WO2021259331A1 - Eight-membered n-containing heterocyclic compound - Google Patents

Eight-membered n-containing heterocyclic compound Download PDF

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Publication number
WO2021259331A1
WO2021259331A1 PCT/CN2021/101868 CN2021101868W WO2021259331A1 WO 2021259331 A1 WO2021259331 A1 WO 2021259331A1 CN 2021101868 W CN2021101868 W CN 2021101868W WO 2021259331 A1 WO2021259331 A1 WO 2021259331A1
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compound
added
pharmaceutically acceptable
synthesis
stirred
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PCT/CN2021/101868
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French (fr)
Chinese (zh)
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王廷
洪训
周根源
高娜
沈春莉
吴成德
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2021259331A1 publication Critical patent/WO2021259331A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the present invention relates to a new type of eight-membered N-containing heterocyclic compounds, in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof.
  • the first RAS oncogene was found in rat sarcoma (rat sarcoma), hence the name.
  • the RAS protein is a product expressed by the RAS gene, which refers to a closely related monomer globulin consisting of 189 amino acids with a molecular weight of 21KDa. It can be combined with guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP).
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the active state of RAS protein has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc. Its activity is regulated by the combination with GTP or GDP.
  • the RAS protein When the RAS protein binds to GDP, it is in a dormant state, that is, an "inactive" state; when stimulated by a specific upstream cell growth factor, the RAS protein is induced to exchange GDP and bind to GTP, which is called “activated” at this time. state.
  • the RAS protein bound to GTP can activate downstream proteins for signal transmission.
  • RAS protein itself has weak GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transformation from the activated state to the inactivated state can be realized.
  • GAP GTPase activating proteins
  • GAP GTPase activating proteins
  • RAS protein will affect its interaction with GAP, which will also affect its ability to hydrolyze GTP to GDP, making it always in an activated state.
  • the activated RAS protein continuously gives growth signals to downstream proteins, which eventually leads to the continuous growth and differentiation of cells, and eventually tumors.
  • RAS gene family There are many members of the RAS gene family, among which the subfamilies closely related to various cancers are mainly Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus carcinogenic homolog (HRAS) and nerve Blastoma rat sarcoma virus oncogene homolog (NRAS).
  • KRAS Kirsten rat sarcoma virus oncogene homolog
  • HRAS Harvey rat sarcoma virus carcinogenic homolog
  • NRAS nerve Blastoma rat sarcoma virus oncogene homolog
  • the G12C mutation is one of the more common mutations in the KRAS gene. It refers to the mutation of glycine 12 to cysteine. KRAS G12C mutations are the most common in lung cancer. According to data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutations account for about 10% of all lung cancer patients.
  • the present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl,
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are each independently optionally substituted by 1, 2 or 3 R b replace
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 7 is selected from H
  • R 3 and R 7 and the connected atoms form a five-membered heteroaryl group
  • R a is independently selected from F, Cl, Br and I;
  • R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from F, Cl, Br, I and CN;
  • R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the R 3 and R 7 and the connected atoms form a five-membered heteroaryl group, so that the structural fragment form Other variables are as defined in the present invention.
  • the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
  • the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
  • the R b is independently selected from F, Cl, Br, I, Other variables are as defined in the present invention.
  • the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl and The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, Cyclobutyl and Each independently is optionally substituted by 1, 2, or 3 R b , and other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl are each independently optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 7 is selected from H
  • R 3 and R 7 form a five-membered heteroaryl group with the connected atoms, making the structure fragment form
  • R a is independently selected from F, Cl, Br and I;
  • R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from F, Cl, Br, I and CN;
  • R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl,
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from H, F, Cl, Br and I;
  • R b is each independently selected from H, F, Cl, Br, I, N(CH 3 ) 2 and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from H, F, Cl, Br, I and CN;
  • R is each independently selected from H, F, Cl, Br, I, and CH 3 .
  • R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and Cyclopropyl is optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from H, F, Cl, Br and I;
  • R b is each independently selected from H, F, Cl, Br, I and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from H, F, Cl, Br, I and CN;
  • R is each independently selected from H, F, Cl, Br, I, and CH 3 .
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
  • the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
  • the R b is independently selected from H, F, Cl, Br, I and Other variables are as defined in the present invention.
  • the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 5 is selected from H, And cyclopropyl, other variables are as defined in the present invention.
  • the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, selected from
  • the compound or a pharmaceutically acceptable salt thereof is selected from
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a KRAS G12C mutein inhibitor.
  • the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a medicine for treating KRAS G12C mutation non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • 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, and diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformations.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • 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 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 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 enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
  • the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed 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 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-4 alkylamino group includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino group and the like.
  • C 1-4 alkylamino examples include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring, and 9
  • 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, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultivated single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the compound is based on conventional naming principles in the field or The software is named, and the commercially available compounds use the supplier catalog name.
  • the compound of the present invention has a certain inhibitory effect on KRAS G12C mutant protein, and has high selectivity for KRAS G12C.
  • the compound of the present invention has low clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties.
  • the compound of the present invention has a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously in nude mice.
  • the compound of the present invention has significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.
  • anhydrous sodium sulfate 500g, 3.52mol, 357.14mL was added to the raw material chloral hydrate (47.88g, 289.45mmol) in deionized water (750mL), and the raw material 1-1 (50g, 263.14mmol) ), sulfuric acid (1M, 200mL) and hydroxylamine hydrochloride (54.86g, 789.42mmol), the resulting mixture was heated to 130°C under reflux and stirred for 0.5 hours, then the reaction solution was cooled to 50°C, a large amount of light brown solid precipitated, filtered, water ( 1000 mL) was washed, the filter cake was collected, and dried under reduced pressure to obtain compound 1-2.
  • Formamidine acetate (135.72 g, 1.30 mol) was added to a solution of raw material 1-5 (35 g, 130.37 mmol) in ethanol (300 mL), and the resulting mixture was heated to reflux at 80° C. and stirred for 40 hours.
  • the reaction solution was concentrated under reduced pressure to remove ethanol, water (200 mL) was added to the residue, stirred for 10 minutes, filtered, washed with water (200 mL), and the filter cake was dried to obtain compound 1-6.
  • N-chlorosuccinimide 8mg, 59.91 ⁇ mol was added to a solution of raw material 4-3 (15mg, 29.88 ⁇ mol) in N,N-dimethylformamide (0.5mL) to obtain The mixture was heated to 65°C and stirred for 1 hour. Water (50mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL*3). The organic phase was collected and concentrated under reduced pressure. The crude product obtained was purified by thin-layer chromatography to obtain compound 4. -4. LCMS (ESI) m/z: 470.3/472.3 [M-Boc+1] + .
  • Trifluoroacetic acid (0.8 mL, 10.80 mmol) was added to the dichloromethane (1 mL) solution of raw material 5-5 (50 mg, 93.56 ⁇ mol), and stirring was continued for 1 hour at room temperature and 20°C. The reaction solution was concentrated under reduced pressure to obtain the crude product 5-6.
  • Potassium phosphate (3.95g, 18.61mmol) was added to a solution of raw material 6-3 (2.6g, 4.65mmol) and compound 1-10 (2.08g, 9.30mmol) in toluene (30mL) and water (3mL) and replaced with nitrogen three times , Add catalyst chlorination (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) )] Palladium (0.67g, 0.93mmol), and the resulting mixture was heated to 70°C and stirred for 6 hours.
  • Tetrahydrofuran 50 mL
  • compound 8-4 50 mg, 73.97 ⁇ mol
  • sodium hydrogen 14.79 mg, 369.83 ⁇ mol, 60% purity
  • Saturated aqueous ammonium chloride solution 100 mL
  • ethyl acetate 50 mL
  • Trifluoroacetic acid (0.43 mL) was added to a solution of raw material 10-10 (0.2 g, 0.29 mmol) in dichloromethane (3 mL), the resulting mixture was stirred at room temperature and 25°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 10-11 The trifluoroacetate.
  • Trifluoroacetic acid (0.22mL) was added to a solution of raw material 12-10 (0.1g, 0.15mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 12-11 The trifluoroacetate.
  • Trifluoroacetic acid (0.15mL) was added to a solution of the starting material 13-5 (75mg, 0.10mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 13-6. Trifluoroacetate. LCMS (ESI) m/z: 625.1/627.2 [M+1] + .
  • Tetrahydrofuran (62 mL), compound 17-5 (62 mg, 86.06 ⁇ mol) and sodium hydrogen (17.21 mg, 430.30 ⁇ mol, 60% purity) were added to a three-necked flask, and heated to 65° C. for 1 hour under nitrogen protection.
  • the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (1 mL) was added, and the mixture was concentrated under reduced pressure.
  • Dichloromethane (20 mL) was added to the residue, filtered, and the filtrate was concentrated to obtain compound 17-6.
  • Tetrahydrofuran (710 mL), compound 18-2 (710 mg, 912.06 ⁇ mol) and sodium hydrogen (182.41 mg, 4.56 mmol, 60% purity) were added to the three-necked flask, and the mixture was heated to 65°C for 1 hour under the protection of nitrogen.
  • the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (2 mL) was added, and the mixture was concentrated under reduced pressure.
  • Dichloromethane 50 mL was added to the residue, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain compound 18-3.
  • 1 H NMR 400MHz, CD 3 OD
  • This experiment aims to verify the proliferation inhibitory effect of the compound of the present invention on KRAS G12C mutant NCI-H358 human non-small cell lung cancer cells and wild-type A375 human malignant melanoma cells.
  • Cell line NCI-H358 purchasedd from the Cell Bank of the Chinese Academy of Sciences
  • cell line A375 purchased from the Cell Bank of the Chinese Academy of Sciences
  • DMEM medium penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo cell viability chemiluminescence detection reagent
  • Plant NCI-H358 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 4000 NCI-H358 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up.
  • the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 1.52 nM.
  • the cell plate was placed in a carbon dioxide incubator for 5 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of dosing to participate in data analysis. Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Use multi-marker analyzer to read. Add 25 ⁇ L of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use multi-marker analyzer to read.
  • Plant A375 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 2000 A375 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up.
  • Add 78 ⁇ L of culture medium to the middle plate and then transfer 2 ⁇ L of each well of the gradient dilution compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate.
  • the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 1.52 nM.
  • the cell plate was placed in a carbon dioxide incubator for 5 days.
  • IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
  • NA 0.015 NA 8 0.017 NA 9 0.196 NA 10 0.189 NA 11 0.059 NA 14 0.005 NA 16 0.029 NA 17 0.105 NA 18 0.135 NA twenty one 0.003 NA twenty two 0.143 NA twenty four 0.019 NA 26 0.112 NA 27 0.020 NA
  • the compound of the present invention shows excellent cell anti-proliferation activity against KRAS G12C mutant cell NCI-H358.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • CD-1 male mice aged 7 to 10 weeks were selected, and the doses for intravenous and oral administration were 3 mg/kg and 10 mg/kg, respectively.
  • the test animals eat and drink freely throughout the test period.
  • the animals in the intravenous group were given a single injection of the compound through the tail vein with a volume of 3 mL/kg; the oral group was given the compound through a single gavage with a volume of 10 mL/kg.
  • the sample collection time is: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, 24h.
  • Approximately 30 ⁇ L of whole blood was collected through the saphenous vein at each time point to prepare plasma for high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for concentration determination. All animals were euthanized by CO 2 anesthesia after collecting PK samples at the last time point.
  • mice The evaluation results of PK properties in mice are shown in Table 2.
  • C max represents the maximum plasma concentration
  • T max represents the peak time
  • T 1/2 represents the half-life
  • Vdss represents the apparent volume of distribution
  • Cl represents the clearance rate
  • AUC 0-last represents the area of the curve (0-t)
  • AUC 0-inf represents the area of the curve (0-inf); NA represents not tested.
  • the compound of the present invention has a good clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties.
  • Cell culture Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) are cultured in a monolayer in vitro, and the culture conditions are DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubation Box culture. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, resuspended in an appropriate amount of PBS, and matrigel is added 1:1 to obtain a cell suspension with a cell density of 25 x 10 6 cells/mL .
  • Mia PaCa-2 cells were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 118mm At 3 o'clock, randomly grouped according to tumor volume, each group has 6 animals, the dose of the blank group is 0, the dose of the test group is 10 mg/kg, the dose volume is 10 ⁇ L/g, oral administration, 22 days of administration, Once a day.
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • test compound of the present invention exhibits a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously into a tumor Balb/c Nude mouse model.
  • Cell culture Human non-small cell lung cancer NCI-H358 is cultured in a monolayer in vitro.
  • the culture conditions are DMEM/F12 medium with 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubator.
  • the cells are collected, counted, and resuspended in an appropriate amount of PBS.
  • Matrigel is added 1:1 to obtain a cell suspension with a cell density of 25 ⁇ 10 6 cells/mL .
  • NCI-H358 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 102mm 3 At the time, random grouping was carried out according to the tumor volume, each group of 6 animals, the dose of the blank group was 0, the dose of the test group was 20mg/kg, the dose volume was 10 ⁇ L/g, orally administered for 30 days, every day once.
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • test compound of the present invention exhibits significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.

Abstract

Disclosed is an eight-membered N-containing heterocyclic compound as shown in formula (P) and the use thereof in the preparation of a KRAS G12C mutant protein inhibitor.

Description

八元含N杂环类化合物Eight-membered N-containing heterocyclic compounds
本发明主张如下优先权：The present invention claims the following priority:
CN202010590949.7，申请日：2020年06月24日；CN202010590949.7, application date: June 24, 2020;
CN202011222484.6，申请日：2020年11月05日。CN202011222484.6, application date: November 05, 2020.
技术领域Technical field
本发明涉及新的一类八元含N杂环类化合物，具体涉及式(P)所示化合物及其药学上可接受的盐。The present invention relates to a new type of eight-membered N-containing heterocyclic compounds, in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof.
背景技术Background technique
第一个RAS癌基因发现自大鼠肉瘤(rat sarcoma)，因此得名。RAS蛋白是由RAS基因表达的产物，指一类紧密相关的，由189个氨基酸组成的单体球蛋白，其分子量为21KDa。它可以与鸟嘌呤三核苷酸磷酸(GTP)或鸟嘌呤二核苷酸磷酸(GDP)结合。RAS蛋白的活性状态对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响，其活性是通过与GTP或GDP的结合进行调节。当RAS蛋白与GDP结合时，它处于休眠状态，也就是“失活”状态；当有上游特定的细胞生长因子刺激时，RAS蛋白被诱导交换GDP，与GTP结合，此时称为“活化”状态。与GTP结合的RAS蛋白能够活化下游的蛋白，进行信号传递。RAS蛋白自身具有弱的水解GTP水解活性，能够水解GTP到GDP。这样就可以实现从活化状态到失活状态的转化。在这个水解过程中，还需要GAP(GTPase activating proteins,GTP水解酶活化蛋白)参与。它能与RAS蛋白作用，大大促进其水解GTP到GDP的能力。RAS蛋白的突变将影响其与GAP的作用，也就影响了其水解GTP到GDP的能力，使其一直处于活化状态。活化的RAS蛋白持续的给予下游蛋白生长信号，最终导致细胞不停的生长和分化，最终产生肿瘤。RAS基因家族成员众多，其中与各种癌症密切相关的亚家族主要有克尔斯滕大鼠肉瘤病毒致癌基因同源物(KRAS)、哈维大鼠肉瘤病毒致癌同源物(HRAS)和神经母细胞瘤大鼠肉瘤病毒致癌基因同源物(NRAS)。人们发现大约30％的人类肿瘤中都携带某些突变的RAS基因，其中以KRAS突变最为显著，占到所有RAS突变中的86％。对于KRAS突变，最为常见的突变出现在12号甘氨酸(G12)，13号甘氨酸(G13)和61号谷氨酰胺(Q61)残基上，其中G12突变占到83％。The first RAS oncogene was found in rat sarcoma (rat sarcoma), hence the name. The RAS protein is a product expressed by the RAS gene, which refers to a closely related monomer globulin consisting of 189 amino acids with a molecular weight of 21KDa. It can be combined with guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP). The active state of RAS protein has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc. Its activity is regulated by the combination with GTP or GDP. When the RAS protein binds to GDP, it is in a dormant state, that is, an "inactive" state; when stimulated by a specific upstream cell growth factor, the RAS protein is induced to exchange GDP and bind to GTP, which is called "activated" at this time. state. The RAS protein bound to GTP can activate downstream proteins for signal transmission. RAS protein itself has weak GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transformation from the activated state to the inactivated state can be realized. In this hydrolysis process, GAP (GTPase activating proteins) is also required to participate. It can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP. The mutation of RAS protein will affect its interaction with GAP, which will also affect its ability to hydrolyze GTP to GDP, making it always in an activated state. The activated RAS protein continuously gives growth signals to downstream proteins, which eventually leads to the continuous growth and differentiation of cells, and eventually tumors. There are many members of the RAS gene family, among which the subfamilies closely related to various cancers are mainly Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus carcinogenic homolog (HRAS) and nerve Blastoma rat sarcoma virus oncogene homolog (NRAS). It has been found that about 30% of human tumors carry certain mutated RAS genes, of which KRAS mutations are the most significant, accounting for 86% of all RAS mutations. For KRAS mutations, the most common mutations appear on glycine 12 (G12), glycine 13 (G13) and glutamine (Q61) residues, of which G12 mutation accounts for 83%.
G12C突变是KRAS基因突变中比较常见的一个，它是指12号甘氨酸突变为半胱氨酸。KRAS G12C突变在肺癌中最为常见，根据文献(Nat Rev Drug Discov 2014；13:828-851)报道的数据推算，KRAS G12C突变占到所有肺癌患者的10％左右。The G12C mutation is one of the more common mutations in the KRAS gene. It refers to the mutation of glycine 12 to cysteine. KRAS G12C mutations are the most common in lung cancer. According to data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutations account for about 10% of all lung cancer patients.
发明内容Summary of the invention
本发明提供了式(P)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021101868-appb-000001
Figure PCTCN2021101868-appb-000001
其中，in,
R 1、R 2分别独立地选自H、F、Cl、Br、I和NH 2； R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
R 3选自H、F、Cl、Br、I、NH 2、CN、-C(＝O)C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 3 is selected from H, F, Cl, Br, I, NH 2 , CN, -C(=O)C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a replaces
R 4选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
R 5选自H、F、Cl、Br、I、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基分别独立地任选被1、2或3个R b取代； R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, The C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are each independently optionally substituted by 1, 2 or 3 R b replace
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
R 7选自H； R 7 is selected from H;
或者，R 3和R 7与相连的原子形成五元杂芳基； Alternatively, R 3 and R 7 and the connected atoms form a five-membered heteroaryl group;
R a分别独立地选自F、Cl、Br和I； R a is independently selected from F, Cl, Br and I;
R b分别独立地选自F、Cl、Br、I、C 1-4烷氨基、C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基，所述C 1-4烷氨基、-C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基分别独立地任选被1、2或3个R取代； R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
R c分别独立地选自F、Cl、Br、I和CN； R c are each independently selected from F, Cl, Br, I and CN;
R分别独立地选自F、Cl、Br、I、CH 3、-CH 2N(CH 3) 2。 R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
在本发明的一些方案中，所述结构单元
Figure PCTCN2021101868-appb-000002
选自
Figure PCTCN2021101868-appb-000003
Figure PCTCN2021101868-appb-000004
其他变量如本发明所定义。 In some aspects of the present invention, the structural unit
Figure PCTCN2021101868-appb-000002
Selected from
Figure PCTCN2021101868-appb-000003
Figure PCTCN2021101868-appb-000004
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 3选自F、Cl、Br、CN和-C(＝O)CH 3。 In some aspects of the present invention, the R 3 is selected from F, Cl, Br, CN, and -C(=O)CH 3 .
在本发明的一些方案中，所述R 3和R 7与相连的原子形成五元杂芳基，使结构片段
Figure PCTCN2021101868-appb-000005
形成
Figure PCTCN2021101868-appb-000006
其他变量如本发明所定义。 In some aspects of the present invention, the R 3 and R 7 and the connected atoms form a five-membered heteroaryl group, so that the structural fragment
Figure PCTCN2021101868-appb-000005
form
Figure PCTCN2021101868-appb-000006
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4选自H、Cl和CH 3，所述CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4选自H和Cl，其他变量如本发明所定义。 In some aspects of the present invention, the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R b分别独立地选自F、Cl、Br、I、
Figure PCTCN2021101868-appb-000007
Figure PCTCN2021101868-appb-000008
其他变量如本发明所定义。 In some aspects of the present invention, the R b is independently selected from F, Cl, Br, I,
Figure PCTCN2021101868-appb-000007
Figure PCTCN2021101868-appb-000008
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH 2CH 2CH 3、OCH(CH 3) 2、环丙基、环丁基和
Figure PCTCN2021101868-appb-000009
所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH 2CH 2CH 3、OCH(CH 3) 2、环丙基、环丁基和
Figure PCTCN2021101868-appb-000010
分别独立地任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl and
Figure PCTCN2021101868-appb-000009
The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, Cyclobutyl and
Figure PCTCN2021101868-appb-000010
Each independently is optionally substituted by 1, 2, or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、环丙基、
Figure PCTCN2021101868-appb-000011
Figure PCTCN2021101868-appb-000012
其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H, cyclopropyl,
Figure PCTCN2021101868-appb-000011
Figure PCTCN2021101868-appb-000012
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、环丙基、
Figure PCTCN2021101868-appb-000013
Figure PCTCN2021101868-appb-000014
其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H, cyclopropyl,
Figure PCTCN2021101868-appb-000013
Figure PCTCN2021101868-appb-000014
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 6选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2分别独立地任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the present invention, the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 6选自H和CH 2CN，其他变量如本发明所定义。 In some aspects of the present invention, the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021101868-appb-000015
Figure PCTCN2021101868-appb-000015
其中，in,
R 1、R 2分别独立地选自H、F、Cl、Br、I和NH 2； R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
R 3选自H、F、Cl、Br、I、NH 2、CN、-C(＝O)C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 3 is selected from H, F, Cl, Br, I, NH 2 , CN, -C(=O)C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a replaces
R 4选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
R 5选自C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基分别独立地任选被1、2或3个R b取代； R 5 is selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl are each independently optionally substituted with 1, 2 or 3 R b ;
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
R 7选自H； R 7 is selected from H;
或者，R 3和R 7与相连的原子形成五元杂芳基，使结构片段
Figure PCTCN2021101868-appb-000016
形成
Figure PCTCN2021101868-appb-000017
Or, R 3 and R 7 form a five-membered heteroaryl group with the connected atoms, making the structure fragment
Figure PCTCN2021101868-appb-000016
form
Figure PCTCN2021101868-appb-000017
R a分别独立地选自F、Cl、Br和I； R a is independently selected from F, Cl, Br and I;
R b分别独立地选自F、Cl、Br、I、C 1-4烷氨基、C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基，所述C 1-4烷氨基、-C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基分别独立地任选被1、2或3个R取代； R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
R c分别独立地选自F、Cl、Br、I和CN； R c are each independently selected from F, Cl, Br, I and CN;
R分别独立地选自F、Cl、Br、I、CH 3、-CH 2N(CH 3) 2。 R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021101868-appb-000018
Figure PCTCN2021101868-appb-000018
其中，in,
R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I和NH 2； R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
R 4选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
R 5选自H、F、Cl、Br、I、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基任选被1、2或3个R b取代； R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, The C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are optionally substituted with 1, 2 or 3 R b ;
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
R a分别独立地选自H、F、Cl、Br和I； R a is independently selected from H, F, Cl, Br and I;
R b分别独立地选自H、F、Cl、Br、I、N(CH 3) 2和吡咯烷基，所述吡咯烷基任选被1、2或3个R取代； R b is each independently selected from H, F, Cl, Br, I, N(CH 3 ) 2 and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
R c分别独立地选自H、F、Cl、Br、I和CN； R c are each independently selected from H, F, Cl, Br, I and CN;
R分别独立地选自H、F、Cl、Br、I和CH 3。 R is each independently selected from H, F, Cl, Br, I, and CH 3 .
在本发明的一些方案中，上述式(I)化合物或其药学上接受的盐，In some aspects of the present invention, the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof,
其中，in,
R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I和NH 2； R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
R 4选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
R 5选自H、F、Cl、Br、I、C 1-3烷基、C 1-3烷氧基和环丙基，所述C 1-3烷基、C 1-3烷氧基和环丙基任选被1、2或3个R b取代； R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and Cyclopropyl is optionally substituted with 1, 2 or 3 R b ;
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
R a分别独立地选自H、F、Cl、Br和I； R a is independently selected from H, F, Cl, Br and I;
R b分别独立地选自H、F、Cl、Br、I和吡咯烷基，所述吡咯烷基任选被1、2或3个R取代； R b is each independently selected from H, F, Cl, Br, I and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
R c分别独立地选自H、F、Cl、Br、I和CN； R c are each independently selected from H, F, Cl, Br, I and CN;
R分别独立地选自H、F、Cl、Br、I和CH 3。 R is each independently selected from H, F, Cl, Br, I, and CH 3 .
在本发明的一些方案中，所述结构单元
Figure PCTCN2021101868-appb-000019
选自
Figure PCTCN2021101868-appb-000020
Figure PCTCN2021101868-appb-000021
其他变量如本发明所定义。 In some aspects of the present invention, the structural unit
Figure PCTCN2021101868-appb-000019
Selected from
Figure PCTCN2021101868-appb-000020
Figure PCTCN2021101868-appb-000021
Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元
Figure PCTCN2021101868-appb-000022
选自
Figure PCTCN2021101868-appb-000023
其他变量如本发明所定义。 In some aspects of the present invention, the structural unit
Figure PCTCN2021101868-appb-000022
Selected from
Figure PCTCN2021101868-appb-000023
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4选自H、Cl和CH 3，所述CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4选自H和Cl，其他变量如本发明所定义。 In some aspects of the present invention, the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R b分别独立地选自H、F、Cl、Br、I和
Figure PCTCN2021101868-appb-000024
其他变量如本发明所定义。 In some aspects of the present invention, the R b is independently selected from H, F, Cl, Br, I and
Figure PCTCN2021101868-appb-000024
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH 2CH 2CH 3、OCH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH 2CH 2CH 3、OCH(CH 3) 2和环丙基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、环丙基、
Figure PCTCN2021101868-appb-000025
其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H, cyclopropyl,
Figure PCTCN2021101868-appb-000025
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 5选自H、
Figure PCTCN2021101868-appb-000026
和环丙基，其他变量如本发明所定义。 In some aspects of the present invention, the R 5 is selected from H,
Figure PCTCN2021101868-appb-000026
And cyclopropyl, other variables are as defined in the present invention.
在本发明的一些方案中，所述R 6选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the present invention, the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 6选自H和CH 2CN，其他变量如本发明所定义。 In some aspects of the present invention, the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
本发明还有一些方案由上述变量任意组合而来。There are also some schemes of the present invention that come from any combination of the above-mentioned variables.
本发明还提供了下列所示化合物或其药学上可接受的盐，选自The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, selected from
Figure PCTCN2021101868-appb-000027
Figure PCTCN2021101868-appb-000027
Figure PCTCN2021101868-appb-000028
Figure PCTCN2021101868-appb-000028
在本发明的一些方案中，所述化合物或其药学上可接受的盐，选自In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021101868-appb-000029
Figure PCTCN2021101868-appb-000029
Figure PCTCN2021101868-appb-000030
Figure PCTCN2021101868-appb-000030
本发明提供了一种药物组合物，包括作为活性成分的治疗有效量的本发明所述的化合物或其药学上可接受的盐以及药学上可接受的载体。The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
本发明提供了上述的化合物或其药学上可接受的盐或上述组合物在制备KRAS G12C突变蛋白抑制剂的应用。The present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a KRAS G12C mutein inhibitor.
本发明提供了上述的化合物或其药学上可接受的盐或上述组合物制备治疗KRAS G12C突变的非小细胞肺癌、胰腺癌、结直肠癌药物中的应用。The present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a medicine for treating KRAS G12C mutation non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
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。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、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive 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。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。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 salt" refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be converted into any base or acid addition salt.
