Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/025—Boronic and borinic acid compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/04—Esters of boric acids
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
  • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
• • 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
  • A61K31/69—Boron compounds
• • 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
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a new class of boronic acid compounds, in particular to a compound represented by formula (II) or (II'), a pharmaceutically acceptable salt or a stereoisomer thereof, and a compound thereof in the preparation of a compound for treating bacterial infection-related diseases. application in medicine.
• Beta-lactam antibiotics have saved countless lives since the British scientist Fleming first discovered penicillin in 1928. With the emergence of various ⁇ -lactamases, ⁇ -lactam antibiotics are increasingly losing their due activities, such as serine hydrolase ESBLs, KPCs, metallo- ⁇ -lactamases (MBLs) distribution ratio in various bacteria Increasingly high, the safety risk of bacteria to humans is also increasing. A class of compounds represented by phenylboronic acid has a significant inhibitory effect on metallo- ⁇ -lactamases (MBLs).
• the present invention provides a compound represented by formula (II) or (II') or a pharmaceutically acceptable salt thereof,
• B is boron
• T is -O-, -S- or -Se-;
• each R 1 is independently -OH or C 1-3 alkoxy
• R 2 and R 3 are each independently H or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 independently selected from F, Cl, Br, I, -OH and -OCH 3 substituents are substituted;
• R 4 is H, F, Cl, Br, I, C 1-3 alkyl or C 1-3 alkoxy, wherein each of said C 1-3 alkyl and C 1-3 alkoxy is independently optional substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH and -OCH;
• R 5 is H, F, Cl, Br, I or C 1-3 alkoxy
• R 6 is H, F, Cl, Br, I, -OR a or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 1, 2 or 3 independently selected from F, Cl, Br , I, -OH and -OCH 3 substituents are substituted;
• R 5 and R 6 together with the carbon atoms to which they are attached form a 5-6 membered oxygen-containing non-aryl heterocyclic ring, wherein the 5-6 membered oxygen-containing non-aryl heterocyclic ring is optionally replaced by 1, 2 or 3 Replaced by substituents independently selected from F, Cl , Br, I, -OH and -OCH;
• the group is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH and -OCH;
• R a is H, C 1-6 alkyl, wherein the C 1-6 alkyl, each independently optionally substituted with 1, 2 or 3 R a1 ;
• each R b is independently H or C 1-3 alkyl
• R c is H, C 1-3 alkyl, wherein the C 1-3 alkyl, each independently optionally substituted with 1, 2 or 3 R c1 ;
• Each R a1 is independently F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 alkoxy, each independently optionally substituted with 1, 2 or 3 R;
• each R c1 is independently F, Cl, Br, I, -OH, C 1-3 alkyl or C 1-3 alkoxy;
• Each R is independently F, Cl, Br, I, -OH or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 independently selected from F, Cl, Br, I and substituted by the substituents.
• the above-mentioned compound has the structure represented by formula (II-1), (II'-1), (II-2) or (II'-2):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the present invention.
• the above-mentioned compound has the structure represented by formula (I) or (I'):
• T, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
• the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
• B is boron
• T is -O-, -S- or -Se-;
• R 1 is -OH or C 1-3 alkoxy
• R 2 and R 3 are each independently H or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 independently selected from F, Cl, Br, I, -OH and -OCH 3 substituents are substituted;
• R 4 is H, F, Cl, Br or I
• R 5 is H, F, Cl, Br, I or C 1-3 alkoxy
• R 6 is H, F, Cl, Br, I, -OR a or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 1, 2 or 3 independently selected from F, Cl, Br , I, -OH and -OCH 3 substituents are substituted;
• R a is H or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally composed of 1, 2 or 3 independently selected from F, Cl, Br, I and substituted by the substituents.
• the above-mentioned compound has the structure represented by formula (I-1), (I'-1), (I-2) or (I'-2):
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
• the above-mentioned compound has the structure represented by formula (I-1) or (I-2):
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
• the above-mentioned pharmaceutically acceptable salt has the structure represented by formula (I-3), (I-4), (I-5) or (I-6):
• R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
• the above-mentioned pharmaceutically acceptable salt has the structure represented by formula (I-3) or (I-4):
• R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
• each of the above R 1 is independently -OH or -OCH 3 , and other variables are as defined in the present invention.
• R 1 is -OH or -OCH 3 , and other variables are as defined herein.
• R 2 and R 3 are each independently H or -CH 3 , and other variables are as defined herein.
• R 4 is H, F, Cl, -CH 3 or -OCH 2 CH 3 , and other variables are as defined in the present invention.
• R 5 is H, F, Cl or -OCH 3 , and other variables are as defined in the present invention.
