80,81
合成路线：
synthetic route:
1、化合物27的合成
1. Synthesis of Compound 27
准确称取化合物2-氨基-5-(仲丁基)噻唑-4-羧酸甲酯26a(200mg，0.9mmol)溶于8ml干燥DCM中，冰浴下加入三乙胺(283mg，2.8mmol)、乙酰氯(110mg，1.4mmol)，加毕升温至室温反应，3h后TLC检测反应完全，停止反应，减压浓缩除去DCM，经柱层析纯化(PE：EA＝4：1)得灰 白色固体，即化合物2-乙酰氨基-5-(仲丁基)噻唑-4-羧酸甲酯27b(190mg，收率79.5％)。Accurately weigh the compound 2-amino-5-(sec-butyl)thiazole-4-carboxylate methyl ester 26a (200mg, 0.9mmol) and dissolve it in 8ml of dry DCM, add triethylamine (283mg, 2.8mmol) under ice-cooling , Acetyl chloride (110mg, 1.4mmol), after the addition, the temperature was raised to room temperature for reaction. After 3 hours, TLC detected that the reaction was complete, and the reaction was stopped. DCM was removed by concentration under reduced pressure, and purified by column chromatography (PE:EA=4:1) to obtain ash White solid, compound 2-acetamido-5-(sec-butyl)thiazole-4-carboxylic acid methyl ester 27b (190 mg, yield 79.5%).
以化合物2-乙酰氨基-5-(仲丁基)噻唑-4-羧酸甲酯27b为原料，参照酯水解的一般方法，经柱层析纯化(DCM:MeOH＝10:1)得白色固体，即化合物2-乙酰氨基-5-(仲丁基)噻唑-4-羧酸(化合物27，82mg，收率86.7％)。Using compound 2-acetamido-5-(sec-butyl)thiazole-4-carboxylate methyl ester 27b as raw material, referring to the general method of ester hydrolysis, purified by column chromatography (DCM:MeOH=10:1) to obtain a white solid , namely compound 2-acetylamino-5-(sec-butyl)thiazole-4-carboxylic acid (compound 27, 82 mg, yield 86.7%).
化合物27：HRMS:m/z calcd for C10H14N2O3S[M+H]+243.0798,found 243.0814；[M-H2O+H]+225.0698,found 225.0708；[M+Na]+265.0623,found 265.0622.Compound 27: HRMS: m/z calcd for C 10 H 14 N 2 O 3 S[M+H] + 243.0798, found 243.0814; [MH 2 O+H] + 225.0698, found 225.0708; [M+Na] + 265.0623 , found 265.0622.
2、化合物81的合成2. Synthesis of Compound 81
按照化合物27所述合成方法，将原料乙酰氯替换为苯甲酰氯且将原料2-氨基-5-(仲丁基)噻唑-4-羧酸甲酯7b替换为2-氨基-5-苯乙基噻唑-4-羧酸甲酯5a制备得到化合物81，各化合物的结构如下所示：
According to the synthesis method described in compound 27, the raw material acetyl chloride was replaced by benzoyl chloride and the raw material 2-amino-5-(sec-butyl)thiazole-4-carboxylic acid methyl ester 7b was replaced by 2-amino-5-phenyl ethyl Compound 81 was prepared from methyl thiazole-4-carboxylate 5a, and the structures of each compound were as follows:
各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物81：1H NMR(400MHz,DMSO-d6)δ12.82(s,2H),8.12-8.09(m,2H),7.64(tt,J＝7.2Hz,J＝1.2Hz,1H),7.56-7.52(m,2H),7.32-7.28(m,5H),3.45(t,J＝8.0Hz,2H),2.97(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ165.78,163.97,154.69,141.95,141.12,136.82,133.17,132.20,129.06,128.84,128.82,128.64,126.61,37.29,28.57ppm.Compound 81: 1 H NMR (400MHz, DMSO-d 6 ) δ12.82(s, 2H), 8.12-8.09(m, 2H), 7.64(tt, J=7.2Hz, J=1.2Hz, 1H), 7.56 -7.52 (m, 2H), 7.32-7.28 (m, 5H), 3.45 (t, J = 8.0Hz, 2H), 2.97 (t, J = 8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO- d 6 )δ165.78,163.97,154.69,141.95,141.12,136.82,133.17,132.20,129.06,128.84,128.82,128.64,126.61,37.29,28.57ppm.