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 salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
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, and diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in 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 specified, 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 specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
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 specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise specified, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2021101868-appb-000031
和楔形虚线键
Figure PCTCN2021101868-appb-000032
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021101868-appb-000033
和直形虚线键
Figure PCTCN2021101868-appb-000034
表示立体中心的相对构型，用波浪线
Figure PCTCN2021101868-appb-000035
表示楔形实线键
Figure PCTCN2021101868-appb-000036
或楔形虚线键
Figure PCTCN2021101868-appb-000037
或用波浪线
Figure PCTCN2021101868-appb-000038
表示直形实线键
Figure PCTCN2021101868-appb-000039
和直形虚线键
Figure PCTCN2021101868-appb-000040
Unless otherwise specified, use wedge-shaped solid line keys
Figure PCTCN2021101868-appb-000031
And wedge-shaped dashed key
Figure PCTCN2021101868-appb-000032
Represents the absolute configuration of a three-dimensional center, with a straight solid line key
Figure PCTCN2021101868-appb-000033
And straight dashed key
Figure PCTCN2021101868-appb-000034
Indicates the relative configuration of the three-dimensional center, using wavy lines
Figure PCTCN2021101868-appb-000035
Represents a wedge-shaped solid line key
Figure PCTCN2021101868-appb-000036
Or wedge-shaped dashed key
Figure PCTCN2021101868-appb-000037
Or use wavy lines
Figure PCTCN2021101868-appb-000038
Represents a straight solid line key
Figure PCTCN2021101868-appb-000039
And straight dashed key
Figure PCTCN2021101868-appb-000040
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 compound of the present invention may be specific. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomer (also called prototropic tautomer) includes interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomer) include some recombination of bonding electrons to carry out mutual transformations. A specific example of keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 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 specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to one of the isomers or pairs of 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 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 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％。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 enantiomer excess (ee value) is 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)。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The 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), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
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 compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterium can be substituted for hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the event or condition described later may but does not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent. The substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2021101868-appb-000041
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2021101868-appb-000042
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2021101868-appb-000043
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2021101868-appb-000041
The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2021101868-appb-000042
It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right
Figure PCTCN2021101868-appb-000043
Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
除非另有规定，术语“C 1-3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C 1-3烷基包括C 1-2和C 2-3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)。C 1-3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 indicate a linear or branched saturated hydrocarbon group composed 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“C 1-4烷氨基”表示通过氨基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C 1-4烷氨基包括C 1-3、C 1-2、C 2-4、C 4、C 3和C 2烷氨基等。C 1-4烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。 Unless otherwise specified, the term "C 1-4 alkylamino" refers to those alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule through an amino group. The C 1-4 alkylamino group includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino group and the like. Examples of C 1-4 alkylamino include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
除非另有规定，术语“C 1-3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C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3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" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. 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“C 1-3烷氨基”表示通过氨基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C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。 Unless otherwise specified, the term "C 1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. The C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like. Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
除非另有规定，“C 3-5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C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5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, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, including any range from n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, 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, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
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：
Figure PCTCN2021101868-appb-000044
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 relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultivated single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data, the light source is CuKα radiation, and the scanning method:
Figure PCTCN2021101868-appb-000044
After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
化合物依据本领域常规命名原则或者
Figure PCTCN2021101868-appb-000045
软件命名，市售化合物采用供应商目录名称。 The compound is based on conventional naming principles in the field or
Figure PCTCN2021101868-appb-000045
The software is named, and the commercially available compounds use the supplier catalog name.
技术效果Technical effect
本发明化合物具有一定的KRAS G12C突变蛋白抑制作用，对KRAS G12C有较高的选择性。本发明化合物在小鼠体内清除率低，口服AUC、生物利用度较好，具有良好的药代动力学性质。本发明化合物在人胰腺癌Mia PaCa-2细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型中具有较好的体内药效。本发明化合物在人非小细胞肺癌NCI-H358细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型中具有显著体内药效。The compound of the present invention has a certain inhibitory effect on KRAS G12C mutant protein, and has high selectivity for KRAS G12C. The compound of the present invention has low clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties. The compound of the present invention has a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously in nude mice. The compound of the present invention has significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.
具体实施方式detailed description
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。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 following examples describe the present invention in detail, but they are not meant to limit the present invention in any unfavorable manner. 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, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention. It will be obvious to those skilled in the art that 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.
实施例1Example 1
Figure PCTCN2021101868-appb-000046
Figure PCTCN2021101868-appb-000046
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000047
Figure PCTCN2021101868-appb-000047
1)化合物1-2的合成1) Synthesis of compound 1-2
室温25℃下，向原料水合氯醛(47.88g，289.45mmol)的去离子水(750mL)溶液中加入无水硫酸钠(500g，3.52mol，357.14mL)，原料1-1(50g，263.14mmol)，硫酸(1M，200mL)和盐酸羟胺(54.86g，789.42mmol)，得到的混合物加热到130℃回流搅拌0.5小时，随后反应液降温至50℃，有大量浅褐色固体析出，过滤，水(1000mL)洗涤，收集滤饼，减压干燥，得到化合物1-2。LCMS(ESI)m/z:260.9/262.9[M+1] +。 At room temperature 25°C, anhydrous sodium sulfate (500g, 3.52mol, 357.14mL) was added to the raw material chloral hydrate (47.88g, 289.45mmol) in deionized water (750mL), and the raw material 1-1 (50g, 263.14mmol) ), sulfuric acid (1M, 200mL) and hydroxylamine hydrochloride (54.86g, 789.42mmol), the resulting mixture was heated to 130°C under reflux and stirred for 0.5 hours, then the reaction solution was cooled to 50°C, a large amount of light brown solid precipitated, filtered, water ( 1000 mL) was washed, the filter cake was collected, and dried under reduced pressure to obtain compound 1-2. LCMS (ESI) m/z: 260.9/262.9 [M+1] + .
2)化合物1-3的合成2) Synthesis of compound 1-3
80℃下，向浓硫酸(500mL)中分批加入原料1-2(68g，260.49mmol)，升温明显，得到的褐色混合物搅拌1小时，反应液降至室温25℃倒入碎冰(3000g)中淬灭，随后加入乙酸乙酯(2*500mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过柱层析纯化得到化合物1-3。 1H NMR(400MHz,DMSO-d 6)δppm 11.74(s,1H),7.34-7.41(m,1H),7.27-7.33(m,1H)。 At 80°C, add raw material 1-2 (68g, 260.49mmol) to concentrated sulfuric acid (500mL) in batches. The temperature rise is obvious. The resulting brown mixture is stirred for 1 hour. The reaction solution is cooled to room temperature and 25°C and poured into crushed ice (3000g). After being quenched by the mixture, ethyl acetate (2*500 mL) was added and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-3. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 11.74 (s, 1H), 7.34-7.41 (m, 1H), 7.27-7.33 (m, 1H).
3)化合物1-4的合成3) Synthesis of compound 1-4
冰水浴0℃下，向原料1-3(40g,163.92mmol)和氢氧化钠(2M,409.81mL)的水(150mL)溶液中滴加双氧水(92.93g，819.61mmol，78.75mL,纯度30％)，得到的混合物自然升至室温25℃搅拌20小时，向反应液中加入饱和亚硫酸钠(500mL)溶液，滴加2M稀盐酸至pH～5，有大量白色固体析出，过滤，加入水(500mL)洗涤，收集固体减压浓缩，得到化合物1-4。 1H NMR(400MHz,DMSO-d 6)δppm 7.47(dd,J＝8.66,1.51Hz,1H),6.76(dd,J＝8.66,6.27Hz,1H)。LCMS(ESI)m/z:234.1/236.1[M+1] +。 In an ice-water bath at 0°C, add hydrogen peroxide (92.93g, 819.61mmol, 78.75mL, purity 30%) to a water (150mL) solution of raw materials 1-3 (40g, 163.92mmol) and sodium hydroxide (2M, 409.81mL). ), the resulting mixture was naturally warmed to room temperature 25°C and stirred for 20 hours, a saturated sodium sulfite (500mL) solution was added to the reaction solution, 2M dilute hydrochloric acid was added dropwise to pH ~ 5, a large amount of white solid precipitated, filtered, and water (500mL) was added After washing, the collected solid was concentrated under reduced pressure to obtain compound 1-4. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 7.47 (dd, J=8.66, 1.51 Hz, 1H), 6.76 (dd, J=8.66, 6.27 Hz, 1H). LCMS (ESI) m/z: 234.1/236.1 [M+1] + .
4)化合物1-5的合成4) Synthesis of compound 1-5
向原料1-4(36g，143.99mmol)的N,N-二甲基甲酰胺(350mL)溶液中加入N-氯代丁二酰亚胺(19.23g，143.99mmol)，得到的混合物加热到75℃搅拌16小时。向反应液中加入乙酸乙酯(1000mL)和水(400mL)搅拌10分钟，除去水相，有机相减压浓缩，得到化合物1-5。 1H NMR(399MHz,DMSO-d 6)δppm 7.95(s,1H),7.69(d,J＝1.75Hz,1H)。 To the raw material 1-4 (36g, 143.99mmol) in N,N-dimethylformamide (350mL) was added N-chlorosuccinimide (19.23g, 143.99mmol), the resulting mixture was heated to 75 Stir at °C for 16 hours. Ethyl acetate (1000 mL) and water (400 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain compound 1-5. 1 H NMR (399MHz, DMSO-d 6 ) δ ppm 7.95 (s, 1H), 7.69 (d, J=1.75 Hz, 1H).
5)化合物1-6的合成5) Synthesis of compound 1-6
向原料1-5(35g，130.37mmol)的乙醇(300mL)溶液中加入醋酸甲脒(135.72g，1.30mol)，得到的混合物加热到回流80℃搅拌40小时。反应液减压浓缩除去乙醇，向残余物中加入水(200mL)，搅拌10分钟，过滤，水(200mL)洗涤，滤饼干燥，到化合物1-6。 1H NMR(400MHz,DMSO-d 6)δppm 8.05(d,J＝1.88Hz,1H),8.18-8.25(m,1H)。 Formamidine acetate (135.72 g, 1.30 mol) was added to a solution of raw material 1-5 (35 g, 130.37 mmol) in ethanol (300 mL), and the resulting mixture was heated to reflux at 80° C. and stirred for 40 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, water (200 mL) was added to the residue, stirred for 10 minutes, filtered, washed with water (200 mL), and the filter cake was dried to obtain compound 1-6. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.05 (d, J=1.88 Hz, 1H), 8.18-8.25 (m, 1H).
6)化合物1-7的合成6) Synthesis of compounds 1-7
向三口瓶中加入1-6(15.6g，56.22mmol)和三氯氧磷(172.41g，1.12mol)，120℃下搅拌2小时。降至50℃减压浓缩至干得残余物。再向三口瓶中加入二氯甲烷(160mL)，N-叔丁氧羰基哌嗪(12.57g，67.48mmol)和N,N-二异丙基乙胺(29.07g，224.92mmol)。降温至10℃缓慢加入1-1(16.64g，56.23mmol)的二氯甲烷(50mL)溶液。加毕，升温至30℃反应18小时。向反应体系中加入水(100mL)，分液，有机相再用无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化得到化合物1-7。LCMS(ESI)m/z:445/447[M+1] +。 1-6 (15.6g, 56.22mmol) and phosphorus oxychloride (172.41g, 1.12mol) were added to the three-necked flask, and stirred at 120°C for 2 hours. It was reduced to 50°C and concentrated to dryness under reduced pressure to obtain a residue. Then add dichloromethane (160 mL), N-tert-butoxycarbonylpiperazine (12.57 g, 67.48 mmol) and N,N-diisopropylethylamine (29.07 g, 224.92 mmol) into the three-necked flask. The temperature was lowered to 10°C and a solution of 1-1 (16.64 g, 56.23 mmol) in dichloromethane (50 mL) was slowly added. After the addition, the temperature was raised to 30°C and reacted for 18 hours. Water (100 mL) was added to the reaction system, the layers were separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography to obtain compound 1-7. LCMS (ESI) m/z: 445/447 [M+1] + .
7)化合物1-9的合成7) Synthesis of compounds 1-9
冰水浴0℃氮气保护下，向原料1-8(50.0g，277.77mmol)和三乙胺(56.21g，555.53mmol，77.3mL)的二氯甲烷(500mL)溶液中滴加三氟乙酸酐(70.0g，333.32mmol，46.4mL)，得到的浅褐色混合物自然升至室温25℃搅拌16小时。向反应液中加入二氯甲烷(100mL)和水(200mL)搅拌20分钟，除去水相，有机相减压浓缩，残余物经柱层析纯化得到化合物1-9。 1H NMR(400MHz,CDCl 3)δppm 8.40(br s,1H),8.33(d,J＝10.29Hz,1H),7.53(d,J＝7.03Hz,1H)。 Under the protection of nitrogen at 0°C in an ice water bath, to a solution of raw material 1-8 (50.0g, 277.77mmol) and triethylamine (56.21g, 555.53mmol, 77.3mL) in dichloromethane (500mL) was added dropwise trifluoroacetic anhydride ( 70.0g, 333.32mmol, 46.4mL), the obtained light brown mixture was naturally raised to room temperature and 25°C and stirred for 16 hours. Dichloromethane (100 mL) and water (200 mL) were added to the reaction solution and stirred for 20 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-9. 1 H NMR (400MHz, CDCl 3 ) δ ppm 8.40 (br s, 1H), 8.33 (d, J = 10.29 Hz, 1H), 7.53 (d, J = 7.03 Hz, 1H).
8)化合物1-10的合成8) Synthesis of compound 1-10
氮气保护下，向两个三口瓶(1000mL)中分别加入原料1-9(33.0g，119.56mmol)和四氢呋喃(600mL)，随后置于干冰乙醇浴中降温至-70℃，向得到的浅褐色溶液中滴加正丁基锂溶液(105.2mL，263.03mmol，105.2mL)，维持温度不超过-60℃，滴加完毕搅拌1小时，滴加硼酸三异丙酯(56.2g，298.90mmol)，得到的混合物自然升至室温25℃搅拌16小时。向反应液中分别滴加1M盐酸水溶液(250mL)，随后加热到40℃搅拌1小时，反应液合并后再加入乙酸乙酯(500mL)搅拌30分钟，除去水相，有机相减压浓缩得到浅褐色固体。向其中加入二氯甲烷(200mL)打浆搅拌30分钟，过滤，收集固体减压干燥，得到 化合物1-10。 1H NMR(400MHz,CDCl 3)δppm 8.40(br s,1H),8.33(d,J＝10.29Hz,1H),7.53(d,J＝7.03Hz,1H)。LCMS(ESI)m/z:223.9/225.9[M+1] +。 Under the protection of nitrogen, the raw materials 1-9 (33.0g, 119.56mmol) and tetrahydrofuran (600mL) were added to two three-necked flasks (1000mL), and then placed in a dry ice ethanol bath to cool to -70℃. Add n-butyl lithium solution (105.2mL, 263.03mmol, 105.2mL) to the solution dropwise, maintain the temperature not to exceed -60°C, stir for 1 hour after the addition is complete, and add triisopropyl borate (56.2g, 298.90mmol) dropwise, The resulting mixture was naturally raised to room temperature and 25°C and stirred for 16 hours. 1M aqueous hydrochloric acid (250mL) was added dropwise to the reaction solution, and then heated to 40°C and stirred for 1 hour. After the reaction solutions were combined, ethyl acetate (500mL) was added and stirred for 30 minutes. The aqueous phase was removed and the organic phase was concentrated under reduced pressure to obtain a shallow Brown solid. Dichloromethane (200 mL) was added to the mixture to be stirred for 30 minutes, filtered, and the solid was collected and dried under reduced pressure to obtain compound 1-10. 1 H NMR (400MHz, CDCl 3 ) δ ppm 8.40 (br s, 1H), 8.33 (d, J = 10.29 Hz, 1H), 7.53 (d, J = 7.03 Hz, 1H). LCMS (ESI) m/z: 223.9/225.9 [M+1] + .
9)化合物1-11的合成9) Synthesis of compound 1-11
向原料1-10(3.01g，13.46mmol)和1-7(3g，6.73mmol)的四氢呋喃(30mL)和水(3mL)溶液中加入磷酸钾(5.71g，26.92mmol)和催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.48g，0.67mmol)，氮气置换三次，得到的混合物加热到70℃搅拌16小时。向反应液中加入乙酸乙酯(50mL)和水(20mL)搅拌10分钟除去水相，有机相减压浓缩，残余物经柱层析纯化，得到化合物1-11。LCMS(ESI)m/z:544/546[M+1] +。 To raw materials 1-10 (3.01g, 13.46mmol) and 1-7 (3g, 6.73mmol) in tetrahydrofuran (30mL) and water (3mL) were added potassium phosphate (5.71g, 26.92mmol) and catalyst chlorination (2 -Dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (0.48g, 0.67mmol), replaced with nitrogen three times, and the resulting mixture was heated to 70°C and stirred for 16 hours. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction solution and stirred for 10 minutes to remove the aqueous phase, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-11. LCMS (ESI) m/z: 544/546 [M+1] + .
10)化合物1-12的合成10) Synthesis of compounds 1-12
冰水浴0℃氮气保护下，向原料1-11(0.65g，1.19mmol)的二氯甲烷(30mL)溶液中加入三氟化硼***(0.17g，1.19mmol)，随后滴加环氧乙烷(0.15mL，1.19mmol，0.66M二氯甲烷溶液)，得到的混合物搅拌3小时。向反应液中加入饱和碳酸氢钠水溶液(10mL)和二氯甲烷(30mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经柱层析纯化得到化合物1-12。LCMS(ESI)m/z:588/590[M+1] +。 Under the protection of nitrogen at 0℃ in an ice-water bath, add boron trifluoride ether (0.17g, 1.19mmol) to a solution of raw material 1-11 (0.65g, 1.19mmol) in dichloromethane (30mL), and then add ethylene oxide dropwise. (0.15 mL, 1.19 mmol, 0.66 M dichloromethane solution), and the resulting mixture was stirred for 3 hours. Saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (30 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-12. LCMS (ESI) m/z: 588/590 [M+1] + .
11)化合物1-13的合成11) Synthesis of compounds 1-13
室温25℃氮气保护下，向原料1-12(0.35g，0.59mmol)的四氢呋喃(300mL)溶液中加入钠氢(0.12g，2.97mmol，纯度60％)，得到的混合物加热到50℃搅拌5小时。向反应液中加入饱和氯化铵水溶液(100mL)和乙酸乙酯(100mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经柱层析纯化得到化合物1-13。LCMS(ESI)m/z:568/570[M+1] +。 Under nitrogen protection at room temperature 25℃, sodium hydrogen (0.12g, 2.97mmol, purity 60%) was added to a solution of raw material 1-12 (0.35g, 0.59mmol) in tetrahydrofuran (300mL), and the resulting mixture was heated to 50℃ and stirred for 5 Hour. Saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-13. LCMS (ESI) m/z: 568/570 [M+1] + .
12)化合物1-14的合成12) Synthesis of compound 1-14
室温25℃氮气保护下，向原料1-13(0.275g，0.48mmol)的二氯甲烷(50mL)溶液中加入三氟乙酸(0.71mL，9.67mmol)，得到的混合物搅拌2小时。反应液减压浓缩，得到粗品产物1-14直接投入下一步反应。LCMS(ESI)m/z:468/470[M+1] +。 Under nitrogen protection at room temperature and 25°C, trifluoroacetic acid (0.71 mL, 9.67 mmol) was added to a dichloromethane (50 mL) solution of starting material 1-13 (0.275 g, 0.48 mmol), and the resulting mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product 1-14, which was directly put into the next reaction. LCMS (ESI) m/z: 468/470 [M+1] + .
13)化合物1的合成13) Synthesis of compound 1
冰水浴0℃氮气保护下，向原料1-14(0.65g，0.48mmol)和三乙胺(0.19g，1.92mmol)的二氯甲烷(6mL)溶液中加入丙烯酰氯(43mg，0.48mmol)，得到的混合物搅拌1小时。向反应液中加入水(10mL)和二氯甲烷(20mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经制备板纯化得到化合物1。LCMS(ESI)m/z:522.1/524.1[M+1] +。 Add acryloyl chloride (43mg, 0.48mmol) to a solution of raw material 1-14 (0.65g, 0.48mmol) and triethylamine (0.19g, 1.92mmol) in dichloromethane (6mL) under nitrogen protection at 0°C in an ice water bath, The resulting mixture was stirred for 1 hour. Water (10 mL) and dichloromethane (20 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by a preparation plate to obtain compound 1. LCMS (ESI) m/z: 522.1/524.1 [M+1] + .
实施例2Example 2
Figure PCTCN2021101868-appb-000048
Figure PCTCN2021101868-appb-000048
化合物2和3的合成Synthesis of compounds 2 and 3
化合物1(140mg,26.8μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:EtOH(0.1％NH 3H 2O)；梯度:B％＝50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物2(Rt＝1.584min)和化合物3(Rt＝1.751min)。 Compound 1 (140mg, 26.8μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: EtOH (0.1% NH 3 H 2 O) ); Gradient: B%=50% isocratic elution; Flow rate: 70g/min; Column temperature: 35℃; System pressure: 150bar) After separation and purification, compound 2 (Rt=1.584min) and compound 3 (Rt=1.751) min).
化合物2： 1H NMR(400MHz,CDCl 3)δppm 8.81(br s,1H),7.86(br s,1H),7.43(br d,J＝6.27Hz,1H),6.61(br d,J＝10.92Hz,1H),6.39(br d,J＝17.19Hz,1H),5.80(br d,J＝10.29Hz,1H),4.88(br s,1H),4.50(br s,1H),4.40(br s,1H),3.79-4.06(m,8H),3.44-3.53(m,1H),2.99-3.10(m,1H)。LCMS(ESI)m/z:522.1/524.1[M+1] +。 Compound 2: 1 H NMR (400MHz, CDCl 3 ) δppm 8.81 (br s, 1H), 7.86 (br s, 1H), 7.43 (br d, J = 6.27 Hz, 1H), 6.61 (br d, J = 10.92 Hz, 1H), 6.39 (br d, J = 17.19 Hz, 1H), 5.80 (br d, J = 10.29 Hz, 1H), 4.88 (br s, 1H), 4.50 (br s, 1H), 4.40 (br s, 1H), 3.79-4.06 (m, 8H), 3.44-3.53 (m, 1H), 2.99-3.10 (m, 1H). LCMS (ESI) m/z: 522.1/524.1 [M+1] + .
化合物3： 1H NMR(400MHz,CDCl 3)δppm 8.81(s,1H),7.86(br s,1H),7.43(br d,J＝7.15Hz,1H),6.63(br dd,J＝16.63,10.35Hz,1H),6.39(br d,J＝17.07Hz,1H),5.80(br d,J＝10.54Hz,1H),4.87(br s,1H),4.49(br d,1H),4.38(br d,J＝11.42Hz,1H),3.76-4.02(m,8H),3.50(br s,1H),3.03(br d,1H)。LCMS(ESI)m/z:522.1/524.1[M+1] +。 Compound 3: 1 H NMR (400MHz, CDCl 3 ) δppm 8.81 (s, 1H), 7.86 (br s, 1H), 7.43 (br d, J = 7.15 Hz, 1H), 6.63 (br dd, J = 16.63, 10.35Hz, 1H), 6.39 (br d, J = 17.07 Hz, 1H), 5.80 (br d, J = 10.54 Hz, 1H), 4.87 (br s, 1H), 4.49 (br d, 1H), 4.38 ( br d, J = 11.42 Hz, 1H), 3.76-4.02 (m, 8H), 3.50 (br s, 1H), 3.03 (br d, 1H). LCMS (ESI) m/z: 522.1/524.1 [M+1] + .
实施例4Example 4
Figure PCTCN2021101868-appb-000049
Figure PCTCN2021101868-appb-000049
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000050
Figure PCTCN2021101868-appb-000050
1)化合物4-2的合成1) Synthesis of compound 4-2
室温25℃下，向原料1-7(2g，4.49mmol)的二氧六环(20mL)和水(2mL)溶液中加入4-1(1.84g，13.46mmol)，碳酸钠(1.19g，11.22mmol)，四三苯基膦钯(259.26mg，224.36μmol)，得到的混合物加热到90℃搅拌18小时，随后反应液降温至20℃，过滤，水(1000mL)洗涤，收集滤液，减压浓缩，残余物经过柱层析纯化得到化合物4-2。LCMS(ESI)m/z:458.3[M+1] +。 At room temperature 25°C, to a solution of raw material 1-7 (2g, 4.49mmol) in dioxane (20mL) and water (2mL) was added 4-1 (1.84g, 13.46mmol), sodium carbonate (1.19g, 11.22) mmol), tetrakistriphenylphosphine palladium (259.26mg, 224.36μmol), the resulting mixture was heated to 90°C and stirred for 18 hours, then the reaction solution was cooled to 20°C, filtered, washed with water (1000mL), collected the filtrate, and concentrated under reduced pressure The residue was purified by column chromatography to obtain compound 4-2. LCMS (ESI) m/z: 458.3 [M+1] + .
2)化合物4-3的合成2) Synthesis of compound 4-3
室温25℃下，向原料4-2(0.6g，1.31mmol)的二氯甲烷(40mL)溶液中加入三氯化铝(34.94mg，262.05μmol)，搅拌下降至0℃后再加入环氧乙烷(173.16mg，3.93mmol)，并在0℃下反应6小时。向反应体系中倒入水(50mL)，二氯甲烷(50mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过柱层析纯化得到化合物4-3。LCMS(ESI)m/z:502.3[M+1] +。 At room temperature 25°C, add aluminum trichloride (34.94mg, 262.05μmol) to the dichloromethane (40mL) solution of raw material 4-2 (0.6g, 1.31mmol), stir and drop to 0°C before adding ethylene oxide Alkane (173.16mg, 3.93mmol), and react at 0°C for 6 hours. Pour water (50 mL) and dichloromethane (50 mL) into the reaction system, stir for 10 minutes, remove the aqueous phase, and concentrate the organic phase under reduced pressure. The residue is purified by column chromatography to obtain compound 4-3. LCMS (ESI) m/z: 502.3 [M+1] + .
3)化合物4-4的合成3) Synthesis of compound 4-4
室温25℃下，向原料4-3(15mg,29.88μmol)的N,N-二甲基甲酰胺(0.5mL)溶液中加入N-氯代丁二酰亚胺(8mg，59.91μmol)，得到的混合物加热到65℃搅拌1小时，向反应液中加入水(50mL)，再用乙酸乙酯(10mL*3)萃取，收集有机相减压浓缩，得到的粗品经薄层色谱纯化得到化合物4-4。LCMS(ESI)m/z:470.3/472.3[M-Boc+1] +。 At room temperature 25°C, N-chlorosuccinimide (8mg, 59.91μmol) was added to a solution of raw material 4-3 (15mg, 29.88μmol) in N,N-dimethylformamide (0.5mL) to obtain The mixture was heated to 65°C and stirred for 1 hour. Water (50mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL*3). The organic phase was collected and concentrated under reduced pressure. The crude product obtained was purified by thin-layer chromatography to obtain compound 4. -4. LCMS (ESI) m/z: 470.3/472.3 [M-Boc+1] + .
4)化合物4-5的合成4) Synthesis of compound 4-5
向原料4-4(30mg，52.55μmol)的四氢呋喃(30mL)溶液中加入氢化钠(10.51mg，262.76μmol，60％纯度)，得到的混合物20℃搅拌1小时后加热到60℃搅拌5小时。将反应液倒入饱和氯化钠水溶液(20mL)中，再用乙酸乙酯(20mL)萃取两次，有机相减压浓缩，残余物经薄层色谱纯化得到化合物4-5。LCMS(ESI)m/z:550.2/552.2[M+1] +。 Sodium hydride (10.51 mg, 262.76 μmol, 60% purity) was added to a solution of raw material 4-4 (30 mg, 52.55 μmol) in tetrahydrofuran (30 mL), and the resulting mixture was stirred at 20°C for 1 hour and then heated to 60°C and stirred for 5 hours. The reaction solution was poured into a saturated aqueous sodium chloride solution (20 mL), and then extracted twice with ethyl acetate (20 mL), the organic phase was concentrated under reduced pressure, and the residue was purified by thin layer chromatography to obtain compound 4-5. LCMS (ESI) m/z: 550.2/552.2 [M+1] + .
5)化合物4-6的合成5) Synthesis of compound 4-6
室温20℃下，向原料4-5(18mg，32.68μmol)中加入HCl的乙酸乙酯溶液(5mL，4M)，搅拌反应1小时。反应液减压浓缩，得到粗品产物4-6的盐酸盐直接投入下一步反应。LCMS(ESI)m/z:450.2/452.2[M+1] +。 At room temperature and 20°C, HCl ethyl acetate solution (5 mL, 4M) was added to the raw material 4-5 (18 mg, 32.68 μmol), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of the crude product 4-6 directly into the next reaction. LCMS (ESI) m/z: 450.2/452.2 [M+1] + .
