WO2024061257A1 - Polycyclic n-heterocyclic ketone compound and use thereof - Google Patents

Polycyclic n-heterocyclic ketone compound and use thereof Download PDF

Info

Publication number
WO2024061257A1
WO2024061257A1 PCT/CN2023/119931 CN2023119931W WO2024061257A1 WO 2024061257 A1 WO2024061257 A1 WO 2024061257A1 CN 2023119931 W CN2023119931 W CN 2023119931W WO 2024061257 A1 WO2024061257 A1 WO 2024061257A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
add
pharmaceutically acceptable
acceptable salt
stereoisomer
Prior art date
Application number
PCT/CN2023/119931
Other languages
French (fr)
Chinese (zh)
Inventor
冯嘉杰
李鹏
江凯璇
聂伟
曹亚明
贺海鹰
黎健
陈曙辉
Original Assignee
吉斯凯(苏州)制药有限公司
重庆药友制药有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 吉斯凯(苏州)制药有限公司, 重庆药友制药有限责任公司 filed Critical 吉斯凯(苏州)制药有限公司
Publication of WO2024061257A1 publication Critical patent/WO2024061257A1/en

Links

Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a polycyclic nitrogen heterocyclic ketone compound and its application, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • Therapeutic agents for AIDS are mainly selected from a group of reverse transcriptase inhibitors (such as AZT, 3TC) and protease inhibitors (such as indinavir), but they have been shown to be associated with side effects such as kidney disease and the emergence of drug-resistant viruses. Therefore, people are eager to develop anti-HIV drugs with other mechanisms of action.
  • HIV integrase inhibitors are anti-HIV drugs with such a new mechanism of action.
  • the inventors discovered polycyclic azaheterocyclic ketone derivatives with effective HIV integrase inhibitory activity.
  • the present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from H, halogen, CN , OH, NH 2 , C 1-4 alkyl and C 1-4 alkoxy, each of which is Independently optionally substituted by 1, 2 or 3 R a ;
  • Each R a is independently selected from H, halogen, CN, OH, NH 2 and -COOH;
  • Each R 1a is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 H, halogen, CN, OH or NH 2 substituents;
  • Each R b is independently selected from H, halogen, CN, OH and NH 2 ;
  • Each R 3 is independently selected from H, halogen, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 R c ;
  • each R c is independently selected from H, halogen, CN, OH and NH 2 ;
  • L 1 is selected from -(C(R 1b ) 2 ) p - and C 3-5 cycloalkyl, the C 3-5 cycloalkyl is optionally substituted by 1, 2, 3 or 4 Rd;
  • each R 1b is selected from H, F, CI, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 substituents selected from H, F, CI, Br, I, OH and NH 2 ;
  • Each Rd is independently selected from H, halogen, CN, OH and NH 2 ;
  • T1 is selected from CH, N, O and S;
  • T 2 is selected from CH and N;
  • n, q are independently selected from 0, 1, 2, 3 and 4;
  • p is selected from 1 and 2;
  • Ring A is selected from 3-10 membered heterocycloalkyl
  • Ring B is selected from 5-6 membered heteroaryl
  • the 3-10-membered heterocycloalkyl group and the 5-6-membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms or heteroatom groups that are independently selected from N, O, S and NH.
  • each of the above R 1 is independently selected from H, C 1-4 alkyl and C 1-4 alkoxy, and the C 1-4 alkyl and C 1-4 alkoxy are each independently selected. is optionally replaced by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
  • each of the above R 1 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R a , R a and other variables As defined herein.
  • each of the above R 1 is independently selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 3 , the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) CH 2 CH 3 and -C(CH 3 ) 2 CH 3 are optionally substituted by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(OCH 3 )-, -C(OCH 3 ) 2 - and Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from 3-8 membered heterocycloalkyl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • T 1 , R 1 , R 3 , m, q and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IA):
  • T 1 is selected from CH and N;
  • R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, its compound has the formula (I-1), (I-2), (I-3) or (I-4 ) shows the structure:
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention.
  • T 1 is selected from CH and N;
  • T 3 is selected from CH and N;
  • T 4 is selected from N and CH;
  • T5 is selected from CH2 , NH, O and S.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IB):
  • T 1 is selected from O and S;
  • R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (I-5):
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention
  • T 1 is selected from O and S;
  • T6 is selected from CH and N.
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts have the formulas (I-1A), (I-1B), (I-1C), (I-1D ), (I-2A), (I-3A), (I-4A) and (I-5A):
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention.
  • the present invention also provides the following compounds, their stereoisomers or their pharmaceutically acceptable salts:
  • the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:
  • the present invention further provides a pharmaceutical composition, which contains an effective therapeutic dose of a compound of the present invention or a pharmaceutically acceptable salt thereof; which optionally further includes pharmaceutically acceptable excipients, auxiliaries or carriers.
  • this application also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing and/or treating HIV infection.
  • the compound of the present invention has a significant inhibitory effect on HIV integrase activity, and at the same time inhibits HIV pseudovirus or mutant strain pseudovirus at the cellular level. It has shown positive effects in viral gene replication experiments and has good pharmacokinetic properties.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure 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 the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • 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, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. 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 isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key and straight dotted keys
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton transfer tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enamine Isomerization.
  • Valence tautomers involve interconversion through the reorganization of some bonding electrons.
  • keto-enol tautomerization is pentane-2,4-dione and Interconversion between two tautomers of 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or 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 as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • one enantiomer of a compound of the present invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a basic functional group such as an amino group
  • an acidic functional group such as a carboxyl group
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • separation of enantiomers and diastereomers is often accomplished by the use of chromatography employing a chiral stationary phase, optionally coupled with chemical derivatization (eg, formation of carbamates from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or C-14 (14C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs.
  • the bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon.
  • deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All isotopic compositions of the compounds of the invention Transformations, whether radioactive or not, are included within the scope of the invention.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-4 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 2-3 and C 3-4 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-4 alkoxy means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-2 , C 2-3 , C 3-4 , C 4 , C 3 , C 2 alkoxy group, etc.
  • Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkyl is used to mean 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , and C 3 , C 2 alkoxy group, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • C3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a single ring system, and the C3-5 cycloalkyl group includes C3-4 and C4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p,p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-8-membered heterocycloalkyl group includes 3-6-membered, 3-5-membered, 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc.
  • 3-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidiny
  • 5-6 membered heteroaryl in the present invention can be used interchangeably.
  • the term “5-6 membered heteroaryl” refers to a single ring composed of 5 to 6 ring atoms and having a conjugated ⁇ electron system.
  • a ring group in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl , 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4 -Triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl,
  • 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 listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, 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 involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent amount; M represents mol/L; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO Represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; r.t. represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; ACN stands for acetonitrile; mp stands for melting point.
  • the reagent 2,4-difluorobenzylamine (708.73 mg, 4.95 mmol, 3 eq) was added, and the reaction was carried out at 80°C for 16 hours.
  • Water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL ⁇ 3) was added for extraction.
  • the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Dissolve 6a (0.37g, 851.76 ⁇ mol) in acetic acid (4mL), add methanesulfonic acid (24.56mg, 255.53 ⁇ mol, 18.19 ⁇ L), and stir at 65°C for 48 hours.
  • the reaction solution was concentrated to obtain crude product 6b.
  • Dissolve 6b in 1,2-dichloroethane (4 mL) add L-aminopropanol (23.80 mg, 316.89 ⁇ mol, 24.66 ⁇ L), and heat the oil bath to 90°C and stir for 24 hours.
  • Dissolve 6d (40 mg, 89.32 ⁇ mol) in tetrahydrofuran (1 mL), add sodium hydroxide (17.86 mg, 446.61 ⁇ mol), and stir at 60°C for 12 hours. Take the Erlenmeyer flask, add 20 mL of water, pour the reaction solution, and then extract with 20 mL of methylene chloride. The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methanol (1 mL) and filtered to obtain 6.
  • Dissolve 7a (1g, 6.33mmol) in acetonitrile (10mL), add anhydrous potassium carbonate (961.57mg, 6.96mmol) and dimethyl sulfate (877.56mg, 6.96mmol, 659.82 ⁇ L), and stir at 25°C for 12 hours.
  • anhydrous potassium carbonate 961.57mg, 6.96mmol
  • dimethyl sulfate 877.56mg, 6.96mmol, 659.82 ⁇ L
  • Dissolve 7e (0.2g, 430.65 ⁇ mol) in acetic acid (5mL), add methanesulfonic acid (12.42mg, 129.19 ⁇ mol, 9.20 ⁇ L), stir at 65°C for 12 hours, and concentrate the reaction solution to obtain crude 7f.
  • Dissolve 7f in 1,2-dichloroethane (2 mL) add L-aminopropanol (52.11 mg, 693.84 ⁇ mol, 54.00 ⁇ L), and heat the oil bath to 90°C and stir for 12 hours.
  • Dissolve 7g (0.1g, 225.53 ⁇ mol) in acetonitrile (2mL), add trichloroisocyanuric acid (25.16mg, 108.25 ⁇ mol) and 1,4-diazabicyclo[2,2,2]octane ( 1.26 mg, 11.28 ⁇ mol, 1.24 ⁇ L), heat the oil bath to 40°C and stir for 2 hours.
  • trichloroisocyanuric acid 25.16mg, 108.25 ⁇ mol
  • 1,4-diazabicyclo[2,2,2]octane 1.26 mg, 11.28 ⁇ mol, 1.24 ⁇ L
  • reaction solution Cool the reaction solution to room temperature, then add 20 mL of water in a conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine and dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the residue. things.
  • Dissolve 8c (33 mg, 67.09 ⁇ mol) in anhydrous tetrahydrofuran (1 mL), add sodium hydroxide (13.42 mg, 335.47 ⁇ mol), and stir at 60°C for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Dissolve 9a 80 mg, 167.42 ⁇ mol in anhydrous tetrahydrofuran (3 mL), add sodium hydroxide (33.48 mg, 837.09 ⁇ mol), and heat the oil bath to 60°C and stir for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • the crude product was purified by silica gel column chromatography to obtain compound 10f.
  • reaction solution take a conical flask, add 50 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product.
  • the crude product was purified by silica gel column to obtain 10 g of compound.
  • reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL ⁇ 2), and the organic phase was extracted with saturated sodium chloride solution (20 mL ⁇ 2), then dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed. Concentrate to obtain crude product.
  • the antiviral activity of the compounds against HIV pseudovirus was evaluated by determining the half effective concentration (EC 50 ) value of the compounds. HIV pseudovirus reporter gene experiments are widely used in early screening, replacing HIV virus experiments to evaluate the anti-HIV activity of compounds.
  • 293T cells were seeded into a 96-well test plate at a density of 55,000 cells per well and 100 ⁇ L per well, and cultured overnight in a 37°C incubator with 5% CO 2 .
  • the next day add the diluted compound (8 concentration points, double wells), 50 ⁇ L per well. Then the diluted virus was added to the cells at 100 TCID50 per well, 50 ⁇ L per well.
  • Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (culture medium only).
  • the final volume of the experimental culture medium was 200 ⁇ L, and the final concentration of DMSO in the culture medium was 0.5%. Cells were cultured in a 5% CO 2 , 37°C incubator for 3 days.
  • the luciferase reporter gene detection reagent Britelite plus kit (PerkinElmer) was used to detect the luciferase activity in each well of the test plate, and the data was used for antiviral activity analysis of the samples.
  • Cell viability detection reagent CellTiter Glo was used, and a BioTek microplate reader was used to detect cell viability in each well, and the data were used for sample cytotoxicity analysis.
  • Antiviral activity (%) (EC 50 test well reading value - average value of virus control) / (average value of cell control - average value of virus control) ⁇ 100
  • the EC 50 value uses GraphPad Prism (version 5) software to conduct nonlinear fitting analysis of the antibody's inhibitory activity and cell viability.
  • the fitting method is "log(inhibitor) vs. response--Variable slope”.
  • the inhibitory activity of the compounds of the present invention against HIV pseudovirus is shown in Table 1.
  • the compounds of the present invention show positive effects in the test of inhibiting HIV pseudovirus gene replication at the cellular level.
  • the clear solution of the test compound was injected into SD rats (overnight fasting, 7-10 weeks old) through the tail vein, and the test compound was administered orally to SD rats (overnight fasting, 7-10 weeks old).
  • About 200 ⁇ L of blood was collected from the jugular vein or tail vein of the animals at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and placed in anticoagulant tubes with EDTA-K2 added, 4°C, 3200g Centrifuge for 10 minutes to collect plasma.
  • the LC-MS/MS method was used to determine the blood drug concentration, and the PhoenixWinNonlin6.3 pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters using the non-compartmental model open linear logarithmic trapezoidal method.
  • Table 2 The experimental results are shown in Table 2.

Abstract

Disclosed are a polycyclic N-heterocyclic ketone compound and use thereof, and specifically disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

多环氮杂环酮类化合物及其应用Polycyclic nitrogen heterocyclic ketone compounds and their applications
本申请要求于2022年09月20日提交中国专利局、申请号为202211146951.0、发明名称为“多环氮杂环酮类化合物及其应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims priority to the Chinese patent application submitted to the China Patent Office on September 20, 2022, with the application number 202211146951.0 and the invention name "Polycyclic nitrogen heterocyclic ketone compounds and their applications", the entire content of which is incorporated by reference. in this application.
技术领域Technical field
本发明涉及一种多环氮杂环酮类化合物及其应用，具体涉及式(I)所示化合物或其药学上可接受的盐。The present invention relates to a polycyclic nitrogen heterocyclic ketone compound and its application, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
背景技术Background technique
在病毒中，已知人免疫缺陷病毒(HIV)，一种逆转录病毒，引起获得性免疫缺陷综合征(AIDS)。用于AIDS的治疗剂主要选自一组逆转录酶抑制剂(如AZT、3TC)和蛋白酶抑制剂(如茚地那韦)，但它们被证实伴有副作用如肾病和出现抗药性病毒。因此，人们渴望开发具有其它作用机制的抗HIV药物。Among viruses, human immunodeficiency virus (HIV), a retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). Therapeutic agents for AIDS are mainly selected from a group of reverse transcriptase inhibitors (such as AZT, 3TC) and protease inhibitors (such as indinavir), but they have been shown to be associated with side effects such as kidney disease and the emergence of drug-resistant viruses. Therefore, people are eager to develop anti-HIV drugs with other mechanisms of action.
另一方面，由于耐药突变体的频繁出现，有报道表明联合疗法可有效治疗AIDS，逆转录酶抑制剂和蛋白酶抑制剂已在临床上用作抗-HIV药物。然而具有相同作用机制的药物常常显示交叉抗药性或者仅具有附加的活性，因此基于以上情况，抗HIV药物的开发集中在新的作用机制上。HIV整合酶抑制剂为具有这样的新作用机制的抗HIV药物，本发明人经大量研究发现具有有效HIV整合酶抑制活性的多环氮杂环酮类衍生物。On the other hand, due to the frequent emergence of drug-resistant mutants, there are reports that combination therapy is effective in treating AIDS, and reverse transcriptase inhibitors and protease inhibitors have been used clinically as anti-HIV drugs. However, drugs with the same mechanism of action often show cross-resistance or only have additive activity. Therefore, based on the above situation, the development of anti-HIV drugs focuses on new mechanisms of action. HIV integrase inhibitors are anti-HIV drugs with such a new mechanism of action. After extensive research, the inventors discovered polycyclic azaheterocyclic ketone derivatives with effective HIV integrase inhibitory activity.
发明内容Summary of the invention
本发明提供式(I)所示化合物、其立体异构体或其药学上可接受的盐，
The present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，是单键或者双键；in, Is it a single bond or a double bond;
各R1独立地选自H、卤素、CN、OH、NH2、C1-4烷基和C1-4烷氧基，所述C1-4烷基和C1-4烷氧基各自独立地任选被1、2或3个Ra取代；Each R 1 is independently selected from H, halogen, CN , OH, NH 2 , C 1-4 alkyl and C 1-4 alkoxy, each of which is Independently optionally substituted by 1, 2 or 3 R a ;
各Ra独立地选自H、卤素、CN、OH、NH2和-COOH；Each R a is independently selected from H, halogen, CN, OH, NH 2 and -COOH;
各R2独立地选自H、卤素、CN、OH、NH2、-C(＝O)N(R1a)2、-S(＝O)2N(R1a)2、-N(R1a)C(＝O)N(R1a)2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基各自独立地任选被1、2或3个Rb取代； Each R 2 is independently selected from H, halogen, CN, OH, NH 2 , -C(=O)N(R 1a ) 2 , -S(=O) 2 N(R 1a ) 2 , -N(R 1a )C(=O)N(R 1a ) 2 , C 1-3 alkyl and C 1-3 alkoxy, each of the C 1-3 alkyl and C 1-3 alkoxy is independently optionally 1, 2 or 3 R b substitutions;
各R1a独立地选自H、C1-3烷基和C1-3烷氧基，其中，所述C1-3烷基和C1-3烷氧基任选被1、2或3个H、卤素、CN、OH或NH2取代基；Each R 1a is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 H, halogen, CN, OH or NH 2 substituents;
各Rb独立地选自H、卤素、CN、OH和NH2；Each R b is independently selected from H, halogen, CN, OH and NH 2 ;
各R3独立地选自H、卤素、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 R c ;
各Rc独立地选自H、卤素、CN、OH和NH2；each R c is independently selected from H, halogen, CN, OH and NH 2 ;
L1选自-(C(R1b)2)p-和C3-5环烷基，所述C3-5环烷基任选被1、2、3或4个Rd取代；L 1 is selected from -(C(R 1b ) 2 ) p - and C 3-5 cycloalkyl, the C 3-5 cycloalkyl is optionally substituted by 1, 2, 3 or 4 Rd;
各R1b选自H、F、CI、Br、I、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个选自H、F、CI、Br、I、OH和NH2的取代基取代；each R 1b is selected from H, F, CI, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 substituents selected from H, F, CI, Br, I, OH and NH 2 ;
各Rd独立地选自H、卤素、CN、OH和NH2；Each Rd is independently selected from H, halogen, CN, OH and NH 2 ;
T1选自CH、N、O和S； T1 is selected from CH, N, O and S;
T2选自CH和N；T 2 is selected from CH and N;
m、n和q分别独立地选自0、1、2、3和4；m, n and q are independently selected from 0, 1, 2, 3 and 4;
p选自1和2；p is selected from 1 and 2;
环A选自3-10元杂环烷基；Ring A is selected from 3-10 membered heterocycloalkyl;
环B选自5-6元杂芳基；Ring B is selected from 5-6 membered heteroaryl;
所述3-10元杂环烷基和5-6元杂芳基分别独立地包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团。The 3-10-membered heterocycloalkyl group and the 5-6-membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms or heteroatom groups that are independently selected from N, O, S and NH.
本发明的一些方案中，上述各R1独立地选自H、C1-4烷基和C1-4烷氧基，所述C1-4烷基和C1-4烷氧基各自独立地任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the present invention, each of the above R 1 is independently selected from H, C 1-4 alkyl and C 1-4 alkoxy, and the C 1-4 alkyl and C 1-4 alkoxy are each independently selected. is optionally replaced by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
本发明的一些方案中，上述各R1独立地选自H和C1-4烷基，所述C1-4烷基任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some embodiments of the present invention, each of the above R 1 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R a , R a and other variables As defined herein.
本发明的一些方案中，上述各R1独立地选自H、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)CH2CH3、-C(CH3)2CH3，所述-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)CH2CH3、-C(CH3)2CH3任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the invention, each of the above R 1 is independently selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 3 , the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) CH 2 CH 3 and -C(CH 3 ) 2 CH 3 are optionally substituted by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
本发明的一些方案中，上述各R2独立地选自H、F、Cl、Br、I、CN、-C(＝O)NH2、-S(＝O)2NH2、-NHC(＝O)NH和C1-3烷氧基，所述C1-3烷氧基独立地任选被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some aspects of the present invention, each of the above R 2 is independently selected from H, F, Cl, Br, I, CN, -C(=O)NH 2 , -S(=O) 2 NH 2 , -NHC(= O) NH and C 1-3 alkoxy group, the C 1-3 alkoxy group is independently optionally substituted by 1, 2 or 3 R b , R b and other variables are as defined in the present invention.
本发明的一些方案中，上述各R2独立地选自H、F、Cl、CN、-C(＝O)NH2、-S(＝O)2NH2、-NHC(＝O)NH2、 -OCH3、-OCH2CH3和-OCH2CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, each of the above R 2 is independently selected from H, F, Cl, CN, -C(=O)NH 2 , -S(=O) 2 NH 2 , -NHC(=O)NH 2 , -OCH 3 , -OCH 2 CH 3 and -OCH 2 CH 2 CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述L1选自-CH2-、-CH(CH3)-、-C(CH3)2-、-CH(OCH3)-、-C(OCH3)2-和其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned L 1 is selected from -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(OCH 3 )-, -C(OCH 3 ) 2 - and Other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自3-8元杂环烷基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is selected from 3-8 membered heterocycloalkyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 其中，T1、R1、R3、m、q和环B如本发明所定义。In some solutions of the present invention, the above structural units Selected from Among them, T 1 , R 1 , R 3 , m, q and ring B are as defined in the present invention.
本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其化合物具有式(I-A)所示的结构：
In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IA):
其中T1选自CH和N；Where T 1 is selected from CH and N;
R1、R2、R3、L1、T2、m、n、q、环A和环B如本发明所定义。R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其化合物具有式(I-1)、(I-2)、(I-3)或(I-4)所示的结构：
In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, its compound has the formula (I-1), (I-2), (I-3) or (I-4 ) shows the structure:
其中，R1、R2、R3、L1、q和n如本发明所定义；Wherein, R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention;
T1选自CH和N；T 1 is selected from CH and N;
T3选自CH和N；T 3 is selected from CH and N;
T4选自N和CH；T 4 is selected from N and CH;
T5选自CH2、NH、O和S。 T5 is selected from CH2 , NH, O and S.
本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其化合物具有式(I-B)所示的结构：
In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IB):
其中，T1选自O和S；Among them, T 1 is selected from O and S;
R1、R2、R3、L1、T2、m、n、q、环A和环B如本发明所定义。R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其化合物具有式(I-5)所示的结构：
In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (I-5):
其中，R1、R2、R3、L1、q和n如本发明所定义；wherein R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention;
T1选自O和S；T 1 is selected from O and S;
T6选自CH和N。 T6 is selected from CH and N.
本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其化合物具有式(I-1A)、(I-1B)、(I-1C)、(I-1D)、(I-2A)、(I-3A)、(I-4A)和(I-5A)所示的结构：

In some embodiments of the present invention, the above compounds, their stereoisomers or their pharmaceutically acceptable salts have the formulas (I-1A), (I-1B), (I-1C), (I-1D ), (I-2A), (I-3A), (I-4A) and (I-5A):

其中，R1、R2、R3、L1、q和n如本发明所定义；Wherein, R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention;
本发明还有一些方案是由上述各变量任意组合而来。Some other solutions of the present invention are obtained by arbitrarily combining the above variables.
本发明还提供了下列所示化合物、其立体异构体或其药学上可接受的盐：


The present invention also provides the following compounds, their stereoisomers or their pharmaceutically acceptable salts:


本发明的一些方案中，上面所述化合物、其立体异构体或其药学上可接受的盐，其选自：







In some embodiments of the present invention, the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:







本发明进一步提供了一种药物组合物，其包含有效治疗剂量的本发明化合物或其药学上可接受的盐；其任选地还包括药学上可接受的辅料、辅助剂或载体。The present invention further provides a pharmaceutical composition, which contains an effective therapeutic dose of a compound of the present invention or a pharmaceutically acceptable salt thereof; which optionally further includes pharmaceutically acceptable excipients, auxiliaries or carriers.
另一方面，本申请还提供了上述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物，在制备用于预防和/或治疗HIV感染的药物上的用途。On the other hand, this application also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing and/or treating HIV infection.
技术效果Technical effect
本发明化合物对HIV整合酶活性有着显著的抑制作用，同时在细胞水平抑制HIV假病毒或突变株假 病毒基因复制试验中展示出积极效应，并且具有良好的药代动力学性质。The compound of the present invention has a significant inhibitory effect on HIV integrase activity, and at the same time inhibits HIV pseudovirus or mutant strain pseudovirus at the cellular level. It has shown positive effects in viral gene replication experiments and has good pharmacokinetic properties.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其他问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure 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. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, 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.
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。 Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键和直形虚线键 Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key and straight dotted keys
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in specific species. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine Isomerization. Valence tautomers involve interconversion through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is pentane-2,4-dione and Interconversion between two tautomers of 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer," "enantiomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or 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 as well as D and L 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 diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is often accomplished by the use of chromatography employing a chiral stationary phase, optionally coupled with chemical derivatization (eg, formation of carbamates from amines).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成 的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All isotopic compositions of the compounds of the invention Transformations, whether radioactive or not, are included within the scope of the invention.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a certain group has one or more attachable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group. The chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express. For example, the straight solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group; The straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group; Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that site will be reduced by one and become the corresponding monovalent piperidinyl group.
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C2-3和C3-4烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-4 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 2-3 and C 3-4 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine). Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C1-4烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C1-4烷氧基包括C1-2、C2-3、C3-4、C4和C3、C2烷氧基等。C1-4烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-4 alkoxy" means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-4 alkoxy group includes C 1-2 , C 2-3 , C 3-4 , C 4 , C 3 , C 2 alkoxy group, etc. Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-3 alkyl" is used to mean 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、和C3、C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , and C 3 , C 2 alkoxy group, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。 Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“3-10元杂环烷基”本身或者与其他术语联合分别表示由3至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“3-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-10元杂环烷基包括3-8元、3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-10元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.
除非另有规定，“C3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C3-5环烷基包括C3-4和C4-5环烷基等；其可以是一价、二价或者多价。C3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。Unless otherwise specified, "C3-5 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a single ring system, and the C3-5 cycloalkyl group includes C3-4 and C4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p,p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "3-8 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-8-membered heterocycloalkyl group includes 3-6-membered, 3-5-membered, 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. Examples of 3-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperazinyl Aldyl or dioxepanyl, etc.
除非另有规定，本发明术语“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括 2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the term "5-6 membered heteroaryl" in the present invention can be used interchangeably. The term "5-6 membered heteroaryl" refers to a single ring composed of 5 to 6 ring atoms and having a conjugated π electron system. A ring group in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl , 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4 -Triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.) , Thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), Furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thiophene base, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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 listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。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 involves 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 (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；eq代表当量、等量；M代表mol/L；DCM代表二氯甲烷；PE代表石油醚；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；TFA代表三氟乙酸；DIPEA代表二异丙基乙胺；ACN代表乙腈；mp代表熔点。The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent amount; M represents mol/L; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO Represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; r.t. represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; ACN stands for acetonitrile; mp stands for melting point.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1
Example 1
合成路线:
synthetic route:
步骤1:化合物1b的合成Step 1: Synthesis of Compound 1b
在单口瓶中加入化合物1a(1g,693.64mmol)和N,N-二甲基甲酰胺(10mL)，随后加入氨基乙醛缩二甲醇(911.58mg,1.04mol,113.36mL)和三乙胺(140.38g,1.39mol,193.09mL)，反应在25℃下反应5小时。反应液加入30mL水。用2×50mL乙酸乙酯萃取，30mL饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，浓缩有机相得到粗品。粗品通过硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化得到化合物1b。Compound 1a (1g, 693.64mmol) and N,N-dimethylformamide (10mL) were added to a single-neck bottle, followed by aminoacetaldehyde dimethylacetal (911.58mg, 1.04mol, 113.36mL) and triethylamine ( 140.38g, 1.39mol, 193.09mL), the reaction was carried out at 25°C for 5 hours. Add 30 mL of water to the reaction solution. Extract with 2 × 50 mL ethyl acetate, wash the organic phase with 30 mL saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 1b.
1H NMR(400MHz,CDCl3)δ＝8.11(d,J＝6.1Hz,1H),6.54(d,J＝6.4Hz,1H),4.55(t,J＝5.2Hz,1H),3.45(s,6H),3.40(t,J＝5.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.11 (d, J = 6.1Hz, 1H), 6.54 (d, J = 6.4Hz, 1H), 4.55 (t, J = 5.2Hz, 1H), 3.45 (s ,6H),3.40(t,J=5.4Hz,2H).
步骤2:化合物1c的合成Step 2: Synthesis of Compound 1c
在预先干燥过的单口瓶中加入化合物1b(1g,4.14mmol)和甲醇(12mL)，随后加入甲醇钠(447.08mg,8.28mmol)，反应在60℃下反应12小时。反应用100mL饱和氯化铵溶液淬灭，用2×100mL乙酸乙酯萃取，100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩有机相得到化合物1c。Compound 1b (1 g, 4.14 mmol) and methanol (12 mL) were added to a pre-dried single-mouth bottle, followed by sodium methoxide (447.08 mg, 8.28 mmol), and the reaction was carried out at 60°C for 12 hours. The reaction was quenched with 100 mL of saturated ammonium chloride solution, extracted with 2×100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain compound 1c.
步骤3:化合物1d的合成Step 3: Synthesis of Compound 1d
在干燥的单口瓶中加入化合物1c(1g,4.21mmol)和四氢呋喃(10mL)，随后在0℃下加入试剂甲基溴 化镁(3M,5.62mL)，反应在60℃下反应12小时。反应液用3N柠檬酸溶液搅5小时。检测中间体反应完全，用50mL饱和碳酸氢钠溶液调节pH＝7-8,用3×50mL乙酸乙酯萃取，100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩有机相得到化合物1d。Compound 1c (1g, 4.21mmol) and tetrahydrofuran (10mL) were added to a dry one-neck bottle, and then the reagent methyl bromide was added at 0°C. Magnesium chloride (3M, 5.62mL) was reacted at 60°C for 12 hours. The reaction solution was stirred with 3N citric acid solution for 5 hours. Check that the reaction of the intermediate is complete, adjust the pH to 7-8 with 50 mL of saturated sodium bicarbonate solution, extract with 3 × 50 mL of ethyl acetate, wash with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain compound 1d.
1H NMR(400MHz,CDCl3)δ＝7.84(d,J＝6.4Hz,1H),6.28(d,J＝6.1Hz,1H),4.57(t,J＝5.5Hz,1H),3.99(s,3H),3.44(s,6H),3.36(t,J＝5.5Hz,2H),2.61(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 7.84 (d, J = 6.4Hz, 1H), 6.28 (d, J = 6.1Hz, 1H), 4.57 (t, J = 5.5Hz, 1H), 3.99 (s ,3H),3.44(s,6H),3.36(t,J＝5.5Hz,2H),2.61(s,3H).
步骤4:化合物1f的合成Step 4: Synthesis of Compound 1f
在预先干燥的单口瓶中加入化合物1d(0.7g,2.75mmol)和四氢呋喃(20mL)，加入草酸二甲酯(698.92mg,5.92mmol)随后在0℃下加入叔丁醇钾(1M,4.90mL)，反应在0℃下反应1小时。LCMS显示原料信号消失，有中间体1e信号生成。随后反应液在0℃下缓慢加入到柠檬酸(3M,27.53mL)中，反应缓慢升温至25℃反应12小时。反应液在低温下用100mL饱和碳酸氢钠溶液调节pH＝7-8,用2×50mL乙酸乙酯萃取，50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩有机相得到粗品。粗品通过硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化得到化合物1f。Add compound 1d (0.7g, 2.75mmol) and tetrahydrofuran (20mL) to a pre-dried single-neck bottle, add dimethyl oxalate (698.92mg, 5.92mmol) and then add potassium tert-butoxide (1M, 4.90mL) at 0°C. ), the reaction was carried out at 0°C for 1 hour. LCMS showed that the raw material signal disappeared and the intermediate 1e signal was generated. Then the reaction solution was slowly added to citric acid (3M, 27.53mL) at 0°C, and the reaction was slowly heated to 25°C for 12 hours. The reaction solution was adjusted to pH=7-8 with 100 mL saturated sodium bicarbonate solution at low temperature, extracted with 2×50 mL ethyl acetate, washed with 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 1f.
1H NMR(400MHz,CDCl3)δ＝8.21(d,J＝6.4Hz,1H),7.02(d,J＝6.4Hz,1H),6.74(s,1H),4.53(br s,2H),4.49-4.45(m,1H),4.13(s,3H),3.95(s,3H),3.35(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.21 (d, J = 6.4Hz, 1H), 7.02 (d, J = 6.4Hz, 1H), 6.74 (s, 1H), 4.53 (br s, 2H), 4.49-4.45(m,1H),4.13(s,3H),3.95(s,3H),3.35(s,6H).
步骤5:化合物1g的合成Step 5: Synthesis of compound 1g
将1f(3.3g,10.24mmol)溶于乙腈(70mL)中，随后加入醋酸(2.93mL)，甲磺酸(295.19mg)，反应在65℃下反应36小时。然后反应降温，直接用于下一步反应。1f (3.3g, 10.24mmol) was dissolved in acetonitrile (70mL), then acetic acid (2.93mL) and methanesulfonic acid (295.19mg) were added, and the reaction was carried out at 65°C for 36 hours. The reaction is then cooled down and used directly for the next reaction.
步骤6:化合物1h的合成Step 6: Synthesis of Compound 1h
在化合物1g的反应液中加入L-氨基丙醇(3.36g,44.80mmol)，反应在65℃下反应12h。反应液降温，取锥形瓶，加入50mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱层析(二氯甲烷:甲醇＝20:1)纯化得到化合物1h。Add L-aminopropanol (3.36 g, 44.80 mmol) to the reaction solution of compound 1g, and react at 65°C for 12 h. Cool the reaction solution, take a conical flask, add 50 mL of water, pour into the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product is purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain compound 1h.
1H NMR(400MHz,DMSO-d6)δ＝8.24(d,J＝6.3Hz,1H),7.48-7.37(m,1H),6.67(s,1H),5.42(dd,J＝4.3,9.9Hz,1H),5.10-5.01(m,1H),4.44-4.40(m,1H),4.35-4.29(m,1H),3.94(s,3H),3.78-3.66(m,2H),1.34(d,J＝6.3Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.24 (d, J = 6.3 Hz, 1H), 7.48-7.37 (m, 1H), 6.67 (s, 1H), 5.42 (dd, J = 4.3, 9.9 Hz,1H),5.10-5.01(m,1H),4.44-4.40(m,1H),4.35-4.29(m,1H),3.94(s,3H),3.78-3.66(m,2H),1.34( d,J＝6.3Hz,3H).
步骤7:化合物1i的合成Step 7: Synthesis of Compound 1i
将化合物1h(0.2g,663.80μmol)溶于乙腈(3mL)中，随后加入试剂1,4-二氮杂二环[2,2,2]辛烷(3.72mg,33.19μmol,3.65μL)和三氯异氰尿酸(72.51mg,311.98μmol)，反应在40℃下反应12h。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到化合物1i。 Compound 1h (0.2g, 663.80μmol) was dissolved in acetonitrile (3mL), followed by the addition of the reagents 1,4-diazabicyclo[2,2,2]octane (3.72mg, 33.19μmol, 3.65μL) and Trichloroisocyanuric acid (72.51mg, 311.98μmol), reacted at 40°C for 12h. Take an Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 1i.
1H NMR(400MHz,DMSO-d6)δ＝8.29-8.18(m,1H),7.36(d,J＝6.6Hz,1H),5.42(dd,J＝3.8,9.8Hz,1H),4.91(br dd,J＝3.6,12.4Hz,1H),4.40-4.26(m,2H),3.92(s,3H),3.86-3.78(m,1H),3.67(dd,J＝6.4,7.9Hz,1H),1.29(d,J＝6.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.29-8.18 (m, 1H), 7.36 (d, J = 6.6Hz, 1H), 5.42 (dd, J = 3.8, 9.8Hz, 1H), 4.91 ( br dd,J＝3.6,12.4Hz,1H),4.40-4.26(m,2H),3.92(s,3H),3.86-3.78(m,1H),3.67(dd,J＝6.4,7.9Hz,1H ),1.29(d,J＝6.1Hz,3H).
步骤8:化合物1j的合成Step 8: Synthesis of Compound 1j
将化合物1i(0.5g,1.49mmol)溶解到乙腈(12mL)中,随后加入碘化钠(669.68mg,4.47mmol)和七水合氯化铈(1.66g,4.47mmol,424.64μL)，反应在100℃下反应12h，反应液直接过滤，滤饼减压浓缩得到残余物。甲醇溶解通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:柱型Phenomenex Luna 80×30mm×3μm；流动相:[H2O(HCl)-ACN]；ACN％:1％-25％,8min)分离得到化合物1j。Compound 1i (0.5g, 1.49mmol) was dissolved in acetonitrile (12mL), and then sodium iodide (669.68mg, 4.47mmol) and cerium chloride heptahydrate (1.66g, 4.47mmol, 424.64μL) were added, and the reaction was carried out at 100 The reaction was carried out for 12 hours at ℃, the reaction solution was directly filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The methanol solution was filtered through an organic phase syringe filter to obtain crude product. The crude product was separated by preparative reverse phase liquid chromatography (separation conditions: column type Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O (HCl)-ACN]; ACN%: 1%-25%, 8min) to obtain the compound. 1j.
1HNMR(400MHz,DMSO-d6)δ＝7.64(br d,J＝7.7Hz,1H),6.64(br d,J＝7.7Hz,1H),5.43(dd,J＝3.5,9.6Hz,1H),4.83(br dd,J＝3.6,12.2Hz,1H),4.38-4.30(m,2H),3.84-3.67(m,3H),1.31(d,J＝5.9Hz,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ = 7.64 (br d, J = 7.7Hz, 1H), 6.64 ( br d, J = 7.7Hz, 1H), 5.43 ( dd, J = 3.5, 9.6Hz, 1H ),4.83(br dd,J＝3.6,12.2Hz,1H),4.38-4.30(m,2H),3.84-3.67(m,3H),1.31(d,J＝5.9Hz,3H).
步骤9:化合物1k的合成Step 9: Synthesis of compound 1k
将化合物1j(0.74g,2.30mmol)溶于N,N-二甲基甲酰胺(7mL)和1,4二氧六环(7mL)中，加入1,8-二氮杂二环十一碳-7-烯(525.27mg,3.45mmol)，六氟磷酸苯并***-1-氧基三(二甲氨基)膦(1.32g,2.99mmol)搅拌0.5h，加入2，4-二氟苄胺(987.70mg,6.90mmol)，80℃搅拌6小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到化合物1k。Compound 1j (0.74g, 2.30mmol) was dissolved in N,N-dimethylformamide (7mL) and 1,4dioxane (7mL), and 1,8-diazabicycloundecane was added -7-ene (525.27mg, 3.45mmol), benzotriazole hexafluorophosphate-1-oxytris(dimethylamino)phosphine (1.32g, 2.99mmol) were stirred for 0.5h, and 2,4-difluorobenzyl was added Amine (987.70 mg, 6.90 mmol), stirred at 80°C for 6 hours. Take a conical flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 1k.
1H NMR(400MHz,DMSO-d6)δ＝10.45(t,J＝5.8Hz,1H),8.12(d,J＝6.3Hz,1H),7.52-7.40(m,1H),7.33-7.18(m,1H),7.10-7.04(m,1H),6.88(d,J＝6.4Hz,1H),5.44(dd,J＝3.8,9.7Hz,1H),4.89(dd,J＝4.0,12.3Hz,1H),4.82-4.71(m,2H),4.42-4.26(m,2H),3.89-3.80(m,1H),3.75-3.68(m,1H),1.33(d,J＝6.0Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ＝10.45 (t, J＝5.8 Hz, 1H), 8.12 (d, J＝6.3 Hz, 1H), 7.52-7.40 (m, 1H), 7.33-7.18 (m, 1H), 7.10-7.04 (m, 1H), 6.88 (d, J＝6.4 Hz, 1H), 5.44 (dd, J＝3.8, 9.7 Hz, 1H), 4.89 (dd, J＝4.0, 12.3 Hz, 1H), 4.82-4.71 (m, 2H), 4.42-4.26 (m, 2H), 3.89-3.80 (m, 1H), 3.75-3.68 (m, 1H), 1.33 (d, J＝6.0 Hz, 3H).
步骤10:化合物1的合成Step 10: Synthesis of Compound 1
将化合物1k(50mg,111.90μmol)溶于无水乙醇(1mL)中，随后加入氢氧化钠(22.38mg,559.49μmol)，反应在65℃下反应16小时。取锥形瓶，倒入反应液，加入1N的柠檬酸溶液，调至pH＝4，然后加入10mL乙酸乙酯，再加入10mL饱和碳酸氢钠溶液洗涤有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。残余物用甲醇溶解后通过有机相针头式滤器过滤，得到粗品。粗品经制备反向液相色谱(分离条件:Waters Xbridge BEH C18 100×30mm×10μm；流动相:[H2O(NH3H2O+NH4HCO3)-ACN]；ACN％:45％-65％,8min)分离得到化合物1。MS(ESI,m/z):429.2[M+1].Compound 1k (50 mg, 111.90 μmol) was dissolved in absolute ethanol (1 mL), then sodium hydroxide (22.38 mg, 559.49 μmol) was added, and the reaction was carried out at 65°C for 16 hours. Take the Erlenmeyer flask, pour the reaction solution, add 1N citric acid solution, adjust to pH=4, then add 10mL ethyl acetate, then add 10mL saturated sodium bicarbonate solution to wash the organic phase, wash with saturated brine, anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The residue was dissolved in methanol and filtered through an organic phase syringe filter to obtain crude product. The crude product was subjected to preparative reverse phase liquid chromatography (separation conditions: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [H 2 O (NH 3 H 2 O+NH 4 HCO 3 )-ACN]; ACN%: 45% -65%, 8min) to obtain compound 1. MS(ESI,m/z):429.2[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.84-11.67(m,1H),10.56(br t,J＝5.7Hz,1H),7.98(d,J＝6.4Hz,1H),7.43-7.35(m,1H),7.27-7.21(m,1H),7.06-7.00(m,1H),6.84(d,J＝6.6Hz,1H),5.36(dd,J＝4.2,9.8Hz, 1H),5.10(br dd,J＝4.2,12.4Hz,1H),4.74(br d,J＝5.3Hz,2H),4.47-4.32(m,2H),3.73-3.60(m,2H),1.37(d,J＝6.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.84-11.67 (m, 1H), 10.56 (br t, J = 5.7Hz, 1H), 7.98 (d, J = 6.4Hz, 1H), 7.43-7.35 (m,1H),7.27-7.21(m,1H),7.06-7.00(m,1H),6.84(d,J＝6.6Hz,1H),5.36(dd,J＝4.2,9.8Hz, 1H),5.10(br dd,J＝4.2,12.4Hz,1H),4.74(br d,J＝5.3Hz,2H),4.47-4.32(m,2H),3.73-3.60(m,2H),1.37 (d,J＝6.2Hz,3H).
实施例2
Example 2
合成路线:
synthetic route:
步骤1:化合物2a的合成Step 1: Synthesis of Compound 2a
在预先干燥的三口瓶中加入原料4,6-二氯-5-嘧啶甲醛(2g,11.30mmol)和溶剂四氢呋喃(20mL)，随后在0℃下加入试剂甲基溴化镁(3M,15.07mL)，反应在25℃下搅拌1个小时。反应液用饱和氯化铵溶液淬灭，用乙酸乙酯(100mL×3)萃取，合并有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物2a。Add the raw material 4,6-dichloro-5-pyrimidinecarboxaldehyde (2g, 11.30mmol) and the solvent tetrahydrofuran (20mL) to the pre-dried three-necked flask, and then add the reagent methylmagnesium bromide (3M, 15.07mL) at 0°C. ) and the reaction was stirred at 25°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with 200 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2a.
步骤2:化合物2b的合成Step 2: Synthesis of Compound 2b
在预先干燥的单口瓶中加入2a(1.5g,7.77mmol)，加入溶剂二氯甲烷(20mL)，随后加入试剂戴斯—马丁(3.63g,8.55mmol)，反应在20℃下搅拌12个小时。反应液用饱和碳酸氢钠溶液调至pH＝7，用乙酸乙酯(80mL×3)萃取，合并有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗 品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-90:10)分离得到2b。Add 2a (1.5g, 7.77mmol) to the pre-dried single-neck bottle, add the solvent dichloromethane (20mL), and then add the reagent Dess-Martin (3.63g, 8.55mmol). The reaction is stirred at 20°C for 12 hours. . The reaction solution was adjusted to pH=7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (80mL×3), the organic phases were combined, washed with 200mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude Taste. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-90:10) to obtain 2b.
步骤3:化合物2c的合成Step 3: Synthesis of Compound 2c
在预先干燥过的单口瓶中加入2b(0.950g,4.97mmol)，和溶剂N,N-二甲基甲酰胺(10mL)，开启搅拌，随后加入氨基乙醛缩二甲醇(522.88mg,4.97mmol)，三乙胺(1.01g,9.95mmol)，反应在0℃下搅拌5个小时。向反应液中加入水20mL，用乙酸乙酯(50mL×3)萃取，合并有机相，用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-80:20)分离得到2c。Add 2b (0.950 g, 4.97 mmol) and solvent N,N-dimethylformamide (10 mL) to a pre-dried single-mouth bottle, start stirring, then add aminoacetaldehyde dimethyl acetal (522.88 mg, 4.97 mmol) and triethylamine (1.01 g, 9.95 mmol), and stir the reaction at 0°C for 5 hours. Add 20 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-80:20) to obtain 2c.
1H NMR(400MHz,DMSO-d6)δ＝8.36(d,J＝1.6Hz,1H),8.14(br s,1H),4.58-4.52(m,1H),3.52(br t,J＝4.6Hz,2H),3.31-3.24(m,6H),2.62-2.55(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.36 (d, J = 1.6 Hz, 1H), 8.14 (br s, 1H), 4.58-4.52 (m, 1H), 3.52 (br t, J = 4.6 Hz,2H),3.31-3.24(m,6H),2.62-2.55(m,3H).
步骤4:化合物2d的合成Step 4: Synthesis of Compound 2d
在预先干燥的单口瓶中加入2c(10.24g,39.43mmol)和溶剂甲醇(50mL)，随后加入甲醇钠(4.26g,78.86mmol)，氮气置换3次，置于60℃下反应2个小时。反应用50mL饱和氯化铵溶液淬灭，乙酸乙酯(80mL×3)萃取，合并有机相，用150mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-90:10)分离得到2d。Add 2c (10.24g, 39.43mmol) and solvent methanol (50mL) to a pre-dried one-neck bottle, then add sodium methoxide (4.26g, 78.86mmol), replace with nitrogen three times, and react at 60°C for 2 hours. The reaction was quenched with 50 mL saturated ammonium chloride solution, extracted with ethyl acetate (80 mL × 3), the organic phases were combined, washed with 150 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-90:10) to obtain 2d.
1H NMR(400MHz,CDCl3)δ＝9.82(br s,1H),8.23(s,1H),4.50(t,J＝5.4Hz,1H),4.00(s,3H),3.68(t,J＝5.6Hz,2H),3.39(s,6H),2.55(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 9.82 (br s, 1H), 8.23 (s, 1H), 4.50 (t, J = 5.4Hz, 1H), 4.00 (s, 3H), 3.68 (t, J =5.6Hz,2H),3.39(s,6H),2.55(s,3H).
步骤5:化合物2f的合成Step 5: Synthesis of Compound 2f
在预先干燥的三口瓶中加入2d(0.7g,2.74mmol)和溶剂四氢呋喃(10mL)，加入草酸二甲酯(696.23mg,5.90mmol)，随后在0℃下加入叔丁醇钾(1M,4.88mL)，反应在0℃下反应5min。得到化合物2e。在0℃下缓慢加入柠檬酸(3M,27.42mL)，置换氮气3次，升至20℃搅拌24个小时。反应液在低温下用饱和碳酸氢钠溶液调节pH＝7-8,用二氯甲烷:甲醇＝10:1(20mL×3)萃取，合并有机相，用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-0:100)分离得到2f。Add 2d (0.7g, 2.74mmol) and solvent tetrahydrofuran (10mL) to a pre-dried three-necked flask, add dimethyl oxalate (696.23mg, 5.90mmol), and then add potassium tert-butoxide (1M, 4.88) at 0°C. mL), the reaction was carried out at 0°C for 5 min. Compound 2e was obtained. Citric acid (3M, 27.42mL) was slowly added at 0°C, nitrogen was replaced three times, and the mixture was raised to 20°C and stirred for 24 hours. The reaction solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution at low temperature, extracted with dichloromethane:methanol=10:1 (20mL×3), combined organic phases, washed with 100mL saturated brine, and anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to obtain crude product. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-0:100) to obtain 2f.
1H NMR(400MHz,DMSO-d6)δ＝8.88(s,1H),6.59(s,1H),4.92-4.80(m,2H),4.46(t,J＝4.8Hz,1H),4.11(s,3H),3.95(s,3H),3.38(s,3H),3.31(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.88 (s, 1H), 6.59 (s, 1H), 4.92-4.80 (m, 2H), 4.46 (t, J = 4.8Hz, 1H), 4.11 ( s,3H),3.95(s,3H),3.38(s,3H),3.31(s,3H).
步骤6:化合物2g的合成Step 6: Synthesis of Compound 2g
在预先干燥的单口瓶中加入2f(0.1g,309.31μmol)和N,N-二甲基甲酰胺(2mL)，随后加入2，4-二氟苄胺(66.41mg,463.96μmol)和三乙胺(31.30mg,309.31μmol)，在35℃下搅拌12小时。向反应液中加入水5mL，用乙酸乙酯(5mL×3)萃取，合并有机相，用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤， 减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-75:25)分离得到2g。Add 2f (0.1g, 309.31μmol) and N,N-dimethylformamide (2mL) to a pre-dried single-neck bottle, followed by 2,4-difluorobenzylamine (66.41mg, 463.96μmol) and triethyl Amine (31.30 mg, 309.31 μmol), stirred at 35°C for 12 hours. Add 5 mL of water to the reaction solution, extract with ethyl acetate (5 mL × 3), combine the organic phases, wash with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain crude product. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-75:25) to obtain 2 g.
1H NMR(400MHz,CDCl3)δ＝10.78-10.69(m,1H),8.49-8.44(m,1H),7.43-7.35(m,1H),6.88-6.79(m,2H),6.68-6.63(m,1H),4.96(br d,J＝2.9Hz,2H),4.83(d,J＝6.0Hz,2H),4.34(t,J＝5.1Hz,1H),3.95(s,3H),3.35(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.78-10.69 (m, 1H), 8.49-8.44 (m, 1H), 7.43-7.35 (m, 1H), 6.88-6.79 (m, 2H), 6.68-6.63 (m,1H),4.96(br d,J＝2.9Hz,2H),4.83(d,J＝6.0Hz,2H),4.34(t,J＝5.1Hz,1H),3.95(s,3H), 3.35(s,6H).
步骤7:化合物2i的合成Step 7: Synthesis of compound 2i
在预先干燥的单口瓶中加入2g(0.7g,1.61mmol)中加入乙酸(1mL)和甲磺酸(92.93mg,966.87μmol,68.83μL)，在35℃下搅拌一个小时，得到2h。随后降温至20℃，加入乙腈(5mL)，L-氨基丙醇(181.55mg,2.42mmol)，在65℃下搅拌20个小时。向反应液中加入水10mL，用乙酸乙酯(10mL×3)萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝100:0-50:50)分离得到2i。Add acetic acid (1mL) and methanesulfonic acid (92.93mg, 966.87μmol, 68.83μL) to 2g (0.7g, 1.61mmol) in a pre-dried one-neck bottle, and stir at 35°C for one hour to obtain 2h. Then the temperature was lowered to 20°C, acetonitrile (5 mL) and L-aminopropanol (181.55 mg, 2.42 mmol) were added, and the mixture was stirred at 65°C for 20 hours. Add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 100:0-50:50) to obtain 2i.
1H NMR(400MHz,CDCl3)δ＝10.74(br s,1H),8.47(s,1H),7.46-7.31(m,1H),7.12(s,1H),6.83(br t,J＝8.4Hz,2H),5.86(dd,J＝4.1,13.0Hz,1H),5.30-5.19(m,1H),4.88-4.79(m,2H),4.53-4.42(m,2H),3.78-3.65(m,1H),3.32(dd,J＝10.1,12.9Hz,1H),1.46(br d,J＝5.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.74 (br s, 1H), 8.47 (s, 1H), 7.46-7.31 (m, 1H), 7.12 (s, 1H), 6.83 (br t, J = 8.4 Hz,2H),5.86(dd,J＝4.1,13.0Hz,1H),5.30-5.19(m,1H),4.88-4.79(m,2H),4.53-4.42(m,2H),3.78-3.65( m,1H),3.32(dd,J＝10.1,12.9Hz,1H),1.46(br d,J＝5.9Hz,3H).
步骤8:化合物2j的合成Step 8: Synthesis of Compound 2j
在预先干燥过的单口瓶中加入2i(0.07g,169.34μmol)和溶剂乙腈(5mL)，随后加入三氯异氰尿酸(18.89mg,81.28μmol)，1,4-二氮杂二环[2,2,2]辛烷(949.75μg,8.47μmol)，氮气置换3次，置于40℃下反应1个小时。向反应液中加入10mL水，用二氯甲烷:甲醇＝10:1(10mL×3)萃取，合并有机相，用15mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物2j，无需纯化直接投入下一步。Add 2i (0.07g, 169.34μmol) and solvent acetonitrile (5mL) to a pre-dried one-neck bottle, then add trichloroisocyanuric acid (18.89mg, 81.28μmol), 1,4-diazabicyclo [2 ,2,2]octane (949.75μg, 8.47μmol), replaced with nitrogen three times, and placed at 40°C for reaction for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane:methanol=10:1 (10 mL×3), combine the organic phases, wash with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2j , directly enter the next step without purification.
1H NMR(400MHz,CDCl3)δ＝10.69-10.58(m,1H),8.48(s,1H),7.44-7.32(m,1H),6.84(br t,J＝8.4Hz,2H),5.94(br d,J＝1.5Hz,1H),5.31-5.20(m,1H),4.84(br d,J＝5.7Hz,2H),4.47-4.41(m,1H),4.39-4.27(m,1H),3.72(t,J＝8.0Hz,1H),3.32(dd,J＝11.0,12.3Hz,1H),1.46(d,J＝5.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.69-10.58 (m, 1H), 8.48 (s, 1H), 7.44-7.32 (m, 1H), 6.84 (br t, J = 8.4Hz, 2H), 5.94 (br d,J＝1.5Hz,1H),5.31-5.20(m,1H),4.84(br d,J＝5.7Hz,2H),4.47-4.41(m,1H),4.39-4.27(m,1H ), 3.72 (t, J = 8.0Hz, 1H), 3.32 (dd, J = 11.0, 12.3Hz, 1H), 1.46 (d, J = 5.9Hz, 3H).
步骤9:化合物2的合成Step 9: Synthesis of Compound 2
准备一个干燥的单口瓶，加入2j(115.00mg,256.80μmol)和溶剂四氢呋喃(2mL)，随后加入氢氧化钠(51.36mg,1.28mmol)，氮气置换3次，置于60℃反应1小时。反应液减压浓缩，用N,N-二甲基甲酰胺溶解，过滤掉不溶物，向反应液中加入甲醇(约0.2mL)，反应液中析出固体，过滤后用水洗涤固体，冻干；滤饼用甲醇(0.2mL)打浆1小时，过滤，滤饼用水洗涤，冻干得到化合物2。Prepare a dry one-neck bottle, add 2j (115.00 mg, 256.80 μmol) and the solvent tetrahydrofuran (2 mL), then add sodium hydroxide (51.36 mg, 1.28 mmol), replace with nitrogen three times, and react at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in N,N-dimethylformamide, and the insoluble matter was filtered off. Methanol (approximately 0.2 mL) was added to the reaction solution. A solid precipitated from the reaction solution. After filtration, the solid was washed with water and freeze-dried; The filter cake was slurried with methanol (0.2 mL) for 1 hour, filtered, and the filter cake was washed with water and freeze-dried to obtain compound 2.
MS(ESI,m/z):430.1[M+1].MS (ESI, m/z): 430.1 [M+1].
1H NMR(400MHz,CDCl3)δ＝11.72(s,1H),10.78-10.72(m,1H),8.40(s,1H),7.43-7.35(m,1H),6.89-6.79(m,2H),6.05-5.96(m,1H),5.25(br d,J＝0.9Hz,1H),4.91-4.81(m,2H),4.53-4.43(m,2H),3.80-3.70(m, 2H),1.52-1.48(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 11.72 (s, 1H), 10.78-10.72 (m, 1H), 8.40 (s, 1H), 7.43-7.35 (m, 1H), 6.89-6.79 (m, 2H ),6.05-5.96(m,1H),5.25(br d,J＝0.9Hz,1H),4.91-4.81(m,2H),4.53-4.43(m,2H),3.80-3.70(m, 2H),1.52-1.48(m,3H).
实施例3
Example 3
合成路线：
synthetic route:
步骤1：化合物3a的合成Step 1: Synthesis of Compound 3a
在干燥的三口瓶中加入(S)-2-(Boc-氨基)-N-甲氧基-N-甲基丙酰胺(25g,182.33mmol)和四氢呋喃(50mL)，干冰乙醇浴降温到-15℃搅拌10min，氮气置换三次，加入甲基溴化镁的四氢呋喃溶液(3M,14.85mL,44.56mmol)，将反应置于-15℃搅拌10min。向反应液缓慢加入3-丁烯溴化镁的四氢呋喃溶液(0.5M,396.08mL)超过30分钟，25℃搅拌3个小时。反应液用2M稀盐酸(30mL)缓慢淬灭，待不再产生气泡停止淬灭。加入乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝20:1-10:1)分离得到3a。 Add (S)-2-(Boc-amino)-N-methoxy-N-methylpropionamide (25g, 182.33mmol) and tetrahydrofuran (50mL) to a dry three-necked flask, and cool the dry ice ethanol bath to -15 °C for 10 min, replaced with nitrogen three times, added methylmagnesium bromide in tetrahydrofuran (3M, 14.85 mL, 44.56 mmol), and placed the reaction at -15 °C and stirred for 10 min. A solution of 3-butene magnesium bromide in tetrahydrofuran (0.5 M, 396.08 mL) was slowly added to the reaction solution over 30 minutes, and stirred at 25°C for 3 hours. The reaction solution was slowly quenched with 2M dilute hydrochloric acid (30 mL), and quenching was stopped when bubbles no longer occurred. Add ethyl acetate (150 mL × 3) for extraction, combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1-10:1) to obtain 3a.
1H NMR(400MHz,CDCl3)δ＝5.88-5.68(m,1H),5.08-4.92(m,2H),4.38-4.23(m,1H),2.68-2.50(m,2H),2.39-2.26(m,2H),1.47-1.39(m,9H),1.33-1.28(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 5.88-5.68 (m, 1H), 5.08-4.92 (m, 2H), 4.38-4.23 (m, 1H), 2.68-2.50 (m, 2H), 2.39-2.26 (m,2H),1.47-1.39(m,9H),1.33-1.28(m,3H).
步骤2：化合物3b的合成Step 2: Synthesis of Compound 3b