3、化合物78、80的合成3. Synthesis of compounds 78 and 80
按照化合物27所述合成方法，将原料2-氨基-5-(仲丁基)噻唑-4-羧酸甲酯7b替换为2-氨基-5-苄基噻唑-4-羧酸甲酯1a制备得到化合物78，将原料2-氨基-5-(仲丁基)噻唑-4-羧酸甲酯7b替换为2-氨基-5-苯乙基噻唑-4-羧酸甲酯5a制备得到化合物80。各化合物的结构如下所示：
According to the synthesis method described in compound 27, the raw material 2-amino-5-(sec-butyl)thiazole-4-carboxylate methyl ester 7b was replaced by 2-amino-5-benzylthiazole-4-carboxylate methyl ester 1a to prepare To obtain compound 78, the raw material 2-amino-5-(sec-butyl)thiazole-4-carboxylic acid methyl ester 7b was replaced by 2-amino-5-phenethylthiazole-4-carboxylic acid methyl ester 5a to prepare compound 80 . The structure of each compound is shown below:
各化合物的表征数据如下所示：The characterization data of each compound are as follows:
化合物78：1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.33-7.21(m,5H),4.48(s,2H),2.10(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ169.26,164.19,154.71,141.06,140.49,129.05,128.94,128.74,127.04,32.37,22.81ppm.Compound 78: 1 H NMR (400MHz, DMSO-d 6 ) δ12.27(s, 1H), 7.33-7.21(m, 5H), 4.48(s, 2H), 2.10(s, 3H) ppm. 13 C NMR (101MHz,DMSO-d 6 )δ169.26,164.19,154.71,141.06,140.49,129.05,128.94,128.74,127.04,32.37,22.81ppm.
化合物80：1H NMR(400MHz,DMSO-d6)δ12.23(s,2H),7.30-7.17(m,5H),3.39(t,J＝8.0Hz,2H),2.91(t,J＝8.0Hz,2H),2.11(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ169.20,163.94,154.02,141.43,141.10,136.45,128.82,128.79,126.58,37.26,28.55,22.81ppm.Compound 80: 1 H NMR (400MHz, DMSO-d 6 ) δ12.23(s, 2H), 7.30-7.17(m, 5H), 3.39(t, J=8.0Hz, 2H), 2.91(t, J= 8.0Hz,2H),2.11(s,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ169.20,163.94,154.02,141.43,141.10,136.45,128.82,128.79,126.58,37.26,28.55,22. 81ppm.
实施例12、化合物31和82的合成The synthesis of embodiment 12, compound 31 and 82
合成路线
synthetic route
1、化合物31的合成
1. Synthesis of Compound 31
准确称取化合物2-氨基-5-异丁基噻唑-4-羧酸甲酯29a(200mg，0.93mmol)溶于8ml干燥二氯甲烷中，缓慢加入三乙胺(282mg，2.79mmol)后活化0.5h，活化完成后加入溴化苄(318mg，1.86mmol)反应过夜，TLC检测反应完全，减压浓缩除去溶剂，经柱层析(PE:EA＝10:1→PE:EA＝1:1，v/v)纯化，分别得到白色固体化合物b 169mg，收率60.3％。Accurately weigh compound 2-amino-5-isobutylthiazole-4-carboxylate methyl ester 29a (200mg, 0.93mmol) and dissolve it in 8ml of dry dichloromethane, slowly add triethylamine (282mg, 2.79mmol) to activate 0.5h, after activation was completed, benzyl bromide (318mg, 1.86mmol) was added to react overnight, TLC detected that the reaction was complete, concentrated under reduced pressure to remove the solvent, and column chromatography (PE:EA=10:1→PE:EA=1:1 , v/v) purification to obtain white solid compound b 169mg, yield 60.3%.
将化合物b(169mg,0.56mmol)用9mL乙醇和水混合溶剂(乙醇和水 体积比V＝2:1)溶解后，分别加入氢氧化钠(67.0mg,1.68mmol)后升温至65℃进行回流反应，1h后进行TLC点板检测，反应完全后旋干乙醇，使用2M HCl调节pH至7左右，析出白色固体，过滤后用二氯甲烷:甲醇＝20:1(v/v)洗出固体得到白色化合物31(90mg，收率65％)。Compound b (169mg, 0.56mmol) was mixed with 9mL ethanol and water solvent (ethanol and water After the volume ratio V=2:1) was dissolved, sodium hydroxide (67.0mg, 1.68mmol) was added and the temperature was raised to 65°C for reflux reaction. After 1h, TLC spot plate detection was performed. After the reaction was complete, the ethanol was spin-dried, and 2M HCl was used The pH was adjusted to about 7, and a white solid was precipitated. After filtration, the solid was washed out with dichloromethane:methanol=20:1 (v/v) to obtain white compound 31 (90 mg, yield 65%).
化合物31：1H NMR(400MHz,DMSO-d6)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 C15H18N2O2S[M+H]+291.1162,found 291.1152；[M-H2O+H]+273.1062,found 273.1054；[M+Na]+313.0987,found 313.0979.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; [MH 2 O+H] + 273.1062, found 273.1054; [ M+Na] + 313.0987, found 313.0979.