6)化合物4的合成6) Synthesis of compound 4
冰水浴0℃氮气保护下，向原料4-6的盐酸盐(15mg，30.79μmol)和三乙胺(12.46mg，123.15μmol)的二氯甲烷(2mL)溶液中加入丙烯酰氯(2.79mg，30.79μmol)，得到的混合物搅拌0.5小时。向反应液中加入水(10mL)和二氯甲烷(20mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经制备板纯化得到化合物4。 1H NMR(400MHz,CDCl 3)δppm 8.81(s,1H),7.88(s,1H),7.38(d,J＝2.5Hz,1H),7.02(d,J＝2.4Hz,1H),6.63(dd,J＝10.5,16.8Hz,1H),6.39(dd,J＝1.7,16.8Hz,1H),5.80(dd,J＝1.6,10.5Hz,1H),4.72(br s,1H),4.55-4.41(m,1H),4.32(br d,J＝11.3Hz,1H),4.00-3.71(m,8H),3.56(br s,1H),3.07(br d,J＝16.7Hz,1H)。LCMS(ESI)m/z:504.2/506.2[M+1] +。 Under the protection of nitrogen at 0°C in an ice water bath, add acryloyl chloride (2.79mg, 30.79 μmol), and the resulting mixture was stirred for 0.5 hours. Water (10 mL) and dichloromethane (20 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by a preparation plate to obtain compound 4. 1 H NMR (400MHz, CDCl 3 ) δppm 8.81 (s, 1H), 7.88 (s, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.63 ( dd, J = 10.5, 16.8 Hz, 1H), 6.39 (dd, J = 1.7, 16.8 Hz, 1H), 5.80 (dd, J = 1.6, 10.5 Hz, 1H), 4.72 (br s, 1H), 4.55- 4.41 (m, 1H), 4.32 (br d, J=11.3 Hz, 1H), 4.00-3.71 (m, 8H), 3.56 (br s, 1H), 3.07 (br d, J=16.7 Hz, 1H). LCMS (ESI) m/z: 504.2/506.2 [M+1] + .
实施例5Example 5
Figure PCTCN2021101868-appb-000051
Figure PCTCN2021101868-appb-000051
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000052
Figure PCTCN2021101868-appb-000052
1)化合物5-2的合成1) Synthesis of compound 5-2
将5-1(1g，4.46mmol)溶于二氧六环(20mL)中，加入双联嚬哪醇硼酸酯(4.53g，17.82mmol)，乙酸钾(874.48mg，8.91mmol)和催化剂[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(363.83mg，445.52μmol)，氮气置换3次，加热到80℃继续搅拌12小时。自然降至室温25℃得到化合物5-2的溶液。LCMS(ESI)m/z:272[M+1] +。 Dissolve 5-1 (1g, 4.46mmol) in dioxane (20mL), add double-linked lanalol borate (4.53g, 17.82mmol), potassium acetate (874.48mg, 8.91mmol) and catalyst [ 1,1-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane (363.83mg, 445.52μmol), replaced with nitrogen 3 times, heated to 80°C and continued stirring for 12 hours. It was naturally lowered to room temperature and 25°C to obtain a solution of compound 5-2. LCMS (ESI) m/z: 272 [M+1] + .
2)化合物5-3的合成2) Synthesis of compound 5-3
向5-2的反应液中，加入1-7(1.97g，4.42mmol)，磷酸钾(1.56g，7.37mmol)，[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(240.03mg，368.29μmol)和水(4mL)，氮气置换3次，加热到80℃继续搅拌2小时，反应液冷却至室温25℃，加入水(50mL)和乙酸乙酯(100mL*3)萃取，有机相合并后经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经柱层析纯化，得到化合物5-3。 1H NMR(400MHz,CDCl 3)δppm8.79-8.82(m,1H)7.82-7.89(m,1H)7.13-7.20(m,1H)6.90-6.95(m,1H)3.78-3.88(m,4H)3.62-3.73(m,6H)1.48-1.54(m,9H)。 To the reaction solution of 5-2, add 1-7 (1.97g, 4.42mmol), potassium phosphate (1.56g, 7.37mmol), [1,1-bis(di-tert-butylphosphine)ferrocene]dichloride Palladium(II) (240.03mg, 368.29μmol) and water (4mL) were replaced with nitrogen three times, heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature 25°C, and water (50mL) and ethyl acetate ( 100mL*3) extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 5-3. 1 H NMR (400MHz, CDCl 3 ) δppm 8.79-8.82 (m, 1H) 7.82-7.89 (m, 1H) 7.13-7.20 (m, 1H) 6.90-6.95 (m, 1H) 3.78-3.88 (m, 4H) ) 3.62-3.73 (m, 6H) 1.48-1.54 (m, 9H).
3)化合物5-4的合成3) Synthesis of compound 5-4
向干净的反应瓶中加入二氯甲烷(10mL)和5-3(140mg,274.31μmol)，降温至-10℃加入三氟化硼***(0.56g，3.95mmol)和环氧乙烷(0.48M，285.74μL)，-10℃～0℃继续搅拌1小时。向反应液中加入饱和碳酸氢钠水溶液(5mL)和二氯甲烷(15mL*3)萃取，有机相减压浓缩，残余物经制备板纯化，得到化合物5-4。 1H NMR(400MHz,CDCl 3)δppm 8.79-8.81(m,1H),7.82-7.85(m,1H),7.15-7.21(m,1H),6.89-6.93(m,1H),3.80-3.88(m,4H),3.65-3.72(m,4H),3.54-3.64(m,3H),3.16-3.22(m,2H),1.47-1.53(m,9H)。 Add dichloromethane (10mL) and 5-3 (140mg, 274.31μmol) to a clean reaction flask, cool to -10℃, add boron trifluoride ether (0.56g, 3.95mmol) and ethylene oxide (0.48M) , 285.74μL), -10℃～0℃, continue to stir for 1 hour. Saturated aqueous sodium bicarbonate solution (5 mL) and dichloromethane (15 mL*3) were added to the reaction solution for extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by a preparation plate to obtain compound 5-4. 1 H NMR (400MHz, CDCl 3 ) δppm 8.79-8.81 (m, 1H), 7.82-7.85 (m, 1H), 7.15-7.21 (m, 1H), 6.89-6.93 (m, 1H), 3.80-3.88 ( m, 4H), 3.65-3.72 (m, 4H), 3.54-3.64 (m, 3H), 3.16-3.22 (m, 2H), 1.47-1.53 (m, 9H).
4)化合物5-5的合成4) Synthesis of compound 5-5
向原料5-4(62mg，0.11mmol)的四氢呋喃(62mL)溶液中加入钠氢(22.36mg，0.56mmol，纯度60％)，得到的混合物加热到50℃搅拌5小时。反应液冷却至室温，加入水(15mL)，乙酸乙酯(30mL*3)萃取，减压浓缩除去溶剂，得到化合物5-5。LCMS(ESI)m/z:534/536[M+1] +。 Sodium hydrogen (22.36 mg, 0.56 mmol, purity 60%) was added to a solution of raw material 5-4 (62 mg, 0.11 mmol) in tetrahydrofuran (62 mL), and the resulting mixture was heated to 50° C. and stirred for 5 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (30 mL*3), and concentrated under reduced pressure to remove the solvent to obtain compound 5-5. LCMS (ESI) m/z: 534/536 [M+1] + .
5)化合物5-6的合成5) Synthesis of compound 5-6
向原料5-5(50mg，93.56μmol)的二氯甲烷(1mL)溶液中加入三氟乙酸(0.8mL，10.80mmol)，室温20℃继续搅拌1小时。反应液减压浓缩，得到粗品产物5-6。LCMS(ESI)m/z:434/436[M+1] +。 Trifluoroacetic acid (0.8 mL, 10.80 mmol) was added to the dichloromethane (1 mL) solution of raw material 5-5 (50 mg, 93.56 μmol), and stirring was continued for 1 hour at room temperature and 20°C. The reaction solution was concentrated under reduced pressure to obtain the crude product 5-6. LCMS (ESI) m/z: 434/436 [M+1] + .
6)化合物5的合成6) Synthesis of compound 5
冰水浴0℃氮气保护下，向原料5-6(50mg，0.09mmol)和三乙胺(36.91mg，0.36mmol)的二氯甲烷(3mL)溶液中加入丙烯酰氯(4.13mg，45μmol)，得到的混合物搅拌1小时。向反应液中加入水(5mL)，二氯甲烷(8mL*2)萃取，减压浓缩除去溶剂。经制备硅胶板纯化分离得到化合物5。 1H NMR(400MHz,CDCl 3)δppm 8.79-8.83(m,1H),7.86-7.89(m,1H),7.06-7.12(m,1H),6.90-6.95(m,1H),6.59-6.68(m,1H),6.35-6.44(m,1H),5.77-5.83(m,1H),4.44-4.54(m,1H),4.29-4.36(m,2H),3.90-4.01(m,4H),3.77-3.88(m,4H),3.47-3.62(m,1H),2.98-3.10(m,1H)。LCMS(ESI)m/z:488/490[M+1] +。 Under the protection of nitrogen at 0°C in an ice-water bath, add acryloyl chloride (4.13mg, 45μmol) to a solution of raw material 5-6 (50mg, 0.09mmol) and triethylamine (36.91mg, 0.36mmol) in dichloromethane (3mL) to obtain The mixture was stirred for 1 hour. Water (5 mL) was added to the reaction solution, extracted with dichloromethane (8 mL*2), and concentrated under reduced pressure to remove the solvent. The compound 5 was obtained by purification and separation on a preparative silica gel plate. 1 H NMR (400MHz, CDCl 3 ) δppm 8.79-8.83 (m, 1H), 7.86-7.89 (m, 1H), 7.06-7.12 (m, 1H), 6.90-6.95 (m, 1H), 6.59-6.68 ( m,1H),6.35-6.44(m,1H),5.77-5.83(m,1H),4.44-4.54(m,1H),4.29-4.36(m,2H),3.90-4.01(m,4H), 3.77-3.88 (m, 4H), 3.47-3.62 (m, 1H), 2.98-3.10 (m, 1H). LCMS (ESI) m/z: 488/490 [M+1] + .
实施例6Example 6
Figure PCTCN2021101868-appb-000053
Figure PCTCN2021101868-appb-000053
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000054
Figure PCTCN2021101868-appb-000054
1)化合物6-1的合成1) Synthesis of compound 6-1
化合物1-5(20g，74.50mmol)和尿素(89.48g，1.49mmol)的混合物加热到180℃搅拌4小时，反应混合物自然降至室温25℃，加入水(500mL)搅拌30分钟，过滤，水(500mL)洗涤，收集滤饼，干燥后得到化合物6-1的溶液。LCMS(ESI)m/z:290.9/292.9[M+1] +。 The mixture of compound 1-5 (20g, 74.50mmol) and urea (89.48g, 1.49mmol) was heated to 180°C and stirred for 4 hours. The reaction mixture was naturally cooled to room temperature 25°C, water (500mL) was added and stirred for 30 minutes, filtered, and water (500 mL) washing, collecting the filter cake, and drying to obtain a solution of compound 6-1. LCMS (ESI) m/z: 290.9/292.9 [M+1] + .
2)化合物6-2的合成2) Synthesis of compound 6-2
室温25℃下，向三氯氧磷(254g，1.66mmol)中分批加入原料6-1(25g，85.19mmol)，随后滴加N,N-二异丙基乙胺(27.52g，212.96mmol)，得到的混合物加热到120℃继续搅拌16小时，反应液冷却至室温25℃，减压浓缩，向残余物中加入二氯甲烷(50mL)和三乙胺(34.30g，339.02mmol)，随后加入N-叔丁氧羰基哌嗪(18.94g，101.70mmol)，得到的混合物室温25℃搅拌16小时，向反应液中加入二氯甲烷(300mL)和水(200mL)搅拌30分钟，除去水相，有机相减压浓缩，残余物经柱层析纯化，得到化合物6-2。LCMS(ESI)m/z:479.1/481.1[M+1] +。 At room temperature 25°C, to phosphorus oxychloride (254g, 1.66mmol) was added raw material 6-1 (25g, 85.19mmol) in batches, and then N,N-diisopropylethylamine (27.52g, 212.96mmol) was added dropwise ), the resulting mixture was heated to 120°C and stirring continued for 16 hours, the reaction solution was cooled to room temperature 25°C, and concentrated under reduced pressure. Dichloromethane (50mL) and triethylamine (34.30g, 339.02mmol) were added to the residue, followed by N-tert-butoxycarbonylpiperazine (18.94g, 101.70mmol) was added, and the resulting mixture was stirred at room temperature and 25°C for 16 hours. Dichloromethane (300mL) and water (200mL) were added to the reaction solution and stirred for 30 minutes to remove the water phase. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 6-2. LCMS (ESI) m/z: 479.1/481.1 [M+1] + .
3)化合物6-3的合成3) Synthesis of compound 6-3
向原料N-甲基-L-脯氨醇(1.61g，14.00mmol)的N,N-二甲基甲酰胺(60ml)溶液中加入氟化钾(2.71g，46.65mmol)和原料6-2(5.6g，11.67mmol)，得到的混合物加热到120℃搅拌3小时。向反应液中加入水(50mL)和乙酸乙酯(100mL)萃取，有机相减压浓缩，残余物经过过柱机纯化，得到化合物6-3。LCMS(ESI)m/z:558.3/560.3[M+1] +。 To the raw material N-methyl-L-prolinol (1.61g, 14.00mmol) in N,N-dimethylformamide (60ml) solution was added potassium fluoride (2.71g, 46.65mmol) and raw material 6-2 (5.6g, 11.67mmol), the resulting mixture was heated to 120°C and stirred for 3 hours. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution for extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 6-3. LCMS (ESI) m/z: 558.3/560.3 [M+1] + .
4)化合物6-4的合成4) Synthesis of compound 6-4
向原料6-3(2.6g，4.65mmol)和化合物1-10(2.08g，9.30mmol)的甲苯(30mL)和水(3mL)溶液中加入磷酸钾(3.95g，18.61mmol)，氮气置换三次，加入催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.67g，0.93mmol)，得到的混合物加热到70℃搅拌6小时。向反应液中加入乙酸乙酯(30mL)和水(10mL)搅拌10分钟除去水相，有机相减压浓缩，残余物经柱层析纯化，再经制备色谱分离得到化合物6-4。LCMS(ESI)m/z:657.1/659.1[M+1] +。 Potassium phosphate (3.95g, 18.61mmol) was added to a solution of raw material 6-3 (2.6g, 4.65mmol) and compound 1-10 (2.08g, 9.30mmol) in toluene (30mL) and water (3mL) and replaced with nitrogen three times , Add catalyst chlorination (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) )] Palladium (0.67g, 0.93mmol), and the resulting mixture was heated to 70°C and stirred for 6 hours. Ethyl acetate (30 mL) and water (10 mL) were added to the reaction solution and stirred for 10 minutes to remove the aqueous phase, the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography, and then separated by preparative chromatography to obtain compound 6-4. LCMS (ESI) m/z: 657.1/659.1 [M+1] + .
5)化合物6-5的合成5) Synthesis of compound 6-5
冰水浴0℃氮气保护下，向原料6-4(0.2g，0.30mmol)的二氯甲烷(10mL)溶液中加入三氟化硼***(0.56g，3.95mmol)和环氧乙烷(1.09M，0.30mml，278μL)，反应混合物自然升至室温25℃继续搅拌4小时。向反应液中加入饱和碳酸氢钠水溶液(10mL)和二氯甲烷(10mL)萃取，有机相减压浓缩，残余物经制备板纯化，得到化合物6-5。LCMS(ESI)m/z:701.1/703.1[M+1] +。 Under the protection of nitrogen at 0℃ in an ice water bath, add boron trifluoride ether (0.56g, 3.95mmol) and ethylene oxide (1.09M) to a solution of raw material 6-4 (0.2g, 0.30mmol) in dichloromethane (10mL) , 0.30mml, 278μL), the reaction mixture was naturally warmed to room temperature and 25°C and stirred for 4 hours. Saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (10 mL) were added to the reaction solution for extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by a preparation plate to obtain compound 6-5. LCMS (ESI) m/z: 701.1/703.1 [M+1] + .
6)化合物6-6的合成6) Synthesis of compound 6-6
向原料6-5(130mg，0.13mmol)的四氢呋喃(62mL)溶液中加入钠氢(37.03mg，0.92mmol，纯度60％)，得到的混合物加热到50℃搅拌5小时。反应液冷却至室温，加入饱和氯化铵水溶液(50mL)，乙酸乙酯(50mL)萃取，有机相减压浓缩，残余物经柱层析纯化，得到化合物6-6。LCMS(ESI)m/z:681.3/683.1[M+1] +。 Sodium hydrogen (37.03 mg, 0.92 mmol, purity 60%) was added to a solution of raw material 6-5 (130 mg, 0.13 mmol) in tetrahydrofuran (62 mL), and the resulting mixture was heated to 50° C. and stirred for 5 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added, extracted with ethyl acetate (50 mL), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 6-6. LCMS (ESI) m/z: 681.3/683.1 [M+1] + .
7)化合物6-7的合成7) Synthesis of compound 6-7
向原料6-6(110mg，161.29μmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.04mL，0.64mmol)，得到的混合物25℃继续搅拌2小时，反应液减压浓缩，得到粗品产物6-7的三氟乙酸。LCMS(ESI)m/z:581.0/583.0[M+1] +。 Trifluoroacetic acid (0.04mL, 0.64mmol) was added to the dichloromethane (2mL) solution of raw material 6-6 (110mg, 161.29μmol), the resulting mixture was stirred for 2 hours at 25°C, and the reaction solution was concentrated under reduced pressure to obtain the crude product Product 6-7 trifluoroacetic acid. LCMS (ESI) m/z: 581.0/583.0 [M+1] + .
8)化合物6-8的合成8) Synthesis of compounds 6-8
冰水浴0℃氮气保护下，向原料6-7的三氟乙酸(0.11g，158.06μmol)和三乙胺(79.97mg，790.30μmol)的二氯甲烷(3mL)溶液中加入丙烯酰氯(14.31mg，158.06μmol)，得到的混合物搅拌2小时。向反应液中加入水(5mL)，二氯甲烷(5mL*2)萃取，减压浓缩除去溶剂。经制备硅胶板纯化分离得到化合物6-8。LCMS(ESI)m/z:635.1/637.1[M+1] +。 Under the protection of nitrogen at 0°C in an ice-water bath, add acryloyl chloride (14.31mg) to a solution of raw materials 6-7 of trifluoroacetic acid (0.11g, 158.06μmol) and triethylamine (79.97mg, 790.30μmol) in dichloromethane (3mL) , 158.06 μmol), and the resulting mixture was stirred for 2 hours. Water (5 mL) was added to the reaction solution, extracted with dichloromethane (5 mL*2), and concentrated under reduced pressure to remove the solvent. The compound 6-8 is obtained by purification and separation on a silica gel plate. LCMS (ESI) m/z: 635.1/637.1 [M+1] + .
9)化合物6和7的合成9) Synthesis of compounds 6 and 7
化合物6-8(25mg,39.4μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:EtOH(0.1％NH 3H 2O)；梯度:B％＝50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化得到化合物6(Rt＝1.661min)和化合物7(Rt＝1.871)。 Compound 6-8 (25mg, 39.4μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: EtOH (0.1% NH 3 H 2 O); gradient: B% = 50% isocratic elution; flow rate: 70 g/min; column temperature: 35° C.; system pressure: 150 bar) to obtain compound 6 (Rt=1.661min) and compound 7 (Rt= 1.871).
化合物6： 1H NMR(400MHz,CDCl 3)δppm 7.78(s,1H),7.40(d,1H),6.61(dd,1H),6.37(dd,1H),5.74-5.83(m,1H),4.82(br s,1H),4.51-4.61(m,1H),4.32-4.45(m,3H),3.82(br s,8H),3.49(s,1H),3.13-3.23(m,1H),2.95-3.05(m,1H),2.77-2.90(m,1H),2.56(s,3H),2.31-2.41(m,1H),2.05-2.14(m,1H),1.76-1.94(m,3H)。LCMS(ESI)m/z:635.1/637.1[M+1] +。 Compound 6: 1 H NMR (400MHz, CDCl 3 ) δ ppm 7.78 (s, 1H), 7.40 (d, 1H), 6.61 (dd, 1H), 6.37 (dd, 1H), 5.74-5.83 (m, 1H), 4.82 (br s, 1H), 4.51-4.61 (m, 1H), 4.32-4.45 (m, 3H), 3.82 (br s, 8H), 3.49 (s, 1H), 3.13-3.23 (m, 1H), 2.95-3.05(m,1H),2.77-2.90(m,1H),2.56(s,3H),2.31-2.41(m,1H),2.05-2.14(m,1H),1.76-1.94(m,3H) ). LCMS (ESI) m/z: 635.1/637.1 [M+1] + .
化合物7： 1H NMR(400MHz,CDCl 3)δppm 7.78(s,1H),7.41(d,1H),6.58(s,1H),6.40(d,1H),5.79(dd,1H),4.76-4.87(m,1H),4.41(br s,4H),3.82(br s,9H),3.46-3.56(m,1H),3.12(br s,1H),3.00(br d,1H),2.69-2.81(m,1H),2.52(s,3H),2.31(br d,1H),2.00-2.12(m,1H),1.78-1.92(m,3H)。LCMS(ESI)m/z:635.1/637.1[M+1] +。 Compound 7: 1 H NMR (400MHz, CDCl 3 ) δ ppm 7.78 (s, 1H), 7.41 (d, 1H), 6.58 (s, 1H), 6.40 (d, 1H), 5.79 (dd, 1H), 4.76 4.87 (m, 1H), 4.41 (br s, 4H), 3.82 (br s, 9H), 3.46-3.56 (m, 1H), 3.12 (br s, 1H), 3.00 (br d, 1H), 2.69- 2.81 (m, 1H), 2.52 (s, 3H), 2.31 (br d, 1H), 2.00-2.12 (m, 1H), 1.78-1.92 (m, 3H). LCMS (ESI) m/z: 635.1/637.1 [M+1] + .
实施例8Example 8
Figure PCTCN2021101868-appb-000055
Figure PCTCN2021101868-appb-000055
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000056
Figure PCTCN2021101868-appb-000056
1)化合物8-2的合成1) Synthesis of compound 8-2
向三口中加入二甲基亚砜(9mL)，化合物6-2(1.5g，3.12mmol)，化合物8-1(1.39g，15.62mmol)和氟化钾(362.98mg，6.25mmol)，加热到120℃反应2.5小时。反应液倒入水(200mL)中，过滤，滤饼再用水(20mL)淋洗三次后，烘干得化合物8-2。LCMS(ESI)m/z:532/534[M+1] +。 Add dimethyl sulfoxide (9mL), compound 6-2 (1.5g, 3.12mmol), compound 8-1 (1.39g, 15.62mmol) and potassium fluoride (362.98mg, 6.25mmol) to three mouths, and heat to React at 120°C for 2.5 hours. The reaction solution was poured into water (200 mL), filtered, and the filter cake was rinsed three times with water (20 mL) and dried to obtain compound 8-2. LCMS (ESI) m/z: 532/534 [M+1] + .
2)化合物8-3的合成2) Synthesis of compound 8-3
向三口瓶中加入二氧六环(40mL)，化合物8-2(1.86g，3.49mmol)，化合物1-10(1.56g，6.98mmol)，磷酸钾(1.48g，6.98mmol)和氯化((2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯II))(251.55mg，349.08μmol)，氮气置换三次，加热到110℃反应18小时。反应液减压浓缩至干，再加入二氯甲烷(50mL)，水(20mL)，分液，有机相减压浓缩，粗品经柱层析纯化(梯度洗脱：0～10％甲醇/二氯甲烷，流速30mL/min)纯化，再经制备高效液相色谱纯化得到化合物8-3。LCMS(ESI)m/z:631/633[M+1] +。 Add dioxane (40mL), compound 8-2 (1.86g, 3.49mmol), compound 1-10 (1.56g, 6.98mmol), potassium phosphate (1.48g, 6.98mmol) and chloride ( (2-Dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium II) ) (251.55mg, 349.08μmol), replaced with nitrogen three times, and heated to 110°C to react for 18 hours. The reaction solution was concentrated to dryness under reduced pressure, then dichloromethane (50mL), water (20mL) were added, the layers were separated, the organic phase was concentrated under reduced pressure, and the crude product was purified by column chromatography (gradient elution: 0-10% methanol/dichloride). Methane, a flow rate of 30 mL/min) was purified, and then purified by preparative high performance liquid chromatography to obtain compound 8-3. LCMS (ESI) m/z: 631/633 [M+1] + .
3)化合物8-4的合成3) Synthesis of compound 8-4
向三口瓶中加入二氯甲烷(6mL)，化合物8-3(250mg，395.61μmol)，降温至0℃加入三氟化硼***(224.60mg，1.58mmol)和环氧乙烷(8.71mg，197.81μmol)，0℃保温反应0.5小时，将反应液倒入饱和碳酸氢钠水溶液(20mL)中，再加入二氯甲烷(20mL)，分液除去水相，有机相减压浓缩，粗品经柱层析纯化(梯度洗脱：0～10％甲醇/二氯甲烷，流速30mL/min)纯化得到化合物8-4。LCMS(ESI)m/z:675/677[M+1] +。 Add dichloromethane (6mL), compound 8-3 (250mg, 395.61μmol) to a three-necked flask, cool to 0°C, add boron trifluoride ether (224.60mg, 1.58mmol) and ethylene oxide (8.71mg, 197.81) μmol), the reaction was incubated at 0°C for 0.5 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20mL), and dichloromethane (20mL) was added, the aqueous phase was removed by separation, the organic phase was concentrated under reduced pressure, and the crude product was passed through the column Analytical purification (gradient elution: 0-10% methanol/dichloromethane, flow rate 30 mL/min) to obtain compound 8-4. LCMS (ESI) m/z: 675/677 [M+1] + .
4)化合物8-5的合成4) Synthesis of compound 8-5
向三口瓶中加入四氢呋喃(50mL)，化合物8-4(50mg，73.97μmol)和钠氢(14.79mg，369.83μmol，60％纯度)，氮气保护下加热到60℃反应1小时。向反应液中加入饱和氯化铵水溶液(100mL)和乙酸乙酯(50mL)，减压浓缩，粗品薄层色谱纯化得到化合物8-5。LCMS(ESI)m/z:655/657[M+1] +。 Tetrahydrofuran (50 mL), compound 8-4 (50 mg, 73.97 μmol) and sodium hydrogen (14.79 mg, 369.83 μmol, 60% purity) were added to a three-necked flask, and the mixture was heated to 60° C. for 1 hour under the protection of nitrogen. Saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (50 mL) were added to the reaction solution, concentrated under reduced pressure, and the crude product was purified by thin layer chromatography to obtain compound 8-5. LCMS (ESI) m/z: 655/657 [M+1] + .
5)化合物8-6的合成5) Synthesis of compound 8-6
向三口瓶中加入化合物8-5(27mg，41.16μmol)和盐酸-乙酸乙酯(4M，3mL)，20℃搅拌反应1小时，体系减压浓缩得化合物8-6的盐酸盐。LCMS(ESI)m/z:555/557[M+1] +。 Compound 8-5 (27 mg, 41.16 μmol) and hydrochloric acid-ethyl acetate (4M, 3 mL) were added to a three-neck flask, and the reaction was stirred at 20° C. for 1 hour. The system was concentrated under reduced pressure to obtain the hydrochloride salt of compound 8-6. LCMS (ESI) m/z: 555/557 [M+1] + .
6)化合物8的合成6) Synthesis of compound 8
向三口瓶中加入二氯甲烷(5mL)，化合物8-6的盐酸盐(24mg，40.52μmol)和三乙胺(24.60mg，243.12μmol)，降温至0℃加入丙烯酰氯(2.57mg，28.36μmol)，0℃保温反应0.5小时。向反应液中加入水(1mL)，分液，有机相减压浓缩，粗品薄层色谱纯化得到化合物8。 1HNMR(400MHz,CDCl 3)δppm 7.79(s,1H),7.42(d,J＝7.4Hz,1H),6.61(dd,J＝10.5,16.8Hz,1H),6.38(dd,J＝1.8,16.8Hz,1H),5.79(dd,J＝1.7,10.5Hz,1H),4.89-4.59(m,3H),4.46-4.35(m,2H),4.14-3.70(m,8H),3.61-3.40(m,1H),3.10-2.91(m,3H),2.51(s,6H)；LCMS(ESI)m/z:609/611[M+1] +。 Add dichloromethane (5mL), compound 8-6 hydrochloride (24mg, 40.52μmol) and triethylamine (24.60mg, 243.12μmol) into a three-necked flask, cool to 0℃ and add acryloyl chloride (2.57mg, 28.36) μmol), the reaction was incubated at 0°C for 0.5 hours. Water (1 mL) was added to the reaction solution, the layers were separated, the organic phase was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography to obtain compound 8. 1 HNMR(400MHz, CDCl 3 )δppm 7.79(s,1H), 7.42(d,J=7.4Hz,1H), 6.61(dd,J=10.5,16.8Hz,1H), 6.38(dd,J=1.8, 16.8Hz, 1H), 5.79 (dd, J = 1.7, 10.5 Hz, 1H), 4.89-4.59 (m, 3H), 4.46-4.35 (m, 2H), 4.14-3.70 (m, 8H), 3.61-3.40 (m, 1H), 3.10-2.91 (m, 3H), 2.51 (s, 6H); LCMS (ESI) m/z: 609/611 [M+1] + .