在预先干燥过的三口烧瓶中加入9-硼双环[3.3.1]壬烷(0.5M,270mL,135mmol)，氮气抽换气三次，冰水浴降温到0℃。将3a(9.6g,42.24mmol)溶解在溶剂四氢呋喃(60mL)中，缓慢滴加入到反应液中，升温到25℃搅拌4个小时。结束后冰水浴降温到0℃，向反应液中依次缓慢加入氢氧化钠溶液(6M,60mL,360mmol)和过氧化氢溶液(30％,60mL,624mmol)，升温到25℃搅拌1个小时。将不溶物过滤，加入饱和亚硫酸钠水溶液(150mL)淬灭，再加入乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5:1-1:1)分离得到3b。Add 9-borabicyclo[3.3.1]nonane (0.5M, 270mL, 135mmol) to a pre-dried three-necked flask, ventilate with nitrogen three times, and cool to 0℃ in an ice-water bath. Dissolve 3a (9.6g, 42.24mmol) in tetrahydrofuran (60mL), slowly add dropwise to the reaction solution, heat to 25℃ and stir for 4 hours. After completion, cool to 0℃ in an ice-water bath, slowly add sodium hydroxide solution (6M, 60mL, 360mmol) and hydrogen peroxide solution (30%, 60mL, 624mmol) to the reaction solution, heat to 25℃ and stir for 1 hour. Filter the insoluble matter, add saturated sodium sulfite aqueous solution (150mL) to quench, then add ethyl acetate (150mL×3) to extract, combine the organic phases, wash with saturated brine (300mL), dry over anhydrous sodium sulfate, and filter. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-1:1) to obtain 3b.
1H NMR(400MHz,CDCl3)δ＝5.05-4.91(m,1H),3.72-3.55(m,4H),3.11(br s,2H),1.64-1.49(m,3H),1.36(br s,12H),1.10-1.01(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 5.05-4.91 (m, 1H), 3.72-3.55 (m, 4H), 3.11 (br s, 2H), 1.64-1.49 (m, 3H), 1.36 (br s ,12H),1.10-1.01(m,3H).
步骤3：化合物3c的合成Step 3: Synthesis of Compound 3c
在干燥的三口瓶中加入3b(9g,36.39mmol)，随后加入二氯甲烷(150mL)和三氟乙酸(49.79g,436.66mmol)，氮气置换三次，25℃搅拌2个小时。将反应液减压浓缩，加入乙醇(90mL)溶解，再加入氢氧化钠细固体调节pH为碱性。过滤除去多余的氢氧化钠固体，将乙醇减压浓缩得到3c，无需提纯直接用于下一步。3b (9 g, 36.39 mmol) was added to a dry three-necked flask, followed by dichloromethane (150 mL) and trifluoroacetic acid (49.79 g, 436.66 mmol), and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, ethanol (90 mL) was added to dissolve, and fine solid sodium hydroxide was added to adjust the pH to alkaline. Excess sodium hydroxide solid was removed by filtration, and ethanol was concentrated under reduced pressure to obtain 3c, which was used directly in the next step without purification.
1H NMR(400MHz,D2O)δ＝3.66-3.57(m,2H),3.52-3.43(m,1H),2.88-2.78(m,1H),1.69-1.32(m,6H),1.08-0.99(m,3H). 1 H NMR (400 MHz, D 2 O) δ＝3.66-3.57 (m, 2H), 3.52-3.43 (m, 1H), 2.88-2.78 (m, 1H), 1.69-1.32 (m, 6H), 1.08-0.99 (m, 3H).
步骤4：化合物3d的合成Step 4: Synthesis of Compound 3d
在预先干燥过的三口瓶中加入1d(4.78g,17.30mmol)和乙腈(100mL)开启搅拌，随后加入乙酸(5.20g,86.52mmol)，甲磺酸(0.499g,5.19mmol)，升温到65℃搅拌72个小时，加入3c(5.63g,38.24mmol)，继续在65℃搅拌24个小时。向反应液中加入水(150mL)，再加入二氯甲烷(150mL×5)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(二氯甲烷/甲醇＝50:1-20:1)分离，得到3d。Add 1d (4.78g, 17.30mmol) and acetonitrile (100mL) to the pre-dried three-necked flask and start stirring, then add acetic acid (5.20g, 86.52mmol) and methanesulfonic acid (0.499g, 5.19mmol), and raise the temperature to 65 Stir at 65°C for 72 hours, add 3c (5.63g, 38.24mmol), and continue stirring at 65°C for 24 hours. Water (150 mL) was added to the reaction solution, and dichloromethane (150 mL × 5) was added for extraction. The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol=50:1-20:1) to obtain 3d.
1H NMR(400MHz,CDCl3)δ＝8.29-8.20(m,1H),7.14-7.05(m,1H),6.89-6.81(m,1H),5.51-5.40(m,1H),4.67-4.55(m,2H),4.30-4.22(m,1H),4.16-4.08(m,3H),3.78-3.70(m,2H),3.64-3.54(m,1H),1.77-1.59(m,6H),1.39-1.34(m,1H),1.32-1.22(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.29-8.20 (m, 1H), 7.14-7.05 (m, 1H), 6.89-6.81 (m, 1H), 5.51-5.40 (m, 1H), 4.67-4.55 (m,2H),4.30-4.22(m,1H),4.16-4.08(m,3H),3.78-3.70(m,2H),3.64-3.54(m,1H),1.77-1.59(m,6H) ,1.39-1.34(m,1H),1.32-1.22(m,3H).
步骤5：化合物3e的合成Step 5: Synthesis of Compound 3e
在预先干燥过的单口瓶中加入3d(2.73g,7.31mmol)和乙腈(54mL)，随后加入三氯异氰尿酸(0.578g, 2.49mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(41.01g,0.365mmol)，反应在40℃下反应4个小时。向反应液中加入水(150mL)，再加入二氯甲烷(150mL×5)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(二氯甲烷/甲醇＝50:1-20:1)分离，得到化合物3e。Add 3d (2.73g, 7.31mmol) and acetonitrile (54mL) to the pre-dried one-neck bottle, and then add trichloroisocyanuric acid (0.578g, 2.49mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (41.01g, 0.365mmol), the reaction was carried out at 40°C for 4 hours. Water (150 mL) was added to the reaction solution, and dichloromethane (150 mL × 5) was added for extraction. The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol=50:1-20:1) to obtain compound 3e.
1H NMR(400MHz,CDCl3)δ＝8.18-8.12(m,1H),6.78-6.71(m,1H),5.66-5.56(m,1H),4.66-4.57(m,1H),4.54-4.44(m,1H),4.35-4.25(m,1H),4.05-3.98(m,3H),3.76-3.69(m,3H),1.76-1.58(m,6H),1.27(d,J＝6.5Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.18-8.12 (m, 1H), 6.78-6.71 (m, 1H), 5.66-5.56 (m, 1H), 4.66-4.57 (m, 1H), 4.54-4.44 (m,1H),4.35-4.25(m,1H),4.05-3.98(m,3H),3.76-3.69(m,3H),1.76-1.58(m,6H),1.27(d,J＝6.5Hz ,4H).
步骤6：化合物3f的合成Step 6: Synthesis of Compound 3f
在预先干燥过的单口瓶中加入3e(1g,2.45mmol)和乙腈(20mL)，随后加入碘化钠(1.10g,7.36mmol)和七水合氯化铈(2.74g,7.36mmol)，反应在90℃下反应18个小时。反应液直接过滤，滤饼减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件:Phenomenex C18 150*40mm*5μm；流动相:[H2O(HCl)-ACN]；ACN％:1％-30％,10min)分离纯化，得到化合物3f。Add 3e (1g, 2.45mmol) and acetonitrile (20mL) to a pre-dried single-neck bottle, then add sodium iodide (1.10g, 7.36mmol) and cerium chloride heptahydrate (2.74g, 7.36mmol). The reaction is React at 90°C for 18 hours. The reaction solution was directly filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Phenomenex C18 150*40mm*5μm; mobile phase: [H 2 O (HCl)-ACN]; ACN%: 1%-30%, 10min) to obtain the compound 3f.
1H NMR(400MHz,CD3OD)δ＝8.09-7.92(m,1H),7.17-7.03(m,1H),5.71-5.59(m,1H),5.13-4.98(m,1H),4.71-4.56(m,1H),4.45-4.33(m,1H),4.27-4.12(m,1H),3.68-3.55(m,2H),1.82-1.60(m,5H),1.58-1.43(m,1H),1.38-1.22(m,3H). 1 H NMR (400MHz, CD 3 OD) δ = 8.09-7.92 (m, 1H), 7.17-7.03 (m, 1H), 5.71-5.59 (m, 1H), 5.13-4.98 (m, 1H), 4.71- 4.56(m,1H),4.45-4.33(m,1H),4.27-4.12(m,1H),3.68-3.55(m,2H),1.82-1.60(m,5H),1.58-1.43(m,1H ),1.38-1.22(m,3H).
步骤7：化合物3g的合成Step 7: Synthesis of Compound 3g
在预先干燥过的单口瓶中加入3f(650mg,1.65mmol,1eq)，用1,4-二氧六环(6mL)和N,N-二甲基甲酰胺(6mL)溶解，随后加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(376.90mg,2.48mmol,1.5eq)和苯并三氮唑-1-基氧基三(二甲氨基)磷鎓六氟磷酸盐(948.98mg,2.15mmol,1.3eq)，反应在25℃下搅拌0.5个小时。加入试剂2,4-二氟苄胺(708.73mg,4.95mmol,3eq)，80℃反应16个小时。向反应液中加入水(20mL)，再加入乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1-1:9)分离，得到化合物3g。3f (650 mg, 1.65 mmol, 1 eq) was added to a pre-dried single-mouth bottle, dissolved with 1,4-dioxane (6 mL) and N,N-dimethylformamide (6 mL), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (376.90 mg, 2.48 mmol, 1.5 eq) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (948.98 mg, 2.15 mmol, 1.3 eq) were added, and the reaction was stirred at 25°C for 0.5 hours. The reagent 2,4-difluorobenzylamine (708.73 mg, 4.95 mmol, 3 eq) was added, and the reaction was carried out at 80°C for 16 hours. Water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL×3) was added for extraction. The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1-1:9) to obtain 3 g of compound.
1H NMR(400MHz,CDCl3)δ＝10.64-10.49(m,1H),8.27-8.12(m,1H),7.44-7.34(m,1H),6.90-6.75(m,3H),6.42-6.30(m,1H),5.35-5.24(m,1H),4.85-4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H),3.76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.64-10.49 (m, 1H), 8.27-8.12 (m, 1H), 7.44-7.34 (m, 1H), 6.90-6.75 (m, 3H), 6.42-6.30 (m,1H),5.35-5.24(m,1H),4.85-4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H) ,3.76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H).
步骤8：化合物3的合成Step 8: Synthesis of Compound 3
在预先干燥过的单口瓶中加入3g(50mg,0.097mmol)和四氢呋喃(1.5mL)，随后加入磨细的氢氧化钠(19.27mg,0.49mmol)，反应在65℃下反应4个小时。反应液用1M柠檬酸溶液调节pH＝4-5，随后用饱和碳酸氢钠溶液调节pH＝7-8，随后用乙酸乙酯(5mL×5)萃取，合并有机相，减压浓缩。粗品经制备反向液相色谱(分离条件:Xtimate C18 150*40mm*5μm；流动相:[H2O(HCl)-ACN]；ACN％:5％-35％, 10min)分离纯化，得到化合物3。Add 3g (50mg, 0.097mmol) and tetrahydrofuran (1.5mL) to a pre-dried one-neck bottle, then add finely ground sodium hydroxide (19.27mg, 0.49mmol), and react at 65°C for 4 hours. The reaction solution was adjusted to pH=4-5 with 1M citric acid solution, then adjusted to pH=7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (5mL×5). The organic phases were combined and concentrated under reduced pressure. The crude product was subjected to preparative reverse phase liquid chromatography (separation conditions: Xtimate C18 150*40mm*5μm; mobile phase: [H 2 O (HCl)-ACN]; ACN%: 5%-35%, 10 min) was separated and purified to obtain compound 3.
MS(ESI,m/z):501.1[M+1].MS(ESI,m/z):501.1[M+1].
1H NMR(400MHz,CD3OD)δ＝7.90-7.80(m,1H),7.62-7.48(m,1H),7.33-7.21(m,1H),7.20-7.02(m,2H),5.62-5.51(m,1H),5.21-5.08(m,1H),4.95-4.75(m,2H),4.71-4.58(m,1H),4.44-4.27(m,1H),3.95-3.78(m,1H),3.68-3.56(m,2H),1.82-1.58(m,5H),1.57-1.45(m,1H),1.40-1.26(m,3H). 1 H NMR (400MHz, CD 3 OD) δ = 7.90-7.80 (m, 1H), 7.62-7.48 (m, 1H), 7.33-7.21 (m, 1H), 7.20-7.02 (m, 2H), 5.62- 5.51(m,1H),5.21-5.08(m,1H),4.95-4.75(m,2H),4.71-4.58(m,1H),4.44-4.27(m,1H),3.95-3.78(m,1H ),3.68-3.56(m,2H),1.82-1.58(m,5H),1.57-1.45(m,1H),1.40-1.26(m,3H).
实施例4
Example 4
合成路线：
synthetic route:
步骤1：化合物4a的合成Step 1: Synthesis of Compound 4a
在预先干燥过的单口瓶中加入3g(250mg,0.48mmol)和二氯甲烷(5mL)，冰水浴降温到0℃。随后加入试剂戴斯-马丁氧化剂(306.5mg,0.722mmol)，反应在25℃下反应2个小时。反应液用二氯甲烷(10mL)稀释，再用饱和碳酸氢钠(10mL×3)萃取，有机相减压浓缩。粗品经硅胶柱层析(二氯甲烷/甲醇＝30:1-10:1)分离，得到化合物4a。Add 3g (250mg, 0.48mmol) and dichloromethane (5mL) to a pre-dried one-neck bottle, and cool down to 0°C in an ice-water bath. The reagent Dess-Martin oxidant (306.5 mg, 0.722 mmol) was then added and the reaction was carried out at 25°C for 2 hours. The reaction solution was diluted with dichloromethane (10 mL), extracted with saturated sodium bicarbonate (10 mL × 3), and the organic phase was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol=30:1-10:1) to obtain compound 4a.
步骤2：化合物4b的合成Step 2: Synthesis of Compound 4b
在预先干燥过的单口瓶中加入4a(160mg,0.309mmol)和二甲基亚砜(6.4mL)，加入2-甲基-2-丁烯(451.52mg,6.44mmol)的四氢呋喃(3.2mL)溶液，再加入磷酸二氢钠(308.23mg,2.57mmol)和亚氯酸钠(44.79mg,0.495mmol)的水(1.6mL)溶液，反应在25℃下反应16个小时。缓慢加亚硫酸钠稀溶液(6.4mL) 淬灭剩余的次氯酸钠，过滤的滤液粗品直接经制备反向液相色谱(分离条件:Xtimate C18 150*40mm*5μm；流动相:[H2O(HCl)-ACN]；ACN％:15％-45％,10min)分离纯化，得到化合物4b。Add 4a (160 mg, 0.309 mmol) and dimethyl sulfoxide (6.4 mL) to a pre-dried single-mouth bottle, add a solution of 2-methyl-2-butene (451.52 mg, 6.44 mmol) in tetrahydrofuran (3.2 mL), and then add a solution of sodium dihydrogen phosphate (308.23 mg, 2.57 mmol) and sodium chlorite (44.79 mg, 0.495 mmol) in water (1.6 mL), and react at 25 ° C for 16 hours. Slowly add a dilute sodium sulfite solution (6.4 mL) The remaining sodium hypochlorite was quenched, and the crude filtrate was directly separated and purified by preparative reverse liquid chromatography (separation conditions: Xtimate C18 150*40mm*5μm; mobile phase: [H2O(HCl)-ACN]; ACN%: 15%-45%, 10min) to obtain compound 4b.
1H NMR(400MHz,CD3OD)δ＝8.06-7.94(m,1H),7.61-7.49(m,1H),7.30-7.20(m,1H),7.17-6.99(m,2H),5.67-5.36(m,1H),4.95-4.80(m,3H),4.70-4.58(m,1H),4.47-4.32(m,1H),4.18-3.89(m,1H),2.49-2.38(m,2H),1.95-1.81(m,1H),1.80-1.66(m,3H),1.34-1.24(m,3H). 1 H NMR (400MHz, CD 3 OD) δ = 8.06-7.94 (m, 1H), 7.61-7.49 (m, 1H), 7.30-7.20 (m, 1H), 7.17-6.99 (m, 2H), 5.67- 5.36(m,1H),4.95-4.80(m,3H),4.70-4.58(m,1H),4.47-4.32(m,1H),4.18-3.89(m,1H),2.49-2.38(m,2H ),1.95-1.81(m,1H),1.80-1.66(m,3H),1.34-1.24(m,3H).
步骤3：化合物4的合成Step 3: Synthesis of Compound 4
在预先干燥过的单口瓶中加入4b(60mg,0.112mmol)和四氢呋喃(1.5mL)，随后加入磨细的氢氧化钠(45.03mg,1.13mmol)，反应在65℃下反应12个小时。反应液用1M柠檬酸溶液调节pH＝4-5，随后用饱和碳酸氢钠溶液调节pH＝7-8，随后用乙酸乙酯(5mL×5)萃取，合并有机相，减压浓缩。粗品经制备反向液相色谱(分离条件:Xtimate C18 150*40mm*5μm；流动相:[H2O(HCl)-ACN]；ACN％:15％-35％,10min)分离纯化，得到化合物4。4b (60 mg, 0.112 mmol) and tetrahydrofuran (1.5 mL) were added to a pre-dried single-mouth bottle, followed by the addition of ground sodium hydroxide (45.03 mg, 1.13 mmol), and the reaction was carried out at 65°C for 12 hours. The reaction solution was adjusted to pH 4-5 with 1M citric acid solution, and then adjusted to pH 7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (5 mL×5), the organic phases were combined, and concentrated under reduced pressure. The crude product was separated and purified by preparative reverse liquid chromatography (separation conditions: Xtimate C18 150*40mm*5μm; mobile phase: [H 2 O(HCl)-ACN]; ACN%: 15%-35%, 10min) to obtain compound 4.
MS(ESI,m/z):515.1[M+1].MS(ESI,m/z):515.1[M+1].
1H NMR(400MHz,CD3OD)δ＝7.90-7.80(m,1H),7.61-7.49(m,1H),7.29-7.21(m,1H),7.18-7.01(m,2H),5.63-5.51(m,1H),5.20-5.08(m,1H),5.07-4.75(m,2H),4.69-4.58(m,1H),4.42-4.30(m,1H),3.93-3.80(m,1H),2.48-2.37(m,2H),1.92-1.64(m,4H),1.34-1.30(m,3H). 1 H NMR (400 MHz, CD 3 OD) δ＝7.90-7.80 (m, 1H), 7.61-7.49 (m, 1H), 7.29-7.21 (m, 1H), 7.18-7.01 (m, 2H), 5.63-5.51 (m, 1H), 5.20-5.08 (m, 1H), 5.07-4.75 (m, 2H), 4.69-4.58 (m, 1H), 4.42-4.30 (m, 1H), 3.93-3.80 (m, 1H), 2.48-2.37 (m, 2H), 1.92-1.64 (m, 4H), 1.34-1.30 (m, 3H).
实施例5
Example 5
合成路线:
synthetic route:
步骤1：化合物5a的合成Step 1: Synthesis of Compound 5a
在预先干燥的单口瓶中加入2f(1g,3.09mmol)和溶剂N,N-二甲基甲酰胺(10mL)，随后加入2,4,6-三氟苄胺(747.56mg,4.64mmol)和三乙胺(469.49mg,4.64mmol,645.78μL)，在35℃下搅拌12小时。向反应液中加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相后用20mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-75:25)分离，馏分减压浓缩得到5a。Add 2f (1g, 3.09mmol) and solvent N,N-dimethylformamide (10mL) to a pre-dried single-neck bottle, followed by 2,4,6-trifluorobenzylamine (747.56mg, 4.64mmol) and Triethylamine (469.49 mg, 4.64 mmol, 645.78 μL), stirred at 35°C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-75:25), and the fraction was concentrated under reduced pressure to obtain 5a.
1H NMR(400MHz,CDCl3)δ＝10.64(br s,1H),8.50(s,1H),6.69(t,J＝8.1Hz,2H),6.62(s,1H),4.95(br s,2H),4.86(d,J＝5.5Hz,2H),4.33(t,J＝5.1Hz,1H),3.94(s,3H),3.35(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.64 (br s, 1H), 8.50 (s, 1H), 6.69 (t, J = 8.1Hz, 2H), 6.62 (s, 1H), 4.95 (br s, 2H), 4.86 (d, J = 5.5Hz, 2H), 4.33 (t, J = 5.1Hz, 1H), 3.94 (s, 3H), 3.35 (s, 6H).
步骤2：化合物5c的合成Step 2: Synthesis of Compound 5c
在预先干燥的单口瓶中加入5a(0.1g,221.05μmol)中加入乙酸(1mL)和甲磺酸(12.75mg,132.63μmol,9.44μL)，在35℃下搅拌1个小时，得到5b。随后降温至20℃，加入溶剂乙腈(5mL)和L-氨基丙醇(24.25mg,331.58μmol,33.17μL)，在65℃下搅拌72个小时。向反应液中加入水(5mL)，用乙酸乙酯(10mL×3)萃取，合并有机相后用10mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-50:50)分离，馏分减压浓缩得到5c。Add acetic acid (1 mL) and methanesulfonic acid (12.75 mg, 132.63 μmol, 9.44 μL) to 5a (0.1 g, 221.05 μmol) in a pre-dried one-neck bottle, and stir at 35°C for 1 hour to obtain 5b. Then the temperature was lowered to 20°C, the solvent acetonitrile (5 mL) and L-aminopropanol (24.25 mg, 331.58 μmol, 33.17 μL) were added, and the mixture was stirred at 65°C for 72 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-50:50), and the fraction was concentrated under reduced pressure to obtain 5c.
1H NMR(400MHz,CDCl3)δ＝10.64(br d,J＝5.0Hz,1H),8.49(s,1H),7.09(s,1H),6.74-6.65(m,2H),5.86(dd,J＝4.3,13.0Hz,1H),5.25(dd,J＝4.2,10.1Hz,1H),4.87(d,J＝5.6Hz,2H),4.53-4.42(m,2H),3.77-3.68(m,1H),3.32(dd,J＝10.1,12.9Hz,1H),1.46(d,J＝6.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.64 (br d, J = 5.0Hz, 1H), 8.49 (s, 1H), 7.09 (s, 1H), 6.74-6.65 (m, 2H), 5.86 (dd ,J＝4.3,13.0Hz,1H),5.25(dd,J＝4.2,10.1Hz,1H),4.87(d,J＝5.6Hz,2H),4.53-4.42(m,2H),3.77-3.68( m,1H),3.32(dd,J＝10.1,12.9Hz,1H),1.46(d,J＝6.0Hz,3H).
步骤3：化合物5d的合成Step 3: Synthesis of Compound 5d
在预先干燥过的单口瓶中加入5c(0.07g,162.27μmol)和溶剂乙腈(1mL)，随后加入三氯异氰尿酸(18.10mg,77.89μmol)和1,4-二氮杂二环[2,2,2]辛烷(910.12μg,8.11μmol,0.89μL)，氮气置换三次，置于40℃下反应1个小时。向反应液中加入10mL水，用二氯甲烷/甲醇(10:1，10mL×3)萃取，合并有机相后用15mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到5d，无需纯化直接投入下一步。1H NMR(400MHz,CDCl3)δ＝10.58-10.52(m,1H),8.53-8.49(m,1H),6.75-6.66(m,2H),6.04-5.96(m,1H),5.28-5.16(m,1H),4.92-4.86(m,2H),4.54-4.38(m,2H),3.72(t,J＝8.0Hz,1H),3.36-3.24(m,1H),1.46(d,J＝6.1Hz,3H).Add 5c (0.07g, 162.27μmol) and solvent acetonitrile (1mL) to a pre-dried one-neck bottle, then add trichloroisocyanuric acid (18.10mg, 77.89μmol) and 1,4-diazabicyclo [2 ,2,2]octane (910.12μg, 8.11μmol, 0.89μL), replaced with nitrogen three times, and placed at 40°C for reaction for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane/methanol (10:1, 10 mL × 3), combine the organic phases, wash with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 5d, Go directly to the next step without purification. 1 H NMR (400MHz, CDCl 3 ) δ = 10.58-10.52 (m, 1H), 8.53-8.49 (m, 1H), 6.75-6.66 (m, 2H), 6.04-5.96 (m, 1H), 5.28-5.16 (m,1H),4.92-4.86(m,2H),4.54-4.38(m,2H),3.72(t,J＝8.0Hz,1H),3.36-3.24(m,1H),1.46(d,J =6.1Hz,3H).
步骤4：化合物5的合成Step 4: Synthesis of Compound 5
准备一个干燥的单口瓶，加入5d(0.06g,128.81μmol)和四氢呋喃(1mL)，随后加入氢氧化钠(25.76mg,644.04μmol)，氮气置换三次，置于60℃反应1小时。反应液减压浓缩，用甲醇(1mL)打浆1个小时，过滤后滤饼用水洗涤，冻干得到5。 Prepare a dry one-mouth bottle, add 5d (0.06g, 128.81μmol) and tetrahydrofuran (1mL), then add sodium hydroxide (25.76mg, 644.04μmol), replace with nitrogen three times, and place at 60°C for reaction for 1 hour. The reaction solution was concentrated under reduced pressure, and slurried with methanol (1 mL) for 1 hour. After filtration, the filter cake was washed with water and freeze-dried to obtain 5.
MS(ESI,m/z):447.1[M+1].MS(ESI,m/z):447.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.81(s,1H),10.67-10.59(m,1H),8.52-8.37(m,1H),7.35-7.15(m,2H),5.74-5.58(m,1H),5.38-5.29(m,1H),4.90(s,2H),4.49-4.28(m,2H),3.74-3.57(m,1H),3.20-3.13(m,1H),1.44-1.28(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.81 (s, 1H), 10.67-10.59 (m, 1H), 8.52-8.37 (m, 1H), 7.35-7.15 (m, 2H), 5.74-5.58 (m,1H),5.38-5.29(m,1H),4.90(s,2H),4.49-4.28(m,2H),3.74-3.57(m,1H),3.20-3.13(m,1H),1.44 -1.28(m,3H).
实施例6
Example 6
合成路线:
synthetic route:
步骤1：化合物6a的合成Step 1: Synthesis of Compound 6a
在圆底烧瓶中加入2f(358.86mg,1.11mmol)、N,N-二甲基甲酰胺(4mL)、2,6-二氟苄胺(238.11mg,1.67mmol,198.43μL)和三乙胺(168.34mg,1.67mmol,231.55μL)，35℃下反应12小时。取锥形瓶，加入20mL水后倒入反应液，加入20mL乙酸乙酯萃取，分离出有机相后用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝10:1)分离，馏分减压浓缩得到6a。Add 2f (358.86mg, 1.11mmol), N,N-dimethylformamide (4mL), 2,6-difluorobenzylamine (238.11mg, 1.67mmol, 198.43μL) and triethylamine to the round-bottomed flask. (168.34mg, 1.67mmol, 231.55μL), react at 35°C for 12 hours. Take an Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 10:1), and the fraction was concentrated under reduced pressure to obtain 6a.
1H NMR(400MHz,DMSO-d6)δ＝10.73(t,J＝5.7Hz,1H),8.59(s,1H),7.61-7.43(m,1H),7.20(t,J＝8.0Hz,2H),6.67-6.49(m,1H),4.93(d,J＝5.8Hz,2H),4.84(br s,2H),4.45-4.39(m,1H),3.94(s,3H),3.30(s,6H). 1 H NMR (400MHz, DMSO-d6) δ = 10.73 (t, J = 5.7Hz, 1H), 8.59 (s, 1H), 7.61-7.43 (m, 1H), 7.20 (t, J = 8.0Hz, 2H ),6.67-6.49(m,1H),4.93(d,J＝5.8Hz,2H),4.84(br s,2H),4.45-4.39(m,1H),3.94(s,3H),3.30(s ,6H).
步骤2：化合物6c的合成 Step 2: Synthesis of Compound 6c
将6a(0.37g,851.76μmol)溶于乙酸中(4mL)中，加入甲磺酸(24.56mg,255.53μmol,18.19μL)，65℃搅拌48小时。反应液浓缩得到粗品6b。将6b溶于1,2-二氯乙烷中(4mL)中，加入L-氨基丙醇(23.80mg,316.89μmol,24.66μL)，油浴升温到90℃搅拌24小时。将反应液降温，然后取锥形瓶加入20mL水，然后倒入反应液，用20mL乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品，经硅胶柱层析(乙酸乙酯/石油醚＝1:1)分离纯化得到6c。Dissolve 6a (0.37g, 851.76μmol) in acetic acid (4mL), add methanesulfonic acid (24.56mg, 255.53μmol, 18.19μL), and stir at 65°C for 48 hours. The reaction solution was concentrated to obtain crude product 6b. Dissolve 6b in 1,2-dichloroethane (4 mL), add L-aminopropanol (23.80 mg, 316.89 μmol, 24.66 μL), and heat the oil bath to 90°C and stir for 24 hours. Cool the reaction solution, then add 20 mL of water in a conical flask, then pour the reaction solution into the reaction solution, extract three times with 20 mL of ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1:1) to obtain 6c.
步骤4：化合物6d的合成Step 4: Synthesis of Compound 6d
在干燥过的圆底烧瓶中加入6c(70mg,169.34μmol)和乙腈(1mL)，然后加入三氯异氰尿酸(18.89mg,81.28μmol)和1,4-二氮杂二环[2,2,2]辛烷(949.75μg,8.47μmol,0.93μL)，反应在40℃搅拌2小时。将反应液降温，然后取锥形瓶加入20mL水，然后倒入反应液，用20mL乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品，经硅胶柱层析(乙酸乙酯/石油醚＝1:1)分离纯化得到6d。Add 6c (70 mg, 169.34 μmol) and acetonitrile (1 mL) to a dried round-bottomed flask, then add trichloroisocyanuric acid (18.89 mg, 81.28 μmol) and 1,4-diazabicyclo [2,2 ,2]octane (949.75μg, 8.47μmol, 0.93μL), the reaction was stirred at 40°C for 2 hours. Cool the reaction solution, then add 20 mL of water into a conical flask, then pour the reaction solution into it, extract with 20 mL of ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. , separated and purified through silica gel column chromatography (ethyl acetate/petroleum ether = 1:1) to obtain 6d.
步骤5：化合物6的合成Step 5: Synthesis of Compound 6
将6d(40mg,89.32μmol)溶于四氢呋喃(1mL)中，加入氢氧化钠(17.86mg,446.61μmol)，60℃搅拌12小时。取锥形瓶，加入20mL水后倒入反应液，然后用20mL二氯甲烷萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品用甲醇(1mL)打浆后过滤，得到6。Dissolve 6d (40 mg, 89.32 μmol) in tetrahydrofuran (1 mL), add sodium hydroxide (17.86 mg, 446.61 μmol), and stir at 60°C for 12 hours. Take the Erlenmeyer flask, add 20 mL of water, pour the reaction solution, and then extract with 20 mL of methylene chloride. The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methanol (1 mL) and filtered to obtain 6.
MS(ESI,m/z):429.1[M+1].MS(ESI,m/z):429.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.04-10.31(m,1H),8.30(br s,1H),7.61-7.32(m,1H),7.25-6.96(m,2H),5.96-5.68(m,1H),5.43-5.12(m,1H),4.85(br d,J＝2.9Hz,2H),4.44-4.29(m,1H),4.15(q,J＝5.3Hz,2H),3.72-3.56(m,1H),3.17(d,J＝5.1Hz,3H). 1 H NMR (400MHz, DMSO-d6)δ=11.04-10.31(m,1H),8.30(br s,1H),7.61-7.32(m,1H),7.25-6.96(m,2H),5.96-5.68 (m,1H),5.43-5.12(m,1H),4.85(br d,J＝2.9Hz,2H),4.44-4.29(m,1H),4.15(q,J＝5.3Hz,2H),3.72 -3.56(m,1H),3.17(d,J＝5.1Hz,3H).
实施例7
Example 7
合成路线:
synthetic route:
步骤1：化合物7b的合成Step 1: Synthesis of Compound 7b
将7a(1g,6.33mmol)溶于乙腈(10mL)中，加入无水碳酸钾(961.57mg,6.96mmol)和硫酸二甲酯(877.56mg,6.96mmol,659.82μL)，25℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液后加入50mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到7b，无需纯化直接投入下一步。Dissolve 7a (1g, 6.33mmol) in acetonitrile (10mL), add anhydrous potassium carbonate (961.57mg, 6.96mmol) and dimethyl sulfate (877.56mg, 6.96mmol, 659.82μL), and stir at 25°C for 12 hours. Take an Erlenmeyer flask, add 50 mL of water, pour the reaction solution and add 50 mL of ethyl acetate for extraction. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7b, which is directly put into the next step without purification.
步骤2：化合物7c的合成Step 2: Synthesis of Compound 7c
将7b(1g,5.81mmol)溶于无水乙醇(10mL)中，加入盐酸羟胺(1.21g,17.43mmol)和乙酸钠(1.91g,23.24mmol)，升温到80℃搅拌2小时。取锥形瓶，加入50mL水，倒入反应液后加入50mL乙酸乙酯萃取，分离出有机相后用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到7c，无需纯化直接投入下一步。Dissolve 7b (1g, 5.81mmol) in absolute ethanol (10mL), add hydroxylamine hydrochloride (1.21g, 17.43mmol) and sodium acetate (1.91g, 23.24mmol), raise the temperature to 80°C and stir for 2 hours. Take the Erlenmeyer flask, add 50 mL of water, pour the reaction solution, add 50 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain 7c, put it into the solution without purification. Next step.
步骤3：化合物7d的合成Step 3: Synthesis of Compound 7d
在氢化瓶中加入钯碳(0.4g,含10％钯)和溶剂无水乙醇(100mL)，然后加入7c(4g,23.11mmol)和盐酸(12M,11.34mL)，反应在25℃和50psi的条件下搅拌16小时。反应液降温，然后通过硅藻土过滤，减压浓缩得到7d，无需纯化直接投入下一步。Add palladium on carbon (0.4g, containing 10% palladium) and solvent absolute ethanol (100mL) into the hydrogenation bottle, then add 7c (4g, 23.11mmol) and hydrochloric acid (12M, 11.34mL), and react at 25°C and 50psi. Stir under these conditions for 16 hours. The reaction solution was cooled down, then filtered through diatomaceous earth, and concentrated under reduced pressure to obtain 7d, which was directly put into the next step without purification.
步骤4：化合物7e的合成Step 4: Synthesis of Compound 7e
将2f(310mg,0.96mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入7d(249.05mg,1.44mmol)和三乙胺(145.54mg,1.44mmol,200.19μL)，35℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液后加入 50mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝50:50)分离纯化，馏分减压浓缩得到7e。Dissolve 2f (310mg, 0.96mmol) in N,N-dimethylformamide (5mL), add 7d (249.05mg, 1.44mmol) and triethylamine (145.54mg, 1.44mmol, 200.19μL), 35℃ Stir for 12 hours. Take a conical flask, add 50mL of water, pour the reaction solution and then add Extract with 50 mL of ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 50:50), and the fraction was concentrated under reduced pressure to obtain 7e.
步骤5：化合物7g的合成Step 5: Synthesis of Compound 7g
将7e(0.2g,430.65μmol)溶于乙酸(5mL)中，加入甲磺酸(12.42mg,129.19μmol,9.20μL)，65℃下搅拌12小时，反应液浓缩后得到7f粗品。将7f溶于1,2-二氯乙烷(2mL)中，加入L-氨基丙醇(52.11mg,693.84μmol,54.00μL)，油浴升温到90℃搅拌12小时。反应液降温，取锥形瓶，加入20mL水，倒入反应液后加入20mL二氯甲烷萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝50:50)分离纯化，馏分减压浓缩得到7g。Dissolve 7e (0.2g, 430.65μmol) in acetic acid (5mL), add methanesulfonic acid (12.42mg, 129.19μmol, 9.20μL), stir at 65°C for 12 hours, and concentrate the reaction solution to obtain crude 7f. Dissolve 7f in 1,2-dichloroethane (2 mL), add L-aminopropanol (52.11 mg, 693.84 μmol, 54.00 μL), and heat the oil bath to 90°C and stir for 12 hours. Cool the reaction solution, take an Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of methylene chloride and extract three times, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 50:50), and the fraction was concentrated under reduced pressure to obtain 7 g.
1H NMR(400MHz,DMSO-d6)δ＝10.63(t,J＝5.5Hz,1H),8.50(s,1H),6.97-6.81(m,2H),6.70(s,1H),5.49(dd,J＝4.3,12.4Hz,1H),5.35(dd,J＝4.3,10.0Hz,1H),4.76-4.68(m,2H),4.39(dd,J＝6.8,8.6Hz,1H),4.30-4.20(m,1H),3.91-3.86(m,3H),3.66-3.51(m,2H),1.34-1.27(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.63 (t, J = 5.5Hz, 1H), 8.50 (s, 1H), 6.97-6.81 (m, 2H), 6.70 (s, 1H), 5.49 ( dd,J＝4.3,12.4Hz,1H),5.35(dd,J＝4.3,10.0Hz,1H),4.76-4.68(m,2H),4.39(dd,J＝6.8,8.6Hz,1H),4.30 -4.20(m,1H),3.91-3.86(m,3H),3.66-3.51(m,2H),1.34-1.27(m,3H).
步骤6：化合物7h的合成Step 6: Synthesis of Compound 7h
将7g(0.1g,225.53μmol)溶于乙腈(2mL)中，加入三氯异氰尿酸(25.16mg,108.25μmol)和1,4-二氮杂二环[2,2,2]辛烷(1.26mg,11.28μmol,1.24μL)，油浴升温到40℃搅拌2小时。反应液降温，然后取锥形瓶，加入20mL水，倒入反应液后加入20mL乙酸乙酯萃取，用饱和食盐水洗涤一次，无水硫酸钠干燥后过滤，减压浓缩得到粗品，粗品经硅胶柱层析(乙酸乙酯/石油醚＝50:50)分离纯化得到7h。Dissolve 7g (0.1g, 225.53μmol) in acetonitrile (2mL), add trichloroisocyanuric acid (25.16mg, 108.25μmol) and 1,4-diazabicyclo[2,2,2]octane ( 1.26 mg, 11.28 μmol, 1.24 μL), heat the oil bath to 40°C and stir for 2 hours. Cool the reaction solution, then take a conical flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate to extract, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is filtered through silica gel Column chromatography (ethyl acetate/petroleum ether=50:50) separated and purified 7h.
1H NMR(400MHz,DMSO-d6)δ＝6.98-6.79(m,2H),5.74(s,1H),5.62-5.54(m,1H),5.40-5.30(m,1H),4.75(d,J＝5.5Hz,1H),4.37(dd,J＝6.6,8.6Hz,1H),4.33-4.24(m,1H),3.93-3.87(m,3H),3.65(dd,J＝7.0,8.3Hz,1H),3.61-3.51(m,1H),3.32(s,2H),1.29(d,J＝6.1Hz,3H) 1 H NMR (400MHz, DMSO-d 6 ) δ = 6.98-6.79 (m, 2H), 5.74 (s, 1H), 5.62-5.54 (m, 1H), 5.40-5.30 (m, 1H), 4.75 (d ,J＝5.5Hz,1H),4.37(dd,J＝6.6,8.6Hz,1H),4.33-4.24(m,1H),3.93-3.87(m,3H),3.65(dd,J＝7.0,8.3 Hz,1H),3.61-3.51(m,1H),3.32(s,2H),1.29(d,J＝6.1Hz,3H)
步骤7：化合物7的合成Step 7: Synthesis of Compound 7
将7h(80mg,167.42μmol)溶于无水四氢呋喃(3mL)中，加入氢氧化钠(33.48mg,837.09μmol)，油浴升温到60℃搅拌12小时。取锥形瓶，加入20mL水，倒入反应液后加入20mL二氯甲烷萃取，有机相用无水硫酸钠干燥后过滤，减压浓缩后用甲醇溶解，通过有机相针头式过滤器过滤后得到粗品。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80×30mm×3μm；流动相:[H2O(HCl)-ACN]；ACN％:30％-60％,8min)分离得到化合物7。Dissolve 7h (80 mg, 167.42 μmol) in anhydrous tetrahydrofuran (3 mL), add sodium hydroxide (33.48 mg, 837.09 μmol), and heat the oil bath to 60°C and stir for 12 hours. Take the Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of methylene chloride for extraction, dry the organic phase with anhydrous sodium sulfate and filter, concentrate under reduced pressure, dissolve with methanol, and filter through the organic phase syringe filter to obtain Crude. The crude product was separated by preparative reverse phase liquid chromatography (separation conditions: Phenomenex Luna 80×30mm×3μm; mobile phase: [H 2 O (HCl)-ACN]; ACN%: 30%-60%, 8 min) to obtain compound 7.
MS(ESI,m/z):459.1[M+1].MS(ESI,m/z):459.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝12.00-11.57(m,1H),10.61(t,J＝5.5Hz,1H),8.42(s,1H),7.01-6.85(m,2H),5.66(dd,J＝4.3,12.4Hz,1H),5.34(dd,J＝4.2,10.0Hz,1H),4.76(d,J＝5.5Hz,2H),4.44(dd,J＝7.0,8.5Hz,1H),4.37-4.30(m,1H),3.92(s,3H),3.68(dd,J＝6.8,8.5Hz,2H),1.37(d,J＝6.3Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 12.00-11.57 (m, 1H), 10.61 (t, J = 5.5Hz, 1H), 8.42 (s, 1H), 7.01-6.85 (m, 2H), 5.66(dd,J＝4.3,12.4Hz,1H),5.34(dd,J＝4.2,10.0Hz,1H),4.76(d,J＝5.5Hz,2H),4.44(dd,J＝7.0,8.5Hz ,1H),4.37-4.30(m,1H),3.92(s,3H),3.68(dd,J＝6.8,8.5Hz,2H),1.37(d,J＝6.3Hz,3H).
实施例8
Example 8
合成路线：
synthetic route:
步骤1：化合物8b的合成Step 1: Synthesis of Compound 8b
将5a(0.4g,884.21μmol)溶于乙酸(3mL)中，加入甲磺酸(25.49mg,265.26μmol,18.88μL)，65℃搅拌48小时得到5b。将反应液浓缩后，加入1,2-二氯乙烷(3.5mL)和8a(144.38mg,1.43mmol)，油浴升温到90℃搅拌24小时。将反应液降温到室温，然后取锥形瓶加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用饱和食盐水洗涤后用无水硫酸钠干燥，过滤后减压浓缩得到残余物。粗品经过硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化，馏分减压浓缩得到8b。Dissolve 5a (0.4g, 884.21μmol) in acetic acid (3mL), add methanesulfonic acid (25.49mg, 265.26μmol, 18.88μL), and stir at 65°C for 48 hours to obtain 5b. After the reaction solution was concentrated, 1,2-dichloroethane (3.5 mL) and 8a (144.38 mg, 1.43 mmol) were added, and the oil bath was heated to 90°C and stirred for 24 hours. Cool the reaction solution to room temperature, then add 20 mL of water in a conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine and dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the residue. things. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain 8b.