2、化合物82的合成2. Synthesis of Compound 82
按照化合物31所述合成方法，将原料2-氨基-5-异丁基噻唑-4-羧酸甲酯29a替换为2-氨基-5-苯乙基噻唑-4-羧酸甲酯5a制备得到化合物82。化合物的结构如下所示：
According to the synthesis method described in compound 31, the raw material 2-amino-5-isobutylthiazole-4-carboxylate methyl ester 29a was replaced by 2-amino-5-phenethylthiazole-4-carboxylate methyl ester 5a to obtain Compound 82. The structure of the compound is shown below:
化合物82的表征数据：1H NMR(400MHz,DMSO-d6)δ8.51(s,H),7.35-7.28(m,4H),7.25-7.11(m,6H),4.29(s,2H),3.34(t,J＝8.0Hz,2H),2.79(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ166.84,164.90,141.86,139.34,129.86,128.79,128.74,128.61,127.92,127.84,127.44,126.25,48.86,37.86,28.93ppm.Characterization data of compound 82: 1 H NMR (400MHz, DMSO-d 6 ) δ8.51(s, H), 7.35-7.28(m, 4H), 7.25-7.11(m, 6H), 4.29(s, 2H) ,3.34(t,J=8.0Hz,2H),2.79(t,J=8.0Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ166.84,164.90,141.86,139.34,129.86,128.79,128.74 ,128.61,127.92,127.84,127.44,126.25,48.86,37.86,28.93ppm.
实施例13、化合物77和79的合成Synthesis of Embodiment 13, Compounds 77 and 79
合成路线：
synthetic route:
1、化合物77的合成
1. Synthesis of compound 77
准确称取化合物2-氨基-5-苄基噻唑-4-羧酸甲酯1a(200mg，0.8mmol)溶于8ml干燥乙腈中，冰浴下缓慢加入亚硝酸叔丁酯(412mg，4.0mmol)，反应20分钟后加入水(29mg，1.6mmol)后移至常温反应12h，TLC检测反应完全，减压浓缩除去溶剂，经柱层析(PE:EA＝5:1→PE:EA＝1:2，v/v)纯化，分别得到淡黄色液体化合物b 150mg，收率80.1％。Accurately weigh compound 2-amino-5-benzylthiazole-4-carboxylate methyl ester 1a (200mg, 0.8mmol) and dissolve it in 8ml of dry acetonitrile, slowly add tert-butyl nitrite (412mg, 4.0mmol) under ice bath After 20 minutes of reaction, water (29mg, 1.6mmol) was added and moved to normal temperature for 12h. TLC detected that the reaction was complete, and concentrated under reduced pressure to remove the solvent. After column chromatography (PE:EA=5:1→PE:EA=1: 2, v/v) purification to obtain light yellow liquid compound b 150mg, yield 80.1%.
将化合物b(150mg,0.64mmol)用9mL乙醇和水混合溶剂(乙醇和水体积比V＝2:1)溶解后，分别加入氢氧化钠(76.8mg,1.92mmol)后升温至65℃进行回流反应，1h后进行TLC点板检测，反应完全后旋干乙醇，使用2M HCl调节pH至7左右，析出白色固体，过滤后用二氯甲烷:甲醇＝20:1(v/v)洗出固体得到白色化合物77(88mg，收率60％)。Compound b (150mg, 0.64mmol) was dissolved in 9mL of ethanol and water mixed solvent (volume ratio of ethanol and water V=2:1), and sodium hydroxide (76.8mg, 1.92mmol) was added respectively, and the temperature was raised to 65°C for reflux Reaction, TLC spot plate detection after 1h, after the reaction is complete, spin dry the ethanol, use 2M HCl to adjust the pH to about 7, a white solid precipitates, and wash out the solid with dichloromethane:methanol=20:1 (v/v) after filtration White compound 77 (88 mg, yield 60%) was obtained.
化合物77的表征数据：1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),8.91(s,1H),7.35-7.22(m,5H),4.57(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ163.90,152.04,148.87,142.65,140.30,129.13,128.98,127.23,32.78ppm.Characterization data of compound 77: 1 H NMR (400MHz, DMSO-d 6 ) δ13.05(s,1H),8.91(s,1H),7.35-7.22(m,5H),4.57(s,2H)ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ163.90, 152.04, 148.87, 142.65, 140.30, 129.13, 128.98, 127.23, 32.78ppm.
2、化合物79的合成2. Synthesis of compound 79
按照化合物77所述合成方法，将原料2-氨基-5-苄基噻唑-4-羧酸甲酯1a替换为2-氨基-5-苯乙基噻唑-4-羧酸甲酯5a制备得到化合物79。化合物的结构如下所示：
According to the synthesis method described in compound 77, the raw material 2-amino-5-benzylthiazole-4-carboxylate methyl ester 1a was replaced by 2-amino-5-phenethylthiazole-4-carboxylate methyl ester 5a to obtain the compound 79. The structure of the compound is shown below:
化合物79的表征数据：1H NMR(400.MHz,DMSO-d6)δ12.91(s br,1H),8.87(s,1H),7.30-7.18(m,5H),3.50(t,J＝8.0Hz,2H),2.94(t,J＝8.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ163.74,151.24,148.57,142.73,140.83,128.87,128.81,126.68,37.27,28.90ppm.Characterization data of compound 79: 1 H NMR (400.MHz, DMSO-d 6 ) δ12.91(s br,1H),8.87(s,1H),7.30-7.18(m,5H),3.50(t,J ＝8.0Hz, 2H), 2.94(t, J＝8.0Hz, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ163.74, 151.24, 148.57, 142.73, 140.83, 128.87, 128.81, 126.68, 37.27, 28.90 ppm.