实施例9Example 9
Figure PCTCN2021101868-appb-000057
Figure PCTCN2021101868-appb-000057
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000058
Figure PCTCN2021101868-appb-000058
1)化合物9-1的合成1) Synthesis of compound 9-1
氮气保护下，向原料6-2(2g，4.17mmol)的乙二醇二甲醚(20mL)溶液中加入氟化钾(4.84g，83.31mmol)，得到的混合物加热到140℃搅拌4小时。向反应液中加入饱和氯化铵水溶液(50mL)和乙酸乙酯(50mL*2)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物9-1。LCMS(ESI)m/z:463.0/465.0[M+1] +。 Under nitrogen protection, potassium fluoride (4.84 g, 83.31 mmol) was added to a solution of raw material 6-2 (2 g, 4.17 mmol) in ethylene glycol dimethyl ether (20 mL), and the resulting mixture was heated to 140° C. and stirred for 4 hours. Saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL*2) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 9-1. LCMS (ESI) m/z: 463.0/465.0 [M+1] + .
2)化合物9-2的合成2) Synthesis of compound 9-2
氮气保护下，向原料9-1(1.8g，3.88mmol)和6-氨基-3-氯-2氟苯硼酸(1.84g，9.70mmol)的四氢呋喃(30mL)和水(3mL)的溶液中加入磷酸钾(1.65g，7.76mmol)，氮气置换三次，随后加入催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.30g，0.39mmol)，得到的混合物加热到70℃搅拌6小时。向反应液中加入10毫升碳酸氢钠水溶液(10mL)和乙酸乙酯(20mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物9-2。LCMS(ESI)m/z:528.19/530.1[M+1] +。 Under nitrogen protection, add raw material 9-1 (1.8g, 3.88mmol) and 6-amino-3-chloro-2 fluorophenylboronic acid (1.84g, 9.70mmol) in tetrahydrofuran (30mL) and water (3mL) solution Potassium phosphate (1.65g, 7.76mmol), replaced with nitrogen three times, and then added catalyst chlorination (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)]palladium (0.30 g, 0.39 mmol), and the resulting mixture was heated to 70°C and stirred for 6 hours. To the reaction solution were added 10 mL of sodium bicarbonate aqueous solution (10 mL) and ethyl acetate (20 mL) and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 9-2. LCMS (ESI) m/z: 528.19/530.1 [M+1] + .
3)化合物9-3的合成3) Synthesis of compound 9-3
向原料9-2(1.17g，2.21mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入N-氯代丁二酰亚胺(0.32g，2.44mmol)，得到的混合物得到的混合物加热到50℃搅拌6小时。向反应液中加入乙酸乙酯(50mL)和 水溶液(50mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物9-3。LCMS(ESI)m/z:562.3/564.3[M+1] +。 To the raw material 9-2 (1.17g, 2.21mmol) in N,N-dimethylformamide (30mL) solution was added N-chlorosuccinimide (0.32g, 2.44mmol), the resulting mixture obtained The mixture was heated to 50°C and stirred for 6 hours. Ethyl acetate (50 mL) and aqueous solution (50 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 9-3. LCMS (ESI) m/z: 562.3/564.3 [M+1] + .
4)化合物9-4的合成4) Synthesis of compound 9-4
冰水浴0℃氮气保护下，向原料9-3(1.1g，1.95mmol)的二氯甲烷(40mL)溶液中加入三氟化硼***(0.28g，1.97mmol)，随后滴加环氧乙烷(3.01mL，1.95mmol，0.65M的二氯甲烷溶液)，得到的混合物搅拌4小时。向反应液中加入二氯甲烷(20mL)和饱和碳酸氢钠水溶液(20mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物9-4。LCMS(ESI)m/z:606.3/608.3[M+1] +。 Under the protection of nitrogen at 0°C in an ice-water bath, add boron trifluoride ether (0.28g, 1.97mmol) to a solution of raw material 9-3 (1.1g, 1.95mmol) in dichloromethane (40mL), and then add ethylene oxide dropwise. (3.01 mL, 1.95 mmol, 0.65 M dichloromethane solution), the resulting mixture was stirred for 4 hours. Dichloromethane (20 mL) and saturated sodium bicarbonate aqueous solution (20 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 9-4. LCMS (ESI) m/z: 606.3/608.3 [M+1] + .
5)化合物9-6的合成5) Synthesis of compound 9-6
向原料9-4(0.11g，0.51mmol)和9-5(0.13g，0.90mmol)的二甲基亚砜(5mL)溶液中加入氟化钾(0.02g，0.90mmol)，得到的混合物加热到120℃搅拌12小时。向反应液中加入乙酸乙酯(10mL)和水(5mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经过柱层析纯化得到化合物9-6。LCMS(ESI)m/z:731.4/733.5[M+1] +。 Potassium fluoride (0.02g, 0.90mmol) was added to a solution of raw materials 9-4 (0.11g, 0.51mmol) and 9-5 (0.13g, 0.90mmol) in dimethyl sulfoxide (5mL), and the resulting mixture was heated Stir at 120°C for 12 hours. Ethyl acetate (10 mL) and water (5 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 9-6. LCMS (ESI) m/z: 731.4/733.5 [M+1] + .
6)化合物9-7的合成6) Synthesis of compound 9-7
向原料9-6(0.08g，0.11mmol)的四氢呋喃(80mL)溶液中加入钠氢(0.022g，0.55mmol，60％纯度)，得到的混合物加热到50℃搅拌5小时。向残余物中加入饱和氯化铵水溶液(10mL)和乙酸乙酯(10mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过纯化后得到化合物9-7。LCMS(ESI)m/z:711.2/713.2[M+1] +。 Sodium hydrogen (0.022 g, 0.55 mmol, 60% purity) was added to a solution of raw material 9-6 (0.08 g, 0.11 mmol) in tetrahydrofuran (80 mL), and the resulting mixture was heated to 50° C. and stirred for 5 hours. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added to the residue, stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified to obtain compound 9-7. LCMS (ESI) m/z: 711.2/713.2 [M+1] + .
7)化合物9-8的合成7) Synthesis of compounds 9-8
向原料9-7(52mg，0.07mmol)的二氯甲烷(0.5mL)溶液中加入三氟乙酸(0.11mL)，得到的混合物室温25℃搅拌1小时，反应液减压浓缩得到化合物9-8的三氟乙酸盐。LCMS(ESI)m/z:611.2/613.2[M+1] +。8)化合物9的合成 Trifluoroacetic acid (0.11 mL) was added to a solution of raw material 9-7 (52 mg, 0.07 mmol) in dichloromethane (0.5 mL), the resulting mixture was stirred at room temperature and 25°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 9-8 The trifluoroacetate. LCMS (ESI) m/z: 611.2/613.2 [M+1] + . 8) Synthesis of compound 9
冰水浴0℃氮气保护下，向原料9-8(55mg，0.075mmol，三氟乙酸盐)和三乙胺(38mg，0.378mmol)的二氯甲烷(2mL)溶液中加入丙烯酰氯(5.5mg，0.06mmol)，得到的混合物搅拌1小时。向反应液中加入水(2mL)和二氯甲烷(5mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经Pre-HPLC纯化，得到化合物9。 1H NMR(400MHz,CD 3OD)δppm 8.00(s,1H),7.43-7.51(m,1H),6.82(dd,J＝16.76,10.63Hz,1H),6.28(dd,J＝16.76,1.88Hz,1H),5.81(dd,J＝10.63,1.88Hz,1H),4.74-4.77(m,2H),4.64(s,2H),4.58(br s,8H),4.29-4.35(m,2H),4.02-4.11(m,2H),3.95(br s,2H),2.39(s,2H),2.22(s,6H)；LCMS(ESI)m/z:665.1/667.1[M+1] +。 Under the protection of nitrogen at 0℃ in an ice-water bath, add acryloyl chloride (5.5mg , 0.06 mmol), and the resulting mixture was stirred for 1 hour. Water (2 mL) and dichloromethane (5 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain compound 9. 1 H NMR (400MHz, CD 3 OD) δppm 8.00 (s, 1H), 7.43-7.51 (m, 1H), 6.82 (dd, J = 16.76, 10.63 Hz, 1H), 6.28 (dd, J = 16.76, 1.88 Hz, 1H), 5.81 (dd, J = 10.63, 1.88 Hz, 1H), 4.74-4.77 (m, 2H), 4.64 (s, 2H), 4.58 (br s, 8H), 4.29-4.35 (m, 2H) ),4.02-4.11(m,2H),3.95(br s,2H),2.39(s,2H),2.22(s,6H); LCMS(ESI)m/z:665.1/667.1[M+1] + .
实施例10Example 10
Figure PCTCN2021101868-appb-000059
Figure PCTCN2021101868-appb-000059
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000060
Figure PCTCN2021101868-appb-000060
1)化合物10-2的合成1) Synthesis of compound 10-2
冰水浴0℃氮气保护下，向原料10-1(8.0g，29.8mmol)的甲醇(10mL)和四氢呋喃(60mL)溶液中滴加三甲基硅基重氮甲烷(22.35mL，44.7mmol，2M)，得到的混合物搅拌16小时。反应液减压浓缩，残余物经过柱层析纯化得到化合物10-2。LCMS(ESI)m/z:281.9/283.9[M+1] +。 Under the protection of nitrogen in an ice-water bath at 0°C, trimethylsilyldiazomethane (22.35mL, 44.7mmol, 2M) was added dropwise to a solution of raw material 10-1 (8.0g, 29.8mmol) in methanol (10mL) and tetrahydrofuran (60mL). ), the resulting mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 10-2. LCMS (ESI) m/z: 281.9/283.9 [M+1] + .
2)化合物10-3的合成2) Synthesis of compound 10-3
氮气保护-60℃下，向原料氯乙腈(5.93g，78.6mmol)和原料10-2(7.4g，26.2mmol)的二氧六环溶液中通入盐酸气体30分钟，得到的混合物置于闷罐中加热到100℃搅拌16小时。反应液减压浓缩，残余物经过柱层析纯化得到化合物10-3。LCMS(ESI)m/z:325.9/328.0[M+1] +。 Under the protection of nitrogen, at -60℃, pour hydrochloric acid gas into the dioxane solution of raw material chloroacetonitrile (5.93g, 78.6mmol) and raw material 10-2 (7.4g, 26.2mmol) for 30 minutes. The pot was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 10-3. LCMS (ESI) m/z: 325.9/328.0 [M+1] + .
3)化合物10-4的合成3) Synthesis of compound 10-4
向三氯氧磷(50mL)中分批加入原料10-3(7.0g，21.5mmol)，随后滴加N,N-二异丙基乙胺(8.33g，64.4mmol)，得到的混合物加热到120℃搅拌16小时，反应液减压浓缩，残余物经过柱层析纯化得到化合物10-4。 1H NMR(400MHz,CDCl3)δppm 8.24(d,1H),4.86(s,2H)。 To phosphorus oxychloride (50mL) was added raw material 10-3 (7.0g, 21.5mmol) in batches, and then N,N-diisopropylethylamine (8.33g, 64.4mmol) was added dropwise, and the resulting mixture was heated to After stirring at 120°C for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 10-4. 1 H NMR (400MHz, CDCl3) δ ppm 8.24 (d, 1H), 4.86 (s, 2H).
4)化合物10-5的合成4) Synthesis of compound 10-5
室温25℃下，向原料10-4(2.0g，5.81mmol)和N-叔丁氧羰基-哌嗪(1.1g，5.81mmol)的异丙醇(50mL)溶液中加入三乙胺(0.70g，6.97mmol)，得到的混合物加热到75℃搅拌2小时，反应液直接减压浓缩，残余物经过柱层析纯化得到化合物10-5。LCMS(ESI)m/z:493.1/495.1[M+1] +。 At room temperature 25°C, add triethylamine (0.70g , 6.97 mmol), the resulting mixture was heated to 75°C and stirred for 2 hours, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 10-5. LCMS (ESI) m/z: 493.1/495.1 [M+1] + .
5)化合物10-6的合成5) Synthesis of compound 10-6
氮气保护下，向原料10-5(2.2g，4.45mmol)和氮甲基哌嗪(0.54g，5.34mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入碳酸钾(1.23g，8.9mmol)，得到的混合物25℃搅拌2小时。向反应液中加入水(50mL)和乙酸乙酯(50mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物10-6。 1H NMR(400MHz,CDCl 3)δppm 7.75(d,1H),3.87(s,2H),3.73-3.82(m,4H),3.59-3.70(m,4H),2.46-2.89(m,8H),2.34(br s,3H),1.51(s,9H)。LCMS(ESI)m/z:557.2/559.3[M+1] +。 Under nitrogen protection, add potassium carbonate (1.23g , 8.9 mmol), and the resulting mixture was stirred at 25°C for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 10-6. 1 H NMR (400MHz, CDCl 3 ) δppm 7.75 (d, 1H), 3.87 (s, 2H), 3.73-3.82 (m, 4H), 3.59-3.70 (m, 4H), 2.46-2.89 (m, 8H) , 2.34 (br s, 3H), 1.51 (s, 9H). LCMS (ESI) m/z: 557.2/559.3 [M+1] + .
6)化合物10-7的合成6) Synthesis of compound 10-7
氮气保护下，向原料10-6(2.1g，3.76mmol)和6-氨基-3-氯-2氟苯硼酸(1.43g，7.53mmol)的二氧六环(50mL)溶液中加入磷酸钾(1.6g，7.53mmol)，氮气置换三次，随后加入催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.27g，0.38mmol)，得到的混合物加热到110℃搅拌16小时。向反应液中加入水(20mL)和乙酸乙酯(50mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物10-7。LCMS(ESI)m/z:622.1/624.2[M+1] +。 Under the protection of nitrogen, add potassium phosphate ( 1.6g, 7.53mmol), replaced with nitrogen three times, and then added catalyst chlorination (2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl) [2-(2′ -Amino-1,1'-biphenyl)]palladium (0.27g, 0.38mmol), and the resulting mixture was heated to 110°C and stirred for 16 hours. Water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 10-7. LCMS (ESI) m/z: 622.1/624.2 [M+1] + .
7)化合物10-8的合成7) Synthesis of compound 10-8
冰水浴0℃氮气保护下，向原料10-7(0.88g，1.41mmol)和三氯化铁(0.82g，5.1mmol)的乙酸乙酯(20mL)溶液中加入环氧乙烷的二氯甲烷溶液(4.1mL，2.83mmol，0.69M)，得到的混合物搅拌3小时。向反应液中加入碳酸氢钠水溶液(10mL)和乙酸乙酯(20mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物10-8。LCMS(ESI)m/z:666.2/668.2[M+1] +。 Under the protection of nitrogen at 0℃ in an ice water bath, add ethylene oxide in dichloromethane to a solution of raw material 10-7 (0.88g, 1.41mmol) and ferric chloride (0.82g, 5.1mmol) in ethyl acetate (20mL) Solution (4.1 mL, 2.83 mmol, 0.69M), and the resulting mixture was stirred for 3 hours. Aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 10-8. LCMS (ESI) m/z: 666.2/668.2 [M+1] + .
8)化合物10-9的合成8) Synthesis of compound 10-9
向原料10-8(0.80g，1.21mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入N-氯代丁二酰亚胺(177.4mg，1.33mmol)，得到的混合物得到的混合物加热到70℃搅拌6小时。向反应液中加入乙酸乙酯(20mL)和 饱和食盐水溶液(10mL)搅拌10分钟，除去水相，有机相减压浓缩，得到化合物10-9。LCMS(ESI)m/z:700.2/702.2[M+1] +。 To the raw material 10-8 (0.80g, 1.21mmol) in N,N-dimethylformamide (20mL) was added N-chlorosuccinimide (177.4mg, 1.33mmol), the resulting mixture was obtained The mixture was heated to 70°C and stirred for 6 hours. To the reaction solution were added ethyl acetate (20 mL) and a saturated aqueous salt solution (10 mL) and stirred for 10 minutes, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain compound 10-9. LCMS (ESI) m/z: 700.2/702.2 [M+1] + .
9)化合物10-10的合成9) Synthesis of compound 10-10
向原料10-9(0.61g，0.87mmol)的四氢呋喃(650mL)溶液中加入钠氢(0.17g，4.35mmol，60％纯度)，得到的混合物加热到50℃搅拌6小时。向残余物中加入饱和氯化铵水溶液(100mL)和乙酸乙酯(200mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过纯化后得到化合物10-10。LCMS(ESI)m/z:680.2/682.2[M+1] +。 Sodium hydrogen (0.17 g, 4.35 mmol, 60% purity) was added to a solution of raw material 10-9 (0.61 g, 0.87 mmol) in tetrahydrofuran (650 mL), and the resulting mixture was heated to 50° C. and stirred for 6 hours. Saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (200 mL) were added to the residue, stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified to obtain compound 10-10. LCMS (ESI) m/z: 680.2/682.2 [M+1] + .
10)化合物10-11的合成10) Synthesis of compound 10-11
向原料10-10(0.2g，0.29mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(0.43mL)，得到的混合物室温25℃搅拌3小时，反应液减压浓缩得到化合物10-11的三氟乙酸盐。LCMS(ESI)m/z:580.1/582.1[M+1] +。 Trifluoroacetic acid (0.43 mL) was added to a solution of raw material 10-10 (0.2 g, 0.29 mmol) in dichloromethane (3 mL), the resulting mixture was stirred at room temperature and 25°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 10-11 The trifluoroacetate. LCMS (ESI) m/z: 580.1/582.1 [M+1] + .
12)化合物10的合成12) Synthesis of compound 10
冰水浴0℃氮气保护下，向原料10-11的三氟乙酸盐(0.2g，0.29mmol)和三乙胺(145.6mg，1.44mmol)的二氯甲烷(5mL)溶液中加入丙烯酰氯(23.4mg，0.26mmol)，得到的混合物搅拌2小时。向反应液中加入水(10mL)和二氯甲烷(10mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经Pre-HPLC纯化，得到化合物12。 1H NMR(400MHz,CD 3OD)δppm 8.04(s,1H),7.48(d,1H),6.79(s,1H),6.22-6.32(m,1H),5.82(s,1H),5.49(s,1H),4.31-4.40(m,1H),4.25(br d,1H),4.03-4.13(m,1H),3.75-3.99(m,8H),3.01-3.10(m,1H),2.42-2.89(m,10H),2.32(s,3H)。LCMS(ESI)m/z:634.1/636.1[M+1] +。 Under the protection of nitrogen at 0℃ in an ice-water bath, add acryloyl chloride ( 23.4 mg, 0.26 mmol), and the resulting mixture was stirred for 2 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain compound 12. 1 H NMR (400MHz, CD 3 OD) δppm 8.04 (s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 6.22-6.32 (m, 1H), 5.82 (s, 1H), 5.49 ( s,1H),4.31-4.40(m,1H),4.25(br d,1H),4.03-4.13(m,1H),3.75-3.99(m,8H),3.01-3.10(m,1H),2.42 -2.89(m,10H), 2.32(s,3H). LCMS (ESI) m/z: 634.1/636.1 [M+1] + .
实施例11Example 11
Figure PCTCN2021101868-appb-000061
Figure PCTCN2021101868-appb-000061
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000062
Figure PCTCN2021101868-appb-000062
1)化合物11-2的合成1) Synthesis of compound 11-2
冰水浴0℃氮气保护下，向原料11-1(3.8g，12.9mmol)和1-溴-2,4,6,-三氯-8-氟喹唑啉(3.0g，9.1mmol)的二氯甲烷(50mL)的溶液中加入三乙胺(2.6g，25.7mmol)，得到的混合物室温25℃搅拌16小时。向反应液中加入水(50mL)和二氯甲烷(50mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物11-2。LCMS(ESI)m/z:552.1/554.1[M+1] +。 Under the protection of nitrogen at 0°C in an ice-water bath, the two raw materials 11-1 (3.8g, 12.9mmol) and 1-bromo-2,4,6,-trichloro-8-fluoroquinazoline (3.0g, 9.1mmol) Triethylamine (2.6 g, 25.7 mmol) was added to a solution of methyl chloride (50 mL), and the resulting mixture was stirred at room temperature and 25° C. for 16 hours. Water (50 mL) and dichloromethane (50 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 11-2. LCMS (ESI) m/z: 552.1/554.1 [M+1] + .
2)化合物11-3的合成2) Synthesis of compound 11-3
向原料11-2(3.0g，5.4mmol)和N-甲基-L-脯氨醇(3.12g，27.1mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入氟化钾(0.63g，10.7mmol)，得到的混合物加热到120℃搅拌6小时。向反应液中加入乙酸乙酯(50mL)和水溶液(50mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物11-3。LCMS(ESI)m/z:631.2/633.2[M+1] +。 Add potassium fluoride ( 0.63g, 10.7mmol), and the resulting mixture was heated to 120°C and stirred for 6 hours. Ethyl acetate (50 mL) and aqueous solution (50 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 11-3. LCMS (ESI) m/z: 631.2/633.2 [M+1] + .
3)化合物11-4的合成3) Synthesis of compound 11-4
氮气保护下，向原料11-3(1.2g，1.9mmol)和6-氨基-3,5-二氯-2氟苯硼酸(1.84g，8.25mmol)的四氢呋喃(30mL)和水(3mL)的溶液中加入磷酸钾(1.65g，7.76mmol)，氮气置换三次，随后加入催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.30g，0.39mmol)，得到的混合物加热到70℃搅拌6小时。向反应液中加入10毫升水(10mL)和乙酸乙酯(20mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物11-4。LCMS(ESI)m/z:730.1/732.1[M+1] +。 Under the protection of nitrogen, the raw materials 11-3 (1.2g, 1.9mmol) and 6-amino-3,5-dichloro-2 fluorophenylboronic acid (1.84g, 8.25mmol) in tetrahydrofuran (30mL) and water (3mL) Add potassium phosphate (1.65g, 7.76mmol) to the solution, replace with nitrogen three times, and then add catalyst chlorination (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium (0.30 g, 0.39 mmol), and the resulting mixture was heated to 70°C and stirred for 6 hours. 10 mL of water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 11-4. LCMS (ESI) m/z: 730.1/732.1 [M+1] + .
4)化合物11-5的合成4) Synthesis of compound 11-5
向原料11-4(0.16g，0.22mmol)的二氯甲烷(6mL)溶液中加入三氟化硼***(0.12g，0.09mmol)，随后滴加环氧乙烷(0.15mL，0.22mmol，1.45M的二氯甲烷溶液)，得到的混合物搅拌3小时。向反应液中加入二氯甲烷(5mL)和饱和碳酸氢钠水溶液(5mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物11-5。LCMS(ESI)m/z:774.1/776.1[M+1] +。 To a solution of raw material 11-4 (0.16g, 0.22mmol) in dichloromethane (6mL) was added boron trifluoride ether (0.12g, 0.09mmol), followed by dropwise addition of ethylene oxide (0.15mL, 0.22mmol, 1.45) M in dichloromethane), and the resulting mixture was stirred for 3 hours. Dichloromethane (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 11-5. LCMS (ESI) m/z: 774.1/776.1 [M+1] + .
5)化合物11-6的合成5) Synthesis of compound 11-6
向原料11-5(0.04g，0.05mmol)的四氢呋喃(40mL)溶液中加入钠氢(10.3mg，0.26mmol，60％纯度)，得到的混合物加热到50℃搅拌5小时。向残余物中加入饱和氯化铵水溶液(10mL)和乙酸乙酯(10mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过纯化后得到化合物11-6。LCMS(ESI)m/z:754.1/756.1[M+1] +。 Sodium hydrogen (10.3 mg, 0.26 mmol, 60% purity) was added to a solution of raw material 11-5 (0.04 g, 0.05 mmol) in tetrahydrofuran (40 mL), and the resulting mixture was heated to 50° C. and stirred for 5 hours. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added to the residue, stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified to obtain compound 11-6. LCMS (ESI) m/z: 754.1/756.1 [M+1] + .
6)化合物11-7的合成6) Synthesis of compound 11-7
室温25℃下，向11-6(25mg，0.033mmol)的甲醇(2mL)溶液中加入氨水(0.5mL，28％纯度)，氮气置换三次后加入钯碳(50mg，10％纯度)，在氢气(15Psi)氛围下搅拌2小时，混合物过滤，滤液减压浓缩，得到化合物11-7。LCMS(ESI)m/z:620.2/622.2[M+1] +。 At room temperature and 25℃, add ammonia (0.5mL, 28% purity) to 11-6 (25mg, 0.033mmol) in methanol (2mL), replace with nitrogen three times and add palladium on carbon (50mg, 10% purity). After stirring for 2 hours under a (15Psi) atmosphere, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-7. LCMS (ESI) m/z: 620.2/622.2 [M+1] + .
7)化合物11的合成7) Synthesis of compound 11
冰水浴0℃氮气保护下，向原料11-7(15mg，0.025mmol)和三乙胺(4.9mg，0.048mmol)的二氯甲烷(2mL)溶液中加入丙烯酰氯(2.2mg，0.024mmol)，得到的混合物搅拌1小时。向反应液中加入水(1mL)和二氯甲烷(2mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经Pre-HPLC纯化，得到化合物11。LCMS(ESI)m/z:674.1/676.1[M+1] +。 Add acryloyl chloride (2.2mg, 0.024mmol) to a solution of raw material 11-7 (15mg, 0.025mmol) and triethylamine (4.9mg, 0.048mmol) in dichloromethane (2mL) under nitrogen protection at 0°C in an ice water bath, The resulting mixture was stirred for 1 hour. Water (1 mL) and dichloromethane (2 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain compound 11. LCMS (ESI) m/z: 674.1/676.1 [M+1] + .
实施例12Example 12
Figure PCTCN2021101868-appb-000063
Figure PCTCN2021101868-appb-000063
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000064
Figure PCTCN2021101868-appb-000064
1)化合物12-2的合成1) Synthesis of compound 12-2
氮气保护下，向原料12-1(0.5g，2.74mmol)甲醇(5mL)的溶液中加入氨水(3.77mL，27.44mmol，28％纯度)，氮气置换三次，随后加入催化剂雷内镍(47mg，0.55mmol)，在氢气(50Psi)氛围下搅拌16小时，反应液直接过滤，滤液减压浓缩得到化合物12-2。 1H NMR(400MHz,CDCl 3)δppm 4.00(t,2H),3.60(dd,2H),2.90(br s,2H),2.45-2.61(m,1H),1.44(s,9H)。 Under the protection of nitrogen, ammonia water (3.77mL, 27.44mmol, 28% purity) was added to the solution of raw material 12-1 (0.5g, 2.74mmol) methanol (5mL), replaced with nitrogen three times, and then the catalyst Raney nickel (47mg, 0.55 mmol), stirred for 16 hours under a hydrogen (50 Psi) atmosphere, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-2. 1 H NMR (400MHz, CDCl 3 ) δ ppm 4.00 (t, 2H), 3.60 (dd, 2H), 2.90 (br s, 2H), 2.45-2.61 (m, 1H), 1.44 (s, 9H).
2)化合物12-3的合成2) Synthesis of compound 12-3
向原料12-2(0.5g，2.638mmol)的甲醇(20mL)溶液中加入甲醛水溶液(2mL，37％)和醋酸(0.08g，1.34mmol)，搅拌2小时后加入氰基硼氢化钠(0.506g，8.05mmol)。得到的混合物室温25℃搅拌16小时，向反应液中加入水(5mL)和乙酸乙酯(3*10mL)搅拌10分钟，除去水相，有机相减压浓缩，得到化合物12-3。 1H NMR(400MHz,CDCl 3)δppm 4.02(t,2H),3.59(dd,2H),2.64-2.77(m,1H),2.52(d,2H),2.23(s,6H),1.43(s,9H)。LCMS(ESI)m/z:215.2[M+1] +。 To raw material 12-2 (0.5g, 2.638mmol) in methanol (20mL) was added aqueous formaldehyde solution (2mL, 37%) and acetic acid (0.08g, 1.34mmol), stirred for 2 hours and then added sodium cyanoborohydride (0.506 g, 8.05 mmol). The resulting mixture was stirred at room temperature 25°C for 16 hours, water (5 mL) and ethyl acetate (3*10 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain compound 12-3. 1 H NMR (400MHz, CDCl 3 ) δppm 4.02 (t, 2H), 3.59 (dd, 2H), 2.64-2.77 (m, 1H), 2.52 (d, 2H), 2.23 (s, 6H), 1.43 (s) ,9H). LCMS (ESI) m/z: 215.2 [M+1] + .
3)化合物12-4的合成3) Synthesis of compound 12-4
室温25℃下，向原料12-3(0.34g，1.59mmol)中加入盐酸/甲醇溶液(7.93mL，4M)，得到的混合物搅拌2小时，反应液直接减压浓缩得到化合物12-4。At room temperature 25°C, hydrochloric acid/methanol solution (7.93 mL, 4M) was added to raw material 12-3 (0.34 g, 1.59 mmol), the resulting mixture was stirred for 2 hours, and the reaction solution was directly concentrated under reduced pressure to obtain compound 12-4.