MS(ESI,m/z):458.1[M+1].MS(ESI,m/z):458.1[M+1].
步骤2：化合物8c的合成Step 2: Synthesis of Compound 8c
将8b(30mg,65.59μmol)溶于乙腈(1mL)中，加入三氯异氰尿酸(7.16mg,30.83μmol)和1,4-二氮杂二环[2,2,2]辛烷(367.86μg,3.28μmol,0.36μL)，40℃搅拌2小时。反应液降温，取锥形瓶加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤后减压浓缩得到残余物。粗品经过硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化，馏分减压浓缩得到8c。Dissolve 8b (30 mg, 65.59 μmol) in acetonitrile (1 mL), add trichloroisocyanuric acid (7.16 mg, 30.83 μmol) and 1,4-diazabicyclo[2,2,2]octane (367.86 μg, 3.28 μmol, 0.36 μL), stir at 40°C for 2 hours. Cool the reaction solution, add 20 mL of water in a conical flask, pour the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain 8c.
MS(ESI,m/z):492.0[M+1]. MS(ESI,m/z):492.0[M+1].
1H NMR(400MHz,CDCl3)δ＝10.56-10.41(m,1H),8.43(s,1H),6.68-6.53(m,3H),5.71(dd,J＝3.9,13.5Hz,1H),5.27(t,J＝4.0Hz,1H),5.23(s,1H),5.18(dd,J＝3.9,9.7Hz,1H),4.80(d,J＝5.5Hz,2H),4.62-4.57(m,1H),3.36(dd,J＝9.7,13.4Hz,1H),2.09-1.97(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.56-10.41 (m, 1H), 8.43 (s, 1H), 6.68-6.53 (m, 3H), 5.71 (dd, J = 3.9, 13.5Hz, 1H), 5.27(t,J＝4.0Hz,1H),5.23(s,1H),5.18(dd,J＝3.9,9.7Hz,1H),4.80(d,J＝5.5Hz,2H),4.62-4.57(m ,1H),3.36(dd,J=9.7,13.4Hz,1H),2.09-1.97(m,4H).
步骤3：化合物8的合成Step 3: Synthesis of Compound 8
将8c(33mg,67.09μmol)溶于无水四氢呋喃(1mL)中，加入氢氧化钠(13.42mg,335.47μmol)，60℃搅拌12小时。反应液降温，然后取锥形瓶加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取三次，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(NH4HCO3)-ACN]；ACN％:45％-75％,8min)分离得到8。Dissolve 8c (33 mg, 67.09 μmol) in anhydrous tetrahydrofuran (1 mL), add sodium hydroxide (13.42 mg, 335.47 μmol), and stir at 60°C for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by preparative reverse phase liquid chromatography (separation conditions: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; ACN%: 45%-75%, 8min) 8.
MS(ESI,m/z):474.0[M+1].MS(ESI,m/z):474.0[M+1].
1H NMR(400MHz,DMSO-d6)δ＝12.71-12.38(m,1H),10.65(t,J＝5.7Hz,1H),8.40(s,1H),7.31-7.19(m,2H),5.42(dd,J＝4.2,9.3Hz,1H),5.28(dd,J＝4.2,12.9Hz,1H),5.11(br s,1H),4.83(t,J＝6.1Hz,2H),4.62(br s,1H),3.61(dd,J＝9.3,12.9Hz,1H),2.01-1.86(m,5H),1.62-1.55(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 12.71-12.38 (m, 1H), 10.65 (t, J = 5.7Hz, 1H), 8.40 (s, 1H), 7.31-7.19 (m, 2H), 5.42(dd,J＝4.2,9.3Hz,1H),5.28(dd,J＝4.2,12.9Hz,1H),5.11(br s,1H),4.83(t,J＝6.1Hz,2H),4.62( br s,1H),3.61(dd,J＝9.3,12.9Hz,1H),2.01-1.86(m,5H),1.62-1.55(m,1H).
实施例9
Example 9
合成路线：
synthetic route:
步骤1：化合物9a的合成Step 1: Synthesis of Compound 9a
将7g(0.1g,225.53μmol)溶于乙腈(2mL)中，加入三氯异氰尿酸(25.16mg,108.25μmol)和1,4-二氮杂二环[2,2,2]辛烷(1.26mg,11.28μmol,1.24μL)，油浴升温到40℃搅拌2小时。反应液降温，取锥形瓶加入20mL水，倒入反应液后加入20mL乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤后减压浓缩得到残余物。粗品经过硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化，馏分减压浓缩得到化合物9a。 Dissolve 7g (0.1g, 225.53μmol) in acetonitrile (2mL), add trichloroisocyanuric acid (25.16mg, 108.25μmol) and 1,4-diazabicyclo[2,2,2]octane ( 1.26 mg, 11.28 μmol, 1.24 μL), heat the oil bath to 40°C and stir for 2 hours. Cool the reaction solution, add 20 mL of water in a conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1), and the fractions were concentrated under reduced pressure to obtain compound 9a.
MS(ESI,m/z):512.1[M+1].MS(ESI,m/z):512.1[M+1].
步骤2：化合物9的合成Step 2: Synthesis of Compound 9
将9a(80mg,167.42μmol)溶于无水四氢呋喃(3mL)中，加入氢氧化钠(33.48mg,837.09μmol)，油浴升温到60℃搅拌12小时。反应液降温，然后取锥形瓶加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取三次，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[水(HCl)-ACN]；ACN％:30％-60％,8min)分离得到化合物9。Dissolve 9a (80 mg, 167.42 μmol) in anhydrous tetrahydrofuran (3 mL), add sodium hydroxide (33.48 mg, 837.09 μmol), and heat the oil bath to 60°C and stir for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by preparative reverse phase liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; ACN%: 30%-60%, 8min) to obtain compound 9.
MS(ESI,m/z):494.0[M+1].MS(ESI,m/z):494.0[M+1].
1H NMR(400MHz,CDCl3)δ＝11.63(s,1H),10.75-10.57(m,1H),8.34(s,1H),6.50(br d,J＝10.6Hz,1H),5.90(dd,J＝4.2,12.8Hz,1H),5.13(dd,J＝4.3,9.9Hz,1H),4.84-4.74(m,2H),4.42-4.35(m,2H),3.87(s,3H),3.66-3.60(m,1H),3.16(dd,J＝9.9,12.7Hz,1H),1.41(d,J＝5.8Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 11.63 (s, 1H), 10.75-10.57 (m, 1H), 8.34 (s, 1H), 6.50 (br d, J = 10.6Hz, 1H), 5.90 (dd ,J＝4.2,12.8Hz,1H),5.13(dd,J＝4.3,9.9Hz,1H),4.84-4.74(m,2H),4.42-4.35(m,2H),3.87(s,3H), 3.66-3.60(m,1H),3.16(dd,J＝9.9,12.7Hz,1H),1.41(d,J＝5.8Hz,3H).
实施例10
Example 10
合成路线:
synthetic route:
步骤1：化合物10b的合成Step 1: Synthesis of Compound 10b
在单口瓶中加入10a(5g,28.9mmol)和N,N-二甲基甲酰胺(25mL)，随后加入氨基乙醛缩二甲醇(3.34g,31.79mmol)和二异丙基乙基胺(3.74g,28.9mmol)，反应在50℃下反应12小时。反应液加入30mL水。用2×50mL乙酸乙酯萃取，30mL饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，浓缩有机相得到粗品。粗品通过硅胶柱层析纯化得到化合物10b。Add 10a (5g, 28.9mmol) and N,N-dimethylformamide (25mL) to a single-neck bottle, followed by aminoacetaldehyde dimethylacetal (3.34g, 31.79mmol) and diisopropylethylamine ( 3.74g, 28.9mmol), the reaction was carried out at 50°C for 12 hours. Add 30 mL of water to the reaction solution. Extract with 2 × 50 mL ethyl acetate, wash the organic phase with 30 mL saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain crude product. The crude product was purified by silica gel column chromatography to obtain compound 10b.
MS(ESI,m/z):242.0[M+1].MS(ESI,m/z):242.0[M+1].
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.95(s,1H),6.67(s,1H),4.54(t,J＝5.1Hz,1H),3.45(t,J＝5.6Hz,2H),3.32(s,6H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.31 (s, 1H), 7.95 (s, 1H), 6.67 (s, 1H), 4.54 (t, J = 5.1Hz, 1H), 3.45 (t, J＝5.6Hz,2H),3.32(s,6H).
步骤2：化合物10c的合成Step 2: Synthesis of Compound 10c
在预先干燥过的单口瓶中加入10b(1g,4.14mmol)和甲醇(12mL)，随后加入甲醇钠(670.9mg,12.42mmol)，反应在60℃下反应12小时。反应用100mL饱和氯化铵溶液淬灭，用2×100mL乙酸乙酯萃取，100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩有机相，粗品通过硅胶柱层析纯化得到化合物10c。Add 10b (1g, 4.14mmol) and methanol (12mL) to a pre-dried one-neck bottle, then add sodium methoxide (670.9mg, 12.42mmol), and react at 60°C for 12 hours. The reaction was quenched with 100 mL saturated ammonium chloride solution, extracted with 2 × 100 mL ethyl acetate, washed with 100 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 10c.
MS(ESI,m/z):238.0[M+1].MS (ESI, m/z): 238.0 [M+1].
1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝2.8Hz,1H),7.75(d,J＝2.8Hz,1H),6.16(d,J＝6.2Hz,1H),4.53(d,J＝2.5Hz,1H),3.93(d,J＝2.9Hz,3H),3.46–3.38(m,2H),3.31(d,J＝2.9Hz,6H). 1 H NMR (600MHz, DMSO-d 6 ) δ7.97 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 4.53 (d,J＝2.5Hz,1H),3.93(d,J＝2.9Hz,3H),3.46–3.38(m,2H),3.31(d,J＝2.9Hz,6H).
步骤3：化合物10d的合成Step 3: Synthesis of Compound 10d
在干燥的单口瓶中加入10c(3.88g,16.35mmol)和四氢呋喃(25mL)，随后在-20℃下加入甲基溴化镁(1M,49.05mL)，反应在室温下反应12小时。反应液用盐酸溶液调节pH至3，搅拌0.5小时。检测中间体反应完全，用饱和碳酸氢钠溶液调节pH＝7-8,用3×50mL乙酸乙酯萃取，100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩有机相得到化合物10d。Add 10c (3.88g, 16.35mmol) and tetrahydrofuran (25mL) to a dry one-neck bottle, then add methylmagnesium bromide (1M, 49.05mL) at -20°C, and react at room temperature for 12 hours. The pH of the reaction solution was adjusted to 3 with hydrochloric acid solution and stirred for 0.5 hours. Check that the reaction of the intermediate is complete, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract with 3×50 mL of ethyl acetate, wash with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the organic phase to obtain compound 10d.
MS(ESI,m/z):255.0[M+1].MS(ESI,m/z):255.0[M+1].
1H NMR(600MHz,CDCl3)δ8.08(t,J＝5.7Hz,1H),7.92(s,1H),7.70(s,1H),4.58(t,J＝5.6Hz,1H),3.95(d,J＝1.8Hz,3H),3.43(d,J＝2.0Hz,6H),3.38(t,J＝5.6Hz,2H),2.59(d,J＝2.0Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ8.08(t,J＝5.7Hz,1H),7.92(s,1H),7.70(s,1H),4.58(t,J＝5.6Hz,1H),3.95 (d,J＝1.8Hz,3H),3.43(d,J＝2.0Hz,6H),3.38(t,J＝5.6Hz,2H),2.59(d,J＝2.0Hz,3H).
步骤4：化合物10f的合成Step 4: Synthesis of Compound 10f
在预先干燥的单口瓶中加入10d(2g,7.9mmol)和四氢呋喃(20mL)，加入草酸二甲酯(1.4g,11.85mmol)，随后在0℃下加入叔丁醇钾(1.6g)，反应在0℃下反应1小时。TLC显示原料信号消失，有中间体10e信号生成。随后反应液在0℃下缓慢加入到柠檬酸(45.5g,237mmol)中，反应缓慢升温至25℃后继续反应12小时。反应液在低温下用100mL饱和碳酸氢钠溶液调节pH＝7-8,用2×50mL乙酸乙酯萃取，50mL 饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩有机相得到粗品。粗品通过硅胶柱层析纯化得到化合物10f。Add 10d (2g, 7.9mmol) and tetrahydrofuran (20mL) to a pre-dried single-neck bottle, add dimethyl oxalate (1.4g, 11.85mmol), then add potassium tert-butoxide (1.6g) at 0°C, and react. React at 0°C for 1 hour. TLC showed that the raw material signal disappeared and the intermediate 10e signal was generated. Subsequently, the reaction solution was slowly added to citric acid (45.5 g, 237 mmol) at 0°C, and the reaction was slowly heated to 25°C and the reaction was continued for 12 hours. The reaction solution was adjusted to pH=7-8 with 100 mL saturated sodium bicarbonate solution at low temperature, and extracted with 2 × 50 mL ethyl acetate, 50 mL Wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the organic phase to obtain crude product. The crude product was purified by silica gel column chromatography to obtain compound 10f.
MS(ESI,m/z):323.1[M+1].MS(ESI,m/z):323.1[M+1].
1H NMR(600MHz,CDCl3)δ8.82(s,1H),8.19(s,1H),6.67(d,J＝2.2Hz,1H),4.65(d,J＝5.0Hz,2H),4.53(t,J＝4.9Hz,1H),4.08(s,3H),3.96(d,J＝2.2Hz,3H),3.36(d,J＝2.2Hz,6H). 1 H NMR (600MHz, CDCl 3 ) δ8.82 (s, 1H), 8.19 (s, 1H), 6.67 (d, J = 2.2Hz, 1H), 4.65 (d, J = 5.0Hz, 2H), 4.53 (t,J＝4.9Hz,1H),4.08(s,3H),3.96(d,J＝2.2Hz,3H),3.36(d,J＝2.2Hz,6H).
步骤5：化合物10g的合成Step 5: Synthesis of compound 10g
将10f(1.5g,4.7mmol)溶于乙腈(15mL)中，随后加入醋酸(2.8g,23.5mmol)和甲磺酸(406.54mg,4.23mmol)，反应在65℃下反应36小时。然后反应降温，直接用于下一步反应。在反应液中加入L-氨基丙醇(0.78g,10.4mmol)，反应在65℃下反应12小时。反应液降温，取锥形瓶，加入50mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经过硅胶柱纯化得到化合物10g。10f (1.5g, 4.7mmol) was dissolved in acetonitrile (15mL), then acetic acid (2.8g, 23.5mmol) and methanesulfonic acid (406.54mg, 4.23mmol) were added, and the reaction was carried out at 65°C for 36 hours. The reaction is then cooled down and used directly for the next reaction. L-aminopropanol (0.78g, 10.4mmol) was added to the reaction solution, and the reaction was carried out at 65°C for 12 hours. Cool the reaction solution, take a conical flask, add 50 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column to obtain 10 g of compound.
MS(ESI,m/z):302.0[M+1].MS(ESI,m/z):302.0[M+1].
1H NMR(600MHz,CDCl3)δ8.65(dt,J＝9.4,2.8Hz,1H),8.26–8.08(m,1H),7.09–6.90(m,1H),5.40(ddd,J＝11.8,3.9,1.6Hz,1H),4.94(dt,J＝12.0,3.7Hz,1H),4.50(dt,J＝15.3,6.2Hz,1H),4.45(ddd,J＝8.5,6.9,1.6Hz,1H),4.05(dt,J＝7.4,2.1Hz,3H),3.76(ddd,J＝8.5,6.4,1.4Hz,1H),3.70(ddd,J＝12.0,9.8,2.5Hz,1H),1.51–1.43(m,3H). 1 H NMR (600MHz, CDCl 3 ) δ8.65 (dt, J = 9.4, 2.8 Hz, 1H), 8.26–8.08 (m, 1H), 7.09–6.90 (m, 1H), 5.40 (ddd, J = 11.8 ,3.9,1.6Hz,1H),4.94(dt,J＝12.0,3.7Hz,1H),4.50(dt,J＝15.3,6.2Hz,1H),4.45(ddd,J＝8.5,6.9,1.6Hz, 1H), 4.05 (dt, J＝7.4, 2.1Hz, 3H), 3.76 (ddd, J＝8.5, 6.4, 1.4Hz, 1H), 3.70 (ddd, J＝12.0, 9.8, 2.5Hz, 1H), 1.51 –1.43(m,3H).
步骤6：化合物10h的合成Step 6: Synthesis of Compound 10h
将化合物10g(0.72g,2.4mol)溶于溶剂乙腈(3mL)中，随后加入试剂1,4-二氮杂二环[2,2,2]辛烷(13.5mg,0.12mol)和三氯异氰尿酸(195mg,0.84mol)，反应在室温下反应12小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱纯化，馏分减压浓缩得到化合物10h。Compound 10g (0.72g, 2.4mol) was dissolved in the solvent acetonitrile (3mL), and then the reagents 1,4-diazabicyclo[2,2,2]octane (13.5mg, 0.12mol) and trichloro Isocyanuric acid (195 mg, 0.84 mol), react at room temperature for 12 hours. Take an Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10h.
MS(ESI,m/z):336.0[M+1].MS(ESI,m/z):336.0[M+1].
1H NMR(600MHz,CDCl3)δ8.63(s,1H),8.21(s,1H),5.46(dd,J＝9.6,4.0Hz,1H),4.89(dd,J＝12.0,4.0Hz,1H),4.53(q,J＝6.5Hz,1H),4.43(dd,J＝8.8,6.6Hz,1H),4.07(s,3H),3.81–3.75(m,2H),1.49(d,J＝6.2Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ8.63 (s, 1H), 8.21 (s, 1H), 5.46 (dd, J = 9.6, 4.0Hz, 1H), 4.89 (dd, J = 12.0, 4.0Hz, 1H),4.53(q,J＝6.5Hz,1H),4.43(dd,J＝8.8,6.6Hz,1H),4.07(s,3H),3.81–3.75(m,2H),1.49(d,J =6.2Hz,3H).
步骤7：化合物10i的合成Step 7: Synthesis of Compound 10i
将10h(0.31g,0.92mmol)溶解到乙腈(20mL)中，随后加入碘化钠(0.41g,2.76mmol)和氯化铈(0.68g,2.76mmol)，反应在100℃下反应12小时，取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经过硅胶 柱纯化，馏分减压浓缩得到化合物10i。Dissolve 10h (0.31g, 0.92mmol) in acetonitrile (20mL), then add sodium iodide (0.41g, 2.76mmol) and cerium chloride (0.68g, 2.76mmol), and react at 100°C for 12 hours. Take the Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. The crude product passes through silica gel After column purification, the fractions were concentrated under reduced pressure to obtain compound 10i.
MS(ESI,m/z):322.0[M+1].MS(ESI,m/z):322.0[M+1].
步骤8：化合物10j的合成Step 8: Synthesis of compound 10j
将10i(0.021g,0.06mmol)溶解到0.2mL吡啶中，置换氮气，将反应置于冰浴中，随后加入三氟甲磺酸酐，反应在室温下反应12小时，取锥形瓶，加入10mL水，倒入反应液，加入3×10mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱纯化，馏分减压浓缩得到化合物10j。Dissolve 10i (0.021g, 0.06mmol) into 0.2mL pyridine, replace the nitrogen, place the reaction in an ice bath, then add trifluoromethanesulfonic anhydride, react at room temperature for 12 hours, take an Erlenmeyer flask, and add 10mL water, poured into the reaction solution, added 3 × 10 mL of ethyl acetate for extraction, separated the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column, and the fractions were concentrated under reduced pressure to obtain compound 10j.
MS(ESI,m/z):454.0[M+1].MS(ESI,m/z):454.0[M+1].
步骤9：化合物10k的合成Step 9: Synthesis of Compound 10k
将10j(0.12g,0.26mmol)称取到反应管中，随后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(9.4mg,0.013mmol)，磷酸钾(82mg,0.39mmol)，1,1'-双(二苯基膦)二茂铁(14mg,0.002mmol)和2,4-二氟苄胺(74mg,0.52mmol)，置换氮气后，加入3mL甲苯，反应在90℃下反应12小时，取锥形瓶，加入10mL水，倒入反应液，加入3×10mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经过硅胶柱纯化，馏分减压浓缩得到化合物10k。Weigh 10j (0.12g, 0.26mmol) into the reaction tube, and then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9.4mg, 0.013mmol), potassium phosphate ( 82mg, 0.39mmol), 1,1'-bis(diphenylphosphine)ferrocene (14mg, 0.002mmol) and 2,4-difluorobenzylamine (74mg, 0.52mmol), after replacing nitrogen, add 3mL of toluene , react at 90°C for 12 hours, take an Erlenmeyer flask, add 10 mL of water, pour the reaction solution, add 3 × 10 mL of ethyl acetate for extraction, separate the organic phase, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column, and the fractions were concentrated under reduced pressure to obtain compound 10k.
MS(ESI,m/z):447.0[M+1].MS(ESI,m/z):447.0[M+1].
步骤10：化合物10的合成Step 10: Synthesis of Compound 10
将化合物10h(0.02g,0.04mmol)溶解到3mL四氢呋喃中，随后加入氢氧化钠(0.2g,5mmol)，反应在65℃下反应12小时，取锥形瓶，加入10mL水，倒入反应液，加入3×10mL乙酸乙酯萃取，分离出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经过硅胶柱纯化，馏分减压浓缩得到化合物10。Dissolve compound 10h (0.02g, 0.04mmol) into 3mL tetrahydrofuran, then add sodium hydroxide (0.2g, 5mmol), react at 65°C for 12 hours, take a conical flask, add 10mL water, and pour the reaction solution , add 3×10mL ethyl acetate for extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column, and the fractions were concentrated under reduced pressure to obtain compound 10.
MS(ESI,m/z):447.0[M+1].MS(ESI,m/z):447.0[M+1].
1H NMR(600MHz,DMSO-d6)δ9.87(t,J＝6.2Hz,1H),8.44(s,1H),7.69(s,1H),7.48(q,J＝8.1Hz,1H),7.30–7.24(m,1H),7.07(td,J＝8.7,2.6Hz,1H),6.08–5.96(m,1H),5.39(dd,J＝9.9,4.3Hz,1H),5.31(dd,J＝12.1,4.4Hz,1H),4.57(d,J＝6.1Hz,2H),4.44(dd,J＝8.5,6.8Hz,1H),4.37(q,J＝6.5Hz,1H),3.75–3.68(m,2H),1.38(d,J＝6.3Hz,3H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.87 (t, J = 6.2 Hz, 1H), 8.44 (s, 1H), 7.69 (s, 1H), 7.48 (q, J = 8.1 Hz, 1H) ,7.30–7.24(m,1H),7.07(td,J＝8.7,2.6Hz,1H),6.08–5.96(m,1H),5.39(dd,J＝9.9,4.3Hz,1H),5.31(dd ,J＝12.1,4.4Hz,1H),4.57(d,J＝6.1Hz,2H),4.44(dd,J＝8.5,6.8Hz,1H),4.37(q,J＝6.5Hz,1H),3.75 –3.68(m,2H),1.38(d,J＝6.3Hz,3H).
实施例11
Example 11
合成路线：
synthetic route:
步骤1：化合物11a的合成Step 1: Synthesis of Compound 11a
在干燥的三口瓶中加入Boc-L-丙氨醛(8.5g,49.07mmol)和四氢呋喃(160mL)，溶解成无色溶液，冷却至0℃搅拌。缓慢加入3-丁烯溴化镁四氢呋喃溶液(1M,98.15mL,98.15mmol)溶液，25℃搅拌3小时。反应液用饱和氯化铵水溶液(200mL)缓慢淬灭，待不再产生气泡停止淬灭。加入乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝20:1-10:1)分离，馏分减压浓缩得到11a，显示含有异构体，比例为3.5:1。Add Boc-L-alanaldehyde (8.5g, 49.07mmol) and tetrahydrofuran (160mL) to a dry three-necked flask, dissolve into a colorless solution, cool to 0°C and stir. Slowly add 3-butene magnesium bromide solution in tetrahydrofuran (1M, 98.15mL, 98.15mmol), and stir at 25°C for 3 hours. The reaction solution was slowly quenched with saturated aqueous ammonium chloride solution (200 mL), and quenching was stopped when bubbles no longer occurred. Add ethyl acetate (150 mL×3) for extraction, combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1-10:1), and the fraction was concentrated under reduced pressure to obtain 11a, which showed that it contained isomers with a ratio of 3.5:1.
1H NMR(400MHz,CDCl3)δ＝5.93-5.77(m,1H),5.12-4.92(m,2H),4.84-4.68(m,1H),3.75-3.59(m,1H),3.57-3.45(m,1H),2.35-2.08(m,3H),1.50-1.42(m,11H),1.23-1.16(m,3H),1.13-1.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ = 5.93-5.77 (m, 1H), 5.12-4.92 (m, 2H), 4.84-4.68 (m, 1H), 3.75-3.59 (m, 1H), 3.57-3.45 (m,1H),2.35-2.08(m,3H),1.50-1.42(m,11H),1.23-1.16(m,3H),1.13-1.08(m,1H).
步骤2：化合物11b的合成Step 2: Synthesis of Compound 11b
在预先干燥过的三口烧瓶中加入9-硼双环[3.3.1]壬烷(0.5M,217.69mL,108.85mmol)，氮气抽换气三次，冰水浴降温到0℃。将11a(3.9g,17.01mmol)溶解在四氢呋喃(24mL)中，缓慢滴加入到反应液中，升 温到25℃搅拌21个小时。结束后冰水浴降温到0℃，向反应液中依次缓慢加入氢氧化钠溶液(6M,24.16mL,144.92mmol)和过氧化氢溶液(30％,24.15mL,251.37mmol)，升温到25℃搅拌1个小时。将不溶物过滤，加入饱和亚硫酸钠水溶液(150mL)淬灭，再加入乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥后过滤。对有机相用碘化钾试纸检测过氧化氢含量，减压浓缩有机相到剩余一半至四分之一时，再用碘化钾试纸检测。剩余的水相再用饱和亚硫酸钠水溶液(100mL)淬灭。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5:1-1:1)分离，馏分减压浓缩得到11b，显示含有异构体，比例为3:1。Add 9-boranebicyclo[3.3.1]nonane (0.5M, 217.69mL, 108.85mmol) into a pre-dried three-necked flask, purge with nitrogen three times, and cool down to 0°C in an ice-water bath. Dissolve 11a (3.9g, 17.01mmol) in tetrahydrofuran (24mL) and slowly add it dropwise to the reaction solution. Warm to 25°C and stir for 21 hours. After completion, the ice-water bath was cooled to 0°C, sodium hydroxide solution (6M, 24.16mL, 144.92mmol) and hydrogen peroxide solution (30%, 24.15mL, 251.37mmol) were slowly added to the reaction solution in sequence, and the temperature was raised to 25°C and stirred. 1 hour. Filter the insoluble matter, add saturated sodium sulfite aqueous solution (150 mL) to quench, add ethyl acetate (150 mL × 3) for extraction, combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate and filter. Use potassium iodide test paper to detect the hydrogen peroxide content in the organic phase. Concentrate the organic phase under reduced pressure until half to a quarter remains, and then use potassium iodide test paper to detect the content. The remaining aqueous phase was quenched with saturated aqueous sodium sulfite solution (100 mL). The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-1:1), and the fraction was concentrated under reduced pressure to obtain 11b, which showed that it contained isomers with a ratio of 3:1.
1H NMR(400MHz,CDCl3)δ＝4.99-4.77(m,1H),3.88-3.72(m,3H),3.71-3.58(m,3H),1.67-1.55(m,8H),1.53-1.38(m,15H),1.21-1.13(m,2H),1.12-1.05(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ = 4.99-4.77 (m, 1H), 3.88-3.72 (m, 3H), 3.71-3.58 (m, 3H), 1.67-1.55 (m, 8H), 1.53-1.38 (m,15H),1.21-1.13(m,2H),1.12-1.05(m,1H).
步骤3：化合物11c的合成Step 3: Synthesis of Compound 11c
在干燥的三口瓶中加入11b(6.6g,26.68mmol)，随后加入二氯甲烷(230mL)和三氟乙酸(36.51g,320.22mmol)，氮气置换三次，25℃搅拌2个小时。将反应液减压浓缩，加入乙醇(50mL)溶解，再加入氢氧化钠细固体调节pH为碱性。过滤除去多余的氢氧化钠固体，将乙醇减压浓缩得到11c，无需提纯直接用于下一步。Add 11b (6.6g, 26.68mmol) to a dry three-necked flask, then add methylene chloride (230mL) and trifluoroacetic acid (36.51g, 320.22mmol), replace with nitrogen three times, and stir at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, ethanol (50 mL) was added to dissolve, and then sodium hydroxide fine solid was added to adjust the pH to alkaline. The excess sodium hydroxide solid was removed by filtration, and the ethanol was concentrated under reduced pressure to obtain 11c, which was used directly in the next step without purification.
步骤4：化合物11e的合成Step 4: Synthesis of Compound 11e
在预先干燥过的三口瓶中加入1d(4g,12.41mmol)和乙腈(100mL)开启搅拌，随后加入乙酸(3.73g,62.05mmol)和甲磺酸(0.357g,3.72mmol)，升温到65℃搅拌72个小时，加入11c(3.93g,26.7mmol)，继续在65℃搅拌24个小时。向反应液中加入水(150mL)，再加入二氯甲烷(150mL×5)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经硅胶柱层析(二氯甲烷/甲醇＝50:1-20:1)分离，得到11e，显示含有异构体，比例为8.5:1。Add 1d (4g, 12.41mmol) and acetonitrile (100mL) to the pre-dried three-necked flask and start stirring, then add acetic acid (3.73g, 62.05mmol) and methanesulfonic acid (0.357g, 3.72mmol), and raise the temperature to 65°C Stir for 72 hours, add 11c (3.93g, 26.7mmol), and continue stirring at 65°C for 24 hours. Water (150 mL) was added to the reaction solution, and dichloromethane (150 mL × 5) was added for extraction. The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 50:1-20:1) to obtain 11e, which showed that it contained isomers with a ratio of 8.5:1.
1H NMR(400MHz,CDCl3)δ＝8.31-8.07(m,1H),7.13(s,1H),6.87(d,J＝6.5Hz,1H),5.44-5.21(m,1H),4.78(dd,J＝4.3,12.0Hz,1H),4.16-4.06(m,3H),4.02-3.82(m,2H),3.77-3.67(m,2H),3.66-3.53(m,1H),1.85-1.74(m,4H),1.70-1.65(m,2H),1.51-1.45(m,3H),1.33-1.24(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.31-8.07 (m, 1H), 7.13 (s, 1H), 6.87 (d, J = 6.5Hz, 1H), 5.44-5.21 (m, 1H), 4.78 ( dd,J＝4.3,12.0Hz,1H),4.16-4.06(m,3H),4.02-3.82(m,2H),3.77-3.67(m,2H),3.66-3.53(m,1H),1.85- 1.74(m,4H),1.70-1.65(m,2H),1.51-1.45(m,3H),1.33-1.24(m,1H).
步骤6：化合物11f的合成Step 6: Synthesis of Compound 11f
在预先干燥过的单口瓶中加入11e(2.12g,5.68mmol)和乙腈(42mL)，随后加入三氯异氰尿酸(0.448g,1.93mmol)和1,4-二氮杂二环[2,2,2]辛烷(31.84g,0.283mmol,0.03mL)，反应在40℃下反应4个小时。向反应液中加入水(150mL)，再加入二氯甲烷(150mL×5)萃取，合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经硅胶柱层析(二氯甲烷/甲醇＝50:1-20:1)分离，得到化合物11f，异构体比例为8.5:1。Add 11e (2.12g, 5.68mmol) and acetonitrile (42mL) to a pre-dried one-neck bottle, then add trichloroisocyanuric acid (0.448g, 1.93mmol) and 1,4-diazabicyclo [2, 2,2]octane (31.84g, 0.283mmol, 0.03mL), the reaction was carried out at 40°C for 4 hours. Water (150 mL) was added to the reaction solution, and dichloromethane (150 mL × 5) was added for extraction. The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 50:1-20:1) to obtain compound 11f, with an isomer ratio of 8.5:1.
1H NMR(400MHz,CDCl3)δ＝8.34-8.18(m,1H),6.90-6.75(m,1H),5.47-5.39(m,1H),4.80-4.71(m,1H), 4.13-4.08(m,3H),4.00-3.83(m,2H),3.78-3.68(m,2H),3.68-3.60(m,1H),1.77(br s,2H),1.74-1.64(m,4H),1.52-1.47(m,3H),1.33-1.28(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ = 8.34-8.18 (m, 1H), 6.90-6.75 (m, 1H), 5.47-5.39 (m, 1H), 4.80-4.71 (m, 1H), 4.13-4.08(m,3H),4.00-3.83(m,2H),3.78-3.68(m,2H),3.68-3.60(m,1H),1.77(br s,2H),1.74-1.64(m, 4H),1.52-1.47(m,3H),1.33-1.28(m,1H).
步骤7：化合物11g的合成Step 7: Synthesis of Compound 11g
在预先干燥过的单口瓶中加入11f(1.15g,2.82mmol)和乙腈(20mL)，随后加入碘化钠(1.27g,8.46mmol)和七水合氯化铈(3.15g,8.46mmol)，反应在90℃下反应18个小时。反应液直接过滤，滤饼减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件:Phenomenex C18 150*40mm*5um；流动相:[水(HCl)-ACN]；ACN％:1％-30％,10min)分离纯化，得到化合物11g，异构体的比例为9:1。Add 11f (1.15g, 2.82mmol) and acetonitrile (20mL) to a pre-dried single-neck bottle, then add sodium iodide (1.27g, 8.46mmol) and cerium chloride heptahydrate (3.15g, 8.46mmol), and react React at 90°C for 18 hours. The reaction solution was directly filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Phenomenex C18 150*40mm*5um; mobile phase: [water (HCl)-ACN]; ACN%: 1%-30%, 10min) to obtain compound 11g. The ratio of isomers is 9:1.
1H NMR(400MHz,METHANOL-d4)δ＝8.15-8.04(m,1H),7.34-7.26(m,1H),5.61-5.49(m,1H),5.44-5.31(m,1H),4.23-4.11(m,1H),4.05-3.90(m,2H),3.68-3.55(m,2H),1.95-1.55(m,6H),1.53-1.44(m,3H),1.34-1.28(m,1H). 1 H NMR (400MHz, METHANOL-d4)δ=8.15-8.04(m,1H),7.34-7.26(m,1H),5.61-5.49(m,1H),5.44-5.31(m,1H),4.23- 4.11(m,1H),4.05-3.90(m,2H),3.68-3.55(m,2H),1.95-1.55(m,6H),1.53-1.44(m,3H),1.34-1.28(m,1H ).
步骤8：化合物11h的合成Step 8: Synthesis of Compound 11h
在预先干燥过的单口瓶中加入11g(650mg,1.65mmol)，用1,4-二氧六环(6mL)和N,N-二甲基甲酰胺(6mL)溶解，随后加入1,8-二氮杂二环十一碳-7-烯(376.90mg,2.48mmol)和六氟磷酸苯并***-1-氧基三(二甲氨基)膦(948.98mg,2.15mmol)，反应在25℃下搅拌0.5个小时。加入试剂2,4-二氟苄胺(708.73mg,4.95mmol)，80℃反应16个小时。向反应液中加入水(20mL)，再加入乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1-1:9)分离，得到化合物11h，为单一构型。Add 11g (650mg, 1.65mmol) to a pre-dried single-neck bottle, dissolve it with 1,4-dioxane (6mL) and N,N-dimethylformamide (6mL), and then add 1,8- Diazabicycloundec-7-ene (376.90 mg, 2.48 mmol) and benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (948.98 mg, 2.15 mmol), reacted at 25 Stir for 0.5 hours at ℃. Add the reagent 2,4-difluorobenzylamine (708.73 mg, 4.95 mmol) and react at 80°C for 16 hours. Water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1-1:9) to obtain compound 11h in a single configuration.
1H NMR(400MHz,CD3OD)δ＝10.64-10.49(m,1H),8.27-8.12(m,1H),7.44-7.34(m,1H),6.90-6.75(m,3H),6.42-6.30(m,1H),5.35-5.24(m,1H),4.85-4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H),3.76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H). 1 H NMR (400MHz, CD 3 OD) δ = 10.64-10.49 (m, 1H), 8.27-8.12 (m, 1H), 7.44-7.34 (m, 1H), 6.90-6.75 (m, 3H), 6.42- 6.30(m,1H),5.35-5.24(m,1H),4.85-4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H ),3.76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H).
步骤9：化合物11的合成Step 9: Synthesis of Compound 11
在预先干燥过的单口瓶中加入11h(150mg,0.287mmol)和四氢呋喃(2mL)，随后加入磨细的氢氧化钠(57.81mg,1.45mmol)，反应在65℃下反应4个小时。反应液用1M柠檬酸溶液调节pH＝4-5，随后用饱和碳酸氢钠溶液调节pH＝7-8，随后用乙酸乙酯(5mL×5)萃取，合并有机相，减压浓缩。粗品经制备反向液相色谱(分离条件:Xtimate C18 150*40mm*5μm；流动相:[水(HCl)-ACN]；ACN％:5％-35％,10min)分离纯化，得到化合物11。Add 11h (150 mg, 0.287 mmol) and tetrahydrofuran (2 mL) to a pre-dried one-neck bottle, then add finely ground sodium hydroxide (57.81 mg, 1.45 mmol), and react at 65°C for 4 hours. The reaction solution was adjusted to pH=4-5 with 1M citric acid solution, then adjusted to pH=7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (5mL×5). The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Xtimate C18 150*40mm*5μm; mobile phase: [water (HCl)-ACN]; ACN%: 5%-35%, 10min) to obtain compound 11.
MS(ESI,m/z):501.1[M+1].MS(ESI,m/z):501.1[M+1].
1H NMR(400MHz,CD3OD)δ＝7.95-7.83(m,1H),7.61-7.47(m,1H),7.35-7.21(m,2H),7.16-7.02(m,1H),5.50-5.26(m,2H),4.00-3.89(m,2H),3.87-3.73(m,1H),3.59-3.40(m,2H),1.87-1.51(m,6H),1.50-1.43(m, 3H). 1 H NMR (400MHz, CD 3 OD) δ = 7.95-7.83 (m, 1H), 7.61-7.47 (m, 1H), 7.35-7.21 (m, 2H), 7.16-7.02 (m, 1H), 5.50- 5.26(m,2H),4.00-3.89(m,2H),3.87-3.73(m,1H),3.59-3.40(m,2H),1.87-1.51(m,6H),1.50-1.43(m, 3H).
实施例12
Example 12
合成路线：
synthetic route:
步骤1：化合物12a的合成Step 1: Synthesis of Compound 12a
在干燥的三口瓶中加入1d(500mg,1.55mmol)和N,N-二甲基甲酰胺(8mL)，溶解成溶液。加入三乙胺(1.10g,10.83mmol,1.51mL)和1-(2,4-二氟苯基)环丙胺(954.06mg,4.64mmol)，80℃下搅拌15个小时。反应液中加入水(10mL)稀释。加入二氯甲烷(10mL×3)萃取，合并有机相，用饱和碳酸氢钠水溶液(10mL×2)洗涤，无水硫酸镁干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:0-10:1)分离，馏分减压浓缩得到12a。Add 1d (500 mg, 1.55 mmol) and N,N-dimethylformamide (8 mL) to a dry three-necked flask and dissolve into a solution. Triethylamine (1.10g, 10.83mmol, 1.51mL) and 1-(2,4-difluorophenyl)cyclopropylamine (954.06mg, 4.64mmol) were added, and stirred at 80°C for 15 hours. Water (10 mL) was added to the reaction solution to dilute. Add dichloromethane (10 mL × 3) for extraction, combine the organic phases, wash with saturated aqueous sodium bicarbonate solution (10 mL × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0-10:1), and the fraction was concentrated under reduced pressure to obtain 12a.
1H NMR(400MHz,DMSO-d6)δ＝10.98(s,1H),8.51(s,1H),7.81-7.66(m,1H),7.17(ddd,J＝2.5,9.2,11.2Hz,1H),7.02(dt,J＝2.1,8.6Hz,1H),6.56(s,1H),4.76(br s,1H),4.33(t,J＝4.9Hz,1H),3.88(s,3H),3.22(s,6H),1.34-1.28(m,2H),1.27-1.21(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.98 (s, 1H), 8.51 (s, 1H), 7.81-7.66 (m, 1H), 7.17 (ddd, J = 2.5, 9.2, 11.2Hz, 1H ),7.02(dt,J＝2.1,8.6Hz,1H),6.56(s,1H),4.76(br s,1H),4.33(t,J＝4.9Hz,1H),3.88(s,3H), 3.22(s,6H),1.34-1.28(m,2H),1.27-1.21(m,2H).
步骤2：化合物12b的合成Step 2: Synthesis of compound 12b
在预先干燥过的三口烧瓶中加入12a(220mg,477.81μmol)和乙酸(3.7mL)，开启搅拌，随后加入甲磺酸(18.37mg,191.13μmol,13.61μL)，升温到35℃搅拌20个小时。加入1,2-二氯乙烷(2mL)和L-氨基丙醇(140.26mg,1.87mmol,145.35μL)，升温到90℃搅拌12个小时。向反应液中加入水(10mL)，再加入二 氯甲烷(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸镁干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:0-1:1)分离，馏分减压浓缩得到12b。Add 12a (220 mg, 477.81 μmol) and acetic acid (3.7 mL) to the pre-dried three-necked flask, start stirring, then add methanesulfonic acid (18.37 mg, 191.13 μmol, 13.61 μL), raise the temperature to 35°C and stir for 20 hours. . Add 1,2-dichloroethane (2mL) and L-aminopropanol (140.26mg, 1.87mmol, 145.35μL), raise the temperature to 90°C and stir for 12 hours. Add water (10mL) to the reaction solution, then add 2 Extract with methane chloride (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0-1:1), and the fraction was concentrated under reduced pressure to obtain 12b.
1H NMR(400MHz,DMSO-d6)δ＝11.03(s,1H),8.51(s,1H),7.78-7.69(m,1H),7.22-7.14(m,1H),7.05-6.99(m,1H),6.74(s,1H),5.48(dd,J＝4.3,12.3Hz,1H),5.34(dd,J＝4.3,10.1Hz,1H),4.40(dd,J＝6.8,8.4Hz,1H),4.29(td,J＝6.6,13.1Hz,1H),1.35-1.30(m,3H),1.29-1.22(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.03 (s, 1H), 8.51 (s, 1H), 7.78-7.69 (m, 1H), 7.22-7.14 (m, 1H), 7.05-6.99 (m ,1H),6.74(s,1H),5.48(dd,J＝4.3,12.3Hz,1H),5.34(dd,J＝4.3,10.1Hz,1H),4.40(dd,J＝6.8,8.4Hz, 1H), 4.29 (td, J＝6.6, 13.1Hz, 1H), 1.35-1.30 (m, 3H), 1.29-1.22 (m, 4H).