• each of the above R is independently F, Cl, Br, I, -CH3 or wherein the -CH3 or each independently optionally by 1, 2 or 3 independently selected from F, Cl, Br, I and The substituents are substituted, and other variables are as defined in the present invention.
• each of the above R is independently F, Cl, Br, I, -CH 3 , Other variables are as defined in the present invention.
• each of the above R a1 is independently F, Cl, Br, I, -OCH 3 , wherein -OCH 3 , Each independently is optionally substituted with 1, 2 or 3 R, R and other variables as defined herein.
• each of the above R a1 is independently F, Cl, Br, I, -OCH 3 , R and other variables are as defined in the present invention.
• each of the above R a1 is independently F, Cl, Br, I, -OCH 3 ,
• R a is H, -CH 3 , -CH 2 CH 3 , wherein -CH 3 , -CH 2 CH 3 , Each is independently optionally substituted with 1, 2 or 3 R a1 , R a1 and other variables as defined herein.
• R a is H, -CH 3 , -CH 2 CH 3 , R a1 and other variables are as defined in the present invention.
• R a is H, -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
• R a is H, -CH 3 or -CH 2 CH 3 , wherein -CH 3 and -CH 2 CH 3 are optionally 1, 2 or 3 independently selected from F, Cl, Br, I and The substituents are substituted, and other variables are as defined in the present invention.
• R a is H, -CH 3 , -CF 3 , -CH 2 CH 3 or Other variables are as defined in the present invention.
• R 6 is H, F, Cl, Br, I, -OR a or -CH 3 , wherein the -CH 3 is optionally selected from 1, 2 or 3 independently from F, Substituents for Cl, Br, I, -OH and -OCH 3 , R a and other variables are as defined herein.
• R 6 is H, F, Cl, Br, I, -OH, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 OH, -CH 2 OCH 3 ,
• Other variables are as defined in the present invention.
• R 6 is H, F, Cl, Br, I, -OH, -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -CH3 or -CH2OH , other variables are as defined in the present invention.
• each of the above R b is independently H, and other variables are as defined in the present invention.
• each of the above R c1 is independently -OCH 3 , and other variables are as defined in the present invention.
• R c is H, -CH 3 , -CH 2 CH 3 , wherein -CH 3 , -CH 2 CH 3 , Each independently is optionally substituted with 1, 2 or 3 R c1 , R c1 and other variables as defined herein.
• R 7 is H
• Other variables are as defined in the present invention.
• the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
• the present invention also provides compounds of the following formula,
• the above pharmaceutically acceptable salt is the sodium salt.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, a ⁇ -lactam antibacterial agent and a pharmaceutically acceptable carrier.
• the above-mentioned ⁇ -lactam antibacterial agents are penicillins, cephalosporins, cephamycins, oxycephems, carbapenems or monocyclic lactams.
• the above-mentioned ⁇ -lactam antibacterial agent is amoxicillin, piperacillin, ticarcillin, azlocillin, mezlocillin, cefazolin, cefradine, cefotaxime, cefuroxime, ceftriaxone Clorox, cefotiam, cefprozil, cefotaxime, ceftriaxone, ceftazidime, cefoperazone, ceftizoxime, cefmenoxime, cefodizime, cefpodoxime axetil, cefixime, ceftibuten, cefotaxime Pirox, Cefepime, Cefoxitin, Cefmetazole, Panipenem, Aztreonam, Carrumonam, Cefoxitin, Cefmetazole, Lafeoxef, Fluoxef, Imipenem , meropenem, ceftloza, or cefdil.
• the present invention also provides the application of the above compound, its pharmaceutically acceptable salt or the above pharmaceutical composition in preparing a ⁇ -lactamase inhibitor medicine.
• the present invention also provides the application of the above compound, its pharmaceutically acceptable salt or the above pharmaceutical composition in the preparation of a medicament for treating bacterial infection-related diseases.
• the bacterial infection-related disease is caused by a bacterium expressing a beta-lactamase.
• the bacterial infection-related disease is caused by Klebsiella pneumoniae or Escherichia coli.
• the invention discloses a new class of boronic acid beta-lactamase inhibitors, which has strong antibacterial activity when used in combination with antibiotics, especially for various bacteria expressing beta-lactamase, and has good water solubility; whether it is administered orally or intravenously All drugs have good exposure, excellent pharmacokinetic properties; good safety; combined with antibiotics, can significantly restore the vitality of antibiotics, have good efficacy, and will be used to treat diseases related to bacterial infections.
• the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
• base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
• Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
• acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
• the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
• the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
• Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
• enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
• cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
• diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
• tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
• a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
• proton tautomers also called prototropic tautomers
• Valence tautomers include interconversions by recombination of some bonding electrons.
• keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
• the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
• the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
• isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
• Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
• a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
• the diastereoisomers were resolved and the pure enantiomers recovered.
• separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
• the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
• compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
• deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
• an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
• an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
• the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
• substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
• oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
• optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
• any variable eg, R
• its definition in each case is independent.
• the group may optionally be substituted with up to two Rs, with independent options for R in each case.
• combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
• linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
• substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
• the direction of attachment is arbitrary, for example,
• the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
• Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
• any one or more sites in the group can be linked to other groups by chemical bonds.
• connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
• the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
• a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
• the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
• the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
• B in the present invention represents boron
• C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
• the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
• Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
• C 2-8 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 8 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
• the C 2-8 alkenyl includes C 2-6 , C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; it may be monovalent, divalent or polyvalent.
• Examples of C2-8 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexamadienyl, and the like.
• C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
• the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
• C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
• C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
• the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
• Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
• 5-6 membered oxygen-containing non-aryl heterocycle refers to a ring containing the same or different 0 to 3 heteroatoms selected from the group consisting of O, N and S in addition to 1 O.
• the 5-6 membered oxygen-containing non-aryl heterocycles include 5-membered and 6-membered oxygen-containing non-aryl heterocycles and the like.
• the 5-6 membered oxygen-containing non-aryl heterocycle includes 5-6 membered heterocycloalkenyl. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
• Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
• leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
• a substitution reaction eg, a nucleophilic substitution reaction
• representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
• protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
• amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
• Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
• hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
• Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
• alkyl groups such as methyl, ethyl and tert-butyl
• acyl groups such as alkanoyl (eg acetyl)
• arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
• the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
• the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
• SXRD single crystal X-ray diffraction method
• the cultured single crystal is collected by Bruker D8 venture diffractometer
• the light source is CuK ⁇ radiation
• the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
• CH 2 Cl 2 stands for 1,1-bis(diphenyl) phosphino)ferrocene palladium(II) dichloromethane complex
• Pd( Pph3 )2Cl2 represents [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride
• LiHMDS stands for lithium hexamethyldisilazide
• LiAlH 4 stands for lithium tetrahydroaluminum.
• the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
• the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
• compound 1-5 (8.8g, 31.99mmol, 1eq), bispinacol boronate (12.19g, 47.99mmol, 1.5eq), 1,1-bis(diphenylphosphino)
• the ferrocene dichloride palladium(II) dichloromethane complex (5.23 g, 6.40 mmol, 0.2 eq) and potassium acetate (9.42 g, 95.98 mmol, 3 eq) were dissolved in dioxane (100 mL) and washed with N 2 was replaced 3 times, and then the mixed solution was stirred at 65°C for 5 hours.
• the reaction mixture was concentrated under reduced pressure to remove solvent.
• compound 7-4 (3.0 g, 11.93 mmol, 1 eq) was dissolved in TFA (40 mL), and acetone (2.08 g, 35.79 mmol, 2.63 mL, 3 eq), TFAA (7.52 g, 35.79 mmol) were added , 4.98 mL, 3 eq) and DMF (174.40 mg, 2.39 mmol, 183.58 ⁇ L, 0.2 eq). The mixed solution was stirred at 20°C for 0.5 hour. It was then heated to 105°C and stirred for an additional 32 hours.
• compound 10-2 (12.74 g, 54.21 mmol, 1 eq) was dissolved in TFA (100 mL), and acetone (9.45 g, 162.63 mmol, 11.96 mL, 3 eq), TFAA (34.16 g, 162.63 mmol) were added , 22.62 mL, 3 eq) and DMF (792.50 mg, 10.84 mmol, 834.21 ⁇ L, 0.2 eq). It was then stirred at 25°C for 1 hour. The temperature was then raised to 100°C and stirred for an additional 35 hours.
• compound 10-3 (1.78g, 6.47mmol, 1eq), bispinacol boronate (2.46g, 9.71mmol, 1.5eq), bistriphenylphosphine palladium dichloride (454.20 mg, 647.11 ⁇ mol, 0.1 eq), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (549.58 mg, 1.29 mmol, 0.2 eq) and potassium acetate (1.91 g, 19.41 mmol, 3 eq) was added to dioxane (40 mL) and replaced with N 2 three times, then the mixed solution was stirred at 55 °C for 5 h under nitrogen protection.
• compound 10-4 (2.03 g, 6.30 mmol, 1 eq) was dissolved in a mixed solution of THF (20 mL) and water (10 mL), and sodium perborate tetrahydrate (2.91 g, 18.91 mmol, 3.64 g) was added. mL, 3eq). The mixed solution was stirred at 25°C for 1 hour.