4)化合物12-6的合成4) Synthesis of compound 12-6
氮气保护下，向原料12-4(0.3g，1.6mmol)和6-2(0.61g，1.28mmol)的异丙醇(10mL)溶液中加入N,N-二异丙基乙胺(1.04g，8.02mmol)，得到的混合物加热到90℃搅拌3小时。反应液直接减压浓缩，残余物经过过柱机纯化得到化合物12-6。 1H NMR(400MHz,CDCl 3)δppm 7.56(d,1H),4.33(br t,2H),3.89(dd,2H),3.61(br s,8H),2.89-3.01(m,1H),2.69(br d,2H),2.33(s,6H),1.49(s,9H)。LCMS(ESI)m/z:557.0/559.1[M+1] +。 Under the protection of nitrogen, add N,N-diisopropylethylamine (1.04g , 8.02mmol), the resulting mixture was heated to 90°C and stirred for 3 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 12-6. 1 H NMR (400MHz, CDCl 3 ) δppm 7.56 (d, 1H), 4.33 (br t, 2H), 3.89 (dd, 2H), 3.61 (br s, 8H), 2.89-3.01 (m, 1H), 2.69 (br d, 2H), 2.33 (s, 6H), 1.49 (s, 9H). LCMS (ESI) m/z: 557.0/559.1 [M+1] + .
5)化合物12-7的合成5) Synthesis of compound 12-7
氮气保护下，向原料12-6(0.45g，0.81mmol)和6-氨基-3-氯-2氟苯硼酸(0.31g，1.61mmol)的二氧六环(10mL)溶液中加入磷酸钾(0.34g，1.61mmol)，氮气置换三次，随后加入催化剂氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(0.06g，0.08mmol)，得到的混合物加热到110℃搅拌16小时。向反应液中加入水(5mL)和乙酸乙酯(20mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物12-7。LCMS(ESI)m/z:622.2/624.1[M+1] +。 Under the protection of nitrogen, add potassium phosphate ( 0.34g, 1.61mmol), replaced with nitrogen three times, and then added catalyst chlorination (2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl) [2-(2′ -Amino-1,1'-biphenyl)]palladium (0.06g, 0.08mmol), and the resulting mixture was heated to 110°C and stirred for 16 hours. Water (5 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 minutes, the water phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 12-7. LCMS (ESI) m/z: 622.2/624.1 [M+1] + .
6)化合物12-8的合成6) Synthesis of compound 12-8
冰水浴0℃氮气保护下，向原料12-7(0.38g，0.61mmol)和三氯化铁(0.36g，2.2mmol)的乙酸乙酯(10mL)溶液中加入环氧乙烷的二氯甲烷溶液(0.64mL，1.22mmol，1.92M)，得到的混合物搅拌3小时。向反应液中加入碳酸氢钠水溶液(5mL)和乙酸乙酯(2*10mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物12-8。LCMS(ESI)m/z:666.2/668.2[M+1] +。 Under the protection of nitrogen at 0℃ in an ice water bath, add ethylene oxide in dichloromethane to a solution of raw material 12-7 (0.38g, 0.61mmol) and ferric chloride (0.36g, 2.2mmol) in ethyl acetate (10mL) Solution (0.64mL, 1.22mmol, 1.92M), and the resulting mixture was stirred for 3 hours. Aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (2*10 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 12-8. LCMS (ESI) m/z: 666.2/668.2 [M+1] + .
7)化合物12-9的合成7) Synthesis of compound 12-9
向原料12-8(0.2g，0.3mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入N-氯代丁二酰亚胺(0.044g，0.33mmol)，得到的混合物得到的混合物加热到70℃搅拌6小时。向反应液中加入乙酸乙酯(20mL)和饱和碳酸氢钠水溶液(10mL)搅拌10分钟，除去水相，有机相减压浓缩，得到化合物12-9。LCMS(ESI)m/z:700.2/702.2[M+1] +。 To the raw material 12-8 (0.2g, 0.3mmol) in N, N-dimethylformamide (3mL) solution was added N-chlorosuccinimide (0.044g, 0.33mmol), the resulting mixture obtained The mixture was heated to 70°C and stirred for 6 hours. To the reaction solution were added ethyl acetate (20 mL) and saturated sodium bicarbonate aqueous solution (10 mL) and stirred for 10 minutes, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain compound 12-9. LCMS (ESI) m/z: 700.2/702.2 [M+1] + .
8)化合物12-10的合成8) Synthesis of compound 12-10
向原料12-9(0.15g，0.21mmol)的四氢呋喃(150mL)溶液中加入钠氢(0.05g，1.28mmol，60％纯度)，得到的混合物加热到60℃搅拌6小时。向残余物中加入饱和氯化铵水溶液(100mL)和乙酸乙酯(100mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过纯化后得到化合物12-10。LCMS(ESI)m/z:680.2/682.1[M+1] +。 Sodium hydrogen (0.05 g, 1.28 mmol, 60% purity) was added to a solution of raw material 12-9 (0.15 g, 0.21 mmol) in tetrahydrofuran (150 mL), and the resulting mixture was heated to 60° C. and stirred for 6 hours. Saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL) were added to the residue, stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified to obtain compound 12-10. LCMS (ESI) m/z: 680.2/682.1 [M+1] + .
9)化合物12-11的合成9) Synthesis of compound 12-11
向原料12-10(0.1g，0.15mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.22mL)，得到的混合物室温25℃搅拌2小时，反应液减压浓缩得到化合物12-11的三氟乙酸盐。LCMS(ESI)m/z:580.1/582.2[M+1] +。 Trifluoroacetic acid (0.22mL) was added to a solution of raw material 12-10 (0.1g, 0.15mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 12-11 The trifluoroacetate. LCMS (ESI) m/z: 580.1/582.2 [M+1] + .
10)化合物12的合成10) Synthesis of compound 12
冰水浴0℃氮气保护下，向原料12-11的三氟乙酸盐(0.14g，0.15mmol)和三乙胺(76.7mg，0.76mmol)的二氯甲烷(3mL)溶液中加入丙烯酰氯(13.7mg，0.15mmol)，得到的混合物搅拌1.5小时。向反应液中加入水(10mL)和二氯甲烷(10mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经Pre-HPLC纯化，得到化合物12。 1H NMR(400MHz,CD 3OD)δppm 7.80(s,1H),7.43(d,1H),6.81(dd,1H),6.26(dd, 1H),5.79(dd,1H),4.18-4.38(m,4H),3.67-4.00(m,10H),3.35-3.44(m,1H),3.04(br d,1H),2.88-2.99(m,1H),2.69(br d,2H),2.30(s,6H)。LCMS(ESI)m/z:634.2/636.2[M+1] +。 Under the protection of nitrogen at 0℃ in an ice water bath, add acryloyl chloride ( 13.7 mg, 0.15 mmol), and the resulting mixture was stirred for 1.5 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain compound 12. 1 H NMR (400MHz, CD 3 OD) δppm 7.80 (s, 1H), 7.43 (d, 1H), 6.81 (dd, 1H), 6.26 (dd, 1H), 5.79 (dd, 1H), 4.18-4.38 ( m, 4H), 3.67-4.00 (m, 10H), 3.35-3.44 (m, 1H), 3.04 (br d, 1H), 2.88-2.99 (m, 1H), 2.69 (br d, 2H), 2.30 ( s,6H). LCMS (ESI) m/z: 634.2/636.2 [M+1] + .
实施例13Example 13
Figure PCTCN2021101868-appb-000065
Figure PCTCN2021101868-appb-000065
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000066
Figure PCTCN2021101868-appb-000066
1)化合物13-1的合成1) Synthesis of compound 13-1
冰水浴0℃氮气保护下，向原料9-2(1.2g，2.27mmol)和三氯化铁(1.11g，6.81mmol)的乙酸乙酯(25mL)溶液中加入环氧乙烷的二氯甲烷溶液(2.37mL，4.54mmol，1.94M)，得到的混合物搅拌2小时。向反应液中加入碳酸氢钠水溶液(10mL)和乙酸乙酯(20mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物13-1。LCMS(ESI)m/z:572.1/574.1[M+1] +。 Under the protection of nitrogen at 0℃ in an ice water bath, add ethylene oxide in dichloromethane to a solution of raw material 9-2 (1.2g, 2.27mmol) and ferric chloride (1.11g, 6.81mmol) in ethyl acetate (25mL) Solution (2.37mL, 4.54mmol, 1.94M), and the resulting mixture was stirred for 2 hours. Aqueous sodium bicarbonate (10 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 13-1. LCMS (ESI) m/z: 572.1/574.1 [M+1] + .
2)化合物13-2的合成2) Synthesis of compound 13-2
向原料13-1(0.47g，0.83mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入N-氯代丁二酰亚胺(0.12g，0.91mmol，78.75mL)，得到的混合物得到的混合物加热到70℃搅拌6小时。向反应液中加入乙酸乙酯(30mL)和饱和碳酸氢钠水溶液(10mL)搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化得到化合物13-2。LCMS(ESI)m/z:606.1/608.1[M+1] +。 To the raw material 13-1 (0.47g, 0.83mmol) in N,N-dimethylformamide (15mL) was added N-chlorosuccinimide (0.12g, 0.91mmol, 78.75mL) to obtain The resulting mixture was heated to 70°C and stirred for 6 hours. To the reaction solution were added ethyl acetate (30 mL) and saturated sodium bicarbonate aqueous solution (10 mL) and stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine to obtain compound 13-2. LCMS (ESI) m/z: 606.1/608.1 [M+1] + .
3)化合物13-4的合成3) Synthesis of compound 13-4
向原料13-2(0.31g，0.51mmol)和13-3(0.16g，1.02mmol)的二甲基亚砜(2mL)溶液中加入氟化钾(0.06g，1.02mmol)，得到的混合物加热到120℃搅拌12小时。向反应液中加入乙酸乙酯(5mL)和水(2mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物经过柱层析纯化得到化合物13-4。LCMS(ESI)m/z:745.2/747.1[M+1] +。 Potassium fluoride (0.06g, 1.02mmol) was added to a solution of raw materials 13-2 (0.31g, 0.51mmol) and 13-3 (0.16g, 1.02mmol) in dimethyl sulfoxide (2mL), and the resulting mixture was heated Stir at 120°C for 12 hours. Ethyl acetate (5 mL) and water (2 mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 13-4. LCMS (ESI) m/z: 745.2/747.1 [M+1] + .
4)化合物13-5的合成4) Synthesis of compound 13-5
向原料13-4(0.1g，0.13mmol)的四氢呋喃(10mL)溶液中加入钠氢(0.032g，0.80mmol，60％纯度)，得到的混合物加热到60℃搅拌6小时。向残余物中加入水(5mL)和乙酸乙酯(10mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过纯化后得到化合物13-5。LCMS(ESI)m/z:725.2/727.2[M+1] +。 Sodium hydrogen (0.032g, 0.80mmol, 60% purity) was added to a solution of raw material 13-4 (0.1g, 0.13mmol) in tetrahydrofuran (10mL), and the resulting mixture was heated to 60°C and stirred for 6 hours. Water (5 mL) and ethyl acetate (10 mL) were added to the residue, stirred for 10 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified to obtain compound 13-5. LCMS (ESI) m/z: 725.2/727.2 [M+1] + .
5)化合物13-6的合成5) Synthesis of compound 13-6
向原料13-5(75mg，0.10mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.15mL)，得到的混合物室温25℃搅拌2小时，反应液减压浓缩得到化合物13-6的三氟乙酸盐。LCMS(ESI)m/z:625.1/627.2[M+1] +。 Trifluoroacetic acid (0.15mL) was added to a solution of the starting material 13-5 (75mg, 0.10mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 13-6. Trifluoroacetate. LCMS (ESI) m/z: 625.1/627.2 [M+1] + .
6)化合物13和14的合成6) Synthesis of compounds 13 and 14
冰水浴0℃氮气保护下，向原料13-6的三氟乙酸盐(0.07g，0.08mmol)和三乙胺(0.05g，0.49mmol)的二氯甲烷(2mL)溶液中加入丙烯酰氯(7.4mg，0.08mmol)，得到的混合物搅拌2小时。向反应液中加入水(2mL)和二氯甲烷(5mL)搅拌5分钟，除去水相，有机相减压浓缩，残余物13-7经Pre-HPLC纯化，再经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:DAICEL CHIRALCEL OD(250mm*30mm,10um)；流动相:A:CO 2,B:EtOH(0.1％NH 3H 2O)；梯度:B％＝50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物13(Rt＝1.471min)和化合物14(Rt＝1.645)。 Under the protection of nitrogen at 0℃ in an ice water bath, add acryloyl chloride ( 7.4 mg, 0.08 mmol), and the resulting mixture was stirred for 2 hours. Water (2mL) and dichloromethane (5mL) were added to the reaction solution and stirred for 5 minutes, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue 13-7 was purified by Pre-HPLC and then subjected to SFC (instrument model: Waters SFC150). AP preparative SFC; Column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: A: CO 2 , B: EtOH (0.1% NH 3 H 2 O); gradient: B% = 50% isocratic elution Flow rate: 70 g/min; column temperature: 35° C.; system pressure: 150 bar) After separation and purification, compound 13 (Rt=1.471 min) and compound 14 (Rt=1.645) were obtained.
化合物13： 1H NMR(400MHz,CD 3OD)δppm 7.93-8.00(m,1H),7.46(d,J＝7.63Hz,1H),6.82(dd,J＝16.76,10.63Hz,1H),6.23-6.32(m,1H),5.77-5.85(m,1H),5.20-5.40(m,1H),4.57-4.61(m,2H),4.30(s,1H),4.29(br s,1H),4.15-4.23(m,1H),3.85-4.07(m,8H),2.94-3.14(m,3H),2.07-2.33(m,4H),1.99(br s,4H)；LCMS(ESI)m/z:679.1/681.1[M+1] +。SFC：(Rt＝1.468min,ee＝100％) Compound 13: 1 H NMR (400MHz, CD 3 OD) δ ppm 7.93-8.00 (m, 1H), 7.46 (d, J = 7.63 Hz, 1H), 6.82 (dd, J = 16.76, 10.63 Hz, 1H), 6.23 -6.32(m,1H),5.77-5.85(m,1H),5.20-5.40(m,1H),4.57-4.61(m,2H), 4.30(s,1H), 4.29(br s,1H), 4.15-4.23(m,1H),3.85-4.07(m,8H),2.94-3.14(m,3H),2.07-2.33(m,4H),1.99(br s,4H); LCMS(ESI)m/ z:679.1/681.1[M+1] + . SFC: (Rt=1.468min,ee=100%)
化合物14： 1H NMR(400MHz,CD 3OD)δppm 7.94-8.02(m,1H),7.46(d,J＝7.63Hz,1H),6.76-6.89(m,1H),6.28(dd,J＝16.76,1.88Hz,1H),5.82(s,1H),5.21-5.40(m,1H),4.58(br s,2H),4.21-4.32(m,4H),3.94(br s,8H),2.93-3.15(m,3H),2.09-2.39(m,4H),1.82-2.06(m,4H)；LCMS(ESI)m/z:679.1/681.1[M+1] +。SFC：(Rt＝1.635min,ee＝99.42％) Compound 14: 1 H NMR (400MHz, CD 3 OD) δ ppm 7.94-8.02 (m, 1H), 7.46 (d, J = 7.63 Hz, 1H), 6.76-6.89 (m, 1H), 6.28 (dd, J = 16.76, 1.88Hz, 1H), 5.82 (s, 1H), 5.21-5.40 (m, 1H), 4.58 (br s, 2H), 4.21-4.32 (m, 4H), 3.94 (br s, 8H), 2.93 -3.15 (m, 3H), 2.09-2.39 (m, 4H), 1.82-2.06 (m, 4H); LCMS (ESI) m/z: 679.1/681.1 [M+1] + . SFC: (Rt=1.635min,ee=99.42%)
实施例15Example 15
Figure PCTCN2021101868-appb-000067
Figure PCTCN2021101868-appb-000067
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000068
Figure PCTCN2021101868-appb-000068
1)化合物15-2的合成1) Synthesis of compound 15-2
室温20℃下，向反应瓶中加入异丙醇(43mL)，原料6-2(4.3g,8.96mmol)，原料15-1(2.33g,13.43mmol)和N,N-二异丙基乙胺(5.79g,44.78mmol)。加热至90℃反应2小时。将反应液倒入水(500mL)中，过 滤，滤饼再用水(50mL)淋洗两次。滤饼减压干燥得化合物15-2。LCMS(ESI)m/z:543.1/545.1[M+1] +。 At room temperature 20℃, add isopropanol (43mL), raw material 6-2 (4.3g, 8.96mmol), raw material 15-1 (2.33g, 13.43mmol) and N,N-diisopropylethyl into the reaction flask Amine (5.79 g, 44.78 mmol). Heat to 90°C to react for 2 hours. The reaction solution was poured into water (500 mL), filtered, and the filter cake was rinsed twice with water (50 mL). The filter cake was dried under reduced pressure to obtain compound 15-2. LCMS (ESI) m/z: 543.1/545.1 [M+1] + .
2)化合物15-3的合成2) Synthesis of compound 15-3
室温20℃下，向反应瓶中加入二氧六环(15mL)，原料15-2(725mg,1.33mmol)，6-氨基-3-氯-2氟苯硼酸(504.91mg,2.67mmol)，磷酸钾(565.94mg,2.67mmol)和催化剂(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(96.06mg,133.31μmol)。氮气置换三次，油浴110℃反应14小时。反应液过滤，滤饼再用二氯甲烷(25mL)淋洗。滤液减压浓缩至干后经柱层析纯化得到粗品，粗品再经制备色谱纯化到化合物15-3。LCMS(ESI)m/z:608.2/610.1[M+1] +。 At room temperature 20℃, add dioxane (15mL), raw material 15-2 (725mg, 1.33mmol), 6-amino-3-chloro-2 fluorophenylboronic acid (504.91mg, 2.67mmol), phosphoric acid to the reaction flask Potassium (565.94mg, 2.67mmol) and catalyst (2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl) [2-(2′-amino-1,1 '-Biphenyl)] palladium (96.06 mg, 133.31 μmol). Replace with nitrogen three times, and react at 110°C in an oil bath for 14 hours. The reaction solution was filtered, and the filter cake was rinsed with dichloromethane (25 mL). The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to obtain a crude product, which was then purified by preparative chromatography to compound 15-3. LCMS (ESI) m/z: 608.2/610.1 [M+1] + .
3)化合物15-4的合成3) Synthesis of compound 15-4
冰水浴0℃氮气保护下，向原料15-3(2.6g，4.27mmol)的乙酸乙酯(84mL)溶液中加入无水三氯化铁(2.6g，16.03mmol)，随后滴加环氧乙烷(6.97mL，1.19mmol，1.84M二氯甲烷溶液)，得到的混合物搅拌1.5小时。向反应液中加入饱和碳酸氢钠水溶液(100mL)和二氯甲烷(200mL)搅拌10分钟，铺硅藻土过滤，滤液分层，除去水相，有机相减压浓缩得残余物。滤饼再用二氯甲烷(400mL)搅拌0.5小时，过滤，滤液再减压浓缩得残余物。两次残余物合并经柱层析纯化得到化合物15-4。LCMS(ESI)m/z:652.2/654.1[M+1] +。 Anhydrous iron trichloride (2.6g, 16.03mmol) was added to the ethyl acetate (84mL) solution of raw material 15-3 (2.6g, 4.27mmol) under the protection of nitrogen at 0℃ in an ice water bath, and then ethylene oxide was added dropwise. Alkane (6.97 mL, 1.19 mmol, 1.84 M dichloromethane solution), and the resulting mixture was stirred for 1.5 hours. Saturated aqueous sodium bicarbonate solution (100 mL) and dichloromethane (200 mL) were added to the reaction solution and stirred for 10 minutes, spread with Celite and filtered, the filtrate was separated into layers, the aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain a residue. The filter cake was stirred with dichloromethane (400 mL) for 0.5 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The two residues were combined and purified by column chromatography to obtain compound 15-4. LCMS (ESI) m/z: 652.2/654.1 [M+1] + .
4)化合物15-5的合成4) Synthesis of compound 15-5
向反应瓶中加入乙酸(15mL)，原料15-4(1.5g,2.30mmol)和N-氯代丁二酰亚胺(322.29mg,2.41mmol)，20℃搅拌反应14小时。将反应液倒入饱和碳酸氢钠水溶液(200mL)中，再分别用二氯甲烷(50mL)萃取三次，合并有机相再用水(50mL)洗。有机相再用无水硫酸钠干燥，过滤浓缩得化合物15-5。LCMS(ESI)m/z:686.1/688.1[M+1] +。 Acetic acid (15 mL), raw materials 15-4 (1.5 g, 2.30 mmol) and N-chlorosuccinimide (322.29 mg, 2.41 mmol) were added to the reaction flask, and the reaction was stirred at 20°C for 14 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (200 mL), and then extracted three times with dichloromethane (50 mL), and the organic phases were combined and washed with water (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound 15-5. LCMS (ESI) m/z: 686.1/688.1 [M+1] + .
5)化合物15-6的合成5) Synthesis of compound 15-6
室温25℃氮气保护下，向原料15-5(1.6g，2.33mmol)的四氢呋喃(1600mL)溶液中加入钠氢(0.46g，2.97mmol，纯度60％)，得到的混合物加热到65℃搅拌1小时。降至室温，加入饱和氯化铵水溶液(2mL)，减压浓缩至干得粗品。向粗品中再加二氯甲烷(50mL)，过滤。滤液浓缩得化合物15-6。LCMS(ESI)m/z:666.1/668.1[M+1] +。 Under the protection of nitrogen at room temperature and 25°C, sodium hydrogen (0.46g, 2.97mmol, purity 60%) was added to a solution of raw material 15-5 (1.6g, 2.33mmol) in tetrahydrofuran (1600mL), and the resulting mixture was heated to 65°C and stirred for 1 Hour. It was cooled to room temperature, saturated aqueous ammonium chloride solution (2 mL) was added, and concentrated under reduced pressure to dryness to obtain a crude product. Add dichloromethane (50 mL) to the crude product and filter. The filtrate was concentrated to obtain compound 15-6. LCMS (ESI) m/z: 666.1/668.1 [M+1] + .
6)化合物15-7的合成6) Synthesis of compound 15-7
室温20℃氮气保护下，向原料15-6(1.18g，1.77mmol)的二氯甲烷(11mL)溶液中加入三氟乙酸(11mL)，得到的混合物搅拌2小时。反应液减压浓缩，向残余物中加入二氯甲烷(50mL)，饱和碳酸氢钠水溶液(100mL)，分液。水相再分别用二氯甲烷(30mL)萃取三次。合并有机相再用水(20mL)洗，有机相再用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物15-7直接投入下一步反应。LCMS(ESI)m/z:566.1/568.1[M+1] +。 Under nitrogen protection at room temperature and 20°C, trifluoroacetic acid (11 mL) was added to a dichloromethane (11 mL) solution of starting material 15-6 (1.18 g, 1.77 mmol), and the resulting mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (50 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted three times with dichloromethane (30 mL). The combined organic phases were washed with water (20 mL), the organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-7 and directly put into the next reaction. LCMS (ESI) m/z: 566.1/568.1 [M+1] + .
7)化合物15-8的合成7) Synthesis of compound 15-8
向反应瓶中加入二氯甲烷(10mL)，三乙胺(727.00mg,7.18mmol)和原料15-7(980mg,1.61mmol)，降温至0℃后加入丙烯酰氯(145.51mg,1.61mmol)。0℃保温反应1小时。将反应液倒入水(50mL)中，分液。水相再用二氯甲烷(20mL)萃取，合并有机相再用无水硫酸钠干燥，过滤滤液减压浓缩得粗品。粗品经制备色谱纯化得到化合物15-8。Dichloromethane (10 mL), triethylamine (727.00 mg, 7.18 mmol) and raw material 15-7 (980 mg, 1.61 mmol) were added to the reaction flask, and acryloyl chloride (145.51 mg, 1.61 mmol) was added after cooling to 0°C. The reaction was kept at 0°C for 1 hour. The reaction solution was poured into water (50 mL) and separated. The aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 15-8.
8)化合物15和16的合成8) Synthesis of compounds 15 and 16
化合物15-8(140mg,225μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:IPA(0.1％NH 3H 2O)；梯度:B％＝40～60％梯度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物15(Rt＝1.814min)和化合物16(Rt＝1.007min)。化合物15： 1H NMR(400MHz,CDCl 3)δppm 7.65(s,1H),7.38(d,J＝7.5Hz,1H),6.62(dd,J＝10.5,16.8Hz,1H),6.37(dd,J＝1.8,16.8Hz,1H),5.78(dd,J＝1.8,10.5Hz,1H),4.78(br s,1H),4.47(br d,J＝11.4Hz,1H),4.37-4.18(m,3H),4.12-3.61(m,10H),3.50(br s,1H),3.21(br s,1H),2.96(br d,J＝10.3Hz,1H),2.27(br s,6H)。LCMS(ESI)m/z:620.2/622.2[M+1] +。 Compound 15-8 (140mg, 225μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); Gradient: B%=40～60% gradient elution; Flow rate: 70g/min; Column temperature: 35℃; System pressure: 150bar) After separation and purification, compound 15 (Rt=1.814min) and compound 16 (Rt =1.007min). Compound 15: 1 H NMR (400MHz, CDCl 3 ) δ ppm 7.65 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 6.62 (dd, J = 10.5, 16.8 Hz, 1H), 6.37 (dd, J = 1.8, 16.8 Hz, 1H), 5.78 (dd, J = 1.8, 10.5 Hz, 1H), 4.78 (br s, 1H), 4.47 (br d, J = 11.4 Hz, 1H), 4.37-4.18 (m , 3H), 4.12-3.61 (m, 10H), 3.50 (br s, 1H), 3.21 (br s, 1H), 2.96 (br d, J = 10.3 Hz, 1H), 2.27 (br s, 6H). LCMS (ESI) m/z: 620.2/622.2 [M+1] + .
化合物16： 1H NMR(400MHz,CDCl3)δppm 7.65(s,1H),7.38(d,J＝7.5Hz,1H),6.62(dd,J＝10.5,16.8Hz,1H),6.37(dd,J＝1.6,16.8Hz,1H),5.77(dd,J＝1.6,10.5Hz,1H),4.78(br s,1H),4.47(br d,J＝11.3Hz,1H),4.39-4.17(m,3H),4.12-3.59(m,11H),3.50(br s,1H),3.22(br s,1H),2.96(br d,J＝10.0Hz,1H),2.27(br s,6H)。LCMS(ESI)m/z:620.2/622.2[M+1] +。 Compound 16: 1 H NMR (400MHz, CDCl3) δppm 7.65 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 6.62 (dd, J = 10.5, 16.8 Hz, 1H), 6.37 (dd, J ＝1.6,16.8Hz,1H),5.77(dd,J＝1.6,10.5Hz,1H),4.78(br s,1H), 4.47(br d,J=11.3Hz,1H), 4.39-4.17(m, 3H), 4.12-3.59 (m, 11H), 3.50 (br s, 1H), 3.22 (br s, 1H), 2.96 (br d, J=10.0 Hz, 1H), 2.27 (br s, 6H). LCMS (ESI) m/z: 620.2/622.2 [M+1] + .
实施例17Example 17
Figure PCTCN2021101868-appb-000069
Figure PCTCN2021101868-appb-000069
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000070
Figure PCTCN2021101868-appb-000070
Figure PCTCN2021101868-appb-000071
Figure PCTCN2021101868-appb-000071
1)化合物17-2的合成1) Synthesis of compound 17-2
室温20℃下，向反应瓶中加入二甲基亚砜(18mL)，原料6-2(3.0g,6.25mmol)，原料17-1(2.78g,31.24mmol)和氟化钾(725.94mg,12.50mmol)。加热至120℃反应1小时。将反应液倒入水(300mL)中，过滤，滤饼再用水(300mL)淋洗三次。滤饼减压干燥得化合物17-2。LCMS(ESI)m/z:532.3/534.3[M+1] +。 At room temperature 20℃, add dimethyl sulfoxide (18mL), raw material 6-2 (3.0g, 6.25mmol), raw material 17-1 (2.78g, 31.24mmol) and potassium fluoride (725.94mg, 12.50mmol). Heat to 120°C to react for 1 hour. The reaction solution was poured into water (300 mL), filtered, and the filter cake was rinsed with water (300 mL) three times. The filter cake was dried under reduced pressure to obtain compound 17-2. LCMS (ESI) m/z: 532.3/534.3 [M+1] + .
2)化合物17-3的合成2) Synthesis of compound 17-3
室温20℃下，向反应瓶中加入二氧六环(10mL)，原料17-2(500mg,0.94mmol)，原料6-氨基-3-氯-2氟苯硼酸(355.42mg,1.88mmol)，磷酸钾(398.38mg,1.88mmol)和催化剂(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(67.62mg,93.84μmol)。氮气置换三次，油浴110℃反应18小时。反应液过滤，滤饼再用乙酸乙酯(20mL)淋洗。滤液减压浓缩至干后经柱层析纯化得到化合物17-3。LCMS(ESI)m/z:597.4/599.4[M+1] +。 At room temperature 20°C, add dioxane (10mL), raw material 17-2 (500mg, 0.94mmol), raw material 6-amino-3-chloro-2 fluorophenylboronic acid (355.42mg, 1.88mmol) into the reaction flask, Potassium phosphate (398.38mg, 1.88mmol) and catalyst (2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl) [2-(2′-amino-1, 1'-biphenyl)] palladium (67.62 mg, 93.84 μmol). Replace with nitrogen three times and react at 110°C in an oil bath for 18 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to obtain compound 17-3. LCMS (ESI) m/z: 597.4/599.4 [M+1] + .