本以下通过具体试验例证明本发明的有益效果。The beneficial effects of the present invention are demonstrated below through specific test examples.
试验例1、本发明化合物对MBL的抑制活性 Test example 1, the inhibitory activity of compound of the present invention to MBL
1、试验方法1. Test method
活性测试反应在黑色96孔酶标板中进行，总体系为60μL，具体操作步骤如下：The activity test reaction was carried out in a black 96-well microtiter plate, the total volume was 60 μL, and the specific operation steps were as follows:
(1)将待测化合物固体用DMSO配制成浓度为100mM的母液，用测试buffer(20mM Tris-HCl pH 7.5，200mM NaCl，0.01％Triton X-100)将母液稀释成3.6mM或600μM的工作液，再将工作液用测试buffer三倍稀释9个浓度梯度，得到10个不同浓度的工作液。(1) Prepare the solid compound to be tested into a mother solution with a concentration of 100mM in DMSO, and dilute the mother solution into a working solution of 3.6mM or 600μM with a test buffer (20mM Tris-HCl pH 7.5, 200mM NaCl, 0.01% Triton X-100) , and then dilute the working solution three-fold with the test buffer to 9 concentration gradients to obtain 10 working solutions with different concentrations.
(2)将MBL酶用测试buffer配成一定浓度的酶溶液(VIM-2、VIM-1和VIM-5：1.2nM；NDM-1：0.5nM；IMP-1：4.8nM)，将底物FC-5用测试buffer配成30μM的底物溶液以备用。(2) The MBL enzyme is formulated into a certain concentration of enzyme solution (VIM-2, VIM-1 and VIM-5: 1.2nM; NDM-1: 0.5nM; IMP-1: 4.8nM) with the test buffer, and the substrate FC-5 uses the test buffer to prepare a 30μM substrate solution for future use.
(3)在96孔酶标板中，每孔依次加入10μL步骤(1)得到的化合物工作液、30μL测试buffer以及10μL酶溶液，室温孵育10min。(3) In a 96-well ELISA plate, 10 μL of compound working solution obtained in step (1), 30 μL of test buffer and 10 μL of enzyme solution were sequentially added to each well, and incubated at room temperature for 10 min.
(4)于96孔酶标板中每孔加入10μL底物溶液，使用Tecan酶标仪连续检测6分钟内荧光值(λex＝380nm,λem＝460nm)变化。(4) Add 10 μL of substrate solution to each well of a 96-well microplate plate, and use a Tecan microplate reader to continuously detect the change in fluorescence value (λ ex =380nm, λ em =460nm) within 6 minutes.
每次实验均设置不加化合物的反应孔作为对照，并且所有测定均含三组平行实验。根据酶标仪测得的荧光强度的变化，计算每孔中酶的残余活性，计算公示为：残余活性(％)＝(ΔFI)/(ΔFC)×100，ΔFI为一定时间段内含化合物孔的荧光变化值，ΔFC为相同时间段内不加化合物的对照孔内荧光变化值。将处理后的数据用Graphpad Prism 5软件进行拟合，得到IC50值。In each experiment, a reaction well without compound was set as a control, and all determinations contained three sets of parallel experiments. According to the change of the fluorescence intensity measured by the microplate reader, the residual activity of the enzyme in each well is calculated, and the calculation is expressed as: residual activity (%)=(ΔF I )/(ΔF C )×100, and ΔF I is within a certain period of time Fluorescence change value of wells containing compounds, ΔF C is the fluorescence change value of control wells without compound within the same time period. The processed data were fitted with Graphpad Prism 5 software to obtain IC50 values.
2、试验结果2. Test results
表1.各化合物对MBL的抑制活性a



Table 1. The inhibitory activity of each compound on MBL a



a****：代表抑制活性好(IC50<1μM)；***：代表抑制活性中等(1μM<IC50<100μM)；**：代表抑制活性弱(IC50>100μM) a ****: good inhibitory activity (IC 50 <1μM); ***: medium inhibitory activity (1μM<IC 50 <100μM); **: weak inhibitory activity (IC 50 >100μM)
试验结果说明：本发明化合物对MBL有良好的抑制活性，特别是对多个MBL亚型，特别是对临床相关的VIM、NDM、IMP等亚型具有良好的抑制活性，其中化合物64最优。The test results show that the compounds of the present invention have good inhibitory activity on MBL, especially on multiple MBL subtypes, especially clinically relevant subtypes such as VIM, NDM, and IMP, among which compound 64 is the best.
试验例2、本发明化合物与美罗培南联用的抗菌活性Test Example 2: Antibacterial activity of the compound of the present invention combined with meropenem
1、试验方法1. Test method
(1)复苏菌株：从-80℃冰箱复苏菌株，用接种环划线于无抗性的MHA平板上，35℃培养18-20h。(1) Recover the strain: recover the strain from the -80°C refrigerator, streak it on a non-resistant MHA plate with an inoculation loop, and culture it at 35°C for 18-20h.