步骤3：化合物12c的合成Step 3: Synthesis of Compound 12c
在干燥的三口瓶中加入12b(6.6g,26.68mmol)和乙腈(2mL)，随后加入三氯异氰尿酸(25.39mg,109.24μmol)和1,4-二氮杂二环[2,2,2]辛烷(1.28mg,11.38μmol,1.25μL)，反应在40℃下搅拌2个小时。将向反应液中加入水(5mL)，再加入二氯甲烷/甲醇(10:1v/v,5mL×3)萃取，合并有机相，用饱和食盐水(5mL×2)洗涤，无水硫酸镁干燥后过滤，减压浓缩。粗品经制备反向液相色谱(分离条件:Phenomenex C1880*40mm*3μm；流动相:[水(氨水+碳酸氢铵)-ACN]；ACN％:48％-78％,8min)分离纯化，得到12c。Add 12b (6.6g, 26.68mmol) and acetonitrile (2mL) to a dry three-necked flask, then add trichloroisocyanuric acid (25.39mg, 109.24μmol) and 1,4-diazabicyclo [2,2, 2] Octane (1.28 mg, 11.38 μmol, 1.25 μL), the reaction was stirred at 40°C for 2 hours. Add water (5mL) to the reaction solution, then add dichloromethane/methanol (10:1v/v, 5mL×3) for extraction, combine the organic phases, wash with saturated brine (5mL×2), and anhydrous magnesium sulfate. After drying, filter and concentrate under reduced pressure. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Phenomenex C1880*40mm*3μm; mobile phase: [water (ammonia + ammonium bicarbonate)-ACN]; ACN%: 48%-78%, 8min) to obtain 12c.
1H NMR(400MHz,DMSO-d6)δ＝10.91(s,1H),8.53(s,1H),7.78-7.69(m,1H),7.22-7.14(m,1H),7.06-6.98(m,1H),5.57(dd,J＝3.9,12.7Hz,1H),5.34(dd,J＝3.8,9.8Hz,1H),4.41-4.34(m,1H),4.33-4.28(m,1H),3.67(dd,J＝6.8,8.0Hz,1H),3.61(dd,J＝10.0,12.3Hz,1H),1.35-1.30(m,3H),1.29-1.25(m,4H).步骤4：化合物12的合成 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.91 (s, 1H), 8.53 (s, 1H), 7.78-7.69 (m, 1H), 7.22-7.14 (m, 1H), 7.06-6.98 (m ,1H),5.57(dd,J＝3.9,12.7Hz,1H),5.34(dd,J＝3.8,9.8Hz,1H),4.41-4.34(m,1H),4.33-4.28(m,1H), 3.67(dd,J＝6.8,8.0Hz,1H),3.61(dd,J＝10.0,12.3Hz,1H),1.35-1.30(m,3H),1.29-1.25(m,4H). Step 4: Compound Synthesis of 12
在干燥的三口瓶中加入12c(75mg,0.158mmol)和四氢呋喃(0.8mL)，随后加入氢氧化钠(31.65mg,791.37μmol)，反应在60℃下搅拌6个小时。将四氢呋喃浓缩，加2mL水溶解，再加入1M柠檬酸溶液调节pH至5。粗品经制备反向液相色谱(分离条件:Phenomenex C18 150*40mm*5μm；流动相:[水(盐酸)-ACN]；ACN％:40％-70％,10min)分离纯化，得到12。12c (75 mg, 0.158 mmol) and tetrahydrofuran (0.8 mL) were added to a dry three-necked flask, followed by sodium hydroxide (31.65 mg, 791.37 μmol), and the reaction was stirred at 60°C for 6 hours. Concentrate the tetrahydrofuran, add 2 mL of water to dissolve, and then add 1M citric acid solution to adjust the pH to 5. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Phenomenex C18 150*40mm*5μm; mobile phase: [water (hydrochloric acid)-ACN]; ACN%: 40%-70%, 10min) to obtain 12.
MS(ESI,m/z):456.3[M+1].MS(ESI,m/z):456.3[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.09-10.79(m,1H),8.45-8.27(m,1H),7.80-7.62(m,1H),7.28-7.09(m,1H),7.08-6.87(m,1H),5.74-5.49(m,1H),5.41-5.16(m,1H),4.53-4.21(m,2H),3.75-3.60(m,3H),1.43-1.19(m,7H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.09-10.79 (m, 1H), 8.45-8.27 (m, 1H), 7.80-7.62 (m, 1H), 7.28-7.09 (m, 1H), 7.08 -6.87(m,1H),5.74-5.49(m,1H),5.41-5.16(m,1H),4.53-4.21(m,2H),3.75-3.60(m,3H),1.43-1.19(m, 7H).
实施例13
Example 13
合成路线：
synthetic route:
步骤1：化合物13b的合成Step 1: Synthesis of Compound 13b
在预先干燥的单口瓶中加入1d(2g,6.19mmol)和N,N-二甲基甲酰胺(10mL)，加入三乙胺(2.19g,21.65mmol,3.01mL)与13a(2.01g,9.28mmol)，反应在35℃下反应16小时。向反应液中加入20mL水，再用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤。粗品用硅胶柱层析(石油醚/乙酸乙酯＝3:1)纯化，馏分浓缩得到13b。Add 1d (2g, 6.19mmol) and N,N-dimethylformamide (10mL) to a pre-dried single-neck bottle, add triethylamine (2.19g, 21.65mmol, 3.01mL) and 13a (2.01g, 9.28 mmol), the reaction was carried out at 35°C for 16 hours. Add 20 mL of water to the reaction solution, and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with 30 mL of saturated brine, dry over anhydrous sodium sulfate, and filter. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1), and the fractions were concentrated to obtain 13b.
1HNMR(400MHz,CDCl3)δ＝11.34-10.96(m,1H),8.47-8.26(m,1H),7.25(ddd,J＝2.4,8.1,9.1Hz,1H),6.79-6.56(m,1H),5.15-4.83(m,4H),4.43-4.26(m,1H),4.07-3.90(m,3H),3.45-3.26(m,6H). 1 HNMR (400MHz, CDCl 3 ) δ = 11.34-10.96 (m, 1H), 8.47-8.26 (m, 1H), 7.25 (ddd, J = 2.4, 8.1, 9.1Hz, 1H), 6.79-6.56 (m, 1H),5.15-4.83(m,4H),4.43-4.26(m,1H),4.07-3.90(m,3H),3.45-3.26(m,6H).
步骤2：化合物13c的合成Step 2: Synthesis of Compound 13c
将13b(2.5g,5.74mmol)溶于乙酸(31mL)中，加入甲烷磺酸(441.5mg,4.60mmol,327.04μL)，置于35℃下搅拌16小时。向反应液中加入甲烷磺酸(357.41mg,3.72mmol,264.75μL)，在90℃下反应16小时后，加入L-氨基丙醇(279.33mg,3.72mmol,289.46μL)，反应体系在90℃下继续反应16小时。将反应液浓缩，粗品通过硅胶柱层析(二氯甲烷/甲醇＝1:0-10:1)进行分离，得到13c。Dissolve 13b (2.5g, 5.74mmol) in acetic acid (31mL), add methane sulfonic acid (441.5mg, 4.60mmol, 327.04μL), and stir at 35°C for 16 hours. Methanesulfonic acid (357.41mg, 3.72mmol, 264.75μL) was added to the reaction solution, and after reacting at 90°C for 16 hours, L-aminopropanol (279.33mg, 3.72mmol, 289.46μL) was added, and the reaction system was heated at 90°C. Continue the reaction for 16 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0-10:1) to obtain 13c.
步骤3：化合物13d的合成Step 3: Synthesis of Compound 13d
将13c(0.15g,362.00μmol)加入到乙腈(1.5mL)中，然后向其中加入三氯异氰尿酸(40.38mg,173.76μmol)和1,4-二氮杂二环[2,2,2]辛烷(2.03mg,18.10μmol,1.99μL)，氮气置换三次，反应体系在40℃下反应1小时。向其中加入水(5mL)，用二氯甲烷/甲醇(10:1v/v,10mL×3)进行三次萃取，合并有机相后浓缩，粗品通过硅胶柱层析(二氯甲烷/甲醇＝1:0-20:1)进行分离纯化，得到13d。13c (0.15g, 362.00μmol) was added to acetonitrile (1.5mL), then trichloroisocyanuric acid (40.38mg, 173.76μmol) and 1,4-diazabicyclo[2,2,2 ] Octane (2.03 mg, 18.10 μmol, 1.99 μL), replaced with nitrogen three times, and the reaction system was reacted at 40°C for 1 hour. Water (5mL) was added to it, and extraction was performed three times with dichloromethane/methanol (10:1v/v, 10mL×3). The organic phases were combined and concentrated, and the crude product was passed through silica gel column chromatography (dichloromethane/methanol=1: 0-20:1) was separated and purified to obtain 13d.
步骤4：化合物13的合成Step 4: Synthesis of Compound 13
将13d加入到四氢呋喃(7mL)中，然后向其中加入氢氧化钠(30.30mg,757.56μmol)，反应体系在60℃下反应2小时，将反应液浓缩。粗品经制备反向液相色谱(分离条件:Welch Xtimate C18 100*40mm*3μm；流动相:[水(TFA)-ACN]；ACN％:19％-49％,8min)分离纯化，得到13。 13d was added to tetrahydrofuran (7 mL), and then sodium hydroxide (30.30 mg, 757.56 μmol) was added thereto. The reaction system was reacted at 60°C for 2 hours, and the reaction solution was concentrated. The crude product was separated and purified by preparative reverse phase liquid chromatography (separation conditions: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (TFA)-ACN]; ACN%: 19%-49%, 8min) to obtain 13.
MS(ESI,m/z):431.0[M+1].MS(ESI,m/z):431.0[M+1].
1H NMR(400MHz,CDCl3)δ＝11.67(br s,1H),11.28(br s,1H),8.38(s,1H),8.31(d,J＝2.4Hz,1H),6.93(s,1H),5.94(dd,J＝4.3,12.9Hz,1H),5.19-5.14(m,1H),4.97(br s,1H),4.98-4.95(m,1H),4.41(br d,J＝6.0Hz,2H),3.67(s,1H),3.22(dd,J＝9.8,12.7Hz,1H),1.42-1.42(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 11.67 (br s, 1H), 11.28 (br s, 1H), 8.38 (s, 1H), 8.31 (d, J = 2.4Hz, 1H), 6.93 (s, 1H),5.94(dd,J＝4.3,12.9Hz,1H),5.19-5.14(m,1H),4.97(br s,1H),4.98-4.95(m,1H),4.41(br d,J＝ 6.0Hz,2H),3.67(s,1H),3.22(dd,J＝9.8,12.7Hz,1H),1.42-1.42(m,3H).
实施例14
Example 14
合成路线：
synthetic route:
步骤1：化合物14b的合成Step 1: Synthesis of Compound 14b
在预先干燥的三口瓶中加入2,4,6-三氯-5-嘧啶甲醛(14a,10g,47.30mmol,1eq)和四氢呋喃(100mL)，开启搅拌，置换氮气3次，随后在-60℃下加入甲基溴化镁溶液(3M,63.06mL,4eq)，反应在-60℃下搅拌1个小时。反应液用饱和氯化铵溶液(100mL)淬灭，用乙酸乙酯(150mL)萃取3次，合并有机相用饱和食盐水洗涤，并用无水硫酸钠干燥后过滤。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-90:10)分离，馏分减压浓缩得到14b。Add 2,4,6-trichloro-5-pyrimidinecarboxaldehyde (14a, 10g, 47.30mmol, 1eq) and tetrahydrofuran (100mL) to a pre-dried three-necked flask, start stirring, replace nitrogen three times, and then heat at -60°C Methyl magnesium bromide solution (3M, 63.06mL, 4eq) was added at -60°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted three times with ethyl acetate (150 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-90:10), and the fraction was concentrated under reduced pressure to obtain 14b.
MS(ESI,m/z):226.8[M+1]. MS(ESI,m/z):226.8[M+1].
1H NMR(400MHz,CDCl3)δ＝5.58-5.41(m,1H),2.61(br s,1H),1.66(d,J＝6.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 5.58-5.41 (m, 1H), 2.61 (br s, 1H), 1.66 (d, J = 6.9Hz, 3H).
步骤2：化合物14c的合成Step 2: Synthesis of Compound 14c
在预先干燥的单口瓶中加入14b(8.3g,36.49mmol,1eq)，加入二氯甲烷(83mL)，降温至0℃，加入戴斯—马丁试剂(20.12g,47.43mmol,14.69mL,1.3eq)，氮气置换三次，反应在20℃下搅拌1个小时。反应液用饱和碳酸氢钠溶液调至pH＝7，用二氯甲烷(100mL×3)萃取，合并有机相，用300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-95:5)分离，馏分减压浓缩得到14c。Add 14b (8.3g, 36.49mmol, 1eq) to a pre-dried single-neck bottle, add methylene chloride (83mL), cool to 0°C, and add Dess-Martin reagent (20.12g, 47.43mmol, 14.69mL, 1.3eq ), nitrogen was replaced three times, and the reaction was stirred at 20°C for 1 hour. The reaction solution was adjusted to pH=7 with saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with 300 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-95:5), and the fractions were concentrated under reduced pressure to obtain 14c.
MS(ESI,m/z):224.8[M+1].MS(ESI,m/z):224.8[M+1].
1H NMR(400MHz,CDCl3)δ＝2.63(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 2.63 (s, 3H).
步骤3：化合物14d的合成Step 3: Synthesis of Compound 14d
在预先干燥过的单口瓶中加入14c(6.2g,27.50mmol,1eq)和N,N-二甲基甲酰胺(62mL)，开启搅拌，随后加入氨基乙醛缩二甲醇(2.89g,27.50mmol,3.00mL,1eq)和三乙胺(5.57g,55.00mmol,7.66mL,2eq)，氮气置换三次，反应在0℃下搅拌2个小时。向反应液中加入水60mL，用乙酸乙酯(80mL×3)萃取，合并有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-90:10)分离，馏分减压浓缩得到14d。Add 14c (6.2g, 27.50mmol, 1eq) and N,N-dimethylformamide (62mL) to a pre-dried single-neck bottle, start stirring, and then add aminoacetaldehyde dimethyl acetal (2.89g, 27.50mmol) , 3.00mL, 1eq) and triethylamine (5.57g, 55.00mmol, 7.66mL, 2eq), replaced with nitrogen three times, and the reaction was stirred at 0°C for 2 hours. Add 60 mL of water to the reaction solution, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with 200 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-90:10), and the fraction was concentrated under reduced pressure to obtain 14d.
MS(ESI,m/z):293.9[M+1].MS(ESI,m/z):293.9[M+1].
1H NMR(400MHz,CDCl3)δ＝9.25-9.13(m,1H),4.50(t,J＝5.1Hz,1H),3.69(t,J＝5.4Hz,2H),3.46-3.40(m,6H),2.77-2.72(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 9.25-9.13 (m, 1H), 4.50 (t, J = 5.1Hz, 1H), 3.69 (t, J = 5.4Hz, 2H), 3.46-3.40 (m, 6H),2.77-2.72(m,3H).
步骤4：化合物14e的合成Step 4: Synthesis of Compound 14e
在预先干燥的单口瓶中加入14d(6.77g,23.02mmol,1eq)和甲醇(70mL)，随后加入甲醇钠(4.35g,80.56mmol,3.5eq)，氮气置换3次，置于25℃下反应1个小时。反应用50mL饱和氯化铵溶液淬灭，乙酸乙酯(80mL×3)萃取，合并有机相，用150mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-90:10)分离，馏分减压浓缩得到14e。Add 14d (6.77g, 23.02mmol, 1eq) and methanol (70mL) to a pre-dried single-neck bottle, then add sodium methoxide (4.35g, 80.56mmol, 3.5eq), replace with nitrogen three times, and place at 25°C for reaction. 1 hour. The reaction was quenched with 50 mL saturated ammonium chloride solution, extracted with ethyl acetate (80 mL × 3), the organic phases were combined, washed with 150 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-90:10), and the fraction was concentrated under reduced pressure to obtain 14e.
MS(ESI,m/z):285.9[M+1].MS(ESI,m/z):285.9[M+1].
1H NMR(400MHz,DMSO-d6)δ＝10.09-9.93(m,1H),4.53-4.37(m,1H),3.96-3.86(m,6H),3.66-3.52(m,2H),3.40-3.25(m,6H),2.51-2.34(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.09-9.93 (m, 1H), 4.53-4.37 (m, 1H), 3.96-3.86 (m, 6H), 3.66-3.52 (m, 2H), 3.40 -3.25(m,6H),2.51-2.34(m,3H).
步骤5：化合物14g的合成Step 5: Synthesis of Compound 14g
在预先干燥的三口瓶中加入14e(6.8g,23.83mmol,1eq)和四氢呋喃(70mL)，加入草酸二甲酯(5.63g,47.67mmol,2eq)和叔丁醇钾(1M,42.43mL,1.78eq)，反应在20℃下反应0.5个小时，得到14f。在20℃ 下加入柠檬酸(3M,119.17mL,15eq)，置换氮气3次，升至35℃搅拌12个小时。反应液在0℃用饱和碳酸氢钠溶液调节pH＝7-8,用二氯甲烷(70mL×3)萃取，合并有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-0:100)分离，馏分减压浓缩得到14g。Add 14e (6.8g, 23.83mmol, 1eq) and tetrahydrofuran (70mL) to a pre-dried three-necked flask, add dimethyl oxalate (5.63g, 47.67mmol, 2eq) and potassium tert-butoxide (1M, 42.43mL, 1.78 eq), the reaction was carried out at 20°C for 0.5 hours to obtain 14f. at 20℃ Add citric acid (3M, 119.17mL, 15eq), replace nitrogen three times, raise to 35°C and stir for 12 hours. The reaction solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution at 0°C, extracted with dichloromethane (70mL×3), the organic phases were combined, washed with 200mL saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-0:100), and the fraction was concentrated under reduced pressure to obtain 14 g.
MS(ESI,m/z):353.9[M+1].MS(ESI,m/z):353.9[M+1].
1H NMR(400MHz,CDCl3)δ＝6.72(s,1H),4.95(br d,J＝4.3Hz,2H),4.34(t,J＝4.7Hz,1H),4.21(s,3H),4.00(s,3H),3.95(s,3H),3.37(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 6.72 (s, 1H), 4.95 (br d, J = 4.3Hz, 2H), 4.34 (t, J = 4.7Hz, 1H), 4.21 (s, 3H), 4.00(s,3H),3.95(s,3H),3.37(s,6H).
步骤6：化合物14h的合成Step 6: Synthesis of Compound 14h
在预先干燥的单口瓶中加入14g(3g,8.49mmol,1eq)和N,N-二甲基甲酰胺(30mL)，随后加入2,4-二氟苄胺(1.82g,12.74mmol,1.5eq)和三乙胺(1.72g,16.98mmol,2.36mL,2eq)，置换氮气3次，在35℃下搅拌12个小时。向反应液中加入水20mL，用乙酸乙酯(50mL×3)萃取，合并有机相，用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-40:60)分离，馏分减压浓缩得到14h。Add 14g (3g, 8.49mmol, 1eq) and N,N-dimethylformamide (30mL) to a pre-dried single-neck bottle, then add 2,4-difluorobenzylamine (1.82g, 12.74mmol, 1.5eq ) and triethylamine (1.72g, 16.98mmol, 2.36mL, 2eq), replaced with nitrogen three times, and stirred at 35°C for 12 hours. Add 20 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-40:60), and the fraction was concentrated under reduced pressure to obtain 14h.
MS(ESI,m/z):465.1[M+1].MS(ESI,m/z):465.1[M+1].
1H NMR(400MHz,CDCl3)δ＝10.78(br t,J＝5.5Hz,1H),7.47-7.30(m,1H),6.91-6.76(m,2H),6.60(s,1H),4.90(br d,J＝4.5Hz,2H),4.81(d,J＝5.9Hz,2H),4.36(t,J＝5.3Hz,1H),4.00(s,3H),3.94(s,3H),3.35(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.78 (br t, J = 5.5Hz, 1H), 7.47-7.30 (m, 1H), 6.91-6.76 (m, 2H), 6.60 (s, 1H), 4.90 (br d,J＝4.5Hz,2H),4.81(d,J＝5.9Hz,2H),4.36(t,J＝5.3Hz,1H),4.00(s,3H),3.94(s,3H), 3.35(s,6H).
步骤7：化合物14j的合成Step 7: Synthesis of Compound 14j
在预先干燥的单口瓶中加入14h(0.5g,1.08mmol,1eq)、乙酸(0.5mL)和甲磺酸(620.84mg,6.46mmol,459.88μL,6eq)，氮气置换三次，在35℃下搅拌一个小时，得到14i。随后降温至20℃，加入溶剂1,2-二氯乙烷(5mL)，L-氨基丙醇(521.14mg,6.94mmol,540.04μL,6eq)，氮气置换三次，在90℃下搅拌12个小时。向反应液中加入水10mL，用乙酸乙酯(10mL×3)萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-50:50)分离，馏分减压浓缩得到14j。Add 14h (0.5g, 1.08mmol, 1eq), acetic acid (0.5mL) and methanesulfonic acid (620.84mg, 6.46mmol, 459.88μL, 6eq) to the pre-dried single-neck bottle, replace with nitrogen three times, and stir at 35°C. For an hour, get 14i. Then the temperature was lowered to 20°C, the solvent 1,2-dichloroethane (5mL) and L-aminopropanol (521.14mg, 6.94mmol, 540.04μL, 6eq) were added, replaced with nitrogen three times, and stirred at 90°C for 12 hours. . Add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-50:50), and the fraction was concentrated under reduced pressure to obtain 14j.
MS(ESI,m/z):444.0[M+1].MS(ESI,m/z):444.0[M+1].
1H NMR(400MHz,CDCl3)δ＝10.87-10.72(m,1H),7.44-7.32(m,1H),7.05(s,1H),6.89-6.76(m,2H),5.73(dd,J＝4.3,13.0Hz,1H),5.37-5.11(m,1H),4.81(d,J＝5.8Hz,2H),4.55-4.38(m,2H),4.05-3.95(m,3H),3.79-3.64(m,1H),3.40-3.17(m,1H),1.46(d,J＝6.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.87-10.72 (m, 1H), 7.44-7.32 (m, 1H), 7.05 (s, 1H), 6.89-6.76 (m, 2H), 5.73 (dd, J ＝4.3,13.0Hz,1H),5.37-5.11(m,1H),4.81(d,J＝5.8Hz,2H),4.55-4.38(m,2H),4.05-3.95(m,3H),3.79- 3.64(m,1H),3.40-3.17(m,1H),1.46(d,J＝6.1Hz,3H).
步骤8：化合物14k的合成 Step 8: Synthesis of Compound 14k
在预先干燥过的单口瓶中加入14j(0.06g,135.32μmol,1eq)和乙腈(1mL)，随后加入三氯异氰尿酸(15.10mg,64.95μmol,0.48eq)和1,4-二氮杂二环[2,2,2]辛烷(758.93μg,6.77μmol,7.44e-1μL,0.05eq)，氮气置换3次，置于40℃下反应1个小时。向反应液中加入10mL水，用二氯甲烷/甲醇(10:1v/v,10mL×3)萃取，合并有机相，用15mL饱和食盐水洗涤，无水硫酸钠干燥后过滤。粗品经硅胶柱层析(乙酸乙酯/石油醚＝100:0-40:60)分离，馏分减压浓缩得到14k。Add 14j (0.06g, 135.32μmol, 1eq) and acetonitrile (1mL) to a pre-dried single-neck bottle, then add trichloroisocyanuric acid (15.10mg, 64.95μmol, 0.48eq) and 1,4-diazapine Bicyclo[2,2,2]octane (758.93μg, 6.77μmol, 7.44e-1μL, 0.05eq), replaced with nitrogen three times, and reacted at 40°C for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane/methanol (10:1 v/v, 10 mL × 3), combine the organic phases, wash with 15 mL of saturated brine, dry over anhydrous sodium sulfate and filter. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 100:0-40:60), and the fraction was concentrated under reduced pressure to obtain 14k.
MS(ESI,m/z):478.0[M+1].MS(ESI,m/z):478.0[M+1].
1H NMR(400MHz,CDCl3)δ＝10.70(br t,J＝4.8Hz,1H),7.41-7.31(m,1H),6.88-6.79(m,2H),5.90-5.83(m,1H),5.25-5.19(m,1H),4.84-4.79(m,2H),4.53-4.38(m,2H),4.04-3.99(m,3H),3.74-3.68(m,1H),3.34-3.23(m,1H),1.46(d,J＝6.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 10.70 (br t, J = 4.8Hz, 1H), 7.41-7.31 (m, 1H), 6.88-6.79 (m, 2H), 5.90-5.83 (m, 1H) ,5.25-5.19(m,1H),4.84-4.79(m,2H),4.53-4.38(m,2H),4.04-3.99(m,3H),3.74-3.68(m,1H),3.34-3.23( m,1H),1.46(d,J＝6.1Hz,3H).
步骤9：化合物14的合成Step 9: Synthesis of Compound 14
准备一个干燥的单口瓶，加入14k(0.035g,73.25μmol,1eq)和四氢呋喃(2mL)，随后加入氢氧化钠(14.65mg,366.23μmol,5eq)，氮气置换3次，置于60℃反应12个小时。反应液用1M盐酸调节至pH＝3，减压浓缩反应液，浓缩后的反应液用甲醇溶解后用针头式滤器过滤，得到粗品。粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna C18 80*40mm*3μm；流动相:[水(HCl)-ACN]；ACN％:30％-60％,8min)，馏分减压浓缩得到14。Prepare a dry single-mouth bottle, add 14k (0.035g, 73.25μmol, 1eq) and tetrahydrofuran (2mL), then add sodium hydroxide (14.65mg, 366.23μmol, 5eq), replace with nitrogen three times, and place at 60°C for reaction 12 Hours. The reaction solution was adjusted to pH=3 with 1M hydrochloric acid, and the reaction solution was concentrated under reduced pressure. The concentrated reaction solution was dissolved in methanol and filtered with a syringe filter to obtain a crude product. The crude product is separated by reverse preparative liquid chromatography (separation conditions: Phenomenex Luna C18 80*40mm*3μm; mobile phase: [water (HCl)-ACN]; ACN%: 30%-60%, 8min), and the fraction is decompressed Concentration gives 14.
MS(ESI,m/z):460.0[M+1].MS(ESI,m/z):460.0[M+1].
1H NMR(400MHz,CDCl3)δ＝11.66(s,1H),10.79(br t,J＝4.6Hz,1H),7.43(s,1H),6.88-6.79(m,2H),5.91-5.81(m,1H),5.23-5.14(m,1H),4.88-4.79(m,2H),4.53-4.42(m,2H),4.00(s,3H),3.79-3.69(m,1H),3.28-3.19(m,1H),1.51-1.45(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 11.66 (s, 1H), 10.79 (br t, J = 4.6Hz, 1H), 7.43 (s, 1H), 6.88-6.79 (m, 2H), 5.91-5.81 (m,1H),5.23-5.14(m,1H),4.88-4.79(m,2H),4.53-4.42(m,2H),4.00(s,3H),3.79-3.69(m,1H),3.28 -3.19(m,1H),1.51-1.45(m,3H).
实施例15A
Example 15A
合成路线：
synthetic route:
步骤1：化合物15a的合成Step 1: Synthesis of compound 15a
将化合物1d(1g,3.09mmol,1eq)溶于N,N-二甲基甲酰胺(10mL)中，加入2,4-二氟甲基苯甲胺(729.17mg,4.64mmol,1.5eq)和三乙胺(469.48mg,4.64mmol,645.78μL,1.5eq)，80℃搅拌12小时。取锥形瓶，加入50mL水，倒入反应液，加入50mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，馏分减压浓缩得到化合物15a(0.5g,产率36.05％)。MS(ESI,m/z):449.0[M+1].Compound 1d (1g, 3.09mmol, 1eq) was dissolved in N,N-dimethylformamide (10mL), and 2,4-difluoromethylbenzylamine (729.17mg, 4.64mmol, 1.5eq) and Triethylamine (469.48mg, 4.64mmol, 645.78μL, 1.5eq), stir at 80°C for 12 hours. Take an Erlenmeyer flask, add 50 mL of water, pour the reaction solution, add 50 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1), and the fractions were concentrated under reduced pressure to obtain compound 15a (0.5 g, yield 36.05%). MS(ESI,m/z):449.0[M+1].
步骤2：化合物15b的合成Step 2: Synthesis of Compound 15b
将化合物15a(0.5g,1.115mmol,1eq)溶于冰乙酸(4mL)中，加入甲磺酸(32.14mg,334.5μmol,23.9μL,0.3eq)，油浴升温到65℃搅拌12小时即可得到化合物15b(0.46g,粗品)，反应液直接投入到下一步反应。MS(ESI,m/z):417.0[M+1].Dissolve compound 15a (0.5g, 1.115mmol, 1eq) in glacial acetic acid (4mL), add methanesulfonic acid (32.14mg, 334.5μmol, 23.9μL, 0.3eq), heat the oil bath to 65°C and stir for 12 hours. Compound 15b (0.46g, crude product) was obtained, and the reaction solution was directly put into the next step of reaction. MS(ESI,m/z):417.0[M+1].
步骤3：化合物15c的合成Step 3: Synthesis of Compound 15c
将化合物15b(0.5g,1.20mmol,1eq)溶于1,2-二氯乙烷(5mL)中，加入L-氨基丙醇(180.39mg,2.40mmol,186.93μL,2eq)，90℃搅拌24小时。反应液直接减压浓缩得到残余物，粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，馏分减压浓缩得到化合物15c(0.2g,产率38.97％).MS(ESI,m/z):427.40[M+1].Dissolve compound 15b (0.5g, 1.20mmol, 1eq) in 1,2-dichloroethane (5mL), add L-aminopropanol (180.39mg, 2.40mmol, 186.93μL, 2eq), and stir at 90°C for 24 Hour. The reaction solution was directly concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1). The fraction was concentrated under reduced pressure to obtain compound 15c (0.2g, yield 38.97%). MS (ESI ,m/z):427.40[M+1].
步骤4：化合物15d的合成Step 4: Synthesis of Compound 15d
将化合物15c(0.2g,467.94μmol,1eq)溶于乙腈(1mL)中，加入1,4-二氮杂二环[2.2.2]辛烷(2.62mg,23.40μmol,2.57μL,0.05eq)和三氯异氰尿酸(51.11mg,219.93μmol,0.47eq)，油浴升温到40℃搅拌2小时。取锥形瓶，加入20mL水，倒入反应液，用20mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化，馏分减压浓缩得到化合物15d(0.14g,产率67.78％) Compound 15c (0.2g, 467.94μmol, 1eq) was dissolved in acetonitrile (1mL), and 1,4-diazabicyclo[2.2.2]octane (2.62mg, 23.40μmol, 2.57μL, 0.05eq) was added. and trichloroisocyanuric acid (51.11 mg, 219.93 μmol, 0.47 eq), and the oil bath was heated to 40°C and stirred for 2 hours. Take a conical flask, add 20 mL of water, pour the reaction solution, extract with 20 mL of ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain compound 15d (0.14g, yield 67.78%)
步骤5：化合物15e-1和15e-2的合成Step 5: Synthesis of Compounds 15e-1 and 15e-2
化合物15d进行SFC拆分(分离条件：DAICEL CHIRALCEL OJ 250mm*30mm*10μm；流动相:[Neu-EtOH(0.1％NH3·H2O)]％:42％-42％,6min)，拆分后的馏分分别减压浓缩得到化合物15e-1(30mg,10.71％产率)和15e-2(40mg,产率14.29％)Compound 15d was subjected to SFC separation (separation conditions: DAICEL CHIRALCEL OJ 250mm*30mm*10μm; mobile phase: [Neu-EtOH (0.1% NH 3 ·H 2 O)]%: 42%-42%, 6min), split The final fractions were concentrated under reduced pressure to obtain compounds 15e-1 (30 mg, 10.71% yield) and 15e-2 (40 mg, 14.29% yield).
分析方法：柱型：Chiralcel OD-3 50mm*4.6mm*3μm；流动相:[A:CO2；B:EtOH(0.1％IPAm,v/v)]；B％:5％,0.2min；5％-50％,1min；50％,1min；50％-5％,0.4min；5％,0.4min；保留时间：1.574min(15e-1)，1.716min(15e-2)。Analysis method: Column type: Chiralcel OD-3 50mm*4.6mm*3μm; mobile phase: [A:CO 2 ; B: EtOH (0.1% IPAm, v/v)]; B%: 5%, 0.2min; 5 %-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; retention time: 1.574min (15e-1), 1.716min (15e-2).
15e-1:1H NMR(400MHz,CDCl3)δ＝10.74(br d,J＝7.5Hz,1H),8.34(s,1H),7.31-7.23(m,1H),6.80-6.67(m,2H),5.92(dd,J＝3.7,13.1Hz,1H),5.64(quin,J＝7.1Hz,1H),5.17(dd,J＝3.7,10.0Hz,1H),4.45-4.38(m,1H),4.35(dd,J＝6.8,8.6Hz,1H),3.69-3.60(m,1H),3.21(dd,J＝9.9,13.1Hz,1H),1.55(d,J＝7.0Hz,3H),1.39(d,J＝6.1Hz,3H).15e-1: 1 H NMR (400MHz, CDCl 3 ) δ = 10.74 (br d, J = 7.5Hz, 1H), 8.34 (s, 1H), 7.31-7.23 (m, 1H), 6.80-6.67 (m, 2H),5.92(dd,J＝3.7,13.1Hz,1H),5.64(quin,J＝7.1Hz,1H),5.17(dd,J＝3.7,10.0Hz,1H),4.45-4.38(m,1H ),4.35(dd,J＝6.8,8.6Hz,1H),3.69-3.60(m,1H),3.21(dd,J＝9.9,13.1Hz,1H),1.55(d,J＝7.0Hz,3H) ,1.39(d,J＝6.1Hz,3H).
15e-2:1H NMR(400MHz,CDCl3)δ＝10.74(br d,J＝8.0Hz,1H),8.34(s,1H),7.37-7.24(m,1H),6.81-6.69(m,2H),5.90(dd,J＝3.8,13.1Hz,1H),5.64(quin,J＝7.2Hz,1H),5.14(dd,J＝3.8,9.9Hz,1H),4.47-4.31(m,2H),3.64(t,J＝8.0Hz,1H),3.23(dd,J＝9.9,13.1Hz,1H),1.55(d,J＝6.9Hz,3H),1.39(d,J＝6.1Hz,3H).15e-2: 1 H NMR (400MHz, CDCl 3 ) δ = 10.74 (br d, J = 8.0Hz, 1H), 8.34 (s, 1H), 7.37-7.24 (m, 1H), 6.81-6.69 (m, 2H),5.90(dd,J＝3.8,13.1Hz,1H),5.64(quin,J＝7.2Hz,1H),5.14(dd,J＝3.8,9.9Hz,1H),4.47-4.31(m,2H ),3.64(t,J＝8.0Hz,1H),3.23(dd,J＝9.9,13.1Hz,1H),1.55(d,J＝6.9Hz,3H),1.39(d,J＝6.1Hz,3H ).
步骤6：化合物15A的合成Step 6: Synthesis of Compound 15A
将化合物15e-1(30mg,64.96μmol,1eq)溶解于无水四氢呋喃(2mL)中，加入氢氧化钠(12.99mg,324.78μmol,5eq)，60℃搅拌12小时。取锥形瓶，加入10mL水，倒入反应液，加入10mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物，粗产品通过反向制备液相色谱分离(分离条件:Phenomenex Luna C18 75*30mm*3μm；流动相:[H2O(0.04％HCl)-ACN]；ACN:40％-80％,8.0min)，馏分直接冻干得到化合物15A(2个平行反应共同处理得到7mg,产率12.03％).MS(ESI,m/z):444.0[M+1].Compound 15e-1 (30 mg, 64.96 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2 mL), sodium hydroxide (12.99 mg, 324.78 μmol, 5 eq) was added, and the mixture was stirred at 60°C for 12 hours. Take the Erlenmeyer flask, add 10 mL of water, pour the reaction solution, add 10 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the residue. The crude product is prepared in reverse order Liquid chromatography separation (separation conditions: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; ACN: 40%-80%, 8.0min), and the fractions were directly freeze-dried. Compound 15A (2 parallel reactions were performed together to obtain 7 mg, yield 12.03%). MS (ESI, m/z): 444.0 [M+1].
1H NMR(400MHz,CDCl3)δ＝12.00(s,1H),11.91-11.81(m,1H),8.60-8.30(m,1H),7.76-7.63(m,1H),6.88-6.77(m,2H),6.02-5.93(m,2H),5.28-5.15(m,1H),4.55-4.39(m,2H),3.80-3.65(m,1H),3.39-3.27(m,1H),1.72(br d,J＝6.4Hz,3H),1.48(d,J＝5.7Hz,3H) 1 H NMR (400MHz, CDCl 3 ) δ = 12.00 (s, 1H), 11.91-11.81 (m, 1H), 8.60-8.30 (m, 1H), 7.76-7.63 (m, 1H), 6.88-6.77 (m ,2H),6.02-5.93(m,2H),5.28-5.15(m,1H),4.55-4.39(m,2H),3.80-3.65(m,1H),3.39-3.27(m,1H),1.72 (br d,J＝6.4Hz,3H),1.48(d,J＝5.7Hz,3H)
实施例15B
Example 15B
合成路线：
synthetic route:
以15e-2为原料参照实施例15A的合成制备得到化合物15B。MS(ESI,m/z):444.0[M+1]。1H NMR(400MHz,CDCl3)δ＝11.67(s,1H),10.99-10.83(m,1H),8.34-8.28(m,1H),7.39-7.27(m,1H),6.84-6.76(m,2H),5.95(dd,J＝4.3,12.8Hz,1H),5.75-5.65(m,1H),5.20-5.12(m,1H),4.48-4.41(m,2H),3.73-3.68(m,1H),3.29-3.17(m,1H),1.60(d,J＝6.8Hz,3H),1.47(d,J＝5.7Hz,3H).Compound 15B was prepared by using 15e-2 as a raw material and referring to the synthesis of Example 15A. MS(ESI,m/z):444.0[M+1]. 1 H NMR (400MHz, CDCl 3 ) δ = 11.67 (s, 1H), 10.99-10.83 (m, 1H), 8.34-8.28 (m, 1H), 7.39-7.27 (m, 1H), 6.84-6.76 (m ,2H),5.95(dd,J＝4.3,12.8Hz,1H),5.75-5.65(m,1H),5.20-5.12(m,1H),4.48-4.41(m,2H),3.73-3.68(m ,1H),3.29-3.17(m,1H),1.60(d,J＝6.8Hz,3H),1.47(d,J＝5.7Hz,3H).
实施例16
Example 16
合成路线：
synthetic route:
步骤1：化合物16b的合成Step 1: Synthesis of Compound 16b
在预先干燥的三口瓶中加入原料1-溴-3,5-二氟-2-碘苯(16a,15g,47.04mmol,1eq)和溶剂四氢呋喃(150mL)，随后在0℃下加入异丙镁氯化锂络合物溶液(1.3M,37.98mL,1.05eq)，搅拌0.5个小时，加入N-甲酰***啉(1.97g,51.27mmol,5.13mL,1.09eq)，升到25℃搅拌2个小时。反应液用盐酸(1M水溶液)淬灭，用60mL水稀释，再用100mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，硫酸钠干燥，过滤，减压浓缩得到残余物。得到粗品16b(8g).Add the raw material 1-bromo-3,5-difluoro-2-iodobenzene (16a, 15g, 47.04mmol, 1eq) and the solvent tetrahydrofuran (150mL) to the pre-dried three-necked flask, and then add isopropyl magnesium at 0°C. Lithium chloride complex solution (1.3M, 37.98mL, 1.05eq), stir for 0.5 hours, add N-formylmorpholine (1.97g, 51.27mmol, 5.13mL, 1.09eq), raise to 25°C and stir for 2 Hours. The reaction solution was quenched with hydrochloric acid (1M aqueous solution), diluted with 60 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Crude product 16b (8g) was obtained.
MS(ESI,m/z):221.0[M+1].MS(ESI,m/z):221.0[M+1].
步骤2：化合物16c的合成Step 2: Synthesis of Compound 16c
在预先干燥的单口瓶中加入16b(6g,27.14mmol,1eq)，加入溶剂乙醇(100mL)，随后加入试剂盐酸羟胺(5.66g,81.44mmol,3eq)和无水乙酸钠(8.9g,108.6mmol,4eq)，反应在80℃下搅拌2个小时。取锥形瓶，加入200mL水，倒入反应液，加入200mL乙酸乙酯萃取，有机相用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(乙酸乙酯:石油醚＝3:1)分离得到16c(2个平行反应共同处理得到2.9g，产率45.26％)。MS(ESI,m/z):236.01[M+1].Add 16b (6g, 27.14mmol, 1eq) to the pre-dried single-neck bottle, add the solvent ethanol (100mL), and then add the reagents hydroxylamine hydrochloride (5.66g, 81.44mmol, 3eq) and anhydrous sodium acetate (8.9g, 108.6mmol ,4eq), the reaction was stirred at 80°C for 2 hours. Take an Erlenmeyer flask, add 200 mL of water, pour the reaction solution, add 200 mL of ethyl acetate for extraction, wash the organic phase with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain 16c (2.9 g was obtained by two parallel reactions together, yield 45.26%). MS(ESI,m/z):236.01[M+1].
步骤3：化合物16d的合成Step 3: Synthesis of Compound 16d
在预先干燥过的单口瓶中加入16c(3.4g,14.4mmol,1eq)，溶于乙醇(40mL)和乙酸(30mL)的混合溶液中，开启搅拌，随后加入锌粉(3.76g,57.62mmol,4eq)，反应在25℃下搅拌2个小时。将反应液过滤，过滤掉的锌粉必须用0.1～1M浓度的盐酸淬灭，沾过锌粉的称量纸或者勺可以用很稀的盐酸洗涤后即可。 滤液用饱和的碳酸氢钠溶液调节至pH＝8，然后用150mL乙酸乙酯萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝3:1)纯化，馏分减压浓缩得到16d(2个平行反应共同处理得到2.4g，产率75.03％)。Add 16c (3.4g, 14.4mmol, 1eq) to a pre-dried single-neck bottle, dissolve it in a mixed solution of ethanol (40mL) and acetic acid (30mL), start stirring, and then add zinc powder (3.76g, 57.62mmol, 4eq), the reaction was stirred at 25°C for 2 hours. Filter the reaction solution, and the filtered zinc powder must be quenched with hydrochloric acid at a concentration of 0.1 to 1M. The weighing paper or spoon stained with zinc powder can be washed with very dilute hydrochloric acid. The filtrate was adjusted to pH=8 with saturated sodium bicarbonate solution, and then extracted three times with 150 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1), and the fraction was concentrated under reduced pressure to obtain 16d (2.4 g was obtained by two parallel reactions, with a yield of 75.03%).
MS(ESI,m/z):221.8[M+1].MS(ESI,m/z):221.8[M+1].
步骤4：化合物16e的合成Step 4: Synthesis of Compound 16e
在预先干燥的单口瓶中加入2f(1.54g,4.75mmol,1eq)溶于N，N-二甲基甲酰胺(10mL)中，加入16d(1.586g,7.14mmol,1.5eq)和三乙胺(1.446g,14.3mmol,1.989mL,3eq)，35℃搅拌12个小时。取锥形瓶，加入100mL水，倒入反应液，加入100mL乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝10:1)纯化，馏分减压浓缩得到16e(2.1g,产率85.89％)。MS(ESI,m/z):512.9[M+1].Add 2f (1.54g, 4.75mmol, 1eq) and dissolve it in N,N-dimethylformamide (10mL) into a pre-dried single-neck bottle. Add 16d (1.586g, 7.14mmol, 1.5eq) and triethylamine. (1.446g, 14.3mmol, 1.989mL, 3eq), stir at 35°C for 12 hours. Take an Erlenmeyer flask, add 100 mL of water, pour the reaction solution, add 100 mL of ethyl acetate for extraction three times, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1), and the fraction was concentrated under reduced pressure to obtain 16e (2.1 g, yield 85.89%). MS(ESI,m/z):512.9[M+1].