3)化合物17-4的合成3) Synthesis of compound 17-4
向反应瓶中加入乙酸(7mL)，原料17-3(0.65g,1.09mmol)和N-溴代丁二酰亚胺(232.35mg,1.31mmol)，20℃搅拌反应5小时。将反应液倒入饱和碳酸氢钠水溶液(200mL)中，再分别用二氯甲烷(50mL)萃取两次。有机相再用无水硫酸钠干燥，过滤滤液减压浓缩得粗品。粗品经柱层析纯化化合物17-4。LCMS(ESI)m/z:677.3[M+1] +。 Acetic acid (7mL), raw materials 17-3 (0.65g, 1.09mmol) and N-bromosuccinimide (232.35mg, 1.31mmol) were added to the reaction flask, and the reaction was stirred at 20°C for 5 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (200 mL), and then extracted twice with dichloromethane (50 mL). The organic phase was dried with anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to purify compound 17-4. LCMS (ESI) m/z: 677.3 [M+1] + .
4)化合物17-5的合成4) Synthesis of compound 17-5
向三口瓶中加入二氯甲烷(10mL)，化合物17-4(435mg，643.13μmol)，降温至0℃加入三氟化硼***(280.42mg，1.98mmol)和环氧乙烷(28.33mg，643.13μmol)，0℃保温反应0.5小时，向反应液中加入甲醇(20mL)，再加入三乙胺(1.3mL)，二碳酸二叔丁酯(0.34mL)，20℃搅拌30分钟后，反应液减压 浓缩至干。向残余物中加入二氯甲烷(100mL)，饱和氯化铵水溶液(30mL)，分液。有机相再用无水硫酸钠干燥，过滤减压浓缩得粗品。粗品经柱层析纯化得到化合物17-5。LCMS(ESI)m/z:721.3[M+1] +。 Add dichloromethane (10mL), compound 17-4 (435mg, 643.13μmol) to a three-necked flask, cool to 0°C, add boron trifluoride ether (280.42mg, 1.98mmol) and ethylene oxide (28.33mg, 643.13) μmol), the reaction was incubated at 0°C for 0.5 hours, methanol (20mL) was added to the reaction solution, then triethylamine (1.3mL), di-tert-butyl dicarbonate (0.34mL) were added, and the reaction solution was stirred at 20°C for 30 minutes. Concentrate to dryness under reduced pressure. Dichloromethane (100 mL) and saturated ammonium chloride aqueous solution (30 mL) were added to the residue, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 17-5. LCMS (ESI) m/z: 721.3 [M+1] + .
5)化合物17-6的合成5) Synthesis of compound 17-6
向三口瓶中加入四氢呋喃(62mL)，化合物17-5(62mg，86.06μmol)和钠氢(17.21mg，430.30μmol，60％纯度)，氮气保护下加热到65℃反应1小时。反应液降至室温，加入饱和氯化铵水溶液(1mL)，减压浓缩。再向残余物中加入二氯甲烷(20mL)，过滤，滤液浓缩得到化合物17-6。LCMS(ESI)m/z:701.3[M+1] +。 Tetrahydrofuran (62 mL), compound 17-5 (62 mg, 86.06 μmol) and sodium hydrogen (17.21 mg, 430.30 μmol, 60% purity) were added to a three-necked flask, and heated to 65° C. for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (1 mL) was added, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue, filtered, and the filtrate was concentrated to obtain compound 17-6. LCMS (ESI) m/z: 701.3 [M+1] + .
6)化合物17-7的合成6) Synthesis of compound 17-7
向三口瓶中加入化合物17-6(60mg，85.66μmol)和盐酸-乙酸乙酯(4M，2mL)，20℃搅拌反应1小时，体系减压浓缩得化合物17-7的盐酸盐。LCMS(ESI)m/z:601.2[M+1] +。 Compound 17-6 (60 mg, 85.66 μmol) and hydrochloric acid-ethyl acetate (4M, 2 mL) were added to a three-neck flask, and the reaction was stirred at 20° C. for 1 hour. The system was concentrated under reduced pressure to obtain the hydrochloride of compound 17-7. LCMS (ESI) m/z: 601.2 [M+1] + .
7)化合物17的合成7) Synthesis of compound 17
向三口瓶中加入二氯甲烷(5mL)，化合物17-7的盐酸盐(50mg，70.45μmol)和三乙胺(35.65mg，352.27μmol)，降温至0℃加入丙烯酰氯(6.38mg，70.45μmol)，0℃保温反应1小时。将反应液倒入水(30mL)中，再加入二氯甲烷(10mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品制备色谱纯化得到化合物17。 1HNMR(400MHz,CDCl 3)δppm 7.78(s,1H),7.59(d,J＝7.6Hz,1H),6.62(dd,J＝10.7,16.7Hz,1H),6.38(br d,J＝16.8Hz,1H),5.79(br d,J＝10.5Hz,1H),4.84-4.53(m,3H),4.40(br s,2H),4.09-3.70(m,8H),3.48(br s,1H),3.10-2.79(m,3H),2.45(br s,6H)；LCMS(ESI)m/z:655.1[M+1] +。 Add dichloromethane (5mL), compound 17-7 hydrochloride (50mg, 70.45μmol) and triethylamine (35.65mg, 352.27μmol) into a three-necked flask, cool to 0°C and add acryloyl chloride (6.38mg, 70.45) μmol), the reaction was incubated at 0°C for 1 hour. The reaction solution was poured into water (30 mL), dichloromethane (10 mL) was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography to obtain compound 17. 1 HNMR(400MHz, CDCl 3 )δppm 7.78(s,1H), 7.59(d,J＝7.6Hz,1H), 6.62(dd,J＝10.7,16.7Hz,1H), 6.38(br d,J＝16.8 Hz, 1H), 5.79 (br d, J = 10.5 Hz, 1H), 4.84-4.53 (m, 3H), 4.40 (br s, 2H), 4.09-3.70 (m, 8H), 3.48 (br s, 1H) ), 3.10-2.79 (m, 3H), 2.45 (br s, 6H); LCMS (ESI) m/z: 655.1 [M+1] + .
实施例18Example 18
Figure PCTCN2021101868-appb-000072
Figure PCTCN2021101868-appb-000072
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000073
Figure PCTCN2021101868-appb-000073
1)化合物18-1的合成1) Synthesis of compound 18-1
向反应瓶中加入乙酸(7mL)，原料15-3(1.05g,1.73mmol)和N-碘代丁二酰亚胺(407.63mg,1.81mmol)，20℃搅拌反应3小时。将反应液倒入饱和碳酸氢钠水溶液(200mL)中，再分别用二氯甲烷(50mL)萃取三次。合并有机相再用水(50mL)洗一次，有机相再用无水硫酸钠干燥，过滤滤液减压浓缩得粗品。粗品经柱层析纯化化合物18-1。LCMS(ESI)m/z:734.0/736.0[M+1] +。 Acetic acid (7 mL), raw materials 15-3 (1.05 g, 1.73 mmol) and N-iodosuccinimide (407.63 mg, 1.81 mmol) were added to the reaction flask, and the reaction was stirred at 20°C for 3 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (200 mL), and then extracted three times with dichloromethane (50 mL). The combined organic phases were washed once with water (50 mL), the organic phases were dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to compound 18-1. LCMS (ESI) m/z: 734.0/736.0 [M+1] + .
2)化合物18-2的合成2) Synthesis of compound 18-2
向三口瓶中加入二氯甲烷(30mL)，化合物18-1(1.24g，1.69mmol)，降温至0℃加入三氟化硼***(741.52mg，5.22mmol)和环氧乙烷(965μL，1.75M二氯甲烷溶液)，0℃保温反应1小时。将反应液倒入饱和碳酸氢钠水溶液(100mL)中，再分别用二氯甲烷(50mL)萃取两次。合并有机相再用无水硫酸钠干燥，过滤浓缩得粗品。粗品经柱层析纯化得到化合物18-2。LCMS(ESI)m/z:778.0/780.0[M+1] +。 Add dichloromethane (30mL), compound 18-1 (1.24g, 1.69mmol) to a three-necked flask, cool to 0°C, add boron trifluoride ether (741.52mg, 5.22mmol) and ethylene oxide (965μL, 1.75) M dichloromethane solution), incubate and react at 0°C for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (100 mL), and then extracted twice with dichloromethane (50 mL). The organic phases were combined and dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product is purified by column chromatography to obtain compound 18-2. LCMS (ESI) m/z: 778.0/780.0 [M+1] + .
3)化合物18-3的合成3) Synthesis of compound 18-3
向三口瓶中加入四氢呋喃(710mL)，化合物18-2(710mg，912.06μmol)和钠氢(182.41mg，4.56mmol，60％纯度)，氮气保护下加热到65℃反应1小时。反应液降至室温，加入饱和氯化铵水溶液(2mL)，减压浓缩。再向残余物中加入二氯甲烷(50mL)，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化得到化 合物18-3。LCMS(ESI)m/z:758.0/760.0[M+1] +。 Tetrahydrofuran (710 mL), compound 18-2 (710 mg, 912.06 μmol) and sodium hydrogen (182.41 mg, 4.56 mmol, 60% purity) were added to the three-necked flask, and the mixture was heated to 65°C for 1 hour under the protection of nitrogen. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (2 mL) was added, and the mixture was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 18-3. LCMS (ESI) m/z: 758.0/760.0 [M+1] + .
4)化合物18-5的合成4) Synthesis of compound 18-5
向反应瓶中加入二氧六环(3mL)，原料18-3(160mg,210.96μmol)，原料18-4(152.37mg,421.91μmol)，三乙胺(42.69mg,421.91μmol)和双(三苯基膦)二氯化钯(14.81mg,21.10μmol)。氮气置换三次后加热至85℃搅拌反应14小时。反应体系降至室温，再减压浓缩至干，然后加入水(50mL)，再分别用二氯甲烷(10mL)萃取三次。合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经柱层析纯化得到化合物18-5。LCMS(ESI)m/z:702.2/704.2[M+1] +。 Add dioxane (3mL), raw material 18-3 (160mg, 210.96μmol), raw material 18-4 (152.37mg, 421.91μmol), triethylamine (42.69mg, 421.91μmol) and bis(trimethylol) to the reaction flask. Phenylphosphine) palladium dichloride (14.81 mg, 21.10 μmol). After nitrogen replacement three times, it was heated to 85°C and stirred for 14 hours. The reaction system was cooled to room temperature, and then concentrated under reduced pressure to dryness, and then water (50 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 18-5. LCMS (ESI) m/z: 702.2/704.2 [M+1] + .
5)化合物18-6的合成5) Synthesis of compound 18-6
向反应瓶中加入HCl/EtOAc(4M,2mL)和原料18-5(110mg,156.55μmol)，20℃搅拌反应1小时。反应液减压浓缩得化合物18-6的盐酸盐。LCMS(ESI)m/z:574.2/576.2[M+1] +。 HCl/EtOAc (4M, 2mL) and raw material 18-5 (110mg, 156.55μmol) were added to the reaction flask, and the reaction was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 18-6. LCMS (ESI) m/z: 574.2/576.2 [M+1] + .
6)化合物18-7的合成6) Synthesis of compound 18-7
向三口瓶中加入二氯甲烷(5mL)，化合物18-6的盐酸盐(99mg，142.22μmol)和三乙胺(71.95mg，711.08μmol)，降温至0℃加入丙烯酰氯(12.87mg，142.22μmol)，0℃保温反应1小时。将反应液倒入水(30mL)中，再加入二氯甲烷(20mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品制备色谱纯化得到化合物18-7。LCMS(ESI)m/z:628.2/630.2[M+1] +。 Add dichloromethane (5mL), compound 18-6 hydrochloride (99mg, 142.22μmol) and triethylamine (71.95mg, 711.08μmol) into a three-necked flask, and add acryloyl chloride (12.87mg, 142.22) after cooling to 0°C. μmol), the reaction was incubated at 0°C for 1 hour. The reaction solution was poured into water (30 mL), dichloromethane (20 mL) was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative chromatography to obtain compound 18-7. LCMS (ESI) m/z: 628.2/630.2 [M+1] + .
7)化合物18和19的合成7) Synthesis of compounds 18 and 19
化合物18-7(100mg,159μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:MeOH(0.1％NH 3H 2O)；等度:B％＝50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物18(Rt＝1.584min)和化合物19(Rt＝2.094min)。化合物18： 1H NMR(400MHz,CDCl 3)δppm 10.20(br t,J＝6.7Hz,1H),7.87(d,J＝8.2Hz,1H),7.66(s,1H),6.61(dd,J＝10.5,16.8Hz,1H),6.37(dd,J＝1.7,16.7Hz,1H),5.78(dd,J＝1.7,10.5Hz,1H),4.45(br d,J＝10.3Hz,1H),4.37-3.55(m,14H),3.30(br s,1H),2.98-2.85(m,1H),2.62(s,3H),2.33(br s,6H)。LCMS(ESI)m/z:628.2/630.2[M+1] +。 Compound 18-7 (100mg, 159μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: MeOH (0.1% NH 3 H 2 O); isocratic: B% = 50% isocratic elution; flow rate: 70g/min; column temperature: 35°C; system pressure: 150bar) After separation and purification, compound 18 (Rt=1.584min) and compound 19 (Rt =2.094min). Compound 18: 1 H NMR (400MHz, CDCl 3 ) δ ppm 10.20 (br t, J = 6.7 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.66 (s, 1H), 6.61 (dd, J = 10.5, 16.8 Hz, 1H), 6.37 (dd, J = 1.7, 16.7 Hz, 1H), 5.78 (dd, J = 1.7, 10.5 Hz, 1H), 4.45 (br d, J = 10.3 Hz, 1H), 4.37-3.55 (m, 14H), 3.30 (br s, 1H), 2.98-2.85 (m, 1H), 2.62 (s, 3H), 2.33 (br s, 6H). LCMS (ESI) m/z: 628.2/630.2 [M+1] + .
化合物19： 1H NMR(400MHz,CDCl 3)δppm 10.21(br t,J＝6.4Hz,1H),7.87(d,J＝8.3Hz,1H),7.66(s,1H),6.61(dd,J＝10.5,16.8Hz,1H),6.37(dd,J＝1.8,16.8Hz,1H),5.78(dd,J＝1.8,10.5Hz,1H),4.45(br d,J＝10.5Hz,1H),4.36-3.51(m,14H),3.32(br s,1H),3.00-2.83(m,1H),2.62(s,3H),2.51-2.19(m,6H)。LCMS(ESI)m/z:628.2/630.2[M+1] +。 Compound 19: 1 H NMR (400MHz, CDCl 3 ) δ ppm 10.21 (br t, J = 6.4 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 6.61 (dd, J = 10.5, 16.8 Hz, 1H), 6.37 (dd, J = 1.8, 16.8 Hz, 1H), 5.78 (dd, J = 1.8, 10.5 Hz, 1H), 4.45 (br d, J = 10.5 Hz, 1H), 4.36-3.51 (m, 14H), 3.32 (br s, 1H), 3.00-2.83 (m, 1H), 2.62 (s, 3H), 2.51-2.19 (m, 6H). LCMS (ESI) m/z: 628.2/630.2 [M+1] + .
实施例20Example 20
Figure PCTCN2021101868-appb-000074
Figure PCTCN2021101868-appb-000074
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000075
Figure PCTCN2021101868-appb-000075
1)化合物20-2的合成1) Synthesis of compound 20-2
室温20℃下，向氢化瓶中加入甲醇(200mL)，原料20-1(8.0g,46.73mmol)，二乙胺基盐酸盐(10.24g,93.46mmol)，冰乙酸(4.20g,69.94mmol)和10％湿钯炭(5.0g,46.73mmol)。20℃下30psi反应14小时。反应体系过滤，再用甲醇(300mL)淋洗。滤液减压浓缩至干，再向其中加入水(100mL)，再分别用二氯甲烷(20mL)萃取三次。水相再用饱和碳酸氢钠水溶液调至pH约8，再分别用二氯甲烷(50mL)萃取三次，合并有机相再用无水硫酸钠干燥，过滤浓缩得化合物20-2。 1H NMR(400MHz,CDCl 3)δppm 3.97-3.87(m,2H),3.81 (dd,J＝5.9,8.7Hz,2H),3.53-3.42(m,1H),2.53(q,J＝7.2Hz,4H),1.43(s,9H),1.00(t,J＝7.2Hz,6H)。 At room temperature 20℃, add methanol (200mL), raw material 20-1 (8.0g, 46.73mmol), diethylamino hydrochloride (10.24g, 93.46mmol), glacial acetic acid (4.20g, 69.94mmol) into the hydrogenation flask ) And 10% wet palladium on carbon (5.0 g, 46.73 mmol). Reaction at 30 psi at 20°C for 14 hours. The reaction system was filtered and rinsed with methanol (300 mL). The filtrate was concentrated to dryness under reduced pressure, water (100 mL) was added thereto, and the mixture was extracted three times with dichloromethane (20 mL). The aqueous phase was adjusted to pH about 8 with saturated aqueous sodium bicarbonate solution, and then extracted three times with dichloromethane (50 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound 20-2. 1 H NMR (400MHz, CDCl 3 ) δppm 3.97-3.87 (m, 2H), 3.81 (dd, J = 5.9, 8.7 Hz, 2H), 3.53-3.42 (m, 1H), 2.53 (q, J = 7.2 Hz , 4H), 1.43 (s, 9H), 1.00 (t, J = 7.2 Hz, 6H).
2)化合物20-3的合成2) Synthesis of compound 20-3
室温20℃下，向反应瓶中加入二氯甲烷(1mL)和20-2(0.71g,3.11mmol)，再加入再加入盐酸/乙酸乙酯(4M,3.11mL)。20℃搅拌反应2小时。反应液减压浓缩得化合物20-3。 1H NMR(400MHz,CD 3OD)δppm 4.73-4.64(m,2H),4.57(quin,J＝7.7Hz,1H),4.43-4.32(m,2H),4.17-3.95(m,1H),3.24(br s,4H),1.34(t,J＝7.3Hz,6H)。 At room temperature 20°C, dichloromethane (1 mL) and 20-2 (0.71 g, 3.11 mmol) were added to the reaction flask, and then hydrochloric acid/ethyl acetate (4M, 3.11 mL) was added. The reaction was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 20-3. 1 H NMR (400MHz, CD 3 OD) δppm 4.73-4.64 (m, 2H), 4.57 (quin, J = 7.7Hz, 1H), 4.43-4.32 (m, 2H), 4.17-3.95 (m, 1H), 3.24 (br s, 4H), 1.34 (t, J=7.3 Hz, 6H).
3)化合物20-4的合成3) Synthesis of compound 20-4
室温20℃下，向反应瓶中加入异丙醇(15mL)，原料6-2(0.85g,1.77mmol)，原料20-3(0.534g,2.66mmol)和DIPEA(1.14g,8.85mmol)。加热至90℃反应2小时。反应液减压浓缩至干，再加入入水(100mL)中，过滤，滤饼再用水(50mL)淋洗两次。滤饼减压干燥得化合物20-4。LCMS(ESI)m/z:571.1/573.1[M+1] +。 At room temperature and 20°C, add isopropanol (15 mL), raw material 6-2 (0.85 g, 1.77 mmol), raw material 20-3 (0.534 g, 2.66 mmol) and DIPEA (1.14 g, 8.85 mmol) into the reaction flask. Heat to 90°C to react for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, then added to water (100 mL), filtered, and the filter cake was rinsed twice with water (50 mL). The filter cake was dried under reduced pressure to obtain compound 20-4. LCMS (ESI) m/z: 571.1/573.1 [M+1] + .
4)化合物20-5的合成4) Synthesis of compound 20-5
室温20℃下，向反应瓶中加入二氧六环(5.6mL)，原料20-4(280mg,0.49mmol)，原料6-氨基-3-氯-2氟苯硼酸(278.15mg,1.47mmol)，磷酸钾(207.85mg,0.98mmol)和催化剂(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(38.52mg,0.049mmol)。氮气置换三次，油浴110℃反应14小时。反应液过滤，滤饼再用二氯甲烷(100mL)淋洗。滤液减压浓缩至干后经柱层析纯化得到粗品，粗品再经柱层析纯化到化合物20-5。LCMS(ESI)m/z:636.2/638.1[M+1] +。 At room temperature 20℃, add dioxane (5.6mL), raw material 20-4 (280mg, 0.49mmol), raw material 6-amino-3-chloro-2 fluorophenylboronic acid (278.15mg, 1.47mmol) into the reaction flask , Potassium phosphate (207.85mg, 0.98mmol) and catalyst (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1 ,1'-Biphenyl)]palladium (38.52mg, 0.049mmol). Replace with nitrogen three times, and react at 110°C in an oil bath for 14 hours. The reaction solution was filtered, and the filter cake was rinsed with dichloromethane (100 mL). The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to obtain a crude product, which was then purified by column chromatography to compound 20-5. LCMS (ESI) m/z: 636.2/638.1 [M+1] + .
5)化合物20-6的合成5) Synthesis of compound 20-6
冰水浴0℃氮气保护下，向原料20-5(0.39g，0.61mmol)的乙酸乙酯(8mL)溶液中加入无水三氯化铁(0.33g，2.02mmol)，随后滴加环氧乙烷(0.93mL，1.83mmol，1.98M二氯甲烷溶液)，得到的混合物搅拌1小时。向反应液中加入饱和碳酸氢钠水溶液(30mL)和二氯甲烷(200mL)搅拌10分钟，铺硅藻土过滤，滤饼再用二氯甲烷(100mL)淋洗。滤液除去水相，有机相再用无水硫酸钠干燥，过滤减压浓缩得残余物。残余物合并经柱层析纯化得到化合物20-6。LCMS(ESI)m/z:680.2/682.2[M+1] +。 Anhydrous iron trichloride (0.33g, 2.02mmol) was added to the ethyl acetate (8mL) solution of raw material 20-5 (0.39g, 0.61mmol) under the protection of nitrogen at 0℃ in an ice water bath, and then ethylene oxide was added dropwise. Alkane (0.93 mL, 1.83 mmol, 1.98 M dichloromethane solution), and the resulting mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (200 mL) were added to the reaction solution and stirred for 10 minutes, spread with Celite and filtered, and the filter cake was rinsed with dichloromethane (100 mL). The aqueous phase was removed from the filtrate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residues are combined and purified by column chromatography to obtain compound 20-6. LCMS (ESI) m/z: 680.2/682.2 [M+1] + .
6)化合物20-7的合成6) Synthesis of compound 20-7
向反应瓶中加入醋酸(3mL)，原料20-6(0.31g,455.47μmol)和N-氯代丁二酰亚胺(60.82mg,455.47μmol)，20℃搅拌反应14小时。将反应液倒入饱和碳酸氢钠水溶液(200mL)中，再分别用二氯甲烷(50mL)萃取三次，合并有机相再用水(50mL)洗。有机相再用无水硫酸钠干燥，过滤浓缩得化合物20-7。LCMS(ESI)m/z:714.2/716.2[M+1] +。 Acetic acid (3mL), raw materials 20-6 (0.31g, 455.47μmol) and N-chlorosuccinimide (60.82mg, 455.47μmol) were added to the reaction flask, and the reaction was stirred at 20°C for 14 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (200 mL), and then extracted three times with dichloromethane (50 mL), and the organic phases were combined and washed with water (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound 20-7. LCMS (ESI) m/z: 714.2/716.2 [M+1] + .
7)化合物20-8的合成7) Synthesis of compound 20-8
室温25℃氮气保护下，向原料20-7(300mg，419.55μmol)的四氢呋喃(300mL)溶液中加入钠氢(167.82mg，4.20mmol，纯度60％)，得到的混合物加热到65℃搅拌1小时。降至室温，加入饱和氯化铵水溶液(2mL)，减压浓缩至干得粗品。向粗品中再加二氯甲烷(50mL)，过滤。滤液浓缩得化合物20-8。LCMS(ESI)m/z:694.2/696.2[M+1] +。 Under the protection of nitrogen at room temperature and 25°C, sodium hydrogen (167.82mg, 4.20mmol, purity 60%) was added to a solution of raw material 20-7 (300mg, 419.55μmol) in tetrahydrofuran (300mL), and the resulting mixture was heated to 65°C and stirred for 1 hour . It was cooled to room temperature, saturated aqueous ammonium chloride solution (2 mL) was added, and concentrated under reduced pressure to dryness to obtain a crude product. Add dichloromethane (50 mL) to the crude product and filter. The filtrate was concentrated to obtain compound 20-8. LCMS (ESI) m/z: 694.2/696.2 [M+1] + .
8)化合物20-9的合成8) Synthesis of compound 20-9
室温20℃氮气保护下，向原料20-8(170mg，244.59μmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(2mL)，得到的混合物搅拌1小时。反应液减压浓缩，向残余物中加入饱和碳酸氢钠水溶液(500mL)， 再分别用二氯甲烷(20mL)萃取三次。合并有机相再用水(20mL)洗，有机相再用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物20-9直接投入下一步反应。LCMS(ESI)m/z:594.2/596.2[M+1] +。 Under nitrogen protection at room temperature and 20°C, trifluoroacetic acid (2 mL) was added to a dichloromethane (2 mL) solution of raw material 20-8 (170 mg, 244.59 μmol), and the resulting mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (500 mL) was added to the residue, and the mixture was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (20 mL), the organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-9, which was directly put into the next reaction. LCMS (ESI) m/z: 594.2/596.2 [M+1] + .
9)化合物20-10的合成9) Synthesis of compound 20-10
向反应瓶中加入二氯甲烷(10mL)，三乙胺(102.50mg,1.01mmol)和原料20-9(145mg,266.66μmol)，降温至0℃后加入丙烯酰氯(18.46mg,204.00μmol)。0℃保温反应1小时。将反应液倒入水(50mL)中，分液。水相再用二氯甲烷(20mL)萃取，合并有机相再用无水硫酸钠干燥，过滤滤液减压浓缩得粗品。粗品经制备色谱纯化得到化合物20-10。Dichloromethane (10 mL), triethylamine (102.50 mg, 1.01 mmol) and raw material 20-9 (145 mg, 266.66 μmol) were added to the reaction flask, and acryloyl chloride (18.46 mg, 204.00 μmol) was added after cooling to 0°C. The reaction was kept at 0°C for 1 hour. The reaction solution was poured into water (50 mL) and separated. The aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 20-10.
10)化合物20和21的合成10) Synthesis of compounds 20 and 21
化合物20-10(140mg,225μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel AD,250*30mm i.d.10μm；流动相:A:CO 2,B:IPA(0.1％NH 3H 2O)；梯度:B％＝50～50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化得到化合物20(Rt＝1.614min)和化合物21(Rt＝2.117min)。 Compound 20-10 (140mg, 225μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel AD, 250*30mm id10μm; mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); Gradient: B%=50～50% isocratic elution; Flow rate: 70g/min; Column temperature: 35℃; System pressure: 150bar) separation and purification to obtain compound 20 (Rt=1.614min) and compound 21 (Rt =2.117min).
化合物20： 1H NMR(400MHz,CDCl 3)δppmδ＝7.65(s,1H),7.38(d,J＝7.4Hz,1H),6.61(dd,J＝10.4,16.7Hz,1H),6.37(br d,J＝16.8Hz,1H),5.80-5.75(m,1H),4.88-4.71(m,1H),4.52-3.42(m,17H),3.02-2.90(m,1H),2.76-2.59(m,3H),1.15-0.96(m,6H)；LCMS(ESI)m/z:648.2/650.2[M+1] +。 Compound 20: 1 H NMR (400MHz, CDCl 3 )δppmδ=7.65(s,1H), 7.38(d,J=7.4Hz,1H), 6.61(dd,J=10.4,16.7Hz,1H), 6.37(br d, J = 16.8Hz, 1H), 5.80-5.75 (m, 1H), 4.88-4.71 (m, 1H), 4.52-3.42 (m, 17H), 3.02-2.90 (m, 1H), 2.76-2.59 ( m, 3H), 1.15 to 0.96 (m, 6H); LCMS (ESI) m/z: 648.2/650.2 [M+1] + .
化合物21：1H NMR(400MHz,CDCl 3)δppm 7.65(s,1H),7.38(d,J＝7.4Hz,1H),6.61(dd,J＝10.4,16.7Hz,1H),6.37(br d,J＝16.8Hz,1H),5.77(br d,J＝10.6Hz,1H),4.96-4.68(m,1H),4.46(br d,J＝11.4Hz,1H),4.36-3.58(m,17H),3.54-3.39(m,1H),2.96(br d,J＝15.8Hz,1H),1.08(br t,J＝6.9Hz,6H)；LCMS(ESI)m/z:648.2/650.2[M+1] +。 Compound 21: 1H NMR (400MHz, CDCl 3 ) δ ppm 7.65 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 6.61 (dd, J = 10.4, 16.7 Hz, 1H), 6.37 (br d, J = 16.8Hz, 1H), 5.77 (br d, J = 10.6Hz, 1H), 4.96-4.68 (m, 1H), 4.46 (br d, J = 11.4Hz, 1H), 4.36-3.58 (m, 17H) ),3.54-3.39(m,1H),2.96(br d,J=15.8Hz,1H),1.08(br t,J=6.9Hz,6H); LCMS(ESI)m/z:648.2/650.2[M +1] + .