(2)药液稀释：称取美罗培南固体溶于DMSO配成12.8mg/ml的母液，将母液用CAMHB培养基稀释成512μg/mL的工作液。于透明96孔板中加入100μL CAMHB，再加入100μL美罗培南工作液，然后2倍稀释9个浓度，并设置不加美罗培南的生长对照孔。每孔加入2μL浓度为1mg/mL的化合物。(2) Dilution of drug solution: Weigh and dissolve meropenem solid in DMSO to prepare a 12.8 mg/ml mother solution, and dilute the mother solution with CAMHB medium to obtain a 512 μg/mL working solution. Add 100 μL CAMHB to a transparent 96-well plate, then add 100 μL meropenem working solution, then dilute 9 concentrations by 2 times, and set growth control wells without meropenem. Add 2 μL of compound at a concentration of 1 mg/mL per well.
(3)菌液稀释：用接种环从平板上挑单克隆于生理盐水中，调节OD630至0.08-0.13(相当于1×108CFU/mL)，将此菌液用CAMHB稀释100倍， 每孔加入100μL。此时美罗培南浓度分别为128μg/mL至0.25μg/mL，酶抑制剂的浓度为10μg/mL。(3) Bacterial solution dilution: Use an inoculation loop to pick a single clone from the plate and place it in normal saline, adjust the OD 630 to 0.08-0.13 (equivalent to 1×10 8 CFU/mL), and dilute the bacterial solution 100 times with CAMHB. Add 100 μL to each well. At this time, the concentration of meropenem was 128 μg/mL to 0.25 μg/mL, and the concentration of the enzyme inhibitor was 10 μg/mL.
(4)静置培养与结果判定：将96孔板放入35℃孵箱，静置培养16-20h。次日观察结果，以可以完全或明显抑制细菌生长的最小浓度为美罗培南的最低抑菌浓度(MIC)。(4) Static culture and result judgment: put the 96-well plate into a 35°C incubator, and culture it statically for 16-20 hours. The results were observed the next day, and the minimum inhibitory concentration (MIC) of meropenem was defined as the minimum concentration that could completely or significantly inhibit bacterial growth.
2、试验结果2. Test results
表2.各化合物与美罗培南联用对表达MBL的临床分离菌株的抗菌活性

Table 2. Antibacterial activity of each compound combined with meropenem against clinical isolates expressing MBL

上述试验结果说明：本发明化合物中，多数化合物与美罗培南联用对表达MBL的大肠杆菌与肺炎克雷伯菌等临床分离菌株具有良好的抗菌活性，如化合物1、2、21、54、64等。The above test results show that among the compounds of the present invention, most of the compounds in combination with meropenem have good antibacterial activity against clinically isolated strains such as E. coli expressing MBL and Klebsiella pneumoniae, such as compounds 1, 2, 21, 54, 64 wait.
综上，本发明化合物对金属β-内酰胺酶(MBL)有良好的抑制活性，特别是对多个临床相关MBL亚型，如对VIM、NDM、IMP等亚型具有良好的抑制活性，具有较强革兰氏阴性菌菌渗透性，可用于制备广谱MBL抑制剂，作为克服抗菌耐药的药物分子，具有良好的开发前景。 In summary, the compounds of the present invention have good inhibitory activity on metallo-β-lactamases (MBL), especially on multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, and IMP. It has strong gram-negative bacteria permeability, can be used to prepare broad-spectrum MBL inhibitors, and has good development prospects as a drug molecule for overcoming antibacterial drug resistance.