步骤5：化合物16g的合成Step 5: Synthesis of compound 16g
在预先干燥的三口瓶中加入16e(1.2g,2.338mmol,1eq)溶于乙酸(2mL)中，加入甲磺酸(67.4mg,701.36μmol,49.92μL,0.3eq)，反应在65℃下反应24个小时，得到16f。降温至20℃向溶液中加入1,2-二氯乙烷(6mL)和L-氨基丙醇(346.47mg,4.62mmol,359.04μL,2eq)取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，馏分减压浓缩得到16g(三个平行反应共同处理得到0.5g，产率44.04％)。MS(ESI,m/z):491.9[M+1].In a pre-dried three-necked flask, add 16e (1.2g, 2.338mmol, 1eq) and dissolve it in acetic acid (2mL). Add methanesulfonic acid (67.4mg, 701.36μmol, 49.92μL, 0.3eq) and react at 65°C. 24 hours, get 16f. Cool the temperature to 20°C and add 1,2-dichloroethane (6mL) and L-aminopropanol (346.47mg, 4.62mmol, 359.04μL, 2eq) into the solution. Take a conical flask, add 20mL water, and pour the reaction solution , add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain 16 g (three parallel reactions were processed together to obtain 0.5 g, yield 44.04%). MS(ESI,m/z):491.9[M+1].
步骤6：化合物16h的合成Step 6: Synthesis of compound 16h
在预先干燥过的单口瓶中加入16g(37mg,75.16μmol,1eq)和溶剂乙腈(1mL)，随后加入三氯异氰尿酸(8.21mg,35.33μmol,0.47eq)，1,4-二氮杂二环[2,2,2]辛烷(421.54μg,3.76μmol,4.13e-1μL,0.05eq)，氮气置换3次，置于40℃下反应1个小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，馏分减压浓缩得到16h(28mg，产率70.73％)。MS(ESI,m/z):525.9[M+1].Add 16g (37mg, 75.16μmol, 1eq) and solvent acetonitrile (1mL) to a pre-dried single-neck bottle, then add trichloroisocyanuric acid (8.21mg, 35.33μmol, 0.47eq), 1,4-diazapine Bicyclo[2,2,2]octane (421.54μg, 3.76μmol, 4.13e-1μL, 0.05eq), replaced with nitrogen three times, and reacted at 40°C for 1 hour. Take an Erlenmeyer flask, add 20 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain 16h (28 mg, yield 70.73%). MS(ESI,m/z):525.9[M+1].
步骤9：化合物16的合成Step 9: Synthesis of Compound 16
准备一个干燥的单口瓶，加入16h(28mg,53.16μmol,1eq)和溶剂四氢呋喃(1mL)，随后加入氢氧化钠(10.63mg,265.80μmol,5eq)，氮气置换3次，置于60℃反应12个小时。取锥形瓶，加入20mL水，倒入反应液，加入20mL二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到残余物。粗品经制备反向液相色谱(分离条件:Phenomenex Luna 80*30mm*3μm；流动相:[H2O(HCl)-ACN]；B％:35％-65％,8min)分离纯化，得到16(0.003g,产率11.1％)。MS(ESI,m/z):507.9 [M+1].Prepare a dry single-mouth bottle, add 16h (28 mg, 53.16 μmol, 1 eq) and solvent tetrahydrofuran (1 mL), then add sodium hydroxide (10.63 mg, 265.80 μmol, 5 eq), replace with nitrogen 3 times, and place at 60 ° C for 12 hours. Take a conical flask, add 20 mL of water, pour in the reaction solution, add 20 mL of dichloromethane for extraction, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The crude product was separated and purified by preparative reverse liquid chromatography (separation conditions: Phenomenex Luna 80*30mm*3μm; mobile phase: [H 2 O(HCl)-ACN]; B%: 35%-65%, 8min) to obtain 16 (0.003 g, yield 11.1%). MS (ESI, m/z): 507.9 [M+1].
实施例17
Example 17
合成路线：
synthetic route:
步骤1：化合物17a的合成Step 1: Synthesis of compound 17a
在氮气保护下，在干燥的三口瓶中加入2,4,6-三氟苯腈(10g,63.66mmol,1eq)和2-甲基四氢呋喃(160mL)，开启搅拌，随后加入钛酸四异丙酯(19.90g,70.02mmol,20.67mL,1.1eq)，25℃搅拌7分钟。缓慢滴加乙基溴化镁(3M,46.05mL,2.17eq)，25℃搅拌55分钟。缓慢滴加三氟化硼***(18.07g,127.31mmol,15.71mL,2eq)，25℃搅拌55分钟。反应液中加入氯化铵(30mL)淬灭反应，加入氯化氢(1M)调节体系pH到1。加入甲基叔丁基醚(40mL*3)萃取，合并有机相，用饱和食盐水溶液(40mL×3)洗涤，无水硫酸镁干燥后过滤，减压浓缩得到粗品17a(1.55g,产率13.01％)。MS(ESI,m/z):187.9[M+1].Under nitrogen protection, add 2,4,6-trifluorobenzonitrile (10g, 63.66mmol, 1eq) and 2-methyltetrahydrofuran (160mL) into a dry three-necked flask, start stirring, and then add tetraisopropyl titanate Ester (19.90g, 70.02mmol, 20.67mL, 1.1eq), stirred at 25°C for 7 minutes. Ethylmagnesium bromide (3M, 46.05mL, 2.17eq) was slowly added dropwise, and stirred at 25°C for 55 minutes. Slowly add boron trifluoride ether (18.07g, 127.31mmol, 15.71mL, 2eq) dropwise, and stir at 25°C for 55 minutes. Ammonium chloride (30 mL) was added to the reaction solution to quench the reaction, and hydrogen chloride (1M) was added to adjust the pH of the system to 1. Add methyl tert-butyl ether (40mL*3) for extraction, combine the organic phases, wash with saturated aqueous sodium chloride solution (40mL*3), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain crude product 17a (1.55g, yield 13.01 %). MS(ESI,m/z):187.9[M+1].
1H NMR(400MHz,DMSO-d6)δ＝7.16-7.03(m,2H),2.28(br s,2H),0.94-0.83(m,2H),0.77-0.72(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 7.16-7.03 (m, 2H), 2.28 (br s, 2H), 0.94-0.83 (m, 2H), 0.77-0.72 (m, 2H).
步骤2：化合物17b的合成Step 2: Synthesis of Compound 17b
在干燥的三口瓶中加入1d(500mg,1.55mmol,1eq)和DMF(2mL)开启搅拌，加入三乙胺(999.38mg,7.73mmol,1.35mL,5eq)和17a(1.16g,6.19mmol,4eq)，80℃搅拌20个小时。反应液中加入水(10mL)稀释。加入二氯甲烷(10mL×3)萃取，合并有机相，用饱和碳酸氢钠水溶液(10mL×2)洗涤，无水硫酸镁干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:0-1:1)分离，馏分减压浓缩得到17b(274mg，产率37.03％)。MS(ESI,m/z):479.1[M+1].Add 1d (500mg, 1.55mmol, 1eq) and DMF (2mL) to a dry three-necked flask and start stirring. Add triethylamine (999.38mg, 7.73mmol, 1.35mL, 5eq) and 17a (1.16g, 6.19mmol, 4eq). ), stir at 80°C for 20 hours. Water (10 mL) was added to the reaction solution to dilute. Add dichloromethane (10 mL × 3) for extraction, combine the organic phases, wash with saturated aqueous sodium bicarbonate solution (10 mL × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0-1:1), and the fraction was concentrated under reduced pressure to obtain 17b (274 mg, yield 37.03%). MS(ESI,m/z):479.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝10.96(br s,1H),8.50(d,J＝3.3Hz,1H),7.13(br t,J＝8.7Hz,2H),6.56(d,J＝3.5Hz,1H),4.76(br s,2H),4.34(br d,J＝3.5Hz,1H),3.89(br s,3H),3.22(br s,6H),1.33(br s,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.96 (br s, 1H), 8.50 (d, J = 3.3Hz, 1H), 7.13 (br t, J = 8.7Hz, 2H), 6.56 (d, J＝3.5Hz,1H),4.76(br s,2H),4.34(br d,J＝3.5Hz,1H),3.89(br s,3H),3.22(br s,6H),1.33(br s, 4H).
步骤3：化合物17c的合成 Step 3: Synthesis of Compound 17c
在预先干燥过的三口烧瓶中加入17b(509mg,1.06mmol,1eq)和乙酸(5mL)开启搅拌，随后加入甲磺酸(71.57mg,744.74μmol,53.21μL,0.7eq)，65℃搅拌16个小时。加入甲磺酸(40.90mg,425.57μmol,30.41μL,0.4eq)，65℃搅拌16个小时。加入1,2-二氯乙烷(4mL)和L-氨基丙醇(474.50mg,6.32mmol,491.71μL,6eq)，升温到90℃搅拌6个小时。加入L-氨基丙醇(316.34mg,4.21mmol,327.81μL,4eq)，90℃搅拌16个小时。向反应液中加入盐酸(1M,10mL)，再加入二氯甲烷(10mL×3)萃取，合并有机相，用饱和食盐水(15mL×3)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1:0-4:1)分离，馏分减压浓缩得到17c(137mg,产率28.45％)。MS(ESI,m/z):458.1[M+1].Add 17b (509 mg, 1.06 mmol, 1 eq) and acetic acid (5 mL) to the pre-dried three-necked flask and start stirring. Then add methanesulfonic acid (71.57 mg, 744.74 μmol, 53.21 μL, 0.7 eq) and stir at 65°C for 16 seconds. Hour. Add methanesulfonic acid (40.90mg, 425.57μmol, 30.41μL, 0.4eq) and stir at 65°C for 16 hours. Add 1,2-dichloroethane (4mL) and L-aminopropanol (474.50mg, 6.32mmol, 491.71μL, 6eq), raise the temperature to 90°C and stir for 6 hours. Add L-aminopropanol (316.34 mg, 4.21 mmol, 327.81 μL, 4 eq) and stir at 90°C for 16 hours. Add hydrochloric acid (1M, 10mL) to the reaction solution, then add dichloromethane (10mL×3) for extraction, combine the organic phases, wash with saturated brine (15mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. . The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0-4:1), and the fraction was concentrated under reduced pressure to obtain 17c (137 mg, yield 28.45%). MS(ESI,m/z):458.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.00(s,1H),8.49(s,1H),7.12(t,J＝8.9Hz,2H),6.74(s,1H),5.48(dd,J＝4.4,12.4Hz,1H),5.34(dd,J＝4.3,10.0Hz,1H),4.40(dd,J＝6.8,8.5Hz,1H),4.36-4.23(m,1H),3.65(dd,J＝6.8,8.5Hz,1H),3.55(dd,J＝10.0,12.3Hz,1H),1.33(s,4H),1.32(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.00 (s, 1H), 8.49 (s, 1H), 7.12 (t, J = 8.9Hz, 2H), 6.74 (s, 1H), 5.48 (dd, J＝4.4,12.4Hz,1H),5.34(dd,J＝4.3,10.0Hz,1H),4.40(dd,J＝6.8,8.5Hz,1H),4.36-4.23(m,1H),3.65(dd ,J＝6.8,8.5Hz,1H),3.55(dd,J＝10.0,12.3Hz,1H),1.33(s,4H),1.32(s,3H).
步骤4：化合物17d的合成Step 4: Synthesis of Compound 17d
在干燥的三口瓶中加入17c(130mg,284.21μmol,1eq)和乙腈(1mL)，随后加入三氯异氰尿酸(31.71mg,136.42μmol,0.48eq)和三乙烯二胺(1.59mg,14.21μmol,1.56μL,0.05eq)，氮气置换3次，反应在40℃下搅拌1.5个小时。向反应液中加入水(5mL)，再加入二氯甲烷:甲醇(10:1,5mL×3)萃取，合并有机相，用饱和食盐水(2mL×2)洗涤，无水硫酸镁干燥后过滤，减压浓缩。粗品经制备反向液相色谱(分离条件:Xtimate C18 150*25mm*5μm；流动相:[水(0.05％NH3·H2O+10mM NH4HCO3)-ACN]；B％:44％-74％,11min)分离纯化，得到化合物17d(91mg，产率65.10％)。MS(ESI,m/z):492.1[M+1].Add 17c (130mg, 284.21μmol, 1eq) and acetonitrile (1mL) to a dry three-necked flask, then add trichloroisocyanuric acid (31.71mg, 136.42μmol, 0.48eq) and triethylenediamine (1.59mg, 14.21μmol ,1.56μL,0.05eq), nitrogen was replaced three times, and the reaction was stirred at 40°C for 1.5 hours. Add water (5mL) to the reaction solution, then add methylene chloride: methanol (10:1, 5mL×3) for extraction, combine the organic phases, wash with saturated brine (2mL×2), dry over anhydrous magnesium sulfate and filter , concentrated under reduced pressure. The crude product was subjected to preparative reverse phase liquid chromatography (separation conditions: Xtimate C18 150*25mm*5μm; mobile phase: [water (0.05% NH 3 ·H 2 O+10mM NH 4 HCO 3 )-ACN]; B%: 44% -74%, 11 min) was separated and purified to obtain compound 17d (91 mg, yield 65.10%). MS(ESI,m/z):492.1[M+1].
1H NMR(400MHz,DMSO-d6)δ＝10.87(s,1H),8.52(s,1H),7.12(br t,J＝8.8Hz,2H),5.57(dd,J＝3.6,12.2Hz,1H),5.34(dd,J＝3.9,9.9Hz,1H),4.42-4.35(m,1H),4.35-4.27(m,1H),3.71-3.64(m,1H),3.61(dd,J＝10.0,12.5Hz,1H),1.36(s,3H),1.31(d,J＝6.3Hz,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ＝10.87 (s, 1H), 8.52 (s, 1H), 7.12 (br t, J＝8.8 Hz, 2H), 5.57 (dd, J＝3.6, 12.2 Hz, 1H), 5.34 (dd, J＝3.9, 9.9 Hz, 1H), 4.42-4.35 (m, 1H), 4.35-4.27 (m, 1H), 3.71-3.64 (m, 1H), 3.61 (dd, J＝10.0, 12.5 Hz, 1H), 1.36 (s, 3H), 1.31 (d, J＝6.3 Hz, 4H).
步骤5：化合物17的合成Step 5: Synthesis of Compound 17
在干燥的三口瓶中加入17d(64mg,130.12μmol,1eq)和四氢呋喃(2mL)，随后加入氢氧化钠(26.02mg,650.61μmol,5eq)，氮气置换3次，反应在60℃下搅拌16个小时。向反应液中加入水(5mL)，再加入二氯甲烷(10mL×3)萃取，合并有机相，用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥后过滤，减压浓缩。粗品经制备反向液相色谱(分离条件:Xtimate C18 150*40mm*5μm；流动相:[水(HCl)-ACN]；B％:40％-80％,10min)分离纯化，得到化合物17(10mg，产率16.23％)。17d (64 mg, 130.12 μmol, 1 eq) and tetrahydrofuran (2 mL) were added to a dry three-necked flask, followed by sodium hydroxide (26.02 mg, 650.61 μmol, 5 eq), and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 60 °C for 16 hours. Water (5 mL) was added to the reaction solution, and then dichloromethane (10 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative reverse liquid chromatography (separation conditions: Xtimate C18 150*40mm*5μm; mobile phase: [water (HCl)-ACN]; B%: 40%-80%, 10 min) to obtain compound 17 (10 mg, yield 16.23%).
MS(ESI,m/z):474.2[M+1]. MS(ESI,m/z):474.2[M+1].
1H NMR(400MHz,CD3OD)δ＝8.39(s,1H),6.86(t,J＝8.7Hz,2H),5.86(dd,J＝4.3,12.8Hz,1H),5.32(dd,J＝4.1,9.9Hz,1H),4.58-4.40(m,2H),3.76(dd,J＝6.8,8.3Hz,1H),3.43(dd,J＝10.0,12.8Hz,1H),1.48(d,J＝6.0Hz,4H),1.45(br s,3H). 1 H NMR (400MHz, CD 3 OD) δ = 8.39 (s, 1H), 6.86 (t, J = 8.7Hz, 2H), 5.86 (dd, J = 4.3, 12.8Hz, 1H), 5.32 (dd, J ＝4.1,9.9Hz,1H),4.58-4.40(m,2H),3.76(dd,J＝6.8,8.3Hz,1H),3.43(dd,J＝10.0,12.8Hz,1H),1.48(d, J＝6.0Hz,4H),1.45(br s,3H).
实施例18
Example 18
合成路线：
synthetic route:
步骤1:化合物18b的合成Step 1: Synthesis of Compound 18b
将化合物18a(10g,120.35mmol,1eq)和碳酸钾(18.30g,132.39mmol,1.1eq)加到N,N-二甲基甲酰胺(100mL)中，体系降温至0℃，滴加二硫化碳(10.08g,132.39mmol,8.00mL,1.1eq)，反应在25℃搅拌2小时。反应液过滤后向滤液中加入碘甲烷(34.18g,240.71mmol,14.98mL,2eq)，反应在20℃搅拌2小时。反应液中加入水(200mL)，乙酸乙酯(200mL×2)萃取，有机相用饱和氯化钠溶液(200mL×2)洗涤，减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-70:30)分离得到化合物18b(14.3g，产率63.44％)。MS(ESI,m/z):187.8[M+1].Compound 18a (10g, 120.35mmol, 1eq) and potassium carbonate (18.30g, 132.39mmol, 1.1eq) were added to N,N-dimethylformamide (100mL), the system was cooled to 0°C, and carbon disulfide ( 10.08g, 132.39mmol, 8.00mL, 1.1eq), the reaction was stirred at 25°C for 2 hours. After the reaction liquid was filtered, methyl iodide (34.18g, 240.71mmol, 14.98mL, 2eq) was added to the filtrate, and the reaction was stirred at 20°C for 2 hours. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL × 2), the organic phase was washed with saturated sodium chloride solution (200 mL × 2), and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-70:30) to obtain compound 18b (14.3g, yield 63.44%). MS(ESI,m/z):187.8[M+1].
1H NMR(400MHz,CDCl3)δ＝2.79(s,3H),2.59(s,3H),2.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 2.79 (s, 3H), 2.59 (s, 3H), 2.48 (s, 3H).
步骤2:化合物18c的合成Step 2: Synthesis of Compound 18c
将化合物18b(14g,74.75mmol,1eq)和氨基乙缩醛二甲醇(4.72g,44.85mmol,4.89mL,0.6eq)加到 甲醇(150mL)中，反应在25℃搅拌10分钟。反应液中加入水(200mL)，乙酸乙酯(300mL×2)萃取，有机相用饱和氯化钠溶液(200mL)洗涤，减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-70:30)分离得到化合物18c(11g，产率59.87％)。MS(ESI,m/z):245.0[M+1].Compound 18b (14g, 74.75mmol, 1eq) and aminoacetal dimethanol (4.72g, 44.85mmol, 4.89mL, 0.6eq) were added to The reaction was stirred in methanol (150 mL) at 25°C for 10 min. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (300 mL × 2), the organic phase was washed with saturated sodium chloride solution (200 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-70:30) to obtain compound 18c (11g, yield 59.87%). MS(ESI,m/z):245.0[M+1].
1H NMR(400MHz,CDCl3)δ＝4.47(t,J＝5.1Hz,1H),3.75(t,J＝5.5Hz,2H),3.45(s,6H),2.70(s,3H),2.37(s,3H),2.36(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 4.47 (t, J = 5.1Hz, 1H), 3.75 (t, J = 5.5Hz, 2H), 3.45 (s, 6H), 2.70 (s, 3H), 2.37 (s,3H),2.36(s,3H).
步骤3:化合物18d的合成Step 3: Synthesis of Compound 18d
将化合物18c(10g,40.93mmol,1eq)加到乙醇(50mL)和水(50mL)中，体系降温至0℃，加入50％羟胺水溶液(2.70g,40.93mmol,1eq)，反应在25℃搅拌2小时。反应液中加入水(200mL)，乙酸乙酯(300mL×2)萃取，有机相用饱和氯化钠溶液(200mL)洗涤，减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-50:50)分离得到化合物18d(6g,产率56.46％)。MS(ESI,m/z):251.9[M+23].Compound 18c (10g, 40.93mmol, 1eq) was added to ethanol (50mL) and water (50mL), the system was cooled to 0°C, 50% hydroxylamine aqueous solution (2.70g, 40.93mmol, 1eq) was added, and the reaction was stirred at 25°C. 2 hours. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (300 mL × 2), the organic phase was washed with saturated sodium chloride solution (200 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-50:50) to obtain compound 18d (6g, yield 56.46%). MS(ESI,m/z):251.9[M+23].
1H NMR(400MHz,DMSO-d6)δ＝7.76(s,2H),6.26(br t,J＝5.8Hz,1H),4.52(t,J＝5.4Hz,1H),3.28(s,6H),3.15(t,J＝5.8Hz,2H),2.23(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ＝7.76(s, 2H), 6.26(br t, J＝5.8 Hz, 1H), 4.52(t, J＝5.4 Hz, 1H), 3.28(s, 6H), 3.15(t, J＝5.8 Hz, 2H), 2.23(s, 3H).
步骤4:化合物18e的合成Step 4: Synthesis of Compound 18e
将化合物18d(14.2g,61.95mmol,1eq)、4-二甲氨基吡啶(2.27g,18.58mmol,0.3eq)加到四氢呋喃(150mL)中，再加入二碳酸二叔丁酯(20.28g,92.92mmol,21.35mL,1.5eq)，反应在-30℃搅拌1小时。反应液用柠檬酸水溶液调节pH＝5-6，乙酸乙酯(200mL×2)萃取。有机相用饱和氯化钠溶液(200mL×2)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-50:50)分离得到化合物18e(4g,产率19.12％)。MS(ESI,m/z):351.9[M+23].Add compound 18d (14.2g, 61.95mmol, 1eq) and 4-dimethylaminopyridine (2.27g, 18.58mmol, 0.3eq) to tetrahydrofuran (150mL), and then add di-tert-butyl dicarbonate (20.28g, 92.92 mmol, 21.35mL, 1.5eq), the reaction was stirred at -30°C for 1 hour. The reaction solution was adjusted to pH=5-6 with citric acid aqueous solution, and extracted with ethyl acetate (200 mL×2). The organic phase was washed with saturated sodium chloride solution (200 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-50:50) to obtain compound 18e (4g, yield 19.12%). MS(ESI,m/z):351.9[M+23].
1H NMR(400MHz,DMSO-d6)δ＝10.56(s,1H),6.26(t,J＝6.0Hz,1H),4.56(t,J＝5.4Hz,1H),3.29(s,6H),3.22(t,J＝5.8Hz,2H),2.31(s,3H),1.47(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.56 (s, 1H), 6.26 (t, J = 6.0Hz, 1H), 4.56 (t, J = 5.4Hz, 1H), 3.29 (s, 6H) ,3.22(t,J＝5.8Hz,2H),2.31(s,3H),1.47(s,9H).
步骤5:化合物18f的合成Step 5: Synthesis of Compound 18f
将化合物18e(4.5g,13.66mmol,1eq)溶于四氢呋喃(35mL)中，加入草酸二甲酯(3.23g,27.33mmol,2eq)和叔丁醇钾的四氢呋喃溶液(1M,27.33mL,2eq)，反应在20℃搅拌0.5小时。加入水(50mL)，乙酸乙酯(50mL×2)萃取，有机相用饱和氯化钠溶液(50mL×2)洗涤，然后用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-70:30)分离得到化合物18f(两个平行反应共同处理得到7g,产率61.48％)。MS(ESI,m/z):438.1[M+23].Compound 18e (4.5g, 13.66mmol, 1eq) was dissolved in tetrahydrofuran (35mL), and dimethyl oxalate (3.23g, 27.33mmol, 2eq) and potassium tert-butoxide in tetrahydrofuran (1M, 27.33mL, 2eq) were added. , the reaction was stirred at 20°C for 0.5 hours. Water (50 mL) was added, extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-70:30) to obtain compound 18f (two parallel reactions were processed together to obtain 7 g, yield 61.48%). MS(ESI,m/z):438.1[M+23].
1H NMR(400MHz,DMSO-d6)δ＝10.67(s,1H),7.30(s,1H),4.60(t,J＝5.3Hz,1H),3.67(s,3H),3.28(d,J＝6.5Hz,6H),2.95-2.89(m,1H),2.85-2.78(m,1H),1.44(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.67 (s, 1H), 7.30 (s, 1H), 4.60 (t, J = 5.3Hz, 1H), 3.67 (s, 3H), 3.28 (d, J＝6.5Hz,6H),2.95-2.89(m,1H),2.85-2.78(m,1H),1.44(s,9H).
步骤6:化合物18g的合成 Step 6: Synthesis of compound 18g
将化合物18f(7g,18.85mmol,1eq)加到四氢呋喃(70mL)中，再加入三氟乙酸(48.84g,428.34mmol,31.82mL,25.42eq)。反应在20℃搅拌1小时。反应液用饱和碳酸氢钠溶液调节pH＝7-8，水相用乙酸乙酯(20mL×2)萃取，有机相用饱和氯化钠溶液(20mL×2)洗涤，然后用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-50:50)分离得到化合物18g(5.7g,产率85.12％)。MS(ESI,m/z):420.0[M+23].Compound 18f (7g, 18.85mmol, 1eq) was added to tetrahydrofuran (70mL), and then trifluoroacetic acid (48.84g, 428.34mmol, 31.82mL, 25.42eq) was added. The reaction was stirred at 20°C for 1 hour. The reaction solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phase was washed with saturated sodium chloride solution (20mL×2), and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-50:50) to obtain compound 18g (5.7g, yield 85.12%). MS(ESI,m/z):420.0[M+23].
步骤7:化合物18h的合成Step 7: Synthesis of Compound 18h
将化合物18g(4.5g,11.32mmol,1eq)加到乙腈(35mL)中，再加入乙酸(35mL)和甲磺酸(544.18mg,5.66mmol,404.60μL,0.5eq)，反应在65℃搅拌1小时。反应降温至20℃，加入L-氨基丙醇(8.51g,113.24mmol,8.81mL,10eq)的乙腈(10mL)溶液，反应继续在20℃搅拌1小时。反应液用饱和碳酸氢钠溶液调节pH＝7-8，乙酸乙酯(50mL×2)萃取，有机相用饱和氯化钠溶液(50mL)洗涤，然后用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-70:30)分离得到化合物18h(2.5g,产率72.92％)。MS(ESI,m/z):276.9[M+1].Add compound 18g (4.5g, 11.32mmol, 1eq) to acetonitrile (35mL), then add acetic acid (35mL) and methanesulfonic acid (544.18mg, 5.66mmol, 404.60μL, 0.5eq), and the reaction is stirred at 65°C for 1 Hour. The reaction temperature was cooled to 20°C, a solution of L-aminopropanol (8.51g, 113.24mmol, 8.81mL, 10eq) in acetonitrile (10mL) was added, and the reaction was continued to stir at 20°C for 1 hour. The reaction solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50mL×2), the organic phase was washed with saturated sodium chloride solution (50mL), then dried over anhydrous sodium sulfate and filtered, and the filtrate was reduced to Concentrate under pressure to obtain crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-70:30) to obtain compound 18h (2.5g, yield 72.92%). MS(ESI,m/z):276.9[M+1].
1HNMR(400MHz,DMSO-d6)δ＝8.50(br s,2H),6.12(s,1H),5.38(dd,J＝4.6,9.8Hz,1H),4.39-4.30(m,2H),4.29-4.23(m,1H),3.65-3.56(m,2H),1.30(d,J＝6.3Hz,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ = 8.50 (br s, 2H), 6.12 (s, 1H), 5.38 (dd, J = 4.6, 9.8Hz, 1H), 4.39-4.30 (m, 2H), 4.29-4.23(m,1H),3.65-3.56(m,2H),1.30(d,J＝6.3Hz,3H).
步骤8:化合物18i的合成Step 8: Synthesis of Compound 18i
将化合物18h(500mg,1.81mmol,1eq)溶于四氢呋喃(7.5mL)中，氮气置换后体系降温至0℃，加入氢化钠(108.60mg,2.71mmol,60％含量,1.5eq)，反应在0℃搅拌0.5小时，再加入2,4-二氟苄溴(374.69mg,1.81mmol,1eq)的四氢呋喃(1mL)溶液。反应在20℃搅拌12小时。反应液加到水(20mL)中淬灭，乙酸乙酯(20mL×2)萃取，有机相用饱和氯化钠溶液(20mL×2)萃取，然后用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-50:50)分离得到化合物18i(300mg,产率41.20％)。MS(ESI,m/z):402.9[M+1].Compound 18h (500 mg, 1.81 mmol, 1 eq) was dissolved in tetrahydrofuran (7.5 mL). After nitrogen replacement, the system was cooled to 0°C. Sodium hydride (108.60 mg, 2.71 mmol, 60% content, 1.5 eq) was added, and the reaction was carried out at 0 Stir for 0.5 hours at ℃, and then add a solution of 2,4-difluorobenzyl bromide (374.69 mg, 1.81 mmol, 1 eq) in tetrahydrofuran (1 mL). The reaction was stirred at 20°C for 12 hours. The reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was extracted with saturated sodium chloride solution (20 mL × 2), then dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed. Concentrate to obtain crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 100:0-50:50) to obtain compound 18i (300 mg, yield 41.20%). MS(ESI,m/z):402.9[M+1].
1H NMR(400MHz,DMSO-d6)δ＝9.32(br s,1H),7.43(dt,J＝6.8,8.7Hz,1H),7.25(ddd,J＝2.6,9.5,10.5Hz,1H),7.09(tt,J＝1.4,8.5Hz,1H),6.15(s,1H),5.37(dd,J＝4.5,9.8Hz,1H),4.66(br s,2H),4.40-4.30(m,2H),4.29-4.24(m,1H),3.64-3.56(m,2H),1.30(d,J＝6.3Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.32 (br s, 1H), 7.43 (dt, J = 6.8, 8.7Hz, 1H), 7.25 (ddd, J = 2.6, 9.5, 10.5Hz, 1H) ,7.09(tt,J＝1.4,8.5Hz,1H),6.15(s,1H),5.37(dd,J＝4.5,9.8Hz,1H),4.66(br s,2H),4.40-4.30(m, 2H),4.29-4.24(m,1H),3.64-3.56(m,2H),1.30(d,J＝6.3Hz,3H).
步骤9:化合物18j的合成Step 9: Synthesis of Compound 18j
化合物18i(300mg,745.62μmol,1eq)溶于乙腈(6mL)中，然后加入三氯异氰尿酸(58.92mg,253.51μmol,0.34eq)和三乙烯二胺(4.18mg,37.28μmol,4.10μL,0.05eq)。反应在20℃搅拌1小时。反应液中加入水(20mL)，二氯甲烷(20mL×2)萃取。有机相减压浓缩得到粗品。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-90:10)分离得到化合物18j(两个平行反应共同处理得到350mg,产率43.69％)。MS(ESI,m/z): 436.8[M+1]。1H NMR(400MHz,DMSO-d6)δ＝9.56(t,J＝6.1Hz,1H),7.49-7.41(m,1H),7.30-7.23(m,1H),7.10(dt,J＝1.6,8.6Hz,1H),5.40(dd,J＝4.0,9.8Hz,1H),4.66(br s,2H),4.38-4.25(m,3H),3.69-3.60(m,2H),1.30(d,J＝6.0Hz,3H).Compound 18i (300 mg, 745.62 μmol, 1 eq) was dissolved in acetonitrile (6 mL), and then trichloroisocyanuric acid (58.92 mg, 253.51 μmol, 0.34 eq) and triethylenediamine (4.18 mg, 37.28 μmol, 4.10 μL) were added. 0.05eq). The reaction was stirred at 20°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was concentrated under reduced pressure to obtain crude product. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 100:0-90:10) to obtain compound 18j (two parallel reactions were processed together to obtain 350 mg, yield 43.69%). MS(ESI,m/z): 436.8[M+1]. 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.56 (t, J = 6.1 Hz, 1H), 7.49-7.41 (m, 1H), 7.30-7.23 (m, 1H), 7.10 (dt, J = 1.6 ,8.6Hz,1H),5.40(dd,J＝4.0,9.8Hz,1H),4.66(br s,2H),4.38-4.25(m,3H),3.69-3.60(m,2H),1.30(d ,J＝6.0Hz,3H).
步骤10:化合物18的合成Step 10: Synthesis of Compound 18
将化合物18j(20mg,45.79μmol,1eq)加到环丁砜(2mL)中，再加入氢氧化钠(45.78mg,1.14mmol,25eq)，反应在80℃搅拌20小时。向反应液中加入水(20mL)中，用柠檬酸溶液调节pH＝4-5，乙酸乙酯(20mL)萃取，有机相用水(20mL×2)洗涤，然后用无水硫酸干燥后过滤，滤液减压浓缩得到粗品。粗品经制备反向液相色谱(分离条件:Welch Xtimate C18 150×30mm×5μm；流动相:[H2O(FA)-ACN]；ACN％:20％-60％；9min)分离得到化合物18(三个平行反应共同处理得到4mg,产率6.46％)。MS(ESI,m/z):418.9[M+1].Compound 18j (20 mg, 45.79 μmol, 1 eq) was added to sulfolane (2 mL), then sodium hydroxide (45.78 mg, 1.14 mmol, 25 eq) was added, and the reaction was stirred at 80°C for 20 hours. Add water (20 mL) to the reaction solution, adjust pH = 4-5 with citric acid solution, extract with ethyl acetate (20 mL), wash the organic phase with water (20 mL × 2), then dry with anhydrous sulfuric acid and filter, the filtrate Concentrate under reduced pressure to obtain crude product. The crude product was separated by preparative reverse phase liquid chromatography (separation conditions: Welch Xtimate C18 150×30mm×5μm; mobile phase: [H 2 O(FA)-ACN]; ACN%: 20%-60%; 9 min) to obtain compound 18 (Three parallel reactions were processed together to obtain 4 mg, with a yield of 6.46%). MS(ESI,m/z):418.9[M+1].
1H NMR(400MHz,DMSO-d6)δ＝11.59(s,1H),9.86-9.15(m,1H),7.43(br d,J＝7.5Hz,1H),7.25(br t,J＝10.0Hz,1H),7.18-7.05(m,1H),5.37-5.28(m,1H),4.64(br s,2H),4.43-4.36(m,1H),4.31(br dd,J＝4.6,11.4Hz,2H),3.68-3.59(m,1H),3.50-3.41(m,1H),1.34(br d,J＝6.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.59 (s, 1H), 9.86-9.15 (m, 1H), 7.43 (br d, J = 7.5Hz, 1H), 7.25 (br t, J = 10.0 Hz,1H),7.18-7.05(m,1H),5.37-5.28(m,1H),4.64(br s,2H),4.43-4.36(m,1H),4.31(br dd,J＝4.6,11.4 Hz,2H),3.68-3.59(m,1H),3.50-3.41(m,1H),1.34(br d,J＝6.0Hz,3H).
生物测试biological testing
实验例1：使用HIV假病毒(PsV)***评价受试化合物体外抗病毒的活性Experimental Example 1: Using HIV pseudovirus (PsV) system to evaluate the in vitro antiviral activity of test compounds
通过测定化合物的半数有效浓度(EC50)值来评价化合物对HIV假病毒的抗病毒活性。HIV假病毒报告基因实验被广泛用于早期筛选，替代HIV病毒实验来评价化合物的抗HIV病毒活性。The antiviral activity of the compounds against HIV pseudovirus was evaluated by determining the half effective concentration (EC 50 ) value of the compounds. HIV pseudovirus reporter gene experiments are widely used in early screening, replacing HIV virus experiments to evaluate the anti-HIV activity of compounds.
HIV假病毒报告基因实验：HIV pseudovirus reporter gene experiment:
第一天，293T细胞以每孔55,000个细胞，每孔100μL的密度接种到96孔测试板中，并于5％CO2、37℃培养箱中培养过夜。On the first day, 293T cells were seeded into a 96-well test plate at a density of 55,000 cells per well and 100 μL per well, and cultured overnight in a 37°C incubator with 5% CO 2 .
第二天，加入倍比稀释后的化合物(8个浓度点、双复孔)，50μL每孔。随后稀释好的病毒以每孔100TCID50加入细胞，50μL每孔。设置细胞对照(细胞，无化合物处理或病毒感染)，病毒对照(细胞感染病毒，无化合物处理)和培养液对照(只有培养液)。该实验培养液终体积为200μL，培养液中DMSO的终浓度分别为0.5％。细胞于5％CO2、37℃培养箱中培养3天。The next day, add the diluted compound (8 concentration points, double wells), 50 μL per well. Then the diluted virus was added to the cells at 100 TCID50 per well, 50 μL per well. Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (culture medium only). The final volume of the experimental culture medium was 200 μL, and the final concentration of DMSO in the culture medium was 0.5%. Cells were cultured in a 5% CO 2 , 37°C incubator for 3 days.
使用荧光素酶报告基因检测试剂Britelite plus kit(PerkinElmer)检测测试板中每孔荧光素酶活性，数据用于样品抗病毒活性分析。使用细胞活力检测试剂CellTiter Glo，用BioTek酶标仪检测每孔细胞活力，数据用于样品细胞毒性分析。The luciferase reporter gene detection reagent Britelite plus kit (PerkinElmer) was used to detect the luciferase activity in each well of the test plate, and the data was used for antiviral activity analysis of the samples. Cell viability detection reagent CellTiter Glo was used, and a BioTek microplate reader was used to detect cell viability in each well, and the data were used for sample cytotoxicity analysis.
用GraphPad Prism软件绘制剂量-效应曲线。抗体的抗病毒活性(﹪Inhibition)的计算公式如下：抗病毒活性(％)＝(EC50测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100 Dose-response curves were drawn using GraphPad Prism software. The calculation formula for the antiviral activity (﹪Inhibition) of the antibody is as follows: Antiviral activity (%) = (EC 50 test well reading value - average value of virus control) / (average value of cell control - average value of virus control) × 100
EC50值使用GraphPad Prism(version 5)软件，对抗体的抑制活性和细胞活率进行非线性拟合分析，拟合方法为"log(inhibitor)vs.response--Variable slope"。The EC 50 value uses GraphPad Prism (version 5) software to conduct nonlinear fitting analysis of the antibody's inhibitory activity and cell viability. The fitting method is "log(inhibitor) vs. response--Variable slope".
本发明化合物对HIV假病毒的抑制活性见表1。The inhibitory activity of the compounds of the present invention against HIV pseudovirus is shown in Table 1.
表1本发明化合物对HIV假病毒(PsV)的抑制活性
Table 1 Inhibitory activity of compounds of the present invention against HIV pseudovirus (PsV)
结论：本发明化合物在细胞水平抑制HIV假病毒基因复制试验中展示出积极效应。Conclusion: The compounds of the present invention show positive effects in the test of inhibiting HIV pseudovirus gene replication at the cellular level.
实验例2：使用SD大鼠评价受试化合物药代动力学性质Experimental Example 2: Evaluation of pharmacokinetic properties of test compounds using SD rats
本研究选用SD雄性大鼠受试动物，应用LC/MS/MS法定量测定了大鼠经口服给予测试化合物在不同时间点的血浆中的药物浓度，以评价受试药物在大鼠体内的药代动力学特征。In this study, SD male rats were used as test animals, and the LC/MS/MS method was used to quantitatively determine the drug concentration in the plasma of rats after oral administration of test compounds at different time points to evaluate the effects of test drugs in rats. Dynamic characteristics.
将试验化合物的澄清溶液经尾静脉注射到SD大鼠体内(过夜禁食，7-10周龄)，将试验化合物灌胃给予到SD大鼠(过夜禁食，7-10周龄)。动物均于给药后0.083、0.25、0.5、1、2、4、6、8和24小时从颈静脉或尾静脉采血约200μL置于添加了EDTA-K2的抗凝管中，4℃，3200g离心10min取血浆。采用LC-MS/MS法测定血药浓度，使用PhoenixWinNonlin6.3药动学软件，以非房室模开型线性对数梯形法计算相关药代动力学参数。实验结果见表2。 The clear solution of the test compound was injected into SD rats (overnight fasting, 7-10 weeks old) through the tail vein, and the test compound was administered orally to SD rats (overnight fasting, 7-10 weeks old). About 200 μL of blood was collected from the jugular vein or tail vein of the animals at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and placed in anticoagulant tubes with EDTA-K2 added, 4°C, 3200g Centrifuge for 10 minutes to collect plasma. The LC-MS/MS method was used to determine the blood drug concentration, and the PhoenixWinNonlin6.3 pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters using the non-compartmental model open linear logarithmic trapezoidal method. The experimental results are shown in Table 2.
表2本发明化合物在大鼠中的药代动力学参数
Table 2 Pharmacokinetic parameters of the compounds of the present invention in rats
结论：采用大鼠对化合物的药代动力学参数进行测试，结果显示实施例2和5化合物在清除率、半衰期、最大血药浓度和AUC方面均表现较好，与卡博特韦相当。另外，在口服生物利用度上面，实施例2和5化合物分别达到66％和20％，优于卡博特韦9.9％。 Conclusion: The pharmacokinetic parameters of the compounds were tested in rats, and the results showed that the compounds of Examples 2 and 5 performed well in terms of clearance, half-life, maximum blood concentration and AUC, which were comparable to cabotegravir. In addition, in terms of oral bioavailability, the compounds of Examples 2 and 5 reached 66% and 20%, respectively, which was 9.9% better than cabotegravir.