实施例22Example 22
Figure PCTCN2021101868-appb-000076
Figure PCTCN2021101868-appb-000076
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000077
Figure PCTCN2021101868-appb-000077
1)化合物22-1的合成1) Synthesis of compound 22-1
向预先干燥的封管中加入23-7(0.09g,120.41μmol)，N,N-二甲基甲酰胺(2mL)，氨基甲醛(11mg,240.83μmol)，碘化亚铜(5mg,24.08μmol)，N,N-二甲基乙二胺(5mg,48.17μmol)，磷酸钾(39mg,180.62μmol)。氮气鼓泡10分钟，120℃搅拌16小时。向体系中加入水(6mL)，乙酸乙酯(6mL)，分液，用饱和食盐水(10mL)洗有机相，有机相无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得到化合物22-1。LCMS(ESI)m/z:646/648[M+1] +。 Add 23-7 (0.09g, 120.41μmol), N,N-dimethylformamide (2mL), amino formaldehyde (11mg, 240.83μmol), cuprous iodide (5mg, 24.08μmol) to the pre-dried sealed tube ), N,N-dimethylethylenediamine (5mg, 48.17μmol), potassium phosphate (39mg, 180.62μmol). Nitrogen was bubbled for 10 minutes and stirred at 120°C for 16 hours. Add water (6mL) and ethyl acetate (6mL) to the system, separate the layers, wash the organic phase with saturated brine (10mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography to obtain the compound 22-1. LCMS (ESI) m/z: 646/648 [M+1] + .
2)化合物22-2的合成2) Synthesis of compound 22-2
向预先干燥的反应瓶中加入22-1(0.03g,46.40μmol)，盐酸乙酸乙酯(4M,1mL)，20℃搅拌1小时。体系浓缩得到化合物22-2。LCMS(ESI)m/z:546/548[M+1] +。 Add 22-1 (0.03g, 46.40μmol), hydrochloric acid ethyl acetate (4M, 1mL) to the pre-dried reaction flask, and stir at 20°C for 1 hour. The system was concentrated to obtain compound 22-2. LCMS (ESI) m/z: 546/548 [M+1] + .
3)化合物22的合成3) Synthesis of compound 22
向预先干燥的反应瓶中加入22-2(24.10mg,44.11μmol)，二氯甲烷(3mL)，三乙胺(54mg,529.33μmol)，0℃加入丙烯酰氯(4mg,44.11μmol)。0℃搅拌0.5小时。体系浓缩，甲醇(1mL)溶解，残余物经薄层色谱纯化得到化合物22。 1H NMR(400MHz,CD 3OD)δppm 8.24(s,1H),8.07(s,1H),7.88(d,J＝6.58Hz,1H),6.83(dd,J＝16.76,10.64Hz,1H),6.28(dd,J＝16.76,1.60Hz,1H),5.85–5.78(m,1H),4.67-4.52(m,2H),4.36-4.27(m,2H),4.12–3.78(m,8H),3.51–3.38(m,1H),3.07(br d,J＝16.26Hz,1H),2.83(t,J＝5.62Hz,2H),2.37(s,6H)。LCMS(ESI)m/z:600/602[M+1] +。 Add 22-2 (24.10mg, 44.11μmol), dichloromethane (3mL), triethylamine (54mg, 529.33μmol) to the pre-dried reaction flask, add acryloyl chloride (4mg, 44.11μmol) at 0°C. Stir at 0°C for 0.5 hour. The system was concentrated, methanol (1 mL) was dissolved, and the residue was purified by thin layer chromatography to obtain compound 22. 1 H NMR (400MHz, CD 3 OD) δppm 8.24 (s, 1H), 8.07 (s, 1H), 7.88 (d, J = 6.58 Hz, 1H), 6.83 (dd, J = 16.76, 10.64 Hz, 1H) ,6.28(dd,J=16.76,1.60Hz,1H),5.85-5.78(m,1H),4.67-4.52(m,2H),4.36-4.27(m,2H),4.12-3.78(m,8H) , 3.51-3.38 (m, 1H), 3.07 (br d, J = 16.26 Hz, 1H), 2.83 (t, J = 5.62 Hz, 2H), 2.37 (s, 6H). LCMS (ESI) m/z: 600/602 [M+1] + .
实施例23Example 23
Figure PCTCN2021101868-appb-000078
Figure PCTCN2021101868-appb-000078
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000079
Figure PCTCN2021101868-appb-000079
1)化合物23-2的合成1) Synthesis of compound 23-2
-10℃下，向预先干燥的反应瓶中加入四氢呋喃(30mL)，23-1(1g,6.87mmol)和碳酸钠(1.24g,11.68mmol)，然后缓慢滴加三氟乙酸酐(1.73g,8.24mmol)，滴加完毕，体系浑浊，自然升温至18℃搅拌16小时。向体系中加入乙酸乙酯(10mL)，用0.5M盐酸调节体系pH＝5～6，分液，用饱和食盐水(30mL)洗有机相，有机相无水硫酸钠干燥，过滤，浓缩得到化合物23-2。 1H NMR(400MHz,CDCl 3)δppm 7.66(dd,J＝10.60,1.94Hz,1H),7.39-7.30(m,2H)。 At -10°C, add tetrahydrofuran (30mL), 23-1 (1g, 6.87mmol) and sodium carbonate (1.24g, 11.68mmol) to the pre-dried reaction flask, and then slowly add trifluoroacetic anhydride (1.73g, 8.24mmol). After the addition was completed, the system was turbid, and the temperature was raised to 18°C and stirred for 16 hours. Add ethyl acetate (10mL) to the system, adjust the pH of the system to 5-6 with 0.5M hydrochloric acid, separate the liquids, wash the organic phase with saturated brine (30mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the compound 23-2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.66 (dd, J = 10.60, 1.94 Hz, 1H), 7.39-7.30 (m, 2H).
2)化合物23-3的合成2) Synthesis of compound 23-3
向预先干燥的反应瓶中加入四氢呋喃(200mL)，23-2(14g,57.95mmol)，降温至-78℃，然后缓慢滴加正丁基锂(2.5M,46.36mL)，-78℃搅拌1小时后，缓慢滴加硼酸三异丙酯(23.98g,127.50mmol)，滴加完毕，缓慢升温至20℃搅拌2小时，体系降温至0℃，向体系中加入1M盐酸(112mL)，加热到40℃搅拌1小时，分液，用1M盐酸(100mL*3)洗有机相，收集水相，水相先用氢氧化钠固体调节体系pH＝5～6，然后缓慢加入碳酸氢钠固体调节体系pH＝7～8，加入乙酸乙酯(200mL)萃取水相，用饱和食盐水(50mL)洗有机相，有机相无水硫酸钠干燥，过滤，浓缩得到化合物23-3。 1H NMR(400MHz,CD 3OD)δppm 7.11(br t,J＝8.58Hz,1H),6.48(br d,J＝8.38Hz,1H)。 Add tetrahydrofuran (200mL), 23-2 (14g, 57.95mmol) to the pre-dried reaction flask, cool to -78°C, then slowly add n-butyllithium (2.5M, 46.36mL) dropwise, and stir at -78°C for 1 After hours, slowly add triisopropyl borate (23.98g, 127.50mmol) dropwise. After the addition is complete, slowly warm up to 20°C and stir for 2 hours. The temperature of the system is cooled to 0°C. 1M hydrochloric acid (112mL) is added to the system and heated to Stir for 1 hour at 40°C, separate the liquids, wash the organic phase with 1M hydrochloric acid (100mL*3), collect the aqueous phase, first adjust the pH of the system with sodium hydroxide solids = 5-6, and then slowly add sodium bicarbonate to adjust the system pH=7-8, add ethyl acetate (200 mL) to extract the aqueous phase, wash the organic phase with saturated brine (50 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain compound 23-3. 1 H NMR (400MHz, CD 3 OD) δ ppm 7.11 (br t, J=8.58 Hz, 1H), 6.48 (br d, J=8.38 Hz, 1H).
3)化合物23-4的合成3) Synthesis of compound 23-4
向预先干燥的反应瓶中加入23-3(0.65g,1.22mmol)，8-2(508.25mg,2.68mmol)，然后加入研磨过的磷酸钾(517.88mg,2.44mmol)，二氧六环(14mL)，氮气置换3次，然后加入氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯II)(88mg,121.99μmol)，氮气置换3次，加料完毕，放到预先加热好的110℃油浴中搅拌16小时。体系降温至室温，垫硅藻土过滤，滤液浓缩得到粗品，粗品经柱层析纯化得到化合物23-4。LCMS(ESI)m/z:597/599[M+1] +。 Add 23-3 (0.65g, 1.22mmol), 8-2 (508.25mg, 2.68mmol) to the pre-dried reaction flask, then add ground potassium phosphate (517.88mg, 2.44mmol), dioxane ( 14mL), replace with nitrogen 3 times, then add chloride (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1 ,1'-biphenyl)]palladium II) (88mg, 121.99μmol), replaced with nitrogen 3 times, after the addition is complete, put it in a pre-heated 110°C oil bath and stir for 16 hours. The system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound 23-4. LCMS (ESI) m/z: 597/599 [M+1] + .
4)化合物23-5的合成4) Synthesis of compound 23-5
向预先干燥的反应瓶中加入乙酸(12mL)，23-4(1g,1.67mmol)，然后加入N-碘代丁二酰亚胺(414mg,1.84mmol)。20℃搅拌2小时。向体系中缓慢加入饱和碳酸钠水溶液，调节pH＝7-8，然后加入二氯甲烷(20mL)，分液，用二氯甲烷(20mL)萃取水相，合并有机相，有机相无水硫酸钠干燥，过滤，浓缩得到化合物23-5。LCMS(ESI)m/z:723/725[M+1] +。 Add acetic acid (12 mL), 23-4 (1 g, 1.67 mmol) to the pre-dried reaction flask, and then add N-iodosuccinimide (414 mg, 1.84 mmol). Stir at 20°C for 2 hours. Slowly add saturated sodium carbonate aqueous solution to the system to adjust pH=7-8, then add dichloromethane (20mL), separate the liquids, extract the aqueous phase with dichloromethane (20mL), combine the organic phases, and the organic phase anhydrous sodium sulfate Dry, filter, and concentrate to obtain compound 23-5. LCMS (ESI) m/z: 723/725 [M+1] + .
5)化合物23-6的合成5) Synthesis of compound 23-6
向预先干燥的反应瓶中加入二氯甲烷(30mL)，23-5(1g,1.38mmol)，降温至0℃滴加三氟化硼***(602mg,4.24mmol)，环氧乙烷(60mg,1.38mmol)。0℃反应1小时。将体系倒入饱和碳酸氢钠水溶液(20mL)中，搅拌10分钟，然后加入二氯甲烷(20mL)，分液，用二氯甲烷(20mL)萃取水相，合并有机相，有机相无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经柱层析纯化得到化合物23-6。LCMS(ESI)m/z:767/769[M+1] +。 Add dichloromethane (30mL), 23-5 (1g, 1.38mmol) to the pre-dried reaction flask, drop the temperature to 0℃ and add boron trifluoride ether (602mg, 4.24mmol), ethylene oxide (60mg, 1.38mmol). React at 0°C for 1 hour. Pour the system into saturated sodium bicarbonate aqueous solution (20mL), stir for 10 minutes, then add dichloromethane (20mL), separate the layers, extract the aqueous phase with dichloromethane (20mL), combine the organic phases, and the organic phase anhydrous sulfuric acid Dry with sodium, filter, and concentrate to obtain a crude product. The crude product is purified by column chromatography to obtain compound 23-6. LCMS (ESI) m/z: 767/769 [M+1] + .
6)化合物23-7的合成6) Synthesis of compound 23-7
向预先干燥的反应瓶中加入四氢呋喃(490mL)，23-6(0.49g,638.49μmol)，然后加入钠氢(127.70mg,3.19mmol,60％含量)，60℃搅拌1小时，降至室温，加入饱和氯化铵水溶液(1mL)，有固体析出，过滤，滤液减压浓缩至干得粗品，粗品经柱层析纯化得到化合物23-7。LCMS(ESI)m/z:747/749[M+1] +。 Add tetrahydrofuran (490mL), 23-6 (0.49g, 638.49μmol), and then sodium hydrogen (127.70mg, 3.19mmol, 60% content) into the pre-dried reaction flask, stir for 1 hour at 60°C, and cool to room temperature. Saturated aqueous ammonium chloride solution (1 mL) was added, solids precipitated out, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 23-7. LCMS (ESI) m/z: 747/749 [M+1] + .
7)化合物23-8的合成7) Synthesis of compound 23-8
向预先干燥的反应瓶中加入23-7(0.15g,200.69μmol)，N,N-二甲基甲酰胺(4.5mL)，氰化锌(29mg,240.83μmol)，1,1-双(二苯基膦基)二茂铁(11mg,20.07μmol)，氮气置换3次，然后加入三(二亚苄基丙酮)二钯(9.19mg,10.03μmol)。125℃搅拌1小时。体系降温至室温，向体系中加入水(15mL)，乙酸乙酯(15mL)，分液，用饱和食盐水(20mL)洗有机相，有机相无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得到化合物23-8。LCMS(ESI)m/z:645/647[M+1] +。 Add 23-7 (0.15g, 200.69μmol), N,N-dimethylformamide (4.5mL), zinc cyanide (29mg, 240.83μmol), 1,1-bis(two Phenylphosphino)ferrocene (11mg, 20.07μmol), replaced with nitrogen 3 times, and then added tris(dibenzylideneacetone)dipalladium (9.19mg, 10.03μmol). Stir at 125°C for 1 hour. The system was cooled to room temperature, water (15mL), ethyl acetate (15mL) were added to the system, the layers were separated, the organic phase was washed with saturated brine (20mL), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was passed through a column Chromatographic purification gave compound 23-8. LCMS (ESI) m/z: 645/647 [M+1] + .
8)化合物23-9的合成8) Synthesis of compound 23-9
向预先干燥的反应瓶中加入23-8(0.1g,154.67μmol)，二氯甲烷(1.5mL)，三氟乙酸(811mg,7.11mmol)。20℃搅拌3小时。体系浓缩得到化合物23-9的三氟乙酸盐。LCMS(ESI)m/z:546/548[M+1] +。 Add 23-8 (0.1 g, 154.67 μmol), dichloromethane (1.5 mL), and trifluoroacetic acid (811 mg, 7.11 mmol) to the pre-dried reaction flask. Stir at 20°C for 3 hours. The system was concentrated to obtain the trifluoroacetate salt of compound 23-9. LCMS (ESI) m/z: 546/548 [M+1] + .
9)化合物23-10的合成9) Synthesis of compound 23-10
向预先干燥的反应瓶中加入23-9的三氟乙酸盐(0.1g,154.44μmol)，二氯甲烷(3.6mL)，三乙胺(94mg,926.65μmol)，0℃加入丙烯酰氯(9mg,108.11μmol)。0℃搅拌0.5小时。体系浓缩，甲醇(1mL)溶解，残余物经薄层色谱纯化得到化合物23-10。LCMS(ESI)m/z:600/602[M+1] +。 Add 23-9 trifluoroacetate (0.1g, 154.44μmol), dichloromethane (3.6mL), triethylamine (94mg, 926.65μmol) to the pre-dried reaction flask, add acryloyl chloride (9mg ,108.11μmol). Stir at 0°C for 0.5 hour. The system was concentrated, methanol (1 mL) was dissolved, and the residue was purified by thin layer chromatography to obtain compound 23-10. LCMS (ESI) m/z: 600/602 [M+1] + .
10)化合物23和24的的合成10) Synthesis of compounds 23 and 24
化合物23-10(69mg,114.91μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:(0.1％NH 3H 2O IPA)；梯度:B％＝58％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化得到化合物23(Rt＝1.399min)和化合物24(Rt＝1。788min)。化合物23： 1H NMR(400MHz,CD 3OD)δppm 8.01(s,1H),7.70(d,J＝7.70Hz,1H),6.83(dd,J＝16.76,10.64Hz,1H),6.28(dd,J＝16.76,1.60Hz,1H),5.81(dd,J＝10.64,1.82Hz,1H),4.67-4.52(m,2H),4.36-4.27(m,2H),4.12–3.78(m,8H),3.51–3.38(m,1H),3.07(br d,J＝16.26Hz,1H),2.83(t,J＝5.62Hz,2H),2.37(s,6H)。LCMS(ESI)m/z:600/602[M+1] +。 Compound 23-10 (69mg, 114.91μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: (0.1% NH 3 H 2 O IPA); gradient: B% = 58% isocratic elution; flow rate: 70 g/min; column temperature: 35° C.; system pressure: 150 bar) to obtain compound 23 (Rt=1.399min) and compound 24 (Rt= 1. 788min). Compound 23: 1 H NMR (400MHz, CD 3 OD) δ ppm 8.01 (s, 1H), 7.70 (d, J = 7.70 Hz, 1H), 6.83 (dd, J = 16.76, 10.64 Hz, 1H), 6.28 (dd ,J＝16.76,1.60Hz,1H),5.81(dd,J＝10.64,1.82Hz,1H),4.67-4.52(m,2H),4.36-4.27(m,2H),4.12-3.78(m,8H) ), 3.51–3.38 (m, 1H), 3.07 (br d, J = 16.26 Hz, 1H), 2.83 (t, J = 5.62 Hz, 2H), 2.37 (s, 6H). LCMS (ESI) m/z: 600/602 [M+1] + .
化合物24： 1H NMR(400MHz,CD 3OD)δppm 8.01(s,1H),7.70(d,J＝7.82Hz,1H),6.82(dd,J＝16.82,10.46Hz,1H),6.28(dd,J＝16.76,1.72Hz,1H),5.81(dd,J＝10.76,1.72Hz,1H),4.66-4.51(m,2H),4.38-4.27(m,2H),4.10–3.75(m,8H),3.52–3.38(m,1H),3.07(br d,J＝16.26Hz,1H),2.84(t,J＝5.76Hz,2H),2.38(s,6H)。LCMS(ESI)m/z:600/602[M+1] +。 Compound 24: 1 H NMR (400MHz, CD 3 OD) δ ppm 8.01 (s, 1H), 7.70 (d, J = 7.82 Hz, 1H), 6.82 (dd, J = 16.82, 10.46 Hz, 1H), 6.28 (dd ,J＝16.76,1.72Hz,1H),5.81(dd,J＝10.76,1.72Hz,1H),4.66-4.51(m,2H),4.38-4.27(m,2H),4.10–3.75(m,8H ), 3.52–3.38 (m, 1H), 3.07 (br d, J = 16.26 Hz, 1H), 2.84 (t, J = 5.76 Hz, 2H), 2.38 (s, 6H). LCMS (ESI) m/z: 600/602 [M+1] + .
实施例25Example 25
Figure PCTCN2021101868-appb-000080
Figure PCTCN2021101868-appb-000080
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000081
Figure PCTCN2021101868-appb-000081
1)化合物25-2的合成1) Synthesis of compound 25-2
向预先干燥的氢化瓶中加入甲醇(320mL)，25-1(32g,249.75mmol)，二甲胺水溶液40％(40.73g,499.51mmol)，乙酸(22.50g,374.63mmol)，湿钯碳(21g,10％含量)，氢气(503.46mg,249.75mmol)，氢气置换3次，30psi、25℃搅拌16小时。反应体系过滤，用甲醇(300mL)淋洗。滤液减压浓缩至干，向其中加入乙酸乙酯(200ml)，析出大量固体，过滤。用乙酸乙酯(100mL)淋洗。滤液丢弃，收集滤饼，向滤饼中加入饱和碳酸钠水溶液(300ml)，用乙酸乙酯(300ml*5)萃取水相，合并有机相，用饱和氯化钠水溶液(300ml)洗有机相。有机相用无水硫酸钠干燥，过滤浓缩得到化合物25-2。 1H NMR(400MHz,DMSO-d 6)δppm 3.58(s,3H),2.82-2.71(m,1H),2.54-2.52(m,1H),2.27-2.16(m,2H),1.99(s,6H),1.95-1.83(m,2H)。 Add methanol (320mL), 25-1 (32g, 249.75mmol), 40% dimethylamine aqueous solution (40.73g, 499.51mmol), acetic acid (22.50g, 374.63mmol), wet palladium on carbon ( 21g, 10% content), hydrogen (503.46mg, 249.75mmol), hydrogen replacement 3 times, 30psi, 25°C and stirring for 16 hours. The reaction system was filtered and rinsed with methanol (300 mL). The filtrate was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added thereto, a large amount of solid was precipitated, and it was filtered. Rinse with ethyl acetate (100 mL). The filtrate was discarded, the filter cake was collected, saturated sodium carbonate aqueous solution (300ml) was added to the filter cake, the aqueous phase was extracted with ethyl acetate (300ml*5), the organic phases were combined, and the organic phase was washed with saturated sodium chloride aqueous solution (300ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 25-2. 1 H NMR (400MHz, DMSO-d 6 ) δppm 3.58 (s, 3H), 2.82-2.71 (m, 1H), 2.54-2.52 (m, 1H), 2.27-2.16 (m, 2H), 1.99 (s, 6H), 1.95-1.83 (m, 2H).
2)化合物25-3的合成2) Synthesis of compound 25-3
向预先干燥的反应瓶中加入1,4-二氧六环(20mL)，25-2(29g,184.47mmol)，盐酸(6M,507.50mL)， 70℃搅拌16小时。体系70℃浓缩至干，然后加入乙腈(50mL)，搅拌10分钟，过滤，收集滤饼，得到化合物25-3。 1H NMR(400MHz,D 2O)δppm 3.75-3.65(m,1H),2.09-2.88(m,1H),2.74(s,6H),2.69-2.54(m,2H),2.35(m,2H)。 Add 1,4-dioxane (20 mL), 25-2 (29 g, 184.47 mmol), hydrochloric acid (6M, 507.50 mL) to the pre-dried reaction flask, and stir at 70°C for 16 hours. The system was concentrated to dryness at 70°C, then acetonitrile (50 mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected to obtain compound 25-3. 1 H NMR (400MHz, D 2 O) δppm 3.75-3.65 (m, 1H), 2.09-2.88 (m, 1H), 2.74 (s, 6H), 2.69-2.54 (m, 2H), 2.35 (m, 2H) ).
3)化合物25-4的合成3) Synthesis of compound 25-4
向预先干燥的反应瓶中加入25-3(13g,90.79mmol)，然后加入二氯亚砜(213.20g,1.79mol)，80℃搅拌2小时。体系浓缩至干，然后加入无水甲苯(50mL)，浓缩得到化合物25-4。Add 25-3 (13g, 90.79mmol) to the pre-dried reaction flask, then add thionyl chloride (213.20g, 1.79mol), and stir at 80°C for 2 hours. The system was concentrated to dryness, then anhydrous toluene (50 mL) was added and concentrated to obtain compound 25-4.
4)化合物25-5的合成4) Synthesis of compound 25-5
向预先干燥的反应瓶中加入10-1(6g,22.35mmol)，25-4(13.28g,67.05mmol)，吡啶(58.80g,743.36mmol)。60℃搅拌16小时，得到化合物25-5，反应体系按照理论产量投下一步。Add 10-1 (6g, 22.35mmol), 25-4 (13.28g, 67.05mmol), pyridine (58.80g, 743.36mmol) to the pre-dried reaction flask. Stir at 60°C for 16 hours to obtain compound 25-5. The reaction system was put into the next step according to the theoretical output.
5)化合物25-6的合成5) Synthesis of compound 25-6
-70℃向预先干燥的反应瓶中加入四氢呋喃(60mL)，通入氨气(90.68mg,5.32mmol)0.5小时，25-5(2g,5.32mmol)，然后倒入闷罐中80℃搅拌16小时。体系降温至室温，然后体系浓缩至干，向体系中加入甲醇(50mL)，搅拌0.5小时，过滤，收集滤饼得到化合物25-6。LCMS(ESI)m/z:373.9/375.9[M+1] +。 Add tetrahydrofuran (60mL) to the pre-dried reaction flask at -70°C, pour in ammonia gas (90.68mg, 5.32mmol) for 0.5 hours, 25-5 (2g, 5.32mmol), then pour into a stuffy pot and stir at 80°C for 16 Hour. The system was cooled to room temperature, then the system was concentrated to dryness, methanol (50 mL) was added to the system, stirred for 0.5 hour, filtered, and the filter cake was collected to obtain compound 25-6. LCMS (ESI) m/z: 373.9/375.9 [M+1] + .
6)化合物25-7的合成6) Synthesis of compound 25-7
向预先干燥的反应瓶中加入四氢呋喃(30mL)，25-6(3g,8.01mmol)，N-叔丁氧羰基-哌嗪(2.24g,12.01mmol)，然后加入三乙胺(2.43g,24.02mmol)，六氟磷酸苯并***-1-基-氧基三吡咯烷(6.25g,12.01mmol)，20℃搅拌16小时。向体系中加入水(50mL)，乙酸乙酯(50mL)，分液，用乙酸乙酯(50mL)萃取水相，合并有机相，有机相无水硫酸钠干燥，过滤，浓缩至干，残余物经柱层析纯化，馏分浓缩至干，然后加入甲醇(15mL)，有固体析出，搅拌10分钟，过滤，收集滤饼，得到化合物25-7。LCMS(ESI)m/z:542/544[M+1] +。 To the pre-dried reaction flask was added tetrahydrofuran (30mL), 25-6 (3g, 8.01mmol), N-tert-butoxycarbonyl-piperazine (2.24g, 12.01mmol), and then added triethylamine (2.43g, 24.02 mmol), hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine (6.25g, 12.01mmol), stirred at 20°C for 16 hours. Add water (50 mL) and ethyl acetate (50 mL) to the system, separate the layers, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is After purification by column chromatography, the fractions were concentrated to dryness, then methanol (15 mL) was added, and a solid precipitated out, stirred for 10 minutes, filtered, and collected the filter cake to obtain compound 25-7. LCMS (ESI) m/z: 542/544 [M+1] + .
7)化合物25-8的合成7) Synthesis of compound 25-8
向预先干燥的反应瓶中加入25-7(0.55g,1.01mmol)，23-3(550mg,2.90mmol)，然后加入研磨过的磷酸钾(430mg,2.03mmol)，1,4-二氧六环(20mL)，氮气置换3次，然后加入氯化(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯II(73mg,101.31μmol)，氮气置换3次，加料完毕，放到预先加热好的110℃油浴中搅拌16小时。体系降温至室温，体系垫硅藻土过滤，滤液浓缩得到粗品，残余物经柱层析纯化得到化合物25-8。LCMS(ESI)m/z:606/608[M+1] +。 Add 25-7 (0.55g, 1.01mmol), 23-3 (550mg, 2.90mmol) to the pre-dried reaction flask, then add ground potassium phosphate (430mg, 2.03mmol), 1,4-dioxane Ring (20mL), nitrogen replacement 3 times, and then add chloride (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino -1,1'-biphenyl)]palladium II (73mg, 101.31μmol), replaced with nitrogen 3 times, after the addition is complete, put it in a pre-heated 110°C oil bath and stir for 16 hours. The system was cooled to room temperature, the system was filtered through Celite, the filtrate was concentrated to obtain a crude product, and the residue was purified by column chromatography to obtain compound 25-8. LCMS (ESI) m/z: 606/608 [M+1] + .
8)化合物25-9的合成8) Synthesis of compound 25-9
向预先干燥的反应瓶中加入乙酸乙酯(13mL)，25-8(0.62g,1.02mmol)，降温至0℃加三氯化铁(620mg,3.82mmol)，环氧乙烷(135mg,3.06mmol)。0℃反应1小时。将体系直接倒入到饱和碳酸氢钠水溶液(20mL)中，然后加入二氯甲烷(50mL)，搅拌10分钟，过滤，用二氯甲烷(50mL*2)淋洗滤饼，滤液分液，收集有机相，有机相无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化得到化合物25-9。LCMS(ESI)m/z:651/653[M+1] +。 Add ethyl acetate (13mL), 25-8 (0.62g, 1.02mmol) to the pre-dried reaction flask, reduce the temperature to 0℃, add ferric chloride (620mg, 3.82mmol), ethylene oxide (135mg, 3.06 mmol). React at 0°C for 1 hour. Pour the system directly into saturated sodium bicarbonate aqueous solution (20mL), then add dichloromethane (50mL), stir for 10 minutes, filter, rinse the filter cake with dichloromethane (50mL*2), separate the filtrate, and collect The organic phase, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography to obtain compound 25-9. LCMS (ESI) m/z: 651/653 [M+1] + .