Claims (10)

  1. 式I所示化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药：
    The compound represented by formula I, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug:
    其中，in,
    R1选自氢、C1～C8烷基、卤素、羟基、羧基、氨基、硝基、-NHR1’；R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
    R1’选自被0～5个R3取代的C1～C8烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 5 R 3 , -C(O)R 3 ';
    R3分别独立选自5～10元芳基、5～10元杂芳基； R3 are independently selected from 5-10 membered aryl groups and 5-10 membered heteroaryl groups;
    R3’选自C1～C8烷基、5～10元芳基；R 3 ' is selected from C 1 -C 8 alkyl, 5-10 membered aryl;
    L选自无、被0～5个R4取代的C1～C8亚烷基、-S-、-O-、 L is selected from none, C 1 to C 8 alkylene substituted by 0 to 5 R 4 , -S-, -O-,
    R4分别独立选自C1～C8烷基；R 4 are independently selected from C 1 -C 8 alkyl groups;
    R2选自C1～C8烷基、C2～C8烯基、C2～C8炔基、被0～5个R5取代的5～10元芳基、被0～5个R5取代的3～10元杂芳基、被0～5个R5取代的3～10元杂环基、被0～5个R5取代的3～10元环烷基；R 2 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 5-10 membered aryl substituted by 0-5 R 5 , 0-5 R 5- substituted 3-10-membered heteroaryl, 3-10-membered heterocyclic group substituted by 0-5 R 5 , 3-10-membered cycloalkyl substituted by 0-5 R 5 ;
    R5分别独立选自被0～5个R6取代的C1～C8烷基、被0～5个R6取代的C1～C8烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～5个R6取代的5～10元芳基、被0～5个R6取代的5～10元杂芳基；R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-5 R 6 , C 1 -C 8 alkoxy substituted by 0-5 R 6 , halogen, carboxyl, nitro, amino, Hydroxyl, -C(O)R 7 , -C(O)OR 7 , 5-10-membered aryl substituted by 0-5 R 6 , 5-10-membered heteroaryl substituted by 0-5 R 6 ;
    R6分别独立选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C8炔基、C2～C8烯基、5～10元芳基；R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, 5-10 membered aryl ;
    R7选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、5～10元芳基、5～10元杂芳基；R 7 is selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, 5-10-membered aryl, 5-10-membered heteroaryl;
    当R1选自氨基，R2选自苯基时，L2不选自C1亚烷基；When R 1 is selected from amino, R 2 is selected from phenyl, L 2 is not selected from C 1 alkylene;
    当R1选自氢、R2选自苯基时，L2不选自C1亚烷基、1个C1烷基取代的C1亚烷基、C2亚烷基；When R 1 is selected from hydrogen and R 2 is selected from phenyl, L 2 is not selected from C 1 alkylene, 1 C 1 alkyl substituted C 1 alkylene, C 2 alkylene;
    当R1选自氨基，L选自无时，R2不选自噻吩基、C1～C5烷基；When R 1 is selected from amino, L is selected from none, R 2 is not selected from thienyl, C 1 ~ C 5 alkyl;
    当R1选自氨基，R2选自C1烷基时，L不选自C2～C4亚烷基、无、1个C1烷基取代的C2亚烷基、1个C1烷基取代的C1亚烷基； When R 1 is selected from amino, R 2 is selected from C 1 alkyl, L is not selected from C 2 ~ C 4 alkylene, none, 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 Alkyl substituted C alkylene ;
    当R1选自氢、R2选自C1烷基时，L不选自1个C1烷基取代的C2亚烷基、1个C1烷基取代的C1亚烷基；When R 1 is selected from hydrogen and R 2 is selected from C 1 alkyl, L is not selected from 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 alkyl substituted C 1 alkylene;
    当R1选自氨基，L选自C1亚烷基时，R不选自 When R 1 is selected from amino, L is selected from C 1 alkylene, R is not selected from
  2. 根据权利要求1所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：The compound according to claim 1, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug, is characterized in that:
    R1选自氢、C1～C8烷基、卤素、羟基、羧基、氨基、硝基、-NHR1’；R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
    R1’选自被0～3个R3取代的C1～C8烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 3 R 3 , -C(O)R 3 ';
    R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
    R3’选自C1～C8烷基、苯基；R 3 ' is selected from C 1 ~C 8 alkyl, phenyl;
    L选自无、被0～3个R4取代的C1～C8亚烷基、-S-、-O-、 L is selected from none, C 1 to C 8 alkylene substituted by 0 to 3 R 4 , -S-, -O-,
    R4分别独立选自C1～C8烷基；R 4 are independently selected from C 1 -C 8 alkyl groups;
    R2选自C1～C8烷基、C2～C8烯基、C2～C8炔基、被0～3个R5取代的苯基、被0～3个R5取代的噻吩基、被0～3个R5取代的呋喃基、被0～3个R5取代的吡唑基、被0～3个R5取代的哌啶基、被0～3个R5取代的氮杂环丁烷、被0～3个R5取代的萘基、被0～3个R5取代的被0～3个R5取代的 R 2 is selected from C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, phenyl substituted by 0 to 3 R 5 , thiophene substituted by 0 to 3 R 5 radical, furanyl substituted by 0 to 3 R 5 , pyrazolyl substituted by 0 to 3 R 5 , piperidinyl substituted by 0 to 3 R 5 , nitrogen substituted by 0 to 3 R 5 Heterocyclobutane, naphthyl substituted by 0 to 3 R 5 , substituted by 0 to 3 R 5 Replaced by 0 to 3 R 5
    R5分别独立选自被0～3个R6取代的C1～C8烷基、被0～3个R6取代的C1～C8烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～3个R6取代的苯基、被0～3个R6取代的吡啶基；R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-3 R 6 , C 1 -C 8 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 3 R 6 , pyridyl substituted by 0 to 3 R 6 ;