Claims (19)

  1. 式(I)所示化合物、其立体异构体或其药学上可接受的盐，
    The compound represented by formula (I), its stereoisomer or its pharmaceutically acceptable salt,
    其中，是单键或者双键；in, Is it a single bond or a double bond;
    各R1独立地选自H、卤素、CN、OH、NH2、C1-4烷基和C1-4烷氧基，所述C1-4烷基和C1-4烷氧基各自独立地任选被1、2或3个Ra取代；each R 1 is independently selected from H, halogen, CN, OH, NH 2 , C 1-4 alkyl and C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy being each independently optionally substituted with 1, 2 or 3 R a ;
    各Ra独立地选自H、卤素、CN、OH、NH2和-COOH；Each R a is independently selected from H, halogen, CN, OH, NH 2 and -COOH;
    各R2独立地选自H、卤素、CN、OH、NH2、-C(＝O)N(R1a)2、-S(＝O)2N(R1a)2、-N(R1a)C(＝O)N(R1a)2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基各自独立地任选被1、2或3个Rb取代；Each R 2 is independently selected from H, halogen, CN, OH, NH 2 , -C(=O)N(R 1a ) 2 , -S(=O) 2 N(R 1a ) 2 , -N(R 1a )C(=O)N(R 1a ) 2 , C 1-3 alkyl and C 1-3 alkoxy, each of the C 1-3 alkyl and C 1-3 alkoxy is independently optionally 1, 2 or 3 R b substitutions;
    各R1a独立地选自H、C1-3烷基和C1-3烷氧基，其中，所述C1-3烷基和C1-3烷氧基任选被1、2或3个H、卤素、CN、OH或NH2取代；Each R 1a is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 H, halogen, CN, OH or NH 2 substitution;
    各Rb独立地选自H、卤素、CN、OH和NH2；each R b is independently selected from H, halogen, CN, OH and NH 2 ;
    各R3独立地选自H、卤素、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 R c ;
    各Rc独立地选自H、卤素、CN、OH和NH2；Each R c is independently selected from H, halogen, CN, OH and NH 2 ;
    L1选自-(C(R1b)2)p-和C3-5环烷基，所述C3-5环烷基任选被1、2、3或4个Rd取代；L 1 is selected from -(C(R 1b ) 2 ) p - and C 3-5 cycloalkyl, the C 3-5 cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d ;
    各R1b选自H、F、CI、Br、I、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个选自H、F、CI、Br、I、OH和NH2的取代基取代；Each R 1b is selected from H, F, CI, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy The group is optionally substituted by 1, 2 or 3 substituents selected from H, F, CI, Br, I, OH and NH 2 ;
    各Rd独立地选自H、卤素、CN、OH和NH2；Each R d is independently selected from H, halogen, CN, OH and NH 2 ;
    T1选自CH、N、O和S；T 1 is selected from CH, N, O and S;
    T2选自CH和N；T 2 is selected from CH and N;
    m、n和q分别独立地选自0、1、2、3和4；m, n and q are independently selected from 0, 1, 2, 3 and 4;
    p选自1和2；p is selected from 1 and 2;
    环A选自3-10元杂环烷基； Ring A is selected from 3-10 membered heterocycloalkyl;
    环B选自5-6元杂芳基；Ring B is selected from 5-6 membered heteroaryl;
    所述3-10元杂环烷基和5-6元杂芳基分别独立地包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团。The 3-10 membered heterocycloalkyl and 5-6 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms or heteroatom groups independently selected from N, O, S and NH.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，各R1独立地选自H、C1-4烷基和C1-4烷氧基，所述C1-4烷基和C1-4烷氧基各自独立地任选被1、2或3个Ra取代。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from H, C 1-4 alkyl and C 1-4 alkoxy, so The C 1-4 alkyl group and C 1-4 alkoxy group are each independently optionally substituted by 1, 2 or 3 R a .
  3. 根据权利要求2所述化合物、其立体异构体或其药学上可接受的盐，其中，各R1独立地选自H和C1-4烷基，所述C1-4烷基任选被1、2或3个Ra取代。The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optional Replaced by 1, 2 or 3 R a .
  4. 根据权利要求3所述化合物、其立体异构体或其药学上可接受的盐，其中，各R1独立地选自H、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)CH2CH3、-C(CH3)2CH3，所述-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)CH2CH3、-C(CH3)2CH3任选被1、2或3个Ra取代。The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 3 , the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3. -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 3 is optionally substituted by 1, 2 or 3 R a .
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，各R2独立地选自H、F、Cl、Br、I、CN、-C(＝O)NH2、-S(＝O)2NH2、-NHC(＝O)NH2和C1-3烷氧基，所述C1-3烷氧基独立地任选被1、2或3个Rb取代。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R2 is independently selected from H, F, Cl, Br, I, CN, -C (=O) NH 2 , -S(=O) 2 NH 2 , -NHC(=O)NH 2 and C 1-3 alkoxy group, the C 1-3 alkoxy group is independently optionally substituted by 1, 2 or 3 R b replaced.
  6. 根据权利要求5所述的化合物、其立体异构体或其药学上可接受的盐，其中，各R2独立地选自H、F、Cl、CN、-C(＝O)NH2、-S(＝O)2NH2、-NHC(＝O)NH2、-OCH3、-OCH2CH3和-OCH2CH2CH3。The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from H, F, Cl, CN, -C(=O)NH 2 , - S (=O) 2NH2 , -NHC (=O) NH2 , -OCH3 , -OCH2CH3 and -OCH2CH2CH3 .
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，L1选自-CH2-、-CH(CH3)-、-C(CH3)2-、-CH(OCH3)-、-C(OCH3)2-和 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(OCH 3 )-, -C(OCH 3 ) 2 -and
  8. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，环A选自3-8元杂环烷基。The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein ring A is selected from 3-8 membered heterocycloalkyl.
  9. 根据权利要求8所述化合物、其立体异构体或其药学上可接受的盐，其中，环A选自 The compound according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from
  10. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，结构单元选自 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
    其中，T1、R1、R3、m、q和环B如权利要求1所定义。Wherein, T 1 , R 1 , R 3 , m, q and ring B are as defined in claim 1.
  11. 根据权利要求1-10任意一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物具有式(I-A)所示的结构：
    The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (IA):
    其中T1选自CH和N；Where T 1 is selected from CH and N;
    R1、R2、R3、L1、T2、m、n、q、环A和环B如权利要求1所定义。R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in claim 1 .
  12. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物具有式(I-1)、(I-2)、(I-3)或(I-4)所示的结构：
    The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-1), (I-2), (I-3) or (I-4 ) shows the structure:
    其中，R1、R2、R3、L1、q和n如权利要求1所定义；Wherein, R 1 , R 2 , R 3 , L 1 , q and n are as defined in claim 1;
    T1选自CH和N；T 1 is selected from CH and N;
    T3选自CH和N；T 3 is selected from CH and N;
    T4选自N和CH；T 4 is selected from N and CH;
    T5选自CH2、NH、O和S。 T5 is selected from CH2 , NH, O and S.
  13. 根据权利要求1-10任意一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物具有式(I-B)所示的结构：
    The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (IB):
    其中T1选自O和S；Where T 1 is selected from O and S;
    R1、R2、R3、L1、T2、m、n、q、环A和环B如权利要求1所定义。R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in claim 1 .
  14. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物具有式(I-5)所示的结构：
    The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-5):
    其中，R1、R2、R3、L1、q和n如权利要求1所定义；Wherein, R 1 , R 2 , R 3 , L 1 , q and n are as defined in claim 1;
    T1选自O和S；T 1 is selected from O and S;
    T6选自CH和N。T 6 is selected from CH and N.
  15. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物具有式(I-1A)、(I-1B)、(I-1C)、(I-1D)、(I-2A)、(I-3A)、(I-4A)和(I-5A)所示的结构：