9)化合物25-10的合成9) Synthesis of compound 25-10
向预先干燥的反应瓶中加入乙酸(5mL)，25-9(0.4g,613.90μmol)，然后加入N-氯代丁二酰亚胺(83mg,620.04μmol)。20℃搅拌16小时。将体系缓慢加入到饱和碳酸氢钠水溶液(30mL)中，体系pH＝7～8， 然后加入二氯甲烷(10mL)，分液，用二氯甲烷萃(20mL)取水相，合并有机相，有机相无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化得到化合物25-10。LCMS(ESI)m/z:685/686[M+1]+。Add acetic acid (5 mL), 25-9 (0.4 g, 613.90 μmol), and then N-chlorosuccinimide (83 mg, 620.04 μmol) into the pre-dried reaction flask. Stir at 20°C for 16 hours. The system was slowly added to a saturated aqueous sodium bicarbonate solution (30 mL), pH of the system was 7-8, then dichloromethane (10 mL) was added, the layers were separated, the aqueous phase was extracted with dichloromethane (20 mL), and the organic phases were combined. The phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography to obtain compound 25-10. LCMS (ESI) m/z: 685/686 [M+1]+.
10)化合物25-11的合成10) Synthesis of compound 25-11
向预先干燥的反应瓶中加入四氢呋喃(150mL)，25-10(0.15g,218.65μmol)，然后加入钠氢(88mg,2.19mmol,60％含量)。75℃搅拌1小时。降至室温，加入饱和氯化铵水溶液(2mL)，有固体析出，过滤，滤液减压浓缩至干得粗品，残余物经柱层析纯化得到化合物25-11。LCMS(ESI)m/z:664/666[M+1] +。 Add tetrahydrofuran (150 mL), 25-10 (0.15 g, 218.65 μmol), and then sodium hydrogen (88 mg, 2.19 mmol, 60% content) into the pre-dried reaction flask. Stir at 75°C for 1 hour. After cooling to room temperature, a saturated aqueous solution of ammonium chloride (2 mL) was added, a solid precipitated out, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product, and the residue was purified by column chromatography to obtain compound 25-11. LCMS (ESI) m/z: 664/666 [M+1] + .
11)化合物25-12的合成11) Synthesis of compound 25-12
向预先干燥的反应瓶中加入25-11(0.06g,90.09μmol)，然后加入盐酸/乙酸乙酯(4M,3.00mL)。25℃搅拌1小时。体系浓缩，然后加入二氯甲烷(2mL)，超声5分钟，过滤，得到滤饼，得到化合物25-12的盐酸盐。LCMS(ESI)m/z:564/566[M+1] +。 Add 25-11 (0.06 g, 90.09 μmol) to the pre-dried reaction flask, and then add hydrochloric acid/ethyl acetate (4M, 3.00 mL). Stir at 25°C for 1 hour. The system was concentrated, and then dichloromethane (2 mL) was added, sonicated for 5 minutes, and filtered to obtain a filter cake to obtain the hydrochloride salt of compound 25-12. LCMS (ESI) m/z: 564/566 [M+1] + .
12)化合物25-13的合成12) Synthesis of compound 25-13
0℃下，向预先干燥的反应瓶中加入二氯甲烷(1mL)，25-12的盐酸盐(0.06g,99.61μmol)，然后加入三氟乙酸(61mg,597.65μmol)，然后加入丙烯酰氯(10mg,109.57μmol)，0℃搅拌1小时，体系浓缩，N,N-二甲基甲酰胺(1mL)溶解，残余物经薄层色谱纯化得到化合物25-13。LCMS(ESI)m/z:619/621[M+1] +。 At 0℃, add dichloromethane (1mL), 25-12 hydrochloride (0.06g, 99.61μmol), then add trifluoroacetic acid (61mg, 597.65μmol), and then add acryloyl chloride to the pre-dried reaction flask (10 mg, 109.57 μmol), stirred at 0°C for 1 hour, the system was concentrated, N,N-dimethylformamide (1 mL) was dissolved, and the residue was purified by thin layer chromatography to obtain compound 25-13. LCMS (ESI) m/z: 619/621 [M+1] + .
13)化合物25和26的的合成13) Synthesis of compounds 25 and 26
化合物25-13(125mg,201.63μmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel OD,250*30mm i.d.10μm；流动相:A:CO 2,B:(0.1％NH 3H 2O IPA)；梯度:B％＝60％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物25(Rt＝0.919min)和化合物26(Rt＝1.849min)。 Compound 25-13 (125mg, 201.63μmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel OD, 250*30mm id10μm; mobile phase: A: CO 2 , B: (0.1% NH 3 H 2 O IPA); gradient: B%=60% isocratic elution; flow rate: 70g/min; column temperature: 35°C; system pressure: 150bar) After separation and purification, compound 25 (Rt=0.919min) and compound 26 (Rt =1.849min).
化合物25： 1H NMR(400MHz,CD 3OD)δppm 8.02(s,1H),7.47(d,J＝7.50Hz,1H),6.83(dd,J＝16.82,10.58Hz,1H),6.28(dd,J＝16.76,1.76Hz,1H),5.81(dd,J＝10.58,1.82Hz,1H),4.42-4.23(m,2H),4.08(br d,J＝11.76Hz,2H),4.01–3.75(m,6H),3.49-3.33(m,2H),3.05(br d,J＝16.26Hz,1H),2.88-2.76(m,1H),2.59-2.43(m,2H),2.42-2.28(m,2H),2.24(s,6H)。LCMS(ESI)m/z:619/621[M+1] +。 Compound 25: 1 H NMR (400MHz, CD 3 OD) δ ppm 8.02 (s, 1H), 7.47 (d, J = 7.50 Hz, 1H), 6.83 (dd, J = 16.82, 10.58 Hz, 1H), 6.28 (dd ,J＝16.76,1.76Hz,1H),5.81(dd,J＝10.58,1.82Hz,1H),4.42-4.23(m,2H),4.08(br d,J＝11.76Hz,2H),4.01–3.75 (m, 6H), 3.49-3.33 (m, 2H), 3.05 (br d, J = 16.26 Hz, 1H), 2.88-2.76 (m, 1H), 2.59-2.43 (m, 2H), 2.42-2.28 ( m, 2H), 2.24 (s, 6H). LCMS (ESI) m/z: 619/621 [M+1] + .
化合物26： 1H NMR(400MHz,CD 3OD)δppm 8.02(s,1H),7.48(d,J＝7.50Hz,1H),6.83(dd,J＝16.82,10.58Hz,1H),6.28(dd,J＝16.76,1.76Hz,1H),5.81(dd,J＝10.58,1.82Hz,1H),4.41-4.21(m,2H),4.15–4.03(br d,J＝11.76Hz,2H),4.02–3.80(m,6H),3.48-3.35(m,2H),3.06(br d,J＝16.26Hz,1H),2.63-2.50(m,1H),2.48-2.27(m,2H),2.42-2.28(m,2H),2.24(s,6H)。LCMS(ESI)m/z:619/621[M+1] +。 Compound 26: 1 H NMR (400MHz, CD 3 OD) δ ppm 8.02 (s, 1H), 7.48 (d, J = 7.50 Hz, 1H), 6.83 (dd, J = 16.82, 10.58 Hz, 1H), 6.28 (dd ,J＝16.76,1.76Hz,1H),5.81(dd,J＝10.58,1.82Hz,1H),4.41-4.21(m,2H),4.15-4.03(br d,J＝11.76Hz,2H),4.02 –3.80(m,6H),3.48-3.35(m,2H),3.06(br d,J=16.26Hz,1H),2.63-2.50(m,1H),2.48-2.27(m,2H),2.42- 2.28 (m, 2H), 2.24 (s, 6H). LCMS (ESI) m/z: 619/621 [M+1] + .
实施例27Example 27
Figure PCTCN2021101868-appb-000082
Figure PCTCN2021101868-appb-000082
合成路线：synthetic route:
Figure PCTCN2021101868-appb-000083
Figure PCTCN2021101868-appb-000083
化合物27和28的合成Synthesis of compounds 27 and 28
化合物8(200mg,0.328mmol)经SFC(仪器型号:Waters SFC150 AP preparative SFC；色谱柱:Chiralcel AD,250*30mm i.d.10μm；流动相:A:CO 2,B:IPA(0.1％NH 3H 2O)；梯度:B％＝50～50％等度洗脱；流速:70g/min；柱温:35℃；***压力:150bar)分离纯化后得到化合物27(Rt＝1.348min)和化合物28(Rt＝1.615min)。化合物27： 1H NMR(400MHz,CDCl 3)δppm 7.79(s,1H),7.42(d,J＝7.5Hz,1H),6.62(dd,J＝10.5,16.8Hz,1H),6.38(br d,J＝16.8Hz,1H),5.79(br d,J＝10.6Hz,1H),4.81(br t,J＝6.3Hz,1H),4.74-4.56(m,2H),4.40(br d,J＝4.6Hz,2H),4.02-3.70(m,8H),3.60-3.45(m,1H),3.07-2.84(m,3H),2.46(br s,6H)。 Compound 8 (200mg, 0.328mmol) was subjected to SFC (instrument model: Waters SFC150 AP preparative SFC; column: Chiralcel AD, 250*30mm id10μm; mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O) ); Gradient: B%=50～50% isocratic elution; Flow rate: 70g/min; Column temperature: 35℃; System pressure: 150bar) After separation and purification, compound 27 (Rt=1.348min) and compound 28 (Rt =1.615min). Compound 27: 1 H NMR (400MHz, CDCl 3 ) δppm 7.79 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 6.62 (dd, J = 10.5, 16.8 Hz, 1H), 6.38 (br d ,J=16.8Hz,1H),5.79(br d,J=10.6Hz,1H), 4.81(br t,J=6.3Hz,1H),4.74-4.56(m,2H), 4.40(br d,J = 4.6 Hz, 2H), 4.02-3.70 (m, 8H), 3.60-3.45 (m, 1H), 3.07-2.84 (m, 3H), 2.46 (br s, 6H).
LCMS(ESI)m/z:609.3/611.3[M+1] +。 LCMS (ESI) m/z: 609.3/611.3 [M+1] + .
化合物28： 1H NMR(400MHz,CDCl 3)δppm 7.79(s,1H),7.42(d,J＝7.4Hz,1H),6.62(dd,J＝10.5,16.8Hz,1H),6.38(dd,J＝1.7,16.8Hz,1H),5.79(dd,J＝1.7,10.5Hz,1H),4.82(br t,J＝6.3Hz,1H),4.76-4.54(m,2H),4.48-4.36(m,2H),4.07-3.72(m,8H),3.60-3.43(m,1H),3.07-2.88(m,3H),2.49(br s,6H)。 Compound 28: 1 H NMR (400MHz, CDCl 3 ) δ ppm 7.79 (s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 6.62 (dd, J = 10.5, 16.8 Hz, 1H), 6.38 (dd, J = 1.7, 16.8 Hz, 1H), 5.79 (dd, J = 1.7, 10.5 Hz, 1H), 4.82 (br t, J = 6.3 Hz, 1H), 4.76-4.54 (m, 2H), 4.48-4.36 ( m, 2H), 4.07-3.72 (m, 8H), 3.60-3.43 (m, 1H), 3.07-2.88 (m, 3H), 2.49 (br s, 6H).
LCMS(ESI)m/z:609.3/611.3[M+1] +。 LCMS (ESI) m/z: 609.3/611.3 [M+1] + .
实验例1：细胞实验Experimental example 1: Cell experiment
实验目的：Purpose:
本实验旨在验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞和野生型的A375人恶性黑色素瘤细胞的增殖抑制效果。This experiment aims to verify the proliferation inhibitory effect of the compound of the present invention on KRAS G12C mutant NCI-H358 human non-small cell lung cancer cells and wild-type A375 human malignant melanoma cells.
实验材料：Experimental Materials:
细胞株NCI-H358(购自中国科学院细胞库)、细胞株A375(购自中国科学院细胞库)、DMEM培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。Cell line NCI-H358 (purchased from the Cell Bank of the Chinese Academy of Sciences), cell line A375 (purchased from the Cell Bank of the Chinese Academy of Sciences), DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
实验方法：experimental method:
1)NCI-H358细胞抗增殖实验：1) NCI-H358 cell anti-proliferation experiment:
将NCI-H358细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含4000个NCI-H358细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进3倍稀释至第9个浓度，即从2mM稀释至304nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至1.52nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。Plant NCI-H358 cells in a white 96-well plate, 80μL of cell suspension per well, which contains 4000 NCI-H358 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture. The compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up. Add 78 μL of culture medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. The concentration of the compound transferred to the cell plate ranges from 10 μM to 1.52 nM. The cell plate was placed in a carbon dioxide incubator for 5 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of dosing to participate in data analysis. Add 25μL of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Use multi-marker analyzer to read. Add 25μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use multi-marker analyzer to read.
2)A375细胞抗增殖实验：2) A375 cell anti-proliferation experiment:
将A375细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含2000个A375细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进3倍稀释至第9个浓度，即从2mM稀释至304nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至1.52nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。Plant A375 cells in a white 96-well plate, 80 μL of cell suspension per well, which contains 2000 A375 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture. The compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up. Add 78 μL of culture medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. The concentration of the compound transferred to the cell plate ranges from 10 μM to 1.52 nM. The cell plate was placed in a carbon dioxide incubator for 5 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of dosing to participate in data analysis. Add 25μL of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Use multi-marker analyzer to read. Add 25μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use multi-marker analyzer to read.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。 Using the equation (Sample-Min)/(Max-Min)*100% to convert the original data into the inhibition rate, the value of IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. GraphPad Prism" response--Variable slope" mode).
实验结果：Experimental results:
本发明化合物对NCI-H358(G12C突变)细胞和A375(野生型)细胞的抗增殖活性IC 50的数据在表1中展示。 Compounds of the invention of an anti-proliferative activity IC NCI-H358 (G12C mutation) cells and of A375 (wild-type) data 50 cells is shown in Table 1.
表1Table 1
受试化合物Test compound NCI-H358IC 50(μM) NCI-H358IC 50 (μM) A375IC 50(μM) A375IC 50 (μM)
11 0.210.21 5.035.03
22 0.270.27 NANA
33 1.931.93 NANA
44 3.113.11 NANA
66 0.0150.015 NANA
88 0.0170.017 NANA
99 0.1960.196 NANA
1010 0.1890.189 NANA
1111 0.0590.059 NANA
1414 0.0050.005 NANA
1616 0.0290.029 NANA
1717 0.1050.105 NANA
1818 0.1350.135 NANA
21twenty one 0.0030.003 NANA
22twenty two 0.1430.143 NANA
24twenty four 0.0190.019 NANA
2626 0.1120.112 NANA
2727 0.0200.020 NANA
注：NA代表未测试。Note: NA stands for not tested.
实验结论：Experimental results:
本发明化合物对于KRAS G12C突变型细胞NCI-H358显示了优异的细胞抗增殖活性。The compound of the present invention shows excellent cell anti-proliferation activity against KRAS G12C mutant cell NCI-H358.
实验例2：化合物药代动力学评价Experimental example 2: Evaluation of compound pharmacokinetics
实验目的：Purpose:
本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。The purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
实验操作：Experimental operation:
选取7至10周龄的CD-1雄性小鼠，静脉和口服给药的剂量分别为3毫克每公斤和10毫克每公斤。试验动物在整个试验期间自由饮食、饮水。CD-1 male mice aged 7 to 10 weeks were selected, and the doses for intravenous and oral administration were 3 mg/kg and 10 mg/kg, respectively. The test animals eat and drink freely throughout the test period.
实验当天静脉组动物通过尾静脉单次注射给予化合物，给药体积为3mL/kg；口服组通过单次灌胃给予化合物，给药体积为10mL/kg。在给药前称量动物体重，根据体重计算给药体积。样品采集时间为：0.083(注射组)、0.25、0.5、1、2、4、8、24h。每个时间点通过隐静脉采集大约30μL全血用于制备血浆供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后进行CO 2麻醉安乐死。采用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。 On the day of the experiment, the animals in the intravenous group were given a single injection of the compound through the tail vein with a volume of 3 mL/kg; the oral group was given the compound through a single gavage with a volume of 10 mL/kg. Weigh the animal body weight before administration, and calculate the administration volume based on the body weight. The sample collection time is: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, 24h. Approximately 30 μL of whole blood was collected through the saphenous vein at each time point to prepare plasma for high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for concentration determination. All animals were euthanized by CO 2 anesthesia after collecting PK samples at the last time point. The non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic trapezoidal method was used to calculate the pharmacokinetic parameters.
实验结果：小鼠体内PK性质评价结果见表2。Experimental results: The evaluation results of PK properties in mice are shown in Table 2.
表2 化合物的药代动力学测试结果Table 2 Pharmacokinetic test results of compounds
Figure PCTCN2021101868-appb-000084
Figure PCTCN2021101868-appb-000084
Figure PCTCN2021101868-appb-000085
Figure PCTCN2021101868-appb-000085
注：C max代表最大血药浓度；T max代表达峰时间；T 1/2代表半衰期；Vdss代表表观分布容积；Cl代表清除率；AUC 0-last代表曲线面积(0-t)；AUC 0-inf代表曲线面积(0-inf)；NA代表未测试。 Note: C max represents the maximum plasma concentration; T max represents the peak time; T 1/2 represents the half-life; Vdss represents the apparent volume of distribution; Cl represents the clearance rate; AUC 0-last represents the area of the curve (0-t); AUC 0-inf represents the area of the curve (0-inf); NA represents not tested.
实验结论：Experimental results:
本发明化合物在小鼠体内有良好的清除率，口服AUC、生物利用度较好，具有良好的药代动力学性质。The compound of the present invention has a good clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties.
实验例3：体内药效学研究(一)Experimental example 3: In vivo pharmacodynamic study (1)
实验目的：Purpose:
评价受试化合物在人胰腺癌Mia PaCa-2细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型的体内药效。To evaluate the in vivo efficacy of the test compounds in the Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously in nude mice.
实验操作：Experimental operation:
1.细胞培养和肿瘤组织准备1. Cell culture and tumor tissue preparation
细胞培养：人胰腺癌Mia PaCa-2细胞(ATCC-CRL-1420)体外单层培养，培养条件为DMEM/F12培养基中加20％胎牛血清，1％双抗，37℃5％二氧化碳孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，重悬于适量PBS中，1:1加入基质胶，获取细胞密度为25 x 10 6cells/mL的细胞悬液。 Cell culture: Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) are cultured in a monolayer in vitro, and the culture conditions are DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubation Box culture. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, resuspended in an appropriate amount of PBS, and matrigel is added 1:1 to obtain a cell suspension with a cell density of 25 x 10 6 cells/mL .
细胞接种：将0.2mL(5×10 6cells/mouse个)Mia PaCa-2细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到118mm 3时，根据肿瘤体积进行随机分组，每组6只，空白组给药剂量为0，测试组给药剂量分别为10mg/kg，给药体积10μL/g，口服给药，给药22天，每天一次。 Cell inoculation: 0.2mL (5×10 6 cells/mouse) Mia PaCa-2 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 118mm At 3 o'clock, randomly grouped according to tumor volume, each group has 6 animals, the dose of the blank group is 0, the dose of the test group is 10 mg/kg, the dose volume is 10 μL/g, oral administration, 22 days of administration, Once a day.
2.肿瘤测量和实验指标2. Tumor measurement and experimental indicators
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 The diameter of the tumor was measured with a vernier caliper twice a week. The calculation formula of the tumor volume is: V=0.5a×b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得平均肿瘤体积，Vt为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。The anti-tumor efficacy of the compound was evaluated by TGI (%) or the relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C(%)=TRTV/CRTV×100% (TRTV: treatment group RTV; CRTV: negative control group RTV). Calculate the relative tumor volume (RTV) according to the results of tumor measurement. The calculation formula is RTV=Vt/V0, where V0 is the average tumor volume measured during group administration (ie D0), and Vt is the time of a certain measurement. The average tumor volume, TRTV and CRTV data on the same day.
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药 时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。TGI (%), reflects the tumor growth inhibition rate. TGI(%)=[(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)]×100%.
实验结果：见表3Experimental results: see Table 3
表3table 3
组别Group 肿瘤体积(mm 3)(第22天) Tumor volume (mm 3 ) (day 22) TGI(％)TGI(%)
溶媒对照组Vehicle control group 20162016 ---
化合物27(10mg/kg)Compound 27 (10mg/kg) 10191019 52.552.5
实验结论：Experimental results:
本发明受试化合物在人胰腺癌Mia PaCa-2细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型中展示了较好的体内药效。The test compound of the present invention exhibits a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously into a tumor Balb/c Nude mouse model.
实验例4：体内药效学研究(二)Experimental example 4: In vivo pharmacodynamic study (2)
实验目的：Purpose:
评价受试化合物在人非小细胞肺癌NCI-H358细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型中的体内药效。To evaluate the in vivo efficacy of the test compound in the Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.
实验操作：Experimental operation:
1.细胞培养和肿瘤组织准备1. Cell culture and tumor tissue preparation
细胞培养：人非小细胞肺癌NCI-H358体外单层培养，培养条件为DMEM/F12培养基中加20％胎牛血清，1％双抗，37℃5％二氧化碳孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，重悬于适量PBS中，1:1加入基质胶，获取细胞密度为25×10 6cells/mL的细胞悬液。 Cell culture: Human non-small cell lung cancer NCI-H358 is cultured in a monolayer in vitro. The culture conditions are DMEM/F12 medium with 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubator. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and resuspended in an appropriate amount of PBS. Matrigel is added 1:1 to obtain a cell suspension with a cell density of 25×10 6 cells/mL .
细胞接种：将0.2mL(5×10 6cells/mouse个)NCI-H358细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到102mm 3时，根据肿瘤体积进行随机分组，每组6只，空白组给药剂量为0，测试组给药剂量分别为20mg/kg，给药体积10μL/g，口服给药，给药30天，每天一次。 Cell inoculation: 0.2mL (5×10 6 cells/mouse) NCI-H358 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 102mm 3 At the time, random grouping was carried out according to the tumor volume, each group of 6 animals, the dose of the blank group was 0, the dose of the test group was 20mg/kg, the dose volume was 10μL/g, orally administered for 30 days, every day once.
2.肿瘤测量和实验指标2. Tumor measurement and experimental indicators
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 The diameter of the tumor was measured with a vernier caliper twice a week. The calculation formula of the tumor volume is: V=0.5a×b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得平均肿瘤体积，Vt为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。The anti-tumor efficacy of the compound was evaluated by TGI (%) or the relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C(%)=TRTV/CRTV×100% (TRTV: treatment group RTV; CRTV: negative control group RTV). Calculate the relative tumor volume (RTV) according to the results of tumor measurement. The calculation formula is RTV=Vt/V0, where V0 is the average tumor volume measured during group administration (ie D0), and Vt is the time of a certain measurement. The average tumor volume, TRTV and CRTV data on the same day.
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。TGI (%), reflects the tumor growth inhibition rate. TGI(%)=[(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)]×100%.
实验结果：见表4Experimental results: see Table 4
表4Table 4
组别Group 肿瘤体积(mm 3)(第30天) Tumor volume (mm 3 ) (day 30) TGI(％)TGI(%)
溶媒对照组Vehicle control group 351351 ---
化合物16(20mg/kg)Compound 16 (20mg/kg) 4141 124.8124.8
实验结论：Experimental results:
本发明受试化合物在人非小细胞肺癌NCI-H358细胞裸小鼠皮下移植肿瘤Balb/c Nude小鼠模型中展示了显著体内药效。The test compound of the present invention exhibits significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.

Claims (17)

  1. 式(P)所示化合物或其药学上可接受的盐，The compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021101868-appb-100001
    Figure PCTCN2021101868-appb-100001
    其中，in,
    R 1、R 2分别独立地选自H、F、Cl、Br、I和NH 2； R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
    R 3选自H、F、Cl、Br、I、NH 2、CN、-C(＝O)C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 3 is selected from H, F, Cl, Br, I, NH 2 , CN, -C(=O)C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a replaces
    R 4选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
    R 5选自H、F、Cl、Br、I、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、C 3-5环烷基和氮杂环丁基分别独立地任选被1、2或3个R b取代； R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, The C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are each independently optionally substituted by 1, 2 or 3 R b replace
    R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
    R 7选自H； R 7 is selected from H;
    或者，R 3和R 7与相连的原子形成五元杂芳基； Alternatively, R 3 and R 7 and the connected atoms form a five-membered heteroaryl group;
    R a分别独立地选自F、Cl、Br和I； R a is independently selected from F, Cl, Br and I;
    R b分别独立地选自F、Cl、Br、I、C 1-4烷氨基、-C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基，所述C 1-4烷氨基、-C 1-3烷基-C 1-4烷氨基、氧杂环丁基、吡咯烷基、哌嗪基和六氢-1H-吡咯里嗪基分别独立地任选被1、2或3个R取代； R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl And hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro The hydrogen-1H-pyrrolizinyl group is independently optionally substituted with 1, 2 or 3 R;
    R c分别独立地选自F、Cl、Br、I和CN； R c are each independently selected from F, Cl, Br, I and CN;
    R分别独立地选自F、Cl、Br、I、CH 3、-CH 2N(CH 3) 2。 R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
  2. 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，结构单元
    Figure PCTCN2021101868-appb-100002
    选自
    Figure PCTCN2021101868-appb-100003
    Figure PCTCN2021101868-appb-100004
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
    Figure PCTCN2021101868-appb-100002
    Selected from
    Figure PCTCN2021101868-appb-100003
    Figure PCTCN2021101868-appb-100004
  3. 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，R 3选自F、Cl、Br、CN和-C(＝O)CH 3。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 is selected from F, Cl, Br, CN, and -C(=O)CH 3 .
  4. 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，R 3和R 7与相连的原子形成五元杂芳基， 使结构片段
    Figure PCTCN2021101868-appb-100005
    形成
    Figure PCTCN2021101868-appb-100006
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 7 and the connected atoms form a five-membered heteroaryl group, so that a structural fragment
    Figure PCTCN2021101868-appb-100005
    form
    Figure PCTCN2021101868-appb-100006
  5. 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，R 4选自H、Cl和CH 3，所述CH 3任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a.
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，R 4选自H和Cl。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H and Cl.
  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，R b分别独立地选自F、Cl、Br、I、
    Figure PCTCN2021101868-appb-100007
    Figure PCTCN2021101868-appb-100008
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R b is each independently selected from F, Cl, Br, I,
    Figure PCTCN2021101868-appb-100007
    Figure PCTCN2021101868-appb-100008
  8. 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，R 5选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、环丙基、环丁基和
    Figure PCTCN2021101868-appb-100009
    所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、环丙基、环丁基和
    Figure PCTCN2021101868-appb-100010
    分别独立地任选被1、2或3个R b取代。     The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl and
    Figure PCTCN2021101868-appb-100009
    The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , Cyclopropyl, cyclobutyl and
    Figure PCTCN2021101868-appb-100010
    Each independently is optionally substituted with 1, 2, or 3 R b .
  9. 根据权利要求1、7或8任意一项所述的化合物或其药学上可接受的盐，其中，R 5选自H、环丙基、
    Figure PCTCN2021101868-appb-100011
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 7 or 8, wherein R 5 is selected from H, cyclopropyl,
    Figure PCTCN2021101868-appb-100011
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中，R 5选自H、环丙基、
    Figure PCTCN2021101868-appb-100012
    Figure PCTCN2021101868-appb-100013
    The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, cyclopropyl,
    Figure PCTCN2021101868-appb-100012
    Figure PCTCN2021101868-appb-100013
  11. 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，R 6选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2分别独立地任选被1、2或3个R c取代。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 6 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted with 1, 2, or 3 R c .
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中，R 6选自H和-CH 2CN。 The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H and -CH 2 CN.
  13. 下列所示化合物或其药学上可接受的盐，选自The following compounds or their pharmaceutically acceptable salts are selected from
    Figure PCTCN2021101868-appb-100014
    Figure PCTCN2021101868-appb-100014
    Figure PCTCN2021101868-appb-100015
    Figure PCTCN2021101868-appb-100015
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，选自The compound according to claim 13 or a pharmaceutically acceptable salt thereof, selected from
    Figure PCTCN2021101868-appb-100016
    Figure PCTCN2021101868-appb-100016
    Figure PCTCN2021101868-appb-100017
    Figure PCTCN2021101868-appb-100017
    Figure PCTCN2021101868-appb-100018
    Figure PCTCN2021101868-appb-100018
  15. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  16. 根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐或根据权利要求15所述的组合物在制备KRAS G12C突变蛋白抑制剂的应用。Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the composition according to claim 15 in the preparation of a KRAS G12C mutein inhibitor.
  17. 根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐或根据权利要求15所述的组合物制备治疗KRAS G12C突变的非小细胞肺癌、胰腺癌、结直肠癌药物中的应用。The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the composition according to claim 15 for the preparation of a medicine for treating KRAS G12C mutation non-small cell lung cancer, pancreatic cancer, colorectal cancer Applications.
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