    R6分别独立选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C8炔基、C2～C8烯基、苯基；R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, phenyl;
    R7选自C1～C8烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  3. 根据权利要求2所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：The compound according to claim 2, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug, is characterized in that:
    R1选自氢、卤素、羟基、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
    R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’； R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
    R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
    R3’选自C1～C3烷基、苯基；R 3 ' is selected from C 1 -C 3 alkyl, phenyl;
    L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
    R4分别独立选自C1～C3烷基；R 4 are independently selected from C 1 -C 3 alkyl groups;
    R2选自C1～C7烷基、C2～C4烯基、C2～C4炔基、被0～2个R5取代的苯基、被0～1个R5取代的噻吩基、被0～1个R5取代的呋喃基、被0～1个R5取代的吡唑基、被0～1个R5取代的哌啶基、被0～1个R5取代的氮杂环丁烷、被0～1个R5取代的萘基、被0～1个R5取代的被0～1个R5取代的 R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
    R5分别独立选自被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
    R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
    R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  4. 根据权利要求1所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：所述化合物如式II所示：
    The compound according to claim 1, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II:
    其中，in,
    L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
    R4分别独立选自C1～C3烷基；R 4 are independently selected from C 1 -C 3 alkyl groups;
    R2选自C1～C7烷基、C2～C4烯基、C2～C4炔基、被0～2个R5取代的苯基、被0～1个R5取代的噻吩基、被0～1个R5取代的呋喃基、被0～1个R5取代的吡唑基、被0～1个R5取代的哌啶基、被0～1个R5取代的氮杂环丁烷、被0～1个R5取代的萘基、被0～1个R5取代的被0～1个R5取代的 R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
    R5分别独立选自被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
    R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
    R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  5. 根据权利要求1所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：所述化合物如式III所示：
    The compound according to claim 1, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula III:
    其中，in,
    R1选自氢、卤素、羟基、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
    R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
    R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
    R3’选自C1～C3烷基、苯基；R 3 ' is selected from C 1 -C 3 alkyl, phenyl;
    L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
    R4分别独立选自C1～C3烷基； R 4 are independently selected from C 1 -C 3 alkyl groups;
    R5a、R5b、R5c分别独立选自氢、被0～3个R6取代的C1～C4烷基、被0～3个R6取代的C1～C3烷氧基、卤素、羧基、硝基、氨基、羟基、-C(O)R7、-C(O)OR7、被0～1个R6取代的苯基、被0～1个R6取代的吡啶基；R 5a , R 5b , and R 5c are independently selected from hydrogen, C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen , carboxyl, nitro, amino, hydroxyl, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
    R6分别独立选自C1～C3烷基、卤素、羟基、羧基、氨基、硝基、氰基、C2～C4炔基、C2～C4烯基、苯基；R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
    R7选自C1～C4烷基、卤素、羟基、羧基、氨基、硝基、氰基、苯基、呋喃基。R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  6. 根据权利要求1所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：所述化合物如式IV所示：
    The compound according to claim 1, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula IV:
    其中，in,
    R1选自氢、卤素、氨基、-NHR1’；R 1 is selected from hydrogen, halogen, amino, -NHR 1 ';
    R1’选自被0～1个R3取代的C1～C3烷基、-C(O)R3’；R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
    R3分别独立选自苯基、吡啶基、噻吩基、吡唑基、呋喃基； R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
    R3’选自C1～C3烷基；R 3 'is selected from C 1 -C 3 alkyl;
    L选自无、被0～1个R4取代的C1～C6亚烷基、-S-、-O-、 L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
    R4分别独立选自C1～C3烷基。R 4 are each independently selected from C 1 -C 3 alkyl groups.
  7. 根据权利要求1～6任一项所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药，其特征在于：所述化合物为如下化合物之一：



    The compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug according to any one of claims 1 to 6, characterized in that: the compound is the following compound one:



  8. 权利要求1～7任一项所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药在制备MBL抑制剂和/或制备抗菌药物中的用途。The compound described in any one of claims 1 to 7, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitors and/or the preparation of antibacterial drugs the use of.
  9. 一种药物，其特征在于：它是由权利要求1～7任一项所述的化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。A kind of medicine, it is characterized in that: it is by the compound described in any one of claim 1～7, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug A preparation prepared by adding active ingredients and pharmaceutically acceptable excipients or auxiliary ingredients.