    The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (I-1A), (I-1B), (I-1C), (I-1D ), (I-2A), (I-3A), (I-4A) and (I-5A):

    其中，R1、R2、R3、L1、q和n如权利要求1所定义。Wherein, R 1 , R 2 , R 3 , L 1 , q and n are as defined in claim 1.
  16. 下列所示化合物、其立体异构体或其药学上可接受的盐：


    The following compounds, their stereoisomers or their pharmaceutically acceptable salts:


  17. 根据权利要求16所述化合物、其立体异构体或其药学上可接受的盐，其选自：








    The compound according to claim 16, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from:








  18. 一种药物组合物，其包含有效治疗剂量的权利要求1～17任意一项所述的化合物、其立体异构体或其药学上可接受的盐；任选地还包括药学上可接受的辅料、辅助剂或载体。A pharmaceutical composition, which contains an effective therapeutic dose of the compound described in any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof; optionally also including pharmaceutically acceptable excipients , auxiliary agent or carrier.
  19. 权利要求1～17任意一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求18所述的药物组合物在制备用于预防和/或治疗HIV感染的药物上的应用。 Use of the compound according to any one of claims 1 to 17, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and/or treating HIV infection.
PCT/CN2023/119931 2022-09-20 2023-09-20 Polycyclic n-heterocyclic ketone compound and use thereof WO2024061257A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211146951.0 2022-09-20
CN202211146951 2022-09-20

Publications (1)

Publication Number Publication Date
WO2024061257A1 true WO2024061257A1 (en) 2024-03-28

Family

ID=90453902

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/119931 WO2024061257A1 (en) 2022-09-20 2023-09-20 Polycyclic n-heterocyclic ketone compound and use thereof

Country Status (1)

Country Link
WO (1) WO2024061257A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101346376A (en) * 2005-10-27 2009-01-14 盐野义制药株式会社 Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase
WO2014172188A2 (en) * 2013-04-16 2014-10-23 Merck Sharp & Dohme Corp. 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors
CN104995198A (en) * 2012-12-21 2015-10-21 吉里德科学公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
CN112513042A (en) * 2018-05-31 2021-03-16 盐野义制药株式会社 Polycyclic carbamoylpyridone derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101346376A (en) * 2005-10-27 2009-01-14 盐野义制药株式会社 Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase
CN104995198A (en) * 2012-12-21 2015-10-21 吉里德科学公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2014172188A2 (en) * 2013-04-16 2014-10-23 Merck Sharp & Dohme Corp. 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors
CN112513042A (en) * 2018-05-31 2021-03-16 盐野义制药株式会社 Polycyclic carbamoylpyridone derivatives

Similar Documents

Publication Publication Date Title
CN112955432B (en) Fused aromatic ring derivative, preparation method and medical application thereof
KR20230136636A (en) Pyrimidine aromatic ring compound
WO2022161443A1 (en) Pyrimidopyran compound
WO2021104488A1 (en) Tri-heterocyclic compound as jak inhibitor, and use thereof
WO2022063308A1 (en) Class of 1,7-naphthyridine compounds and application thereof
TW202227422A (en) Small molecule inhibitors of cathepsin c and their medical use
WO2022247757A1 (en) Fluorine-substituted pyrimidopyridine compound and use thereof
CN113825757A (en) Substituted condensed bicyclic derivatives, preparation method and application thereof in medicines
KR20230154953A (en) Glutarimide-based compounds substituted with furan condensed rings
WO2021129817A1 (en) Pyrimidine-based compound having inhibitory effect of ketohexokinase (khk)
WO2021027647A1 (en) Bridged heterocyclyl-substituted pyrimidine compound, preparation method therefor, and pharmaceutical use thereof
WO2024061257A1 (en) Polycyclic n-heterocyclic ketone compound and use thereof
WO2022166721A1 (en) Fused ring derivatives containing 1,4-oxazepane
WO2023160572A1 (en) Pyrazole derivative, pharmaceutical composition, and use
WO2023001069A1 (en) Macrocyclic amide compounds and application thereof
WO2023109878A1 (en) Triazaspiro lpar1 antagonist and use thereof
WO2022262782A1 (en) Glutarimide-substituted isoxazole fused ring compound, and application thereof
TW202322819A (en) A nitrogen-containing tetracyclic compound, a preparation method and medical use thereof
WO2021147953A1 (en) Pyrimido five-membered ring derivative and application thereof
WO2022199635A1 (en) Benzylaminoquinazoline derivatives
WO2021219088A1 (en) Pyrimidine-based tricyclic compound and use thereof
WO2022037680A1 (en) Boracic acid compound
CN113493453A (en) Fused aromatic ring derivative, preparation method and medical application thereof
CN111971285A (en) Imidazolopyrrolone compounds and uses thereof
WO2023208127A1 (en) Heteroaryl-substituted bicyclic compound and use thereof