• 2-iodomethyl-boronic acid pinacol ester (631.32 mg, 2.36 mmol, 2 eq) and compound 10-5 (250 mg, 1.18 mmol, 1 eq) were dissolved in acetonitrile (5 mL) and added to the To the solution was added K2CO3 ( 244.27 mg, 1.77 mmol, 1.5 eq). It was then stirred for 4 hours at 65°C. To the mixed solution was added water (10 mL) and extracted with EA (10 mL ⁇ 3), the combined organic layers were washed with brine (20 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
• the reaction mixture was concentrated under reduced pressure to give a residue, which was quenched by addition to aqueous sodium bicarbonate solution (500 mL) at 0 °C, then extracted with ethyl acetate (200 mL x 1). The organic layer was washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue.
• 2-Iodomethyl-boronic acid pinacol ester (1.69 g, 6.32 mmol, 2 eq) and the crude products of compounds 11-6 and 12-1 (818 mg, 3.16 mmol, 1 eq) were mixed in acetonitrile (10 mL) at 25°C Under this, potassium carbonate (655.64 mg, 4.74 mmol, 1.5 eq) was added. The mixture was then stirred at 65°C for 4 hours.
• compound 13-6 (2.7 g, 8.85 mmol, 1 eq), bispinacol boronate (8.99 g, 35.40 mmol, 4 eq), bistriphenylphosphine palladium dichloride (621.15 mg) , 884.97 ⁇ mol, 0.1eq), potassium acetate (3.47g, 35.40mmol, 4eq), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (751.58mg, 1.77 mmol, 0.2 eq) were mixed in dioxane (30 mL), degassed and replaced with nitrogen 3 times, then the mixture was stirred at 65 °C for 5 h under nitrogen atmosphere.
• reaction mixture was filtered, then diluted with 40 mL of water, extracted with ethyl acetate 60 mL (30 mL ⁇ 2), washed with saturated brine (60 mL ⁇ 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
• LiHMDS (1M in THF, 363.82mL, 3eq) was dissolved in toluene (150mL) solution, cooled to -70°C, and compound 15-1 (17g, 121.27mmol, 17.65mL, 1eq) in toluene was added within 3 minutes (20 mL) solution, stirred for 0.5 h, then added a solution of 4-methylbenzenesulfonyl bromide (59.87 g, 254.67 mmol, 2.1 eq) in tetrahydrofuran (50 mL) over 0.5 h, added LiHMDS (1 M, 121.27 mL, 1 eq) , After the addition was completed, the temperature was slowly raised to 20 °C and stirred for 0.5 hours.
• Dioxane was added to a mixture of compound 21-2 (490mg, 1.63mmol, 1eq), double pinacol boronate (1.65g, 6.51mmol, 4eq), potassium acetate (479.08mg, 4.88mmol, 3eq) (2 mL), additional Pd(dppf)Cl 2 (265.76 mg, 325.44 ⁇ mol, 0.2 eq) was added, then degassed and replaced with nitrogen 3 times, then the mixture was stirred at 65° C. for 8 hours under nitrogen atmosphere. The residue was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2).
• LiAlH 4 (1.50 g, 39.52 mmol, 1.39 eq) was suspended in tetrahydrofuran (70 mL) solution, and 1-(2-trimethylsilylethoxymethyl)pyridine was added dropwise with stirring at 10-20 °C.
• Ethyl oxazole-4-carboxylate ie compound 35-2, 7.7 g, 28.48 mmol, 1 eq
• tetrahydrofuran (30 mL) and stirred at 20°C for 13 hours.
• lithium aluminum tetrahydride (1.15 g, 30.18 mmol, 1.1 eq) was added to tetrahydrofuran (50 mL), and a solution of compound 45-2 (5 g, 27.44 mmol, 1 eq) in tetrahydrofuran (20 mL) was slowly added dropwise, The mixture was stirred at 20°C for 1 hour.
• the reaction mixture was diluted with 10 mL of water and extracted with 10 mL of ethyl acetate, then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a partial crude product.
• the aqueous layer was then adjusted to pH ⁇ 5 with hydrochloric acid (1N), then extracted with 10 mL of ethyl acetate, the organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
• Compound 45-8 was obtained.
• the crude product was used in the next step without purification.
• the compound was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: water and acetonitrile containing 10 mmol/L ammonium bicarbonate; the proportion of acetonitrile in the mobile phase was from 7% to 37%, 8 min) 51.
• Compound 52-5 (200 mg, 584.58 ⁇ mol, 1 eq) was dissolved in isopropanol (2 mL), and sodium hydroxide (2 M, 584.58 ⁇ L, 2 eq) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 52 was purified by preparative HPLC (column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: water and acetonitrile containing 10 mM NH 4 HCO 3 , the ratio of acetonitrile in mobile phase was from 1% to 15%, 9 min).

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