  10. 一种噻唑胺类化合物、或其盐、或其异构体、或其水合物、或其溶剂合物、或其前药在制备MBL抑制剂和/或制备抗菌药物中的用途，其特征在于：所述噻唑胺类化合物为如下化合物之一：
    A thiazole amine compound, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof is used in the preparation of an MBL inhibitor and/or the preparation of an antibacterial drug, characterized in that : the thiazole amine compound is one of the following compounds:
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3282927A (en) * 1964-05-21 1966-11-01 Bristol Myers Co 5-phenyl-4-thiazolylpenicillins
CN105658631A (en) * 2013-06-13 2016-06-08 安塔比奥公司 Antibacterial thiazolecarboxylic acids
WO2021252068A1 (en) * 2020-06-10 2021-12-16 Health Research, Inc. Compositions, methods of treating and preventing fungal infections, and methods of inhibiting prp8 intein expression
CN114230522A (en) * 2021-10-22 2022-03-25 四川大学 Imidazole-2-carboxylic acid metal beta-lactamase inhibitor and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3282927A (en) * 1964-05-21 1966-11-01 Bristol Myers Co 5-phenyl-4-thiazolylpenicillins
CN105658631A (en) * 2013-06-13 2016-06-08 安塔比奥公司 Antibacterial thiazolecarboxylic acids
WO2021252068A1 (en) * 2020-06-10 2021-12-16 Health Research, Inc. Compositions, methods of treating and preventing fungal infections, and methods of inhibiting prp8 intein expression
CN114230522A (en) * 2021-10-22 2022-03-25 四川大学 Imidazole-2-carboxylic acid metal beta-lactamase inhibitor and preparation method and application thereof

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
AN QIAOYU, LIU LEI, TANG ZONGYUAN, LUO HAN, LI YOU, XU MINGCHUAN, LI BAOSHENG: "Access to thiazoles via [3 + 2] cycloaddition of 1,2,3-thiadiazoles with isonitriles", ORGANIC CHEMISTRY FRONTIERS, vol. 8, no. 12, 14 June 2021 (2021-06-14), pages 2909 - 2913, XP093088173, DOI: 10.1039/D1QO00165E *
BADDI M, C. S. MAHAJANSHETTI: "ChemInform Abstract: Synthesis and Antimicrobial Activity of Some Ethyl 2-Amino/Acetamido-5- arylthiothiazole-4-carboxylates and Their Sulfones: An Attempted Synthesis of 2-Amino/Acetamido(1)benzothiopyrano(3,2-d)thiazole-9(H)- ones.", CHEMINFORM, vol. 27, no. 22, 28 May 1996 (1996-05-28), pages 1, XP093088164, DOI: 10.1002/chin.199622138 *
CUI, Y.M. HUANG, Q.Q. XU, J. CHEN, L.L. LI, J.Y. YE, Q.Z. LI, J. NAN, F.J.: "Identification of potent type I MetAP inhibitors by simple bioisosteric replacement. Part 1: Synthesis and preliminary SAR studies of thiazole-4-carboxylic acid thiazol-2-ylamide derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 15, no. 16, 15 August 2005 (2005-08-15), Amsterdam NL , pages 3732 - 3736, XP004985340, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2005.05.055 *
DATABASE REGISTRY STN ; ANONYMOUS : "4-Thiazolecarboxylic acid, 2-amino-5-(2-phenylethyl)-", XP093088145 *
DATABASE REGISTRY STN CAS; ANONYMOUS : "4-Thiazolecarboxylic acid, 2-(acetylamino)-5-(phenylmethyl)- ", XP093088113 *
DATABASE REGISTRY STN; ANONYMOUS : " 4-Thiazolecarboxylic acid, 2-amino-5-(2-furanyl)- (CA INDEX NAME)", XP093088150 *
DATABASE REGISTRY STN; ANONYMOUS : " 4-Thiazolecarboxylic acid, 2-amino-5-butyl- (CA INDEX NAME)", XP093088151 *
DATABASE REGISTRY STN; ANONYMOUS : "4-Thiazolecarboxylic acid, 2-(acetylamino)-5-(2-phenylethyl)- (CA INDEX NAME)", XP093088155 *
DATABASE REGISTRY STN; ANONYMOUS : "4-Thiazolecarboxylic acid, 2-amino-5-(phenylthio)- (CA INDEX NAME)", XP093088157 *
DATABASE REGISTRY STN; ANONYMOUS : "4-Thiazolecarboxylic acid, 2-amino-5-hexyl- (CA INDEX NAME)", XP093088153 *
EI-KERDAWY MOHAMED M, EL-EMAM 1' ALI A, EL-SUBBAGH HUSSEIN I, ABUSHANAB ELIE: "Synthesis of Substituted 4H-Thiazolo[4,5-b] [1]benzothiopyran-4-ones as Possible Schistosomicidal Agents", MONATSHEFTE FÜR CHEMIE - CHEMICAL MONTHLY ; AN INTERNATIONAL JOURNAL OF CHEMISTRY, SPRINGER-VERLAG, AU, vol. 120, 30 November 1989 (1989-11-30), AU , pages 991 - 995, XP093088069, ISSN: 1434-4475, DOI: 10.1007/BF00808770 *
LI RONG; SU HUILIN; CHEN WEI; YAN YU-HANG; ZHOU CONG; MOU LUOHE; YANG HUAN; QIAN SHAN; WANG ZHOUYU; YANG LINGLING; LI GUO-BO: "Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-β-Lactamase Inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 72, 5 September 2022 (2022-09-05), AMSTERDAM, NL, XP087181940, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2022.116993 *
QOSAY AL-BALAS, NAHOUM G. ANTHONY, BILAL AL-JAIDI, AMANI ALNIMR, GRAINNE ABBOTT, ALISTAIR K. BROWN, REBECCA C. TAYLOR, GURDYAL S. : "Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH", PLOS ONE, vol. 4, no. 5, pages e5617, XP055103698, DOI: 10.1371/journal.pone.0005617 *
SEAN CONROY ET AL.: "Synthesis and Evaluation of the First Fluorescent Antagonists of the Human P2Y2 Receptor Based on AR -C118925", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 7, 20 March 2018 (2018-03-20), pages 3089 - 3113, XP055666438, ISSN: 1520-4804, DOI: 10.1021/acs.jmedchem.8b00139 